bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–07–31
250 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Therapeutic Intervention in Cancer by Isoliquiritigenin from Licorice: A Natural Antioxidant and Redox Regulator.
  2. Research Progress of Photothermal Nanomaterials in Multimodal Tumor Therapy.
  3. Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer.
  4. Dietary regulation in health and disease.
  5. PNA-ATP aptamer-capped doxorubicin-loaded silica nanoparticles for targeted cancer therapy.
  6. Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin.
  7. Pull the plug: Anti-angiogenesis potential of natural products in gastrointestinal cancer therapy.
  8. The Role of Natural Products and Their Multitargeted Approach to Treat Solid Cancer.
  9. Chitin and Chitosan: Prospective Biomedical Applications in Drug Delivery, Cancer Treatment, and Wound Healing.
  10. Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy.
  11. Targeted Arginine Metabolism Therapy: A Dilemma in Glioma Treatment.
  12. Folate-Targeted Curcumin-Loaded Niosomes for Site-Specific Delivery in Breast Cancer Treatment: In Silico and In Vitro Study.
  13. Quercetin: A Molecule of Great Biochemical and Clinical Value and Its Beneficial Effect on Diabetes and Cancer.
  14. Nutraceuticals: Focus on Anti-Inflammatory, Anti-Cancer, Antioxidant Properties in Gastrointestinal Tract.
  15. Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.
  16. Solid Self-Nano Emulsifying Nanoplatform Loaded with Tamoxifen and Resveratrol for Treatment of Breast Cancer.
  17. Non-canonical anti-cancer, anti-metastatic, anti-angiogenic and immunomodulatory PDT potentials of water soluble phthalocyanine derivatives with imidazole groups and their intracellular mechanism of action.
  18. Involvement of Resveratrol against Brain Cancer: A Combination Strategy with a Pharmaceutical Approach.
  19. Galactosed and Reduction-Responsive Nanoparticles Assembled from Trimethylchitosan-Camptothecin Conjugates for Enhanced Hepatocellular Carcinoma Therapy.
  20. Advances on Natural Abietane, Labdane and Clerodane Diterpenes as Anti-Cancer Agents: Sources and Mechanisms of Action.
  21. Novel Gemcitabine-Re(I) Bisquinolinyl Complex Combinations and Formulations With Liquid Crystalline Nanoparticles for Pancreatic Cancer Photodynamic Therapy.
  22. Design of ROS-Responsive Hyaluronic Acid-Methotrexate Conjugates for Synergistic Chemo-Photothermal Therapy for Cancer.
  23. Nanomedicine as an Emerging Technology to Foster Application of Essential Oils to Fight Cancer.
  24. An Investigation for Skin Tissue Regeneration Enhancement/Augmentation by Curcumin-Loaded Self-Emulsifying Drug Delivery System (SEDDS).
  25. Photo-enhanced upcycling H2O2 into hydroxyl radicals by IR780-embedded Fe3O4@MIL-100 for intense nanocatalytic tumor therapy.
  26. Adapalene and Doxorubicin Synergistically Promote Apoptosis of TNBC Cells by Hyperactivation of the ERK1/2 Pathway Through ROS Induction.
  27. Mechanism-Based Sonodynamic-Chemo Combinations against Triple-Negative Breast Cancer.
  28. Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review.
  29. Folic acid-functionalized L-cys/ZnS:O nanoparticles for homologous targeting and photodynamic therapy of tumor cells.
  30. Myricetin: targeting signaling networks in cancer and its implication in chemotherapy.
  31. [Preliminary Study on Drug-Loaded Chondroitin Sulfate-Modified Micelles Targeting Golgi Apparatus in Tumor Cells for the Treatment of Tumor Metastasis].
  32. Research Progress of Conjugated Nanomedicine for Cancer Treatment.
  33. Polymeric Nanoparticles in Brain Cancer Therapy: A Review of Current Approaches.
  34. Prediction model for synergistic anti-tumor multi-compound combinations from traditional Chinese medicine based on extreme gradient boosting, targets and gene expression data.
  35. Intravenous Nanocarrier for Improved Efficacy of Quercetin and Curcumin against Breast Cancer Cells: Development and Comparison of Single and Dual Drug-Loaded Formulations Using Hemolysis, Cytotoxicity and Cellular Uptake Studies.
  36. Selecting ideal drugs for encapsulation in thermosensitive liposomes and other triggered nanoparticles.
  37. Natural Products of Marine Origin for the Treatment of Colorectal and Pancreatic Cancers: Mechanisms and Potential.
  38. Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice.
  39. Thermosensitive Hydrogels Loaded with Resveratrol Nanoemulsion: Formulation Optimization by Central Composite Design and Evaluation in MCF-7 Human Breast Cancer Cell Lines.
  40. Polysaccharide-based nanofibers for pharmaceutical and biomedical applications: A review.
  41. Synergetic Effect of Tumor Treating Fields and Zinc Oxide Nanoparticles on Cell Apoptosis and Genotoxicity of Three Different Human Cancer Cell Lines.
  42. Metabolic Adaptation-Mediated Cancer Survival and Progression in Oxidative Stress.
  43. Characterization of a Mesoporous Silica Nanoparticle Formulation Loaded with Mitomycin C Lipidic Prodrug (MLP) and In Vitro Comparison with a Clinical-Stage Liposomal Formulation of MLP.
  44. Polyphenols as Plant-Based Nutraceuticals: Health Effects, Encapsulation, Nano-Delivery, and Application.
  45. The association between the risk of breast cancer and Epigallocatechin-3-Gallate intake: A literature review of a potential chemopreventive agent.
  46. Hydroxyapatite Nanoparticles for Improved Cancer Theranostics.
  47. A Small-Molecule Based Organic Nanoparticle for Photothermal Therapy and Near-Infrared-IIb Imaging.
  48. Quaternized Chitosan Thiol Hydrogel-Thickened Nanoemulsion: A Multifunctional Platform for Upgrading the Topical Applications of Virgin Olive Oil.
  49. Combined Photothermal and Photodynamic Therapy for Cancer Treatment Using a Multifunctional Graphene Oxide.
  50. Vitamin D: an essential adjuvant therapeutic agent in breast cancer.
  51. Platinum-Titania Schottky Junction as Nanosonosensitizer, Glucose Scavenger, and Tumor Microenvironment-Modulator for Promoted Cancer Treatment.
  52. Anticancer Potential and Other Pharmacological Properties of Prunus armeniaca L.: An Updated Overview.
  53. The Mediterranean Diet: An Update of the Clinical Trials.
  54. An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava.
  55. Biocompatibility Study of Curcumin-Loaded Pluronic F127 Nanoformulation (NanoCUR) against the Embryonic Development of Zebrafish (Danio rerio).
  56. Formulation and Optimization of Alogliptin-Loaded Polymeric Nanoparticles: In Vitro to In Vivo Assessment.
  57. Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage.
  58. Applications and perspectives of polyphenol-loaded solid lipid nanoparticles and nanostructured lipid carriers for foods.
  59. Targeting Colorectal Cancer Cells with Niosomes Systems Loaded with Two Anticancer Drugs Models; Comparative In Vitro and Anticancer Studies.
  60. Protective Effects of Diets Rich in Polyphenols in Cigarette Smoke (CS)-Induced Oxidative Damages and Associated Health Implications.
  61. A facile method for anti-cancer drug encapsulation into polymersomes with a core-satellite structure.
  62. Arene-Ruthenium(II)/Osmium(II) Complexes Potentiate the Anticancer Efficacy of Metformin via Glucose Metabolism Reprogramming.
  63. An Oral 3D Printed PLGA-Tocopherol PEG Succinate Nanocomposite Hydrogel for High-Dose Methotrexate Delivery in Maintenance Chemotherapy.
  64. A Review on the Delivery of Plant-Based Antidiabetic Agents Using Nanocarriers: Current Status and Their Role in Combatting Hyperglycaemia.
  65. A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers.
  66. Hyaluronic Acid Modified Nanostructured Lipid Carrier for Targeting Delivery of Kaempferol to NSCLC: Preparation, Optimization, Characterization, and Performance Evaluation In Vitro.
  67. Fabrication of phenyl boronic acid modified pH-responsive zinc oxide nanoparticles as targeted delivery of chrysin on human A549 cells.
  68. Dietary Selenium and Its Antioxidant Properties Related to Growth, Lipid and Energy Metabolism.
  69. Therapeutic Potential of Marine Peptides in Prostate Cancer: Mechanistic Insights.
  70. Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments.
  71. Polymeric Nanosystems Applied for Metal-Based Drugs and Photosensitizers Delivery: The State of the Art and Recent Advancements.
  72. Endophytes, a Potential Source of Bioactive Compounds to Curtail the Formation-Accumulation of Advanced Glycation End Products: A Review.
  73. Does Molecular Profiling of KRAS-Mutant Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Help in Treatment Strategy Planning?
  74. Glucose-Modified Zein Nanoparticles Enhance Oral Delivery of Docetaxel.
  75. Taurine and Its Anticancer Functions: In Vivo and In Vitro Study.
  76. Novel Trends in Hydrogel Development for Biomedical Applications: A Review.
  77. Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy.
  78. Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy.
  79. Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical.
  80. Near-Infrared Photoimmunotherapy for Thoracic Cancers: A Translational Perspective.
  81. Therapeutic potential of human serum albumin nanoparticles encapsulated actinonin in murine model of lung adenocarcinoma.
  82. Preparation of PCL Electrospun Fibers Loaded with Cisplatin and Their Potential Application for the Treatment of Prostate Cancer.
  83. Multifunctional Magnetic CuS/Gd2O3 Nanoparticles for Fluorescence/Magnetic Resonance Bimodal Imaging-Guided Photothermal-Intensified Chemodynamic Synergetic Therapy of Targeted Tumors.
  84. Progress in the treatment of drug-induced liver injury with natural products.
  85. Engineering H2 O2 and O2 self-supplying nanoreactor to conduct synergistic chemiexcited photodynamic and calcium-overloaded therapy in orthotopic hepatic tumors.
  86. A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health.
  87. Tamoxifen Citrate Containing Topical Nanoemulgel Prepared by Ultrasonication Technique: Formulation Design and In Vitro Evaluation.
  88. Antioxidant Effect of Nanoparticles Composed of Zein and Orange (Citrus sinensis) Extract Obtained by Ultrasound-Assisted Extraction.
  89. [Intestinal gluconeogenesis: an insulin-mimetic function].
  90. How Should the Worldwide Knowledge of Traditional Cancer Healing Be Integrated with Herbs and Mushrooms into Modern Molecular Pharmacology?
  91. PLGA-Quercetin Nano-Formulation Inhibits Cancer Progression via Mitochondrial Dependent Caspase-3,7 and Independent FoxO1 Activation with Concomitant PI3K/AKT Suppression.
  92. Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD).
  93. Alginate-based nanocarriers for the delivery and controlled-release of bioactive compounds.
  94. Development and Optimization of Nigella sativa Nanoemulsion Loaded with Pioglitazone for Hypoglycemic Effect.
  95. Folic acid-targeted pluronic F127 micelles improve oxidative stress and inhibit fibrosis for increasing AKI efficacy.
  96. Epithelial-Mesenchymal Transition-Mediated Tumor Therapeutic Resistance.
  97. Engineered hyaluronic acid-decorated niosomal nanoparticles for controlled and targeted delivery of epirubicin to treat breast cancer.
  98. Curcumin Modifies the Activity of Plasmatic Antioxidant Enzymes and the Hippocampal Oxidative Profile in Rats upon Acute and Chronic Exposure to Ozone.
  99. Date fruit as a promising source of functional carbohydrates and bioactive compounds: A review on its nutraceutical potential.
  100. Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype.
  101. Natural Products from Actinobacteria as a Potential Source of New Therapies Against Colorectal Cancer: A Review.
  102. Polymeric nanoparticles for drug delivery in glioblastoma: State of the art and future perspectives.
  103. The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids.
  104. Experience with Photodynamic Therapy Using Indocyanine Green Liposomes for Refractory Cancer.
  105. Copper Nanocluster Enabled Simultaneous Photodynamic and Chemo Therapy for Effective Cancer Diagnosis and Treatment In Vitro.
  106. Unfolding the Potency of Adenosine in Targeting Triple Negative Breast Cancer via Paclitaxel-Incorporated pH-Responsive Stealth Liposomes.
  107. Intelligent Nanoparticles With pH-Sensitive Co-Delivery of Temozolomide and siEGFR to Ameliorate Glioma Therapy.
  108. Polymer-Based Hybrid Nanoarchitectures for Cancer Therapy Applications.
  109. The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: 'Talented' Taxa from the Amaryllidaceae.
  110. Daptomycin-Biomineralized Silver Nanoparticles for Enhanced Photothermal Therapy with Anti-Tumor Effect.
  111. Naringin and Naringenin: Their Mechanisms of Action and the Potential Anticancer Activities.
  112. Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy.
  113. Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: Approaches with Natural Compounds from Traditional Eastern Medicine.
  114. Cyclodextrin-Based Nanoplatforms for Tumor Phototherapy: An Update.
  115. Glutathione Pulse Therapy: Promote Spatiotemporal Delivery of Reduction-Sensitive Nanoparticles at the "Cellular Level" and Synergize PD-1 Blockade Therapy.
  116. Leucine Supplementation in Cancer Cachexia: Mechanisms and a Review of the Pre-Clinical Literature.
  117. Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics.
  118. The Effect of Curcumin on Renal Ischemia/Reperfusion Injury in Diabetic Rats.
  119. Akt protein boosts cancer metabolism through a two-pronged attack.
  120. Improved Delivery Performance of n-Butylidenephthalide-Polyethylene Glycol-Gold Nanoparticles Efficient for Enhanced Anti-Cancer Activity in Brain Tumor.
  121. Iron Overload and Breast Cancer: Iron Chelation as a Potential Therapeutic Approach.
  122. Poly(N-isopropylacrylamide)-Based Hydrogels for Biomedical Applications: A Review of the State-of-the-Art.
  123. Ultrasound-Responsive Liposomes for Targeted Drug Delivery Combined with Focused Ultrasound.
  124. Micro- and Nanosized Carriers for Nose-to-Brain Drug Delivery in Neurodegenerative Disorders.
  125. Self-Supply Oxygen ROS Reactor via Fenton-like Reaction and Modulating Glutathione for Amplified Cancer Therapy Effect.
  126. Targeting the Blood-Brain Tumor Barrier with Tumor Necrosis Factor-α.
  127. Mesoporous Materials as Elements of Modern Drug Delivery Systems for Anti-Inflammatory Agents: A Review of Recent Achievements.
  128. The Role of Nut and Seed Consumption in Colorectal Cancer: A Narrative Review.
  129. Margetuximab conjugated-PEG-PAMAM G4 nano-complex: a smart nano-device for suppression of breast cancer.
  130. Phytosomes as a Plausible Nano-Delivery System for Enhanced Oral Bioavailability and Improved Hepatoprotective Activity of Silymarin.
  131. Research and Development of Natural Product Tanshinone I: Pharmacology, Total Synthesis, and Structure Modifications.
  132. A Comprehensive Update on the Bioactive Compounds from Seagrasses.
  133. Royal Jelly Components Encapsulation in a Controlled Release System-Skin Functionality, and Biochemical Activity for Skin Applications.
  134. Pharmacological targets for the induction of ferroptosis: Focus on Neuroblastoma and Glioblastoma.
  135. Therapeutic Implications of FABP4 in Cancer: An Emerging Target to Tackle Cancer.
  136. Advanced Vesicular Systems for Antifungal Drug Delivery.
  137. Nano-drug delivery system with enhanced tumour penetration and layered anti-tumour efficacy.
  138. CNN1 Represses Bladder Cancer Progression and Metabolic Reprogramming by Modulating HIF-1α Signaling Pathway.
  139. Prognostic Value of KRAS Mutations in Colorectal Cancer Patients.
  140. The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy.
  141. Vitamin D and Visceral Obesity in Humans: What Should Clinicians Know?
  142. Anti-Diabesity Middle Eastern Medicinal Plants and Their Action Mechanisms.
  143. Long-term Stable Disease in a Rectal-cancer Patient Treated by Methionine Restriction With Oral Recombinant Methioninase and a Low-methionine Diet.
  144. Synthesis of Prussian Blue Nanoparticles and Their Antibacterial, Antiinflammation and Antitumor Applications.
  145. Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review.
  146. Formulation, Optimization, and Evaluation of Moringa oleifera Leaf Polyphenol-Loaded Phytosome Delivery System against Breast Cancer Cell Lines.
  147. STAT3 Inactivation and Induction of Apoptosis Associate With Fluoxetine-inhibited Epithelial-mesenchymal Transition and Growth of Triple-negative Breast Cancer In Vivo.
  148. Quercetin Protects Ethanol-Induced Hepatocyte Pyroptosis via Scavenging Mitochondrial ROS and Promoting PGC-1α-Regulated Mitochondrial Homeostasis in L02 Cells.
  149. Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity.
  150. Recent Advances in Honey-Based Nanoparticles for Wound Dressing: A Review.
  151. Chemopreventive Potential of Dietary Nanonutraceuticals for Prostate Cancer: An Extensive Review.
  152. Silencing VDAC1 to Treat Mesothelioma Cancer: Tumor Reprograming and Altering Tumor Hallmarks.
  153. Gelatinase Responsive Nanogel for Antibacterial Phototherapy and Wound Healing.
  154. A Glucokinase-linked Sensor in the Taste System Contributes to Glucose Appetite.
  155. Evaluation of ketogenic diet therapy in children diagnosed with drug-resistant epilepsy: a single-center experience.
  156. Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learnt and Future Directions.
  157. Naturally Occurring Compounds as Potential Inhibitors of Epidermal Growth Factor Receptors (EGFRs).
  158. Emergence of Edible Plant-Derived Nanovesicles as Functional Food Components and Nanocarriers for Therapeutics Delivery: Potentials in Human Health and Disease.
  159. Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy.
  160. Nanosponges for Drug Delivery and Cancer Therapy: Recent Advances.
  161. Design and Validation of Nanofibers Made of Self-Assembled Peptides to Become Multifunctional Stimuli-Sensitive Nanovectors of Anticancer Drug Doxorubicin.
  162. Anti-Colon Cancer Activity of Dietary Phytochemical Soyasaponin I and the Induction of Metabolic Shifts in HCT116.
  163. 3D and 4D Printing in the Fight against Breast Cancer.
  164. Biotin receptor-targeting nanogels loaded with methotrexate for enhanced antitumor efficacy in triple-negative breast cancer in vitro and in vivo models.
  165. Rapid nutrient depletion to below the physiological range by cancer cells cultured in Plasmax.
  166. Relationship between the Antifungal Activity of Chitosan-Capsaicin Nanoparticles and the Oxidative Stress Response on Aspergillus parasiticus.
  167. Microenvironmental Behaviour of Nanotheranostic Systems for Controlled Oxidative Stress and Cancer Treatment.
  168. Simvastatin in the Treatment of Colorectal Cancer: A Review.
  169. Emerging Nanotechnologies and Microbiome Engineering for the Treatment of Inflammatory Bowel Disease.
  170. The Molecular Mechanism of Traditional Chinese Medicine Prescription: Gu-tong Formula in Relieving Osteolytic Bone Destruction.
  171. Therapeutic Benefits of Selenium in Hematological Malignancies.
  172. Therapeutic Potential of Polyphenol and Nanoparticles Mediated Delivery in Periodontal Inflammation: A Review of Current Trends and Future Perspectives.
  173. Novel Self-Assembled Micelles With Increased Tumor Penetration and Anti-Tumor Efficiency Against Breast Cancer.
  174. Development, characterisation, and in vitro anti-tumor effect of self-microemulsifying drug delivery system containing polyphyllin I.
  175. A Recap of Heme Metabolism towards Understanding Protoporphyrin IX Selectivity in Cancer Cells.
  176. Slow release curcumin-containing soy protein nanoparticles as anticancer agents for osteosarcoma: synthesis and characterization.
  177. Quercetin as a JAK-STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases.
  178. Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression.
  179. Preparation, properties, and applications of gelatin-based hydrogels (GHs) in the environmental, technological, and biomedical sectors.
  180. Biological Evaluation, Phytochemical Screening, and Fabrication of Indigofera Linifolia Leaves Extract-Loaded Nanoparticles.
  181. Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair.
  182. Diosgenin promotes cisplatin-induced apoptosis through oxidative DNA damage in A549 non-small cell lung cells.
  183. Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma.
  184. Pharmacological Potential of Lathyrane-Type Diterpenoids from Phytochemical Sources.
  185. Tailoring nanoparticles design for enhanced heating efficiency and improved magneto-chemo therapy for glioblastoma.
  186. Cecropin-Loaded Zeolitic Imidazolate Framework Nanoparticles with High Biocompatibility and Cervical Cancer Cell Toxicity.
  187. Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma.
  188. Addition of grapes to both a standard and a high-fat Western pattern diet modifies hepatic and urinary metabolite profiles in the mouse.
  189. Current Advances in the Development of Hydrogel-Based Wound Dressings for Diabetic Foot Ulcer Treatment.
  190. Development and Optimization of Ciprofloxacin HCl-Loaded Chitosan Nanoparticles Using Box-Behnken Experimental Design.
  191. Chitosan-modified hollow manganese dioxide nanoparticles loaded with resveratrol for the treatment of spinal cord injury.
  192. Nano-Based Theranostic Platforms for Breast Cancer: A Review of Latest Advancements.
  193. Peptide-Mediated Targeted Delivery of Aloe-Emodin as Anticancer Drug.
  194. Co-Delivery of 5-Fluorouracil and Paclitaxel in Mitochondria-Targeted KLA-Modified Liposomes to Improve Triple-Negative Breast Cancer Treatment.
  195. Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma.
  196. Atheroprotective Effects of Glycyrrhiza glabra L.
  197. Inorganic Nanomaterials versus Polymer-Based Nanoparticles for Overcoming Neurodegeneration.
  198. Self-adjuvanting cancer nanovaccines.
  199. Phytochemicals as Regulators of Tumor Glycolysis and Hypoxia Signaling Pathways: Evidence from In Vitro Studies.
  200. Anticancer Activity of Bee Venom Components against Breast Cancer.
  201. Role of Diet in Stem and Cancer Stem Cells.
  202. Therapeutic applications of curcumin nanomedicine formulations in cystic fibrosis.
  203. [Targeted Drug Therapy for Intracranial Tumors].
  204. Angelica gigas: Signature Compounds, In Vivo Anticancer, Analgesic, Neuroprotective and Other Activities, and the Clinical Translation Challenges.
  205. Mediterranean Diet on Sleep: A Health Alliance.
  206. Effect of macronutrient and micronutrient manipulation on avian blood glucose concentration: A systematic review.
  207. Investigation of the Renal Protective Effect of Combined Dietary Polyphenols in Streptozotocin-Induced Diabetic Aged Rats.
  208. Timeline of the Development of Skin-Lightening Active Ingredients in Japan.
  209. Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration.
  210. Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties.
  211. Effects of Toxic AGEs (TAGE) on Human Health.
  212. Present Status, Challenges, and Prospects of Dihydromyricetin in the Battle against Cancer.
  213. Insights Into the Role of Epigenetic Factors Determining the Estrogen Response in Estrogen-Positive Ovarian Cancer and Prospects of Combining Epi-Drugs With Endocrine Therapy.
  214. Chalcones as Anti-Glioblastoma Stem Cell Agent Alone or as Nanoparticle Formulation Using Carbon Dots as Nanocarrier.
  215. Efficient epidermal delivery of antibiotics by self-assembled lecithin/chitosan nanoparticles for enhanced therapy on epidermal bacterial infections.
  216. Dual Drug Loaded, pH-Sensitive Metal-Organic Particles for Synergistic Cancer Therapy.
  217. Phytochemical characterization and bioactivity toward breast cancer cells of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica.
  218. Cellular Calcium Signals in Cancer Chemoprevention and Chemotherapy by Phytochemicals.
  219. Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines.
  220. Construction of Folate-Conjugated and pH-Responsive Cell Membrane Mimetic Mixed Micelles for Desirable DOX Release and Enhanced Tumor-Cellular Target.
  221. Modulation of Gut Microbiota by Essential Oils and Inorganic Nanoparticles: Impact in Nutrition and Health.
  222. Co-Delivery of Repurposing Itraconazole and VEGF siRNA by Composite Nanoparticulate System for Collaborative Anti-Angiogenesis and Anti-Tumor Efficacy against Breast Cancer.
  223. Prenylated Flavonoids in Topical Infections and Wound Healing.
  224. Main Bioactive Components and Their Biological Activities from Natural and Processed Rhizomes of Polygonum sibiricum.
  225. The cross-talk of autophagy and apoptosis in breast carcinoma: implications for novel therapies?
  226. The Potential of Spirulina platensis to Ameliorate the Adverse Effects of Highly Active Antiretroviral Therapy (HAART).
  227. Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation.
  228. Non-Canonical Programmed Cell Death in Colon Cancer.
  229. Localized Controlled Release of Kynurenic Acid Encapsulated in Synthetic Polymer Reduces Implant-Induced Dermal Fibrosis.
  230. Advances in hybrid peptide-based self-assembly systems and their applications.
  231. Mechanism Study on Nanoparticle Negative Surface Charge Modification by Ascorbyl Palmitate and Its Improvement of Tumor Targeting Ability.
  232. Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets.
  233. Protective effects of polyphenols against endocrine disrupting chemicals.
  234. [MUC16: The Novel Target for Tumor Therapy].
  235. A route to rational anticancer combinations.
  236. Preparation of Terbinafin-Encapsulated Solid Lipid Nanoparticles Containing Antifungal Carbopol® Hydrogel with Improved Efficacy: In Vitro, Ex Vivo and In Vivo Study.
  237. Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy.
  238. Nanostructured Lipid Carrier-Based Delivery of Pioglitazone for Treatment of Type 2 Diabetes.
  239. Tannic acid: a versatile polyphenol for design of biomedical hydrogels.
  240. GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors.
  241. Formulation and Evaluation of Moxifloxacin Loaded Bilosomes In-Situ Gel: Optimization to Antibacterial Evaluation.
  242. Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer.
  243. Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden.
  244. Dual Role of Chitin as the Double Edged Sword in Controlling the NLRP3 Inflammasome Driven Gastrointestinal and Gynaecological Tumours.
  245. Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies.
  246. Antioxidant Efficacy of a Spirulina Liquid Extract on Oxidative Stress Status and Metabolic Disturbances in Subjects with Metabolic Syndrome.
  247. Doxorubicin-Loaded Lipid Nanoparticles Coated with Calcium Phosphate as a Potential Tool in Human and Canine Osteosarcoma Therapy.
  248. Natural Compounds: A Hopeful Promise as an Antibiofilm Agent Against Candida Species.
  249. Magnetic-Driven Hydrogel Microrobots Selectively Enhance Synthetic Lethality in MTAP-Deleted Osteosarcoma.
  250. A Review on the Extraction, Bioactivity, and Application of Tea Polysaccharides.
  1. Antioxidants (Basel). 2022 Jul 11. pii: 1349. [Epub ahead of print]11(7):
    Therapeutic Intervention in Cancer by Isoliquiritigenin from Licorice: A Natural Antioxidant and Redox Regulator.
    Zhu Zhang, Ken Kin-Lam Yung, Joshua Ka-Shun Ko.
      Oxidative stress could lead to a variety of body dysfunctions, including neurodegeneration and cancer, which are closely associated with intracellular signal transducers such as reactive oxygen species (ROS). It has been suggested that ROS is the upstream regulator of autophagy, and that it provides a negative feedback regulation to remove oxidative damage. Defects in the ROS-autophagic redox homeostasis could lead to the increased production of ROS and the accumulation of damaged organelles that in turn promote metabolic reprogramming and induce tumorigenesis. One significant characteristic of pancreatic cancer is the reprogramming of cellular energy metabolism, which facilitates the rapid growth, invasiveness, and the survival of cancer cells. Thus, the rectification of metabolic dysfunction is essential in therapeutic cancer targeting. Isoliquiritigenin (ISL) is a chalcone obtained from the plant Glycyrrhiza glabra, which is a powdered root licorice that has been consumed for centuries in different regions of the world. ISL is known to be a natural antioxidant that possesses diversified functions, including redox regulation in cells. This review contains discussions on the herbal source, biological properties, and anticancer potential of ISL. This is the first time that the anticancer activities of ISL in pancreatic cancer has been elucidated, with a coverage of the involvement of antioxidation, metabolic redox regulation, and autophagy in pancreatic cancer development. Furthermore, some remarks on related compounds of the isoflavonoid biosynthetic pathway of ISL will also be discussed.
    Keywords:  autophagy; isoliquiritigenin; natural antioxidant; reactive oxygen species; redox regulation
    DOI:  https://doi.org/10.3390/antiox11071349
  2. Front Oncol. 2022 ;12 939365
    Research Progress of Photothermal Nanomaterials in Multimodal Tumor Therapy.
    Xiaolu Shi, Ye Tian, Yang Liu, Zhengrong Xiong, Shaobo Zhai, Shunli Chu, Fengxiang Gao.
      The aggressive growth of cancer cells brings extreme challenges to cancer therapy while triggering the exploration of the application of multimodal therapy methods. Multimodal tumor therapy based on photothermal nanomaterials is a new technology to realize tumor cell thermal ablation through near-infrared light irradiation with a specific wavelength, which has the advantages of high efficiency, less adverse reactions, and effective inhibition of tumor metastasis compared with traditional treatment methods such as surgical resection, chemotherapy, and radiotherapy. Photothermal nanomaterials have gained increasing interest due to their potential applications, remarkable properties, and advantages for tumor therapy. In this review, recent advances and the common applications of photothermal nanomaterials in multimodal tumor therapy are summarized, with a focus on the different types of photothermal nanomaterials and their application in multimodal tumor therapy. Moreover, the challenges and future applications have also been speculated.
    Keywords:  multimodal therapy; nanomaterial; photothermal agents; photothermal therapy; synergistic effect; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.939365
  3. Nat Commun. 2022 Jul 26. 13(1): 4327
    Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer.
    Caterina Bartolacci, Cristina Andreani, Gonçalo Vale, Stefano Berto, Margherita Melegari, Anna Colleen Crouch, Dodge L Baluya, George Kemble, Kurt Hodges, Jacqueline Starrett, Katerina Politi, Sandra L Starnes, Daniele Lorenzini, Maria Gabriela Raso, Luisa M Solis Soto, Carmen Behrens, Humam Kadara, Boning Gao, Ignacio I Wistuba, John D Minna, Jeffrey G McDonald, Pier Paolo Scaglioni.
      Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, blocking either FASN or the Lands cycle in KMLC, promotes ferroptosis, a reactive oxygen species (ROS)- and iron-dependent cell death, characterized by the intracellular accumulation of oxidation-prone PC. Our work indicates that KM dictates a dependency on newly synthesized FA to escape ferroptosis, establishing a targetable vulnerability in KMLC.
    DOI:  https://doi.org/10.1038/s41467-022-31963-4
  4. Signal Transduct Target Ther. 2022 07 23. 7(1): 252
    Dietary regulation in health and disease.
    Qi Wu, Zhi-Jie Gao, Xin Yu, Ping Wang.
      Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.
    DOI:  https://doi.org/10.1038/s41392-022-01104-w
  5. Nanomedicine. 2022 Jul 26. pii: S1549-9634(22)00074-0. [Epub ahead of print] 102588
    PNA-ATP aptamer-capped doxorubicin-loaded silica nanoparticles for targeted cancer therapy.
    Youkabed Kazemi, Sadegh Dehghani, Fatemeh Soltani, Khalil Abnous, Mona Alibolandi, Seyed Mohammad Taghdisi, Mohammad Ramezani.
      Nanomaterial-based drug delivery has opened new horizons in cancer therapy. This study aimed to investigate the in vitro and in vivo anti-cancer effects of a hyaluronic acid (HA)-targeted nanocarrier based on hollow silica nanoparticles (HSNPs), gated with peptide nucleic acid (PNA) and ATP aptamer (ATPApt) and loaded with doxorubicin (DOX). After formulation of a smart drug delivery nanosystem (HSNPs/DOX/ATPApt/PNA/HA), drug release, cytotoxicity, uptake, and in vivo anti-tumor properties were studied. Drug release test showed the controlled release of encapsulated DOX in response to ATP content. MTT and flow cytometry indicated that HA could improve both cytotoxicity and cellular uptake of the formulation. Moreover, HA-targeted formulation enhanced both the survival rate and tumor inhibition in the tumor-bearing mice compared with free DOX (P < 0.05). Our findings confirmed that HA-targeted nanoformulation, gated with PNA/aptamer and loaded with DOX can provide a novel therapeutic platform with great potential for cancer therapy.
    Keywords:  Aptamer; Doxorubicin; Drug delivery; Hyaluronic acid; Silica nanoparticle
    DOI:  https://doi.org/10.1016/j.nano.2022.102588
  6. Int J Mol Sci. 2022 Jul 11. pii: 7659. [Epub ahead of print]23(14):
    Endothelium-Dependent Induction of Vasculogenic Mimicry in Human Triple-Negative Breast Cancer Cells Is Inhibited by Calcitriol and Curcumin.
    Gabriela Morales-Guadarrama, Edgar A Méndez-Pérez, Janice García-Quiroz, Euclides Avila, Rocío García-Becerra, Alejandro Zentella-Dehesa, Fernando Larrea, Lorenza Díaz.
      In highly aggressive tumors, cancer cells may form channel-like structures through a process known as vasculogenic mimicry (VM). VM is generally associated with metastasis, mesenchymal phenotype, and treatment resistance. VM can be driven by antiangiogenic treatments and/or tumor microenvironment-derived factors, including those from the endothelium. Curcumin, a turmeric product, inhibits VM in some tumors, while calcitriol, the most active vitamin D metabolite, exerts potent antineoplastic effects. However, the effect of these natural products on VM in breast cancer remains unknown. Herein, we studied the effect of both compounds on triple-negative breast cancer (TNBC) VM-capacity in a co-culture model. The process of endothelial cell-induced VM in two human TNBC cell lines was robustly inhibited by calcitriol and partially by curcumin. Calcitriol promoted TNBC cells' morphological change from spindle-like to cobblestone-shape, while curcumin diminished VM 3D-structure. Notably, the treatments dephosphorylated several active kinases, especially those involved in the PI3K/Akt pathway. In summary, calcitriol and curcumin disrupted endothelium-induced VM in TNBC cells partially by PI3K/Akt inactivation and mesenchymal phenotype inhibition. Our results support the possible use of these natural compounds as adjuvants for VM inactivation in patients with malignant tumors inherently capable of forming VM, or those with antiangiogenic therapy, warranting further in vivo studies.
    Keywords:  breast cancer; co-culture; epithelial-to-mesenchymal transition; tubulogenesis; vascular mimicry
    DOI:  https://doi.org/10.3390/ijms23147659
  7. Phytother Res. 2022 Jul 24.
    Pull the plug: Anti-angiogenesis potential of natural products in gastrointestinal cancer therapy.
    Yanling Ai, Ziyi Zhao, Hengyi Wang, Xiaomei Zhang, Weihan Qin, Yanlei Guo, Maoyuan Zhao, Jianyuan Tang, Xiao Ma, Jinhao Zeng.
      Gastrointestinal cancer (GIC), including gastric cancer and colorectal cancer, is a common malignant tumor originating from the gastrointestinal epithelium. Although the pathogenesis of GIC has not been fully elucidated, angiogenesis is recognized as the key pathological basis for the growth, invasion and metastasis of cancer cells, and GIC angiogenesis is closely related to vascular endothelial growth factor family, hypoxia-inducible factor family, fibroblast growth factor family and matrix metalloproteinase family. Recently, many natural products have shown a wide range of pharmacological biological activities against GIC. In this review, the effects and mechanisms of natural compounds on the angiogenesis of gastric and colorectal cancer were summarized. The results show that some natural compounds, especially gallic catechin gallate, astragaloside and curcumin, can effectively inhibit angiogenesis; the HIF-1α/VEGF, COX-2/PGE2, HGF/c-Met and PI3K/Akt/mTOR are involved in these inhibition effects. This review examines the anti-angiogenesis potential of natural products in the GIC treatment and provides clues to the development of vascular targeted agents.
    Keywords:  angiogenesis; colorectal cancer; gastric cancer; gastrointestinal tumor; natural compounds; natural products; phytochemicals
    DOI:  https://doi.org/10.1002/ptr.7492
  8. Cells. 2022 Jul 15. pii: 2209. [Epub ahead of print]11(14):
    The Role of Natural Products and Their Multitargeted Approach to Treat Solid Cancer.
    Naoshad Muhammad, Darksha Usmani, Mohammad Tarique, Huma Naz, Mohammad Ashraf, Ramesh Raliya, Shams Tabrez, Torki A Zughaibi, Ahdab Alsaieedi, Israa J Hakeem, Mohd Suhail.
      Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural products have been used as healing agents. Likewise, most of the medicinal ingredients accessible today are originated from the natural resources. Regardless of achievements, developing bioactive compounds and drugs from natural products has remained challenging, in part because of the problem associated with large-scale sequestration and mechanistic understanding. With significant progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we may have come to a crossroads to review approaches to identify the potential natural products and investigate their therapeutic efficacy. In the present review, we summarize the recent developments in natural products-based cancer research and its application in generating novel systemic strategies with a focus on underlying molecular mechanisms in solid cancer.
    Keywords:  medicinal plants; natural products; phytochemicals and solid cancer
    DOI:  https://doi.org/10.3390/cells11142209
  9. Mar Drugs. 2022 Jul 17. pii: 460. [Epub ahead of print]20(7):
    Chitin and Chitosan: Prospective Biomedical Applications in Drug Delivery, Cancer Treatment, and Wound Healing.
    Parnian Baharlouei, Azizur Rahman.
      Chitin and its derivative chitosan are highly abundant polymers in nature, appearing in both the shells and exoskeletons of various marine and non-marine species. Since they possess favorable properties, such as biocompatibility, biodegradability, non-toxicity, and non-immunogenicity, they have gained recent attention due to their enormous potential biomedical applications. The polycationic surface of chitosan enables it to form hydrogenic and ionic bonds with drug molecules, which is one of its most useful properties. Because chitosan is biocompatible, it can therefore be used in drug delivery systems. The development of chitosan-based nanoparticles has also contributed to the significance of chitin as a drug delivery system that can deliver drugs topically. Furthermore, chitin can be used in cancer treatment as a vehicle for delivering cancer drugs to a specific site and has an antiproliferative effect by reducing the viability of cells. Finally, chitosan can be used as a wound dressing in order to promote the faster regeneration of skin epithelial cells and collagen production by fibroblasts. As discussed in this review, chitin and chitosan have diverse applications in the medical field. Recognizing the biomedical applications of these two polymers is essential for future research in tissue engineering and nanobiotechnology.
    Keywords:  cancer drugs; chitin; chitosan; drug delivery; nanobiotechnology; tissue engineering; wound healing
    DOI:  https://doi.org/10.3390/md20070460
  10. Cancers (Basel). 2022 Jul 19. pii: 3500. [Epub ahead of print]14(14):
    Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy.
    Madison Pereira, Kathy Matuszewska, Alice Glogova, Jim Petrik.
      Tumor cells have the ability to co-opt multiple metabolic pathways, enhance glucose uptake and utilize aerobic glycolysis to promote tumorigenesis, which are characteristics constituting an emerging hallmark of cancer. Mutated tumor suppressor and proto-oncogenes are frequently responsible for enhanced metabolic pathway signaling. The link between mutant p53 and the mevalonate (MVA) pathway has been implicated in the advancement of various malignancies, with tumor cells relying heavily on increased MVA signaling to fuel their rapid growth, metastatic spread and development of therapy resistance. Statin drugs inhibit HMG-CoA reductase, the pathway's rate-limiting enzyme, and as such, have long been studied as a potential anti-cancer therapy. However, whether statins provide additional anti-cancer properties is worthy of debate. Here, we examine retrospective, prospective and pre-clinical studies involving the use of statins in various cancer types, as well as potential issues with statins' lack of efficacy observed in clinical trials and future considerations for upcoming clinical trials.
    Keywords:  metabolism; mevalonate pathway; p53; statins; therapy resistance
    DOI:  https://doi.org/10.3390/cancers14143500
  11. Front Oncol. 2022 ;12 938847
    Targeted Arginine Metabolism Therapy: A Dilemma in Glioma Treatment.
    Xiaoshuang Hou, Sui Chen, Po Zhang, Dongsheng Guo, Baofeng Wang.
      Efforts in the treatment of glioma which is the most common primary malignant tumor of the central nervous system, have not shown satisfactory results despite a comprehensive treatment model that combines various treatment methods, including immunotherapy. Cellular metabolism is a determinant of the viability and function of cancer cells as well as immune cells, and the interplay of immune regulation and metabolic reprogramming in tumors has become an active area of research in recent years. From the perspective of metabolism and immunity in the glioma microenvironment, we elaborated on arginine metabolic reprogramming in glioma cells, which leads to a decrease in arginine levels in the tumor microenvironment. Reduced arginine availability significantly inhibits the proliferation, activation, and function of T cells, thereby promoting the establishment of an immunosuppressive microenvironment. Therefore, replenishment of arginine levels to enhance the anti-tumor activity of T cells is a promising strategy for the treatment of glioma. However, due to the lack of expression of argininosuccinate synthase, gliomas are unable to synthesize arginine; thus, they are highly dependent on the availability of arginine in the extracellular environment. This metabolic weakness of glioma has been utilized by researchers to develop arginine deprivation therapy, which 'starves' tumor cells by consuming large amounts of arginine in circulation. Although it has shown good results, this treatment modality that targets arginine metabolism in glioma is controversial. Exploiting a suitable strategy that can not only enhance the antitumor immune response, but also "starve" tumor cells by regulating arginine metabolism to cure glioma will be promising.
    Keywords:  T lymphocytes; arginine metabolism; glioma; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.938847
  12. Molecules. 2022 Jul 20. pii: 4634. [Epub ahead of print]27(14):
    Folate-Targeted Curcumin-Loaded Niosomes for Site-Specific Delivery in Breast Cancer Treatment: In Silico and In Vitro Study.
    Banafsheh Honarvari, Sara Karimifard, Niyayesh Akhtari, Mehrnoush Mehrarya, Zahra Salehi Moghaddam, Mohammad Javed Ansari, Abduladheem Turki Jalil, Adrián Matencio, Francesco Trotta, Faten Eshrati Yeganeh, Bahareh Farasati Far, Mandana Kazem Arki, Mohammad Reza Naimi-Jamal, Hassan Noorbazargan, Zahra Asghari Lalami, Mohsen Chiani.
      As the most common cancer in women, efforts have been made to develop novel nanomedicine-based therapeutics for breast cancer. In the present study, the in silico curcumin (Cur) properties were investigated, and we found some important drawbacks of Cur. To enhance cancer therapeutics of Cur, three different nonionic surfactants (span 20, 60, and 80) were used to prepare various Cur-loaded niosomes (Nio-Cur). Then, fabricated Nio-Cur were decorated with folic acid (FA) and polyethylene glycol (PEG) for breast cancer suppression. For PEG-FA@Nio-Cur, the gene expression levels of Bax and p53 were higher compared to free drug and Nio-Cur. With PEG-FA-decorated Nio-Cur, levels of Bcl2 were lower than the free drug and Nio-Cur. When MCF7 and 4T1 cell uptake tests of PEG-FA@Nio-Cur and Nio-Cur were investigated, the results showed that the PEG-FA-modified niosomes exhibited the most preponderant endocytosis. In vitro experiments demonstrate that PEG-FA@Nio-Cur is a promising strategy for the delivery of Cur in breast cancer therapy. Breast cancer cells absorbed the prepared nanoformulations and exhibited sustained drug release characteristics.
    Keywords:  ADME prediction; PEG; breast cancer; curcumin; endocytosis; folic acid; in silico studies; molecular docking; niosome
    DOI:  https://doi.org/10.3390/molecules27144634
  13. Diseases. 2022 Jun 29. pii: 37. [Epub ahead of print]10(3):
    Quercetin: A Molecule of Great Biochemical and Clinical Value and Its Beneficial Effect on Diabetes and Cancer.
    Aikaterini-Spyridoula Michala, Agathi Pritsa.
      Quercetin belongs to the broader category of polyphenols. It is found, in particular, among the flavonols, and along with kaempferol, myricetin and isorhamnetin, it is recognized as a foreign substance after ingestion in contrast to vitamins. Quercetin occurs mainly linked to sugars with the most common compounds being quercetin-3-O-glucoside or as an aglycone, especially in the plant population. The aim of this review is to present a recent bibliography on the mechanisms of quercetin absorption and metabolism, bioavailability, and antioxidant and the clinical effects in diabetes and cancer. The literature reports a positive effect of quercetin on oxidative stress, cancer, and the regulation of blood sugar levels. Moreover, research-administered drug dosages of up to 2000 mg per day showed mild to no symptoms of overdose. It should be noted that quercetin is no longer considered a carcinogenic substance. The daily intake of quercetin in the diet ranges 10 mg-500 mg, depending on the type of products consumed. This review highlights that quercetin is a valuable dietary antioxidant, although a specific daily recommended intake for this substance has not yet been determined and further studies are required to decide a beneficial concentration threshold.
    Keywords:  antioxidant; cancer; diabetes; flavonol; quercetin
    DOI:  https://doi.org/10.3390/diseases10030037
  14. Antioxidants (Basel). 2022 Jun 28. pii: 1274. [Epub ahead of print]11(7):
    Nutraceuticals: Focus on Anti-Inflammatory, Anti-Cancer, Antioxidant Properties in Gastrointestinal Tract.
    Giusy Rita Caponio, Tamara Lippolis, Valeria Tutino, Isabella Gigante, Valentina De Nunzio, Rosa Anna Milella, Marica Gasparro, Maria Notarnicola.
      In recent years, nutraceuticals have gained great popularity, owing to their physiological and potential health effects, such as anti-inflammatory, anti-cancer, antioxidant, and prebiotic effects, and their regulation of lipid metabolism. Since the Mediterranean diet is a nutritionally recommended dietary pattern including high-level consumption of nutraceuticals, this review aimed to summarize the main results obtained by our in vitro and in vivo studies on the effects of the major constituents of the Mediterranean diet (i.e., extra virgin olive oil compounds, polyunsaturated fatty acids, and fruit components). Based on experimental studies, the therapeutic purpose of nutraceuticals depends on their bioavailability, solubility, toxicity, and delivery system. This review provides more in-depth knowledge on the effects linked to nutraceuticals administration on human health, focusing the gastrointestinal tract and suggesting specific dietary components for personalized adjuvant therapies.
    Keywords:  bioactive molecule; bioavailability; gut microbiota; phenolic compounds; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/antiox11071274
  15. Int J Oncol. 2022 Sep;pii: 108. [Epub ahead of print]61(3):
    Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells.
    Tokio Terado, Chul Jang Kim, Akiyo Ushio, Kahori Minami, Yukihiro Tambe, Susumu Kageyama, Akihiro Kawauchi, Toshiyuki Tsunoda, Senji Shirasawa, Hiroyuki Tanaka, Hirokazu Inoue.
      Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Previously, knockdown of PDK4 by specific small interfering RNAs (siRNAs) have been shown to suppress the expression of Κirsten rat sarcoma viral oncogene homolog (KRAS) and the growth of lung and colorectal cancer cells, indicating that PDK4 is an attractive target of cancer therapy by altering energy metabolism. The authors previously reported that a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppresses the in vitro three‑dimensional (3D)‑spheroid formation and in vivo tumorigenesis of KRAS‑activated human pancreatic and colorectal cancer cells. The present study investigated the molecular mechanism of CPT‑induced tumor suppression via alteration of glutamine and lipid metabolism in human pancreatic and colon cancer cell lines with mutant and wild‑type KRAS. The antitumor effect of CPT was more pronounced in the cancer cells containing mutant KRAS compared with those containing wild‑type KRAS. CPT treatment decreased glutamine and lipid metabolism, affected redox regulation and increased reactive oxygen species (ROS) production in the pancreatic cancer cell line MIAPaCa‑2 containing mutant KRAS. Suppression of activated KRAS by specific siRNAs decreased 3D‑spheroid formation, the expression of acetyl‑CoA carboxylase 1 and fatty acid synthase (FASN) and lipid synthesis. The suppression also reduced glutathione‑SH/glutathione disulfide and increased the production of ROS. Knockdown of FASN suppressed lipid synthesis in MIAPaCa‑2 cells, partially promoted ROS production and mildly suppressed 3D‑spheroid formation. These results indicated that CPT reduced tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS‑dependent manner. This PDK4 inhibitor could serve as a novel therapeutic drug for KRAS‑driven intractable cancers via alteration of cell metabolism.
    Keywords:  KRAS; PDK4 inhibitor; acetyl‑CoA carboxylase 1; cryptotanshinone; fatty acid synthase; lipid synthesis; pancreatic neoplasm; reactive oxygen species
    DOI:  https://doi.org/10.3892/ijo.2022.5398
  16. Pharmaceutics. 2022 Jul 18. pii: 1486. [Epub ahead of print]14(7):
    Solid Self-Nano Emulsifying Nanoplatform Loaded with Tamoxifen and Resveratrol for Treatment of Breast Cancer.
    Nupur Shrivastava, Ankit Parikh, Rikeshwer Prasad Dewangan, Largee Biswas, Anita Kamra Verma, Saurabh Mittal, Javed Ali, Sanjay Garg, Sanjula Baboota.
      The solid self-nanoemulsifying drug delivery system (s-SNEDDS) is a growing platform for the delivery of drugs via oral route. In the present work, tamoxifen (TAM) was loaded in SNEDDS with resveratrol (RES), which is a potent chemotherapeutic, antioxidant, anti-inflammatory and P-gp inhibitor for enhancing bioavailability and to obtain synergistic anti-cancer effect against breast cancer. SNEDDS were developed using capmul MCM as oil, Tween 80 as surfactant and transcutol-HP as co-surfactant and optimized by central composite rotatable design. Neusilin US2 concentration was optimized for adsorption of liquid SNEDDS to prepare s-SNEDDS. The developed formulation was characterized and investigated for various in vitro and cell line comparative studies. Optimized TAM-RES-s-SNEDDS showed spherical droplets of a size less than 200 nm. In all in vitro studies, TAM-RES-s-SNEDDS showed significantly improved (p ˂ 0.05) release and permeation across the dialysis membrane and intestinal lumen. Moreover, TAM-RES-s-SNEDDS possessed significantly greater therapeutic efficacy (p &lt; 0.05) and better internalization on the MCF-7 cell line as compared to the conventional formulation. Additionally, oral bioavailability of TAM from SNEDDS was 1.63 folds significantly higher (p &lt; 0.05) than that of combination suspension and 4.16 folds significantly higher (p &lt; 0.05) than TAM suspension. Thus, findings suggest that TAM- RES-s-SNEDDS can be the future delivery system that potentially delivers both drugs to cancer cells for better treatment.
    Keywords:  breast cancer; combination therapy; enhanced bioavailability; resveratrol; solid self-nanoemulsifying drug delivery system; synergistic action; tamoxifen
    DOI:  https://doi.org/10.3390/pharmaceutics14071486
  17. Photodiagnosis Photodyn Ther. 2022 Jul 26. pii: S1572-1000(22)00321-0. [Epub ahead of print] 103035
    Non-canonical anti-cancer, anti-metastatic, anti-angiogenic and immunomodulatory PDT potentials of water soluble phthalocyanine derivatives with imidazole groups and their intracellular mechanism of action.
    Furkan Ayaz, Derya Yetkin, Abdulcelil Yüzer, Kübra Demircioğlu, Mine Ince.
      Cancer is currently a leading health issue globally but there has not been an effective treatment regimen deciphered as of today. Chemotherapy is the prominent treatment method but due to the undesired side effects that it is associated with, there has been an urgent need for novel chemotherpaeutic approaches. Photodynamic therapy can be listed among the alternatives for efficient and less detrimental applications of chemotherapy. Canonical photodynamic therapy (PDT) approach requires a light source with a specific wavelength of light, a non-toxic photosensitizer and molecular oxygen. PDT creates the desired effect by the photochemical reaction created through interaction of these components to create reactive oxygen species that will act on the cancer cells to enable anti-cancer activities. In our study we focus on non-canonical PDT application. In this approach we are not only aiming to eliminate cancer cells in the environment but also test the anti-metastatic, anti-angiogenic and possible immunomodulatory activities of the novel photosensitizers. Moreover, in our approach, we studied the intracellular pathways that are crucial for carcinogenesis, cell cycle, apoptosis, angiogenesis, metastasis and immune function to decipher the mechanism of the action for each compound. Reactive oxygen species based explanation was not valid in our study, hence it brings out a non canonical approach to PDT applications. Our results suggests that Phthalocyanine derivatives with imidazole groups can be effectively used against lung, colon, breast and prostate cancer while differentially affecting metastasis, angiogenesis, cell cycle, apoptosis and immune system cells' activities. Based on the results, PDT application of these phthalocyanine derivatives can be an effective treatment option to replace chemotherapy to minimize the potential side effects.
    Keywords:  Angiogenesis; Cancer; Immune system; Immunomodulatory effect; Metastasis; Photodynamic Therapy; Phthalocyanine
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103035
  18. Molecules. 2022 Jul 21. pii: 4663. [Epub ahead of print]27(14):
    Involvement of Resveratrol against Brain Cancer: A Combination Strategy with a Pharmaceutical Approach.
    Chenmala Karthika, Agnieszka Najda, Joanna Klepacka, Mehrukh Zehravi, Rokeya Akter, Muhammad Furqan Akhtar, Ammara Saleem, Majed Al-Shaeri, Banani Mondal, Ghulam Md Ashraf, Priti Tagde, Sarker Ramproshad, Zubair Ahmad, Farhat S Khan, Md Habibur Rahman.
      A brain tumor (BT) is a condition in which there is growth or uncontrolled development of the brain cells, which usually goes unrecognized or is diagnosed at the later stages. Since the mechanism behind BT is not clear, and the various physiological conditions are difficult to diagnose, the success rate of BT is not very high. This is the central issue faced during drug development and clinical trials with almost all types of neurodegenerative disorders. In the first part of this review, we focus on the concept of brain tumors, their barriers, and the types of delivery possible to target the brain cells. Although various treatment methods are available, they all have side effects or toxic effects. Hence, in the second part, a correlation was made between the use of resveratrol, a potent antioxidant, and its advantages for brain diseases. The relationship between brain disease and the blood-brain barrier, multi-drug resistance, and the use of nanomedicine for treating brain disorders is also mentioned. In short, a hypothetical concept is given with a background investigation into the use of combination therapy with resveratrol as an active ingredient, the possible drug delivery, and its formulation-based approach.
    Keywords:  P-glycoprotein; antioxidants; blood–brain barrier; brain tumor; nasal delivery; resveratrol
    DOI:  https://doi.org/10.3390/molecules27144663
  19. Pharmaceutics. 2022 Jun 21. pii: 1315. [Epub ahead of print]14(7):
    Galactosed and Reduction-Responsive Nanoparticles Assembled from Trimethylchitosan-Camptothecin Conjugates for Enhanced Hepatocellular Carcinoma Therapy.
    Chen Fu, Jingcan Qin, Xinlong Liu, Fei Kong.
      The targeted delivery of drugs to tumor cells and prevention of premature release before reaching the target is one of the key challenges to developing nanomedicines. In this paper, galactose decorated trimethyl chitosan (GT)-camptothecin (CPT) prodrug nanoparticles (GT-ss-CPT NPs) were prepared from GT-CPT conjugates linked by dithiodipropionic acid. The obtained GT-ss-CPT NPs were spherical with a particle size of 184.1 nm. GT-ss-CPT NPs displayed low drug release under physiological conditions, whereas efficient drug release was triggered by high GSH concentration. GT-ss-CPT NPs exhibited a higher antitumor effect both in vitro and in vivo than the free drug counterpart. More importantly, GT-ss-CPT NPs reduced the high systematic toxicity of CPT to tumor-bearing mice. In summary, GT-ss-CPT NPs can not only inhibit the premature release of CPT but also have a great potential for targeted hepatocellular carcinoma chemotherapy.
    Keywords:  antitumor; camptothecin; galactosed trimethylchitosan; hepatocellular carcinoma; prodrug nanoparticles; targeted delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14071315
  20. Molecules. 2022 Jul 26. pii: 4791. [Epub ahead of print]27(15):
    Advances on Natural Abietane, Labdane and Clerodane Diterpenes as Anti-Cancer Agents: Sources and Mechanisms of Action.
    Rosaria Acquaviva, Giuseppe A Malfa, Monica R Loizzo, Jianbo Xiao, Simone Bianchi, Rosa Tundis.
      Extensive research over the past decades has identified numerous phytochemicals that could represent an important source of anti-cancer compounds. There is an immediate need for less toxic and more effective preventive and therapeutic strategies for the treatment of cancer. Natural compounds are considered suitable candidates for the development of new anti-cancer drugs due to their pleiotropic actions on target events with multiple manners. This comprehensive review highlighted the most relevant findings achieved in the screening of phytochemicals for anticancer drug development, particularly focused on a promising class of phytochemicals such as diterpenes with abietane, clerodane, and labdane skeleton. The chemical structure of these compounds, their main natural sources, and mechanisms of action were critically discussed.
    Keywords:  apoptosis; cytotoxicity; phytochemicals; plant secondary metabolites; terpenoids; tumor
    DOI:  https://doi.org/10.3390/molecules27154791
  21. Front Pharmacol. 2022 ;13 903210
    Novel Gemcitabine-Re(I) Bisquinolinyl Complex Combinations and Formulations With Liquid Crystalline Nanoparticles for Pancreatic Cancer Photodynamic Therapy.
    Hui Shan Liew, Chun-Wai Mai, Mohd Zulkefeli, Thiagarajan Madheswaran, Lik Voon Kiew, Lesley Jia Wei Pua, Ling Wei Hii, Wei Meng Lim, May Lee Low.
      With less than 10% of 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal types of cancer. Current literature supports that gemcitabine is the first-line treatment of PDAC. However, poor cellular penetration of gemcitabine along with the acquired and intrinsic chemoresistance of tumor against it often reduced its efficacy and hence necessitates the administration of high gemcitabine dose during chemotherapy. Photodynamic therapy (PDT), a more selective and minimally invasive treatment, may be used synergistically with gemcitabine to reduce the doses utilized and dose-related side effects. This study reports the synergistic use of Re(I) bisquinolinyl complex, a transition metal complex photosensitizer with gemcitabine against PDAC. Re(I) bisquinolinyl complex was found to act synergistically with gemcitabine against PDAC in vitro at various ratios. With the aim to enhance cellular uptake and therapeutic efficiency, the Re(I) bisquinolinyl complex and gemcitabine were encapsulated into liquid crystalline nanoparticles (LCNPs) system. The formulations were found to produce homogeneous drug-loaded LCNPs (average size: 159-173 nm, zeta potential +1.06 to -10 mV). Around 70% of gemcitabine and 90% of the Re(I) bisquinolinyl complex were found to be entrapped efficiently in the formulated LCNPs. The release rate of gemcitabine or/and the Re(I) bisquinolinyl complex loaded into LCNPs was evaluated in vitro, and the hydrophilic gemcitabine was released at a faster rate than the lipophilic Re(I) complex. LCNPs loaded with gemcitabine and Re(I) bisquinolinyl complex in a 1:1 ratio illustrated the best anti-cancer activity among the LCNP formulations (IC50 of BxPC3: 0.15 μM; IC50 of SW 1990: 0.76 μM) through apoptosis. The current findings suggest the potential use of transition metal-based photosensitizer as an adjunctive agent for gemcitabine-based chemotherapy against PDAC and the importance of nano-formulation in such application.
    Keywords:  Re(I) tricarbonyl complexes; liquid crystalline nanoparticles; nanomedicine; pancreatic cancer; photodynamic therapy
    DOI:  https://doi.org/10.3389/fphar.2022.903210
  22. Mol Pharm. 2022 Jul 28.
    Design of ROS-Responsive Hyaluronic Acid-Methotrexate Conjugates for Synergistic Chemo-Photothermal Therapy for Cancer.
    Kaiqing Yun, Juntong Guo, Renfang Zhu, Tianyi Wang, Xiaoyan Zhang, Hao Pan, Weisan Pan.
      Combining chemotherapy with photothermal therapy (PTT) for cancer treatment could overcome the inherent limitations of both single-modality chemotherapy and PTT. However, the obstacle of accurate drug delivery to tumor sites based on chemo-photothermal remains challenging. This article describes development of a reactive oxygen species (ROS)-responsive hyaluronic acid-based nanoparticle to overcome these drawbacks. Herein, HA-TK-MTX (HTM) was synthesized by a ROS-responsive cleaved thioketal moiety linker (TK) of methotrexate (MTX) and hyaluronic acid (HA). Through hydrophobic interaction and π-π stacking interaction, a photothermal agent IR780 was integrated into the HTM, and the IR780/HTM nanoparticles (IHTM NPs) were obtained. The IHTM NPs show high photostability, excellent photothermal performance, remarkable tumor-targeting ability, and ROS sensibility. Due to the accurate drug delivery ability and superior chemo-photothermal treatment effect of IHTM NPs, the tumor inhibition rate reached 70.95% for 4T1 tumor-bearing mice. This work serves as a precedent for the chemo-photothermal therapy of cancer by rationally designing ROS-responsive nanoparticles.
    Keywords:  Hyaluronic acid; ROS responsive; chemo-photothermal therapy
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00472
  23. Pharmaceuticals (Basel). 2022 Jun 25. pii: 793. [Epub ahead of print]15(7):
    Nanomedicine as an Emerging Technology to Foster Application of Essential Oils to Fight Cancer.
    Khaled AbouAitah, Witold Lojkowski.
      Natural prodrugs extracted from plants are increasingly used in many sectors, including the pharmaceutical, cosmetic, and food industries. Among these prodrugs, essential oils (EOs) are of particular importance. These biologically active volatile oily liquids are produced by medicinal and aromatic plants and characterized by a distinctive odor. EOs possess high anticancer, antibacterial, antiviral, and antioxidant potential but often are associated with low stability; high volatility; and a high risk of deterioration with exposure to heat, humidity, light, or oxygen. Furthermore, their bioavailability is limited because they are not soluble in water, and enhancements are needed to increase their potential to target specific cells or tissues, as well as for controlled release. Nanomedicine, the application of nanotechnology in medicine, may offer efficient solutions to these problems. The technology is based on creating nanostructures in which the natural prodrug is connected to or encapsulated in nanoparticles or submicron-sized capsules that ensure their solubility in water and their targeting properties, as well as controlled delivery. The potential of EOs as anticancer prodrugs is considerable but not fully exploited. This review focusses on the recent progress towards the practical application of EOs in cancer therapy based on nanotechnology applications.
    Keywords:  cancer; delivery system; essential oil; loading and controlled release; nanoformulation; nanomedicine
    DOI:  https://doi.org/10.3390/ph15070793
  24. Polymers (Basel). 2022 Jul 17. pii: 2904. [Epub ahead of print]14(14):
    An Investigation for Skin Tissue Regeneration Enhancement/Augmentation by Curcumin-Loaded Self-Emulsifying Drug Delivery System (SEDDS).
    Saima Mahmood, Prapanna Bhattarai, Nauman Rahim Khan, Zakia Subhan, Ghulam Razaque, Hassan A Albarqi, Abdulsalam A Alqahtani, Ali Alasiri, Lin Zhu.
      Diabetes, one of the global metabolic disorders, is often associated with delayed wound healing due to the elevated level of free radicals at the wound site, which hampers skin regeneration. This study aimed at developing a curcumin-loaded self-emulsifying drug delivery system (SEDDS) for diabetic wound healing and skin tissue regeneration. For this purpose, various curcumin-loaded SEDDS formulations were prepared and optimized. Then, the SEDDS formulations were characterized by the emulsion droplet size, surface charge, drug content/entrapment efficiency, drug release, and stability. In vitro, the formulations were assessed for the cellular uptake, cytotoxicity, cell migration, and inhibition of the intracellular ROS production in the NIH3T3 fibroblasts. In vivo, the formulations' wound healing and skin regeneration potential were evaluated on the induced diabetic rats. The results indicated that, after being dispersed in the aqueous medium, the optimized SEDDS formulation was readily emulsified and formed a homogenous dispersion with a droplet size of 37.29 ± 3.47 nm, surface charge of -20.75 ± 0.07 mV, and PDI value of less than 0.3. The drug content in the optimized formulation was found to be 70.51% ± 2.31%, with an encapsulation efficiency of 87.36% ± 0.61%. The SEDDS showed a delayed drug release pattern compared to the pure drug solution, and the drug release rate followed the Fickian diffusion kinetically. In the cell culture, the formulations showed lower cytotoxicity, higher cellular uptake, and increased ROS production inhibition, and promoted the cell migration in the scratch assay compared to the pure drug. The in vivo data indicated that the curcumin-loaded SEDDS-treated diabetic rats had significantly faster-wound healing and re-epithelialization compared with the untreated and pure drug-treated groups. Our findings in this work suggest that the curcumin-loaded SEDDS might have great potential in facilitating diabetic wound healing and skin tissue regeneration.
    Keywords:  curcumin; diabetic wound; nanomedicine; self-emulsifying drug delivery system (SEDDS); skin regeneration; wound healing
    DOI:  https://doi.org/10.3390/polym14142904
  25. Biomaterials. 2022 Jul 19. pii: S0142-9612(22)00327-1. [Epub ahead of print]287 121687
    Photo-enhanced upcycling H2O2 into hydroxyl radicals by IR780-embedded Fe3O4@MIL-100 for intense nanocatalytic tumor therapy.
    Ju-E Cun, Yang Pan, Zhuangzhuang Zhang, Yao Lu, Junhua Li, Qingqing Pan, Wenxia Gao, Kui Luo, Bin He, Yuji Pu.
      Reactive oxygen species (ROS)-based nanocatalytic tumor therapy is alluring owing to the capability to generate highly cytotoxic ∙OH radicals from tumoral H2O2. However, the antitumor efficacy is highly dependent on the radical generation efficiency and challenged by the high levels of antioxidative glutathione (GSH) in cancer cells. Herein, we report an IR-780 decorated, GSH-depleting Fe3O4@MIL-100 (IFM) nanocomposite for photo-enhanced tumor catalytic therapy by extensive production of ∙OH, which is realized by an integration of excellent peroxidase-like activity of IFM, selective upregulation of tumoral H2O2 by β-lapachone, and localized hyperthermia by near infrared light irradiation. IFM shows potentiated antiproliferative effect in 4T1 cancer cells by ∙OH overproduction and glutathione scavenging, inducing intracellular redox dyshomeostasis and cell death by concurrent apoptosis and ferroptosis. In vivo antitumor investigation further demonstrates photoacoustic and fluorescence imaging-guided combinational therapy with a tumor inhibition rate of 96.4%. This study provides a strategy of photo-enhanced nanocatalytic tumor therapy by tumor-specific H2O2 amplification and hyperthermia.
    Keywords:  Ferroptosis; Hydrogen peroxide; Metal-organic frameworks; Nanocatalytic tumor therapy; Peroxidase-like activity; Photothermia
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121687
  26. Front Oncol. 2022 ;12 938052
    Adapalene and Doxorubicin Synergistically Promote Apoptosis of TNBC Cells by Hyperactivation of the ERK1/2 Pathway Through ROS Induction.
    Umar Mehraj, Irfan Ahmad Mir, Mahboob Ul Hussain, Mustfa Alkhanani, Nissar Ahmad Wani, Manzoor Ahmad Mir.
      Doxorubicin is a commonly used chemotherapeutic agent to treat several malignancies, including aggressive tumors like triple-negative breast cancer. It has a limited therapeutic index owing to its extreme toxicity and the emergence of drug resistance. As a result, there is a pressing need to find innovative drugs that enhance the effectiveness of doxorubicin while minimizing its toxicity. The rationale of the present study is that combining emerging treatment agents or repurposed pharmaceuticals with doxorubicin might increase susceptibility to therapeutics and the subsequent establishment of improved pharmacological combinations for treating triple-negative breast cancer. Additionally, combined treatment will facilitate dosage reduction, reducing the toxicity associated with doxorubicin. Recently, the third-generation retinoid adapalene was reported as an effective anticancer agent in several malignancies. This study aimed to determine the anticancer activity of adapalene in TNBC cells and its effectiveness in combination with doxorubicin, and the mechanistic pathways in inhibiting tumorigenicity. Adapalene inhibits tumor cell growth and proliferation and acts synergistically with doxorubicin in inhibiting growth, colony formation, and migration of TNBC cells. Also, the combination of adapalene and doxorubicin enhanced the accumulation of reactive oxygen species triggering hyperphosphorylation of Erk1/2 and caspase-dependent apoptosis. Our results demonstrate that adapalene is a promising antitumor agent that may be used as a single agent or combined with present therapeutic regimens for TNBC treatment.
    Keywords:  Chou-Talalay; TNBC; adapalene; breast cancer; combination therapy; doxorubicin; drug resistance
    DOI:  https://doi.org/10.3389/fonc.2022.938052
  27. Int J Mol Sci. 2022 Jul 20. pii: 7981. [Epub ahead of print]23(14):
    Mechanism-Based Sonodynamic-Chemo Combinations against Triple-Negative Breast Cancer.
    Xiaolan Feng, Chen Wu, Wenhao Yang, Jiayi Wu, Pan Wang.
      Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.
    Keywords:  DNA damage response; DOX; SRA737; breast cancer; porphyrin liposomes; sonodynamic therapy
    DOI:  https://doi.org/10.3390/ijms23147981
  28. Molecules. 2022 Jul 15. pii: 4523. [Epub ahead of print]27(14):
    Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review.
    Ruo-Gu Xiong, Si-Yu Huang, Si-Xia Wu, Dan-Dan Zhou, Zhi-Jun Yang, Adila Saimaiti, Cai-Ning Zhao, Ao Shang, Yun-Jian Zhang, Ren-You Gan, Hua-Bin Li.
      Cancer has been a serious public health problem. Berberine is a famous natural compound from medicinal herbs and shows many bioactivities, such as antioxidant, anti-inflammatory, antidiabetic, anti-obesity, and antimicrobial activities. In addition, berberine shows anticancer effects on a variety of cancers, such as breast, lung, gastric, liver, colorectal, ovarian, cervical, and prostate cancers. The underlying mechanisms of action include inhibiting cancer cell proliferation, suppressing metastasis, inducing apoptosis, activating autophagy, regulating gut microbiota, and improving the effects of anticancer drugs. This paper summarizes effectiveness and mechanisms of berberine on different cancers and highlights the mechanisms of action. In addition, the nanotechnologies to improve bioavailability of berberine are included. Moreover, the side effects of berberine are also discussed. This paper is helpful for the prevention and treatment of cancers using berberine.
    Keywords:  anticancer; berberine; bioavailability; mechanism; safety
    DOI:  https://doi.org/10.3390/molecules27144523
  29. J Mater Chem B. 2022 Jul 26.
    Folic acid-functionalized L-cys/ZnS:O nanoparticles for homologous targeting and photodynamic therapy of tumor cells.
    Xiaoxuan Wang, Wenying Wei, Dian Zheng, Zhong Chen, Honglian Dai.
      The combination of photodynamic therapy (PDT) and fluorescence imaging provides a promising approach to theranostics. However, traditional photosensitizers (PSs) have low water solubility and lack active targeting ability. Our ingenious design used L-cys/ZnS:O (LZS) nanoparticles (NPs) modified with folic acid (FA), allowing them to easily enter tumor cells and accurately gather around the nucleus of cancer cells. L-Cysteine were used as intermediates, ZnS:O quantum dots and FA could be connected by a solid-state method and a coupling reaction. In doing so, the cytotoxicity of LZS NPs was further reduced, while the hydrophilicity and dispersibility were improved. Moreover, the as-synthesized FA@LZS NPs had a higher generation of reactive oxygen species (ROS) than commercial Ce6, and they killed HepG2 cells specifically in vitro. These findings give a clear way for the development of advanced PSs with homologous labeling functions. A template for NPs or other fluorophores modified by targeting groups is also provided.
    DOI:  https://doi.org/10.1039/d2tb00719c
  30. Cancer Cell Int. 2022 Jul 28. 22(1): 239
    Myricetin: targeting signaling networks in cancer and its implication in chemotherapy.
    Zeeshan Javed, Khushbukhat Khan, Jesús Herrera-Bravo, Sajid Naeem, Muhammad Javed Iqbal, Qamar Raza, Haleema Sadia, Shahid Raza, Munir Bhinder, Daniela Calina, Javad Sharifi-Rad, William C Cho.
      The gaps between the complex nature of cancer and therapeutics have been narrowed down due to extensive research in molecular oncology. Despite gathering massive insight into the mysteries of tumor heterogeneity and the molecular framework of tumor cells, therapy resistance and adverse side effects of current therapeutic remain the major challenge. This has shifted the attention towards therapeutics with less toxicity and high efficacy. Myricetin a natural flavonoid has been under the spotlight for its anti-cancer, anti-oxidant, and anti-inflammatory properties. The cutting-edge molecular techniques have shed light on the interplay between myricetin and dysregulated signaling cascades in cancer progression, invasion, and metastasis. However, there are limited data available regarding the nano-delivery platforms composed of myricetin in cancer. In this review, we have provided a comprehensive detail of myricetin-mediated regulation of different cellular pathways, its implications in cancer prevention, preclinical and clinical trials, and its current available nano-formulations for the treatment of various cancers.
    Keywords:  Apoptosis; Cancer; Cell cycle; Myricetin; Nano-delivery; Signaling networks
    DOI:  https://doi.org/10.1186/s12935-022-02663-2
  31. Sichuan Da Xue Xue Bao Yi Xue Ban. 2022 Jul;53(4): 619-625
    [Preliminary Study on Drug-Loaded Chondroitin Sulfate-Modified Micelles Targeting Golgi Apparatus in Tumor Cells for the Treatment of Tumor Metastasis].
    Hong-Li Zhou, Shao-Hong Li, Dan Chen, Ting Zhao, Tao Gong, Jia Li.
       Objective: To make preliminary exploration into the Golgi apparatus targeting of chondroitin sulfate-modified micelles (CSmicelles) co-loaded with pirarubicin (THP) and vinorelbine (VRL) in tumor cells, as well as their in vitro anti-tumor metastasis effect.
    Methods: The cellular uptake efficiency and internalization mechanism of CSmicelles in 4T1 mouse breast cancer cell line were investigated by flow cytometry. Preliminary study of the Golgi apparatus targeting CSmicelles in tumor cells was conducted by co-localization experiment. Then, the effect of CSmicelles co-loaded with THP and VRL (THP+VTL-CSmicelles) on the structure of Golgi apparatus was investigated by GM130 immunofluorescence experiment. Finally, the i n vitro anti-tumor metastasis ability of THP+VTL-CSmicelles was evaluated by wound healing assay and Transwell migration/invasion assay.
    Results: It was found that CSmicelles could significantly increase cellular uptake of drugs. CSmicelles were internalized into cells through clathrin-mediated and caveolin-mediated endocytosis, which was energy-dependent active transport and exhibited substantial ability of targeting Golgi apparatus in tumor cells. THP+VTL-CSmicelles could break down the structure of Golgi apparatus and significantly inhibit the migration and invasion of tumor cells.
    Conclusion: THP+VTL-CSmicelles demonstrate high affinity towards Golgi apparatus in tumor cells, exert targeted effects and inhibit tumor cell metastasis, which provides a novel idea and method for the treatment of cancer metastasis.
    Keywords:  Chondroitin sulfate; Golgi apparatus targeting; Micelles; Tumor metastasis; Vinorelbine
    DOI:  https://doi.org/10.12182/20220760103
  32. Pharmaceutics. 2022 Jul 21. pii: 1522. [Epub ahead of print]14(7):
    Research Progress of Conjugated Nanomedicine for Cancer Treatment.
    Bin Zhao, Sa Chen, Ye Hong, Liangliang Jia, Ying Zhou, Xinyu He, Ying Wang, Zhongmin Tian, Zhe Yang, Di Gao.
      The conventional cancer therapeutic modalities include surgery, chemotherapy and radiotherapy. Although immunotherapy and targeted therapy are also widely used in cancer treatment, chemotherapy remains the cornerstone of tumor treatment. With the rapid development of nanotechnology, nanomedicine is believed to be an emerging field to further improve the efficacy of chemotherapy. Until now, there are more than 17 kinds of nanomedicine for cancer therapy approved globally. Thereinto, conjugated nanomedicine, as an important type of nanomedicine, can not only possess the targeted delivery of chemotherapeutics with great precision but also achieve controlled drug release to avoid adverse effects. Meanwhile, conjugated nanomedicine provides the platform for combining several different therapeutic approaches (chemotherapy, photothermal therapy, photodynamic therapy, thermodynamic therapy, immunotherapy, etc.) with the purpose of achieving synergistic effects during cancer treatment. Therefore, this review focuses on conjugated nanomedicine and its various applications in synergistic chemotherapy. Additionally, the further perspectives and challenges of the conjugated nanomedicine are also addressed, which clarifies the design direction of a new generation of conjugated nanomedicine and facilitates the translation of them from the bench to the bedside.
    Keywords:  cancer therapy; conjugated nanomedicine; drug-conjugates; prodrug; synergistic chemotherapy
    DOI:  https://doi.org/10.3390/pharmaceutics14071522
  33. Polymers (Basel). 2022 Jul 21. pii: 2963. [Epub ahead of print]14(14):
    Polymeric Nanoparticles in Brain Cancer Therapy: A Review of Current Approaches.
    Chad A Caraway, Hallie Gaitsch, Elizabeth E Wicks, Anita Kalluri, Navya Kunadi, Betty M Tyler.
      Translation of novel therapies for brain cancer into clinical practice is of the utmost importance as primary brain tumors are responsible for more than 200,000 deaths worldwide each year. While many research efforts have been aimed at improving survival rates over the years, prognosis for patients with glioblastoma and other primary brain tumors remains poor. Safely delivering chemotherapeutic drugs and other anti-cancer compounds across the blood-brain barrier and directly to tumor cells is perhaps the greatest challenge in treating brain cancer. Polymeric nanoparticles (NPs) are powerful, highly tunable carrier systems that may be able to overcome those obstacles. Several studies have shown appropriately-constructed polymeric NPs cross the blood-brain barrier, increase drug bioavailability, reduce systemic toxicity, and selectively target central nervous system cancer cells. While no studies relating to their use in treating brain cancer are in clinical trials, there is mounting preclinical evidence that polymeric NPs could be beneficial for brain tumor therapy. This review includes a variety of polymeric NPs and how their associated composition, surface modifications, and method of delivery impact their capacity to improve brain tumor therapy.
    Keywords:  brain; cancer therapy; drug delivery; glioblastoma multiforme; nanoparticles; polymers
    DOI:  https://doi.org/10.3390/polym14142963
  34. J Bioinform Comput Biol. 2022 Jun;20(3): 2250016
    Prediction model for synergistic anti-tumor multi-compound combinations from traditional Chinese medicine based on extreme gradient boosting, targets and gene expression data.
    Mengqiu Sun, Shengnan She, Hengwei Chen, Jiaxi Cheng, Wei Ji, Dan Wang, Chunlai Feng.
      Traditional Chinese medicine (TCM) is characterized by synergistic therapeutic effect involving multiple compounds and targets, which provide potential new therapy for the treatment of complex cancer conditions. However, the main contributors and the underlying mechanisms of synergistic TCM cancer therapies remain largely undetermined. Machine learning now provides a new approach to determine synergistic compound combinations from complex components of TCM. In this study, a prediction model based on extreme gradient boosting (XGBoost) algorithm was constructed by integrating gene expression data of different cancer cell lines, targets information of natural compounds and drug response data. Radix Paeoniae Rubra (RPR) was selected as a model herbal sample to evaluate the reliability of the constructed model. The optimal XGBoost prediction model achieved a good performance with Mean Square Error (MSE) of 0.66, Mean Absolute Error (MAE) of 0.61, and the Root Mean Squared Error (RMSE) of 0.81 on test dataset. The superior synergistic anti-tumor combinations of D15 (Paeonol[Formula: see text][Formula: see text][Formula: see text]Ethyl gallate) and D13 (Paeoniflorin[Formula: see text][Formula: see text][Formula: see text]Paeonol) were successfully predicted from RPR and experimentally validated on MCF-7 cells. Moreover, the combination of D13 could work as a main contributor to a synergistic anti-proliferative activity in the compatibility of RPR and Cortex Moutan (CM). Our XGBoost model could be a reliable tool for the efficient prediction of synergistic anti-tumor multi-compound combinations from TCM.
    Keywords:  Traditional Chinese medicine; machine learning; multi-compound; prediction model; synergistic anti-tumor effect
    DOI:  https://doi.org/10.1142/S0219720022500160
  35. Membranes (Basel). 2022 Jul 15. pii: 713. [Epub ahead of print]12(7):
    Intravenous Nanocarrier for Improved Efficacy of Quercetin and Curcumin against Breast Cancer Cells: Development and Comparison of Single and Dual Drug-Loaded Formulations Using Hemolysis, Cytotoxicity and Cellular Uptake Studies.
    Mohammad Akhlaquer Rahman, Vineet Mittal, Shadma Wahab, Abdulrhman Alsayari, Abdullatif Bin Muhsinah, Dalia Almaghaslah.
      The present work highlights the suitability of an oil-based nanocarrier to deliver quercetin (Q) and curcumin (C) through the intravenous route for treatment of breast cancer. The nanoemulsion prepared by the modified emulsification-solvent evaporation method resulted in particle size (&lt;30 nm), polydispersity index (&lt;0.2), zeta potential (&lt;10 mV), optimum viscosity, high encapsulation efficiency and drug loading for both drugs. The pH and osmolarity of the nanoemulsion were about 7.0 and 280 mOsm, respectively, demonstrated its suitability for intravenous administration. In-vitro release of drugs from all the formulations demonstrated initial fast release followed by sustained release for a period of 48 h. The fabricated single and dual drug-loaded nanoemulsion (QNE, CNE, QC-NE) exhibited moderate hemolysis at a concentration of 50 μg/mL. The % hemolysis caused by all the formulations was similar to their individual components (p ˃ 0.05) and demonstrated the biocompatibility of the nanoemulsion with human blood. In vitro cytotoxic potential of single and dual drug-loaded nanoemulsions were determined against breast cancer cells (MF-7). The IC50 value for QNE and CNE were found to be 40.2 ± 2.34 µM and 28.12 ± 2.07 µM, respectively. The IC50 value for QC-NE was 21.23 ± 2.16 µM and demonstrated the synergistic effect of both the drugs. The internalization of the drug inside MF-7 cells was detected by cellular uptake study. The cellular uptake of QNE and CNE was approximately 3.9-fold higher than free quercetin and curcumin (p &lt; 0.0001). This strategically designed nanoemulsion appears to be a promising drug delivery system for the proficient primary preclinical development of quercetin and curcumin as therapeutic modalities for the treatment of breast cancer.
    Keywords:  breast cancer; cellular uptake; curcumin; cytotoxicity; hemocompatibility; quercetin
    DOI:  https://doi.org/10.3390/membranes12070713
  36. Int J Hyperthermia. 2022 ;39(1): 998-1009
    Selecting ideal drugs for encapsulation in thermosensitive liposomes and other triggered nanoparticles.
    Krishna K Ramajayam, Danforth A Newton, Dieter Haemmerich.
       OBJECTIVE: Thermosensitive liposomes (TSL) and other triggered drug delivery systems (DDS) are promising therapeutic strategies for targeted drug delivery. However, successful designs with candidate drugs depend on many variables, including nanoparticle formulation, drug properties, and cancer cell properties. We developed a computational model based on experimental data to predict the potential efficacies of drugs when used with triggered DDS, such as TSL.
    METHODS: A computer model based on the Krogh cylinder was developed to predict uptake and cell survival with four anthracyclines when delivered by intravascular triggered DDS (e.g., TSL): doxorubicin (DOX), idarubicin (IDA), pirarubicin (PIR), and aclarubicin (ACLA). We simulated three tumor types derived from SVR angiosarcoma, LLC lung cancer, or SCC-1 oral carcinoma cells. In vitro cellular drug uptake and cytotoxicity data were obtained experimentally and incorporated into the model.
    RESULTS: For all three cell lines, ACLA and IDA had the fastest cell uptake, with slower uptake for DOX and PIR. Cytotoxicity was highest for IDA and lowest for ACLA. The computer model predicted the highest tumor drug uptake for ACLA and IDA, resulting from their rapid cell uptake. Overall, IDA was most effective and produced the lowest tumor survival fraction, with DOX being the second best. Perivascular drug penetration was reduced for drugs with rapid cell uptake, potentially limiting delivery to cancer cells distant from the vasculature.
    CONCLUSION: Combining simple in vitro experiments with a computer model could provide a powerful screening tool to evaluate the potential efficacy of candidate investigative drugs preceding TSL encapsulation and in vivo studies.
    Keywords:  Thermosensitive liposomes; anthracyclines; cancer; computer model; drug delivery systems; nanoparticles
    DOI:  https://doi.org/10.1080/02656736.2022.2086303
  37. Int J Mol Sci. 2022 Jul 21. pii: 8048. [Epub ahead of print]23(14):
    Natural Products of Marine Origin for the Treatment of Colorectal and Pancreatic Cancers: Mechanisms and Potential.
    Nasrin Fares Amer, Tal Luzzatto Knaan.
      Gastrointestinal cancer refers to malignancy of the accessory organs of digestion, and it includes colorectal cancer (CRC) and pancreatic cancer (PC). Worldwide, CRC is the second most common cancer among women and the third most common among men. PC has a poor prognosis and high mortality, with 5-year relative survival of approximately 11.5%. Conventional chemotherapy treatments for these cancers are limited due to severe side effects and the development of drug resistance. Therefore, there is an urgent need to develop new and safe drugs for effective treatment of PC and CRC. Historically, natural sources-plants in particular-have played a dominant role in traditional medicine used to treat a wide spectrum of diseases. In recent decades, marine natural products (MNPs) have shown great potential as drugs, but drug leads for treating various types of cancer, including CRC and PC, are scarce. To date, marine-based drugs have been used against leukemia, metastatic breast cancer, soft tissue sarcoma, and ovarian cancer. In this review, we summarized existing studies describing MNPs that were found to have an effect on CRC and PC, and we discussed the potential mechanisms of action of MNPs as well as future prospects for their use in treating these cancers.
    Keywords:  apoptosis; colon cancer; marine natural products; pancreatic cancer
    DOI:  https://doi.org/10.3390/ijms23148048
  38. Nat Biotechnol. 2022 Jul 25.
    Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice.
    Bhairavi Tolani, Anna Celli, Yanmin Yao, Yong Zi Tan, Richard Fetter, Christina R Liem, Adam J de Smith, Thamiya Vasanthakumar, Paola Bisignano, Adam D Cotton, Ian B Seiple, John L Rubinstein, Marco Jost, Jonathan S Weissman.
      Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.
    DOI:  https://doi.org/10.1038/s41587-022-01386-z
  39. Gels. 2022 Jul 19. pii: 450. [Epub ahead of print]8(7):
    Thermosensitive Hydrogels Loaded with Resveratrol Nanoemulsion: Formulation Optimization by Central Composite Design and Evaluation in MCF-7 Human Breast Cancer Cell Lines.
    Sabna Kotta, Hibah Mubarak Aldawsari, Shaimaa M Badr-Eldin, Anroop B Nair, Mohammed Kaleem, Mahmood Hassan Dalhat.
      The second most common cause of mortality among women is breast cancer. A variety of natural compounds have been demonstrated to be beneficial in the management of various malignancies. Resveratrol is a promising anticancer polyphenolic compound found in grapes, berries, etc. Nevertheless, its low solubility, and hence its low bioavailability, restrict its therapeutic potential. Therefore, in our study, we developed a thermosensitive hydrogel formulation loaded with resveratrol nanoemulsion to enhance its bioavailability. Initially, resveratrol nanoemulsions were formulated and optimized utilizing a central composite-face-centered design. The independent variables for optimization were surfactant level, homogenization speed, and time, while the size and zeta potential were the dependent variables. The optimized nanoemulsion formulation was converted into a sensitive hydrogel using poloxamer 407. Rheological studies proved the formation of gel consistency at physiological temperature. Drug loading efficiency and in vitro drug release from gels were also analyzed. The drug release mechanisms from the gels were assessed using various mathematical models. The effect of the optimized thermosensitive resveratrol nanoemulsion hydrogel on the viability of human breast cancer cells was tested using MCF-7 cancer cell lines. The globule size of the selected formulation was 111.54 ± 4.16 nm, with a zeta potential of 40.96 ± 3.1 mV. Within 6 h, the in vitro release profile demonstrated a release rate of 80%. According to cell line studies, the produced hydrogel of resveratrol nanoemulsion was cytotoxic to breast cancer cells. Overall, the results proved the developed nanoemulsion-loaded thermosensitive hydrogel is a promising platform for the effective delivery of resveratrol for the management of breast cancer.
    Keywords:  breast cancer; cell lines; design of experiments; nanoemulsion; resveratrol; rheology; thermosensitive hydrogel
    DOI:  https://doi.org/10.3390/gels8070450
  40. Int J Biol Macromol. 2022 Jul 21. pii: S0141-8130(22)01550-1. [Epub ahead of print]218 209-224
    Polysaccharide-based nanofibers for pharmaceutical and biomedical applications: A review.
    Sakshi Priya, Unnati Batra, Samshritha R N, Sudhanshu Sharma, Akash Chaurasiya, Gautam Singhvi.
      Nanofibers are fibrous nanocarriers that can be synthesized from natural polymers, synthetic polymers, semiconducting materials, composite materials, and carbon-based materials. Recently, natural polysaccharides-based nanofibers are gaining attention in the field of pharmaceuticals and biomedical as these are biocompatible, biodegradable, non-toxic, and economic. Nanofibers can deliver a significant amount of drug to the targeted site and provide effective interaction of therapeutic agent at the site of action due to a larger surface area. Other important advantages of nanofibers are low density, high porosity, small pore size, high mechanical strength, and low cost. In this review, natural polysaccharides such as alginate, pullulan, hyaluronic acid, dextran, cellulose, chondroitin sulfate, chitosan, xanthan gum, and gellan gum are discussed for their characteristics, pharmaceutical utility, and biomedical applications. The authors have given particular emphasis to the several fabrication processes that utilize these polysaccharides to form nanofibers, and their recent updates in pharmaceutical applications such as drug delivery, tissue engineering, skin disorders, wound-healing dressings, cancer therapy, bioactive molecules delivery, anti-infectives, and solubility enhancement. Despite these many advantages, nanofibers have been explored less for their scale-up and applications in advanced therapeutic delivery.
    Keywords:  Drug delivery; Electrospinning; Nanofibers; Polysaccharides; Tissue engineering
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.118
  41. Molecules. 2022 Jul 08. pii: 4384. [Epub ahead of print]27(14):
    Synergetic Effect of Tumor Treating Fields and Zinc Oxide Nanoparticles on Cell Apoptosis and Genotoxicity of Three Different Human Cancer Cell Lines.
    Mamdouh M Shawki, Alaa El Sadieque, Seham Elabd, Maisa E Moustafa.
      Cancer remains a leading cause of death worldwide, despite extraordinary progress. So, new cancer treatment modalities are needed. Tumor-treating fields (TTFs) use low-intensity, intermediate-frequency alternating electric fields with reported cancer anti-mitotic properties. Moreover, nanomedicine is a promising therapy option for cancer. Numerous cancer types have been treated with nanoparticles, but zinc oxide nanoparticles (ZnO NPs) exhibit biocompatibility. Here, we investigate the activity of TTFs, a sub-lethal dose of ZnO NPs, and their combination on hepatocellular carcinoma (HepG2), the colorectal cancer cell line (HT-29), and breast cancer cell lines (MCF-7). The lethal effect of different ZnO NPs concentrations was assessed by sulforhodamine B sodium salt assay (SRB). The cell death percent was determined by flow cytometer, the genotoxicity was evaluated by comet assay, and the total antioxidant capacity was chemically measured. Our results show that TTFs alone cause cell death of 14, 8, and 17% of HepG2, HT-29, and MCF-7, respectively; 10 µg/mL ZnO NPs was the sub-lethal dose according to SRB results. The combination between TTFs and sub-lethal ZnO NPs increased the cell death to 29, 20, and 33% for HepG2, HT-29, and MCF-7, respectively, without reactive oxygen species increase. Increasing NPs potency using TTFs can be a novel technique in many biomedical applications.
    Keywords:  SRB assay; breast cancer cell line (MCF-7); colorectal cancer cell line (HT-29); comet assay; flow cytometer; hepatocellular carcinoma (HepG2); total antioxidant capacity; tumor-treating electric fields (TTFs); zinc oxide nanoparticles (ZnO NPs)
    DOI:  https://doi.org/10.3390/molecules27144384
  42. Antioxidants (Basel). 2022 Jul 05. pii: 1324. [Epub ahead of print]11(7):
    Metabolic Adaptation-Mediated Cancer Survival and Progression in Oxidative Stress.
    Yongquan Tang, Zhe Zhang, Yan Chen, Siyuan Qin, Li Zhou, Wei Gao, Zhisen Shen.
      Undue elevation of ROS levels commonly occurs during cancer evolution as a result of various antitumor therapeutics and/or endogenous immune response. Overwhelming ROS levels induced cancer cell death through the dysregulation of ROS-sensitive glycolytic enzymes, leading to the catastrophic depression of glycolysis and oxidative phosphorylation (OXPHOS), which are critical for cancer survival and progression. However, cancer cells also adapt to such catastrophic oxidative and metabolic stresses by metabolic reprograming, resulting in cancer residuality, progression, and relapse. This adaptation is highly dependent on NADPH and GSH syntheses for ROS scavenging and the upregulation of lipolysis and glutaminolysis, which fuel tricarboxylic acid cycle-coupled OXPHOS and biosynthesis. The underlying mechanism remains poorly understood, thus presenting a promising field with opportunities to manipulate metabolic adaptations for cancer prevention and therapy. In this review, we provide a summary of the mechanisms of metabolic regulation in the adaptation of cancer cells to oxidative stress and the current understanding of its regulatory role in cancer survival and progression.
    Keywords:  cancer stemness; metabolic adaptation; metabolic reprogramming; oxidative stress; tumor metastasis
    DOI:  https://doi.org/10.3390/antiox11071324
  43. Pharmaceutics. 2022 Jul 17. pii: 1483. [Epub ahead of print]14(7):
    Characterization of a Mesoporous Silica Nanoparticle Formulation Loaded with Mitomycin C Lipidic Prodrug (MLP) and In Vitro Comparison with a Clinical-Stage Liposomal Formulation of MLP.
    Miguel Manzano, Alberto Gabizón, María Vallet-Regí.
      Nanomedicines have revolutionized the treatment of certain types of cancer, as is the case of doxil, liposomal formulation with doxorubicin encapsulated, in the treatment of certain types of ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma. These nanomedicines can improve the performance of conventional chemotherapeutic treatments, with fewer side effects and better efficiency against cancer. Although liposomes have been used in some formulations, different nanocarriers with better features in terms of stability and adsorption capabilities are being explored. Among the available nanoparticles in the field, mesoporous silica nanoparticles (MSNP) have attracted great attention as drug delivery platforms for the treatment of different diseases. Here, a novel formulation based on MSNP loaded with a potent antitumor prodrug that works in vitro as well as in a clinically evaluated liposomal formulation has been developed. This novel formulation shows excellent prodrug encapsulation efficiency and effective release of the anticancer drug only under certain stimuli typical of tumor environments. This behavior is of capital importance for translating this nanocarrier to the clinic in the near future.
    Keywords:  liposomal formulation; mesoporous silica nanoparticles; nanomedicines
    DOI:  https://doi.org/10.3390/pharmaceutics14071483
  44. Foods. 2022 Jul 23. pii: 2189. [Epub ahead of print]11(15):
    Polyphenols as Plant-Based Nutraceuticals: Health Effects, Encapsulation, Nano-Delivery, and Application.
    Zhiheng Zhang, Xiaojing Li, Shangyuan Sang, David Julian McClements, Long Chen, Jie Long, Aiquan Jiao, Zhengyu Jin, Chao Qiu.
      Plant polyphenols have attracted considerable attention because of their key roles in preventing many diseases, including high blood sugar, high cholesterol, and cancer. A variety of functional foods have been designed and developed with plant polyphenols as the main active ingredients. Polyphenols mainly come from vegetables and fruits and can generally be divided according to their structure into flavonoids, astragalus, phenolic acids, and lignans. Polyphenols are a group of plant-derived functional food ingredients with different molecular structures and various biological activities including antioxidant, anti-inflammatory, and anticancer properties. However, many polyphenolic compounds have low oral bioavailability, which limits the application of polyphenols in nutraceuticals. Fortunately, green bio-based nanocarriers are well suited for encapsulating, protecting, and delivering polyphenols, thereby improving their bioavailability. In this paper, the health benefits of plant polyphenols in the prevention of various diseases are summarized, with a review of the research progress into bio-based nanocarriers for the improvement of the oral bioavailability of polyphenols. Polyphenols have great potential for application as key formulations in health and nutrition products. In the future, the development of food-grade delivery carriers for the encapsulation and delivery of polyphenolic compounds could well solve the limitations of poor water solubility and low bioavailability of polyphenols for practical applications.
    Keywords:  bioavailability; functional food; health; nano-delivery; polyphenol compounds
    DOI:  https://doi.org/10.3390/foods11152189
  45. Curr Med Chem. 2022 Jul 26.
    The association between the risk of breast cancer and Epigallocatechin-3-Gallate intake: A literature review of a potential chemopreventive agent.
    Efstratios Athanasiou, Georgios-Ioannis Verras, Savvas Papageorgiou, Ioannis Kelesis, Athanasios Gatsis, Christina Karaoulani, Ioannis Stouras, Panagiotis Kanatas, Elmina-Marina Saitani, Maria-Eleni Oikonomou, Danae-Anastasia Vlassi, Maria Vasileiou, Christos Tsagkaris, Athanasios Alexiou, Mohammad Amjad Kamal.
      According to the latest epidemiological data, breast cancer has recently been acknowledged as the most frequently diagnosed malignancy. To date, a body of evidence has established the involvement of multiple - and frequently interrelated - genetic and environmental factors in the pathogenesis of the disease. Emerging research on cancer prevention has highlighted the deterrence potential of interventions targeting environmental risk factors, particularly diet. In this aspect, the current review reveals the latest scientific results regarding epigallocatechin-3-gallate (EGCG) - a catechin most commonly found in green tea, as a potential chemopreventive dietary agent against breast cancer. In vitro studies on EGCG have demonstrated its effect on cell cycle progression and its potential to suppress several intracellular signaling pathways involved in breast cancer pathogenesis. In addition, EGCG possesses specific apoptosis-inducing characteristics that seem to enhance its role as a regulator of cell survival. Preclinical data seem to support the use of EGCG as an effective adjunct to EGFR-targeting treatments. The authors' appraisal of the literature suggests that although preclinical evidence has documented the anticarcinogenic features of EGCG, limited large-scale epidemiological studies are investigating the consumption of EGCG - containing nutrients in the prevention and management of breast cancer risk. This literature review aims to serve as a liaison between preclinical and epidemiological research, surveying the existing evidence and unraveling relevant knowledge gaps.
    Keywords:  and anti-inflammatory properties; antioxidant properties; breast cancer; chemoprevention; epigallocatechin-3-gallate; green tea; natural products
    DOI:  https://doi.org/10.2174/0929867329666220726153412
  46. J Funct Biomater. 2022 Jul 20. pii: 100. [Epub ahead of print]13(3):
    Hydroxyapatite Nanoparticles for Improved Cancer Theranostics.
    Saeid Kargozar, Sahar Mollazadeh, Farzad Kermani, Thomas J Webster, Simin Nazarnezhad, Sepideh Hamzehlou, Francesco Baino.
      Beyond their well-known applications in bone tissue engineering, hydroxyapatite nanoparticles (HAp NPs) have also been showing great promise for improved cancer therapy. The chemical structure of HAp NPs offers excellent possibilities for loading and delivering a broad range of anticancer drugs in a sustained, prolonged, and targeted manner and thus eliciting lower complications than conventional chemotherapeutic strategies. The incorporation of specific therapeutic elements into the basic composition of HAp NPs is another approach, alone or synergistically with drug release, to provide advanced anticancer effects such as the capability to inhibit the growth and metastasis of cancer cells through activating specific cell signaling pathways. HAp NPs can be easily converted to smart anticancer agents by applying different surface modification treatments to facilitate the targeting and killing of cancer cells without significant adverse effects on normal healthy cells. The applications in cancer diagnosis for magnetic and nuclear in vivo imaging are also promising as the detection of solid tumor cells is now achievable by utilizing superparamagnetic HAp NPs. The ongoing research emphasizes the use of HAp NPs in fabricating three-dimensional scaffolds for the treatment of cancerous tissues or organs, promoting the regeneration of healthy tissue after cancer detection and removal. This review provides a summary of HAp NP applications in cancer theranostics, highlighting the current limitations and the challenges ahead for this field to open new avenues for research.
    Keywords:  bioceramics; cancer treatment; hydroxyapatite; nanomaterials
    DOI:  https://doi.org/10.3390/jfb13030100
  47. ACS Appl Mater Interfaces. 2022 Jul 28.
    A Small-Molecule Based Organic Nanoparticle for Photothermal Therapy and Near-Infrared-IIb Imaging.
    Hongyue Lou, Aiyan Ji, Chunrong Qu, Hongguang Liu, Lei Jiang, Hao Chen, Zhen Cheng.
      Near-infrared window IIb (NIR-IIb, 1500-1700 nm) fluorescence imaging demonstrates attractive properties including low scattering, low absorption, and deep tissue penetration, and photothermal therapy (PTT) is also a promising modality for cancer treatment. However, until now, there is no report on theranostic systems based on small organic molecules combining fluorescence imaging in the NIR-IIb and PTT, highlighting the challenge and strong need for development of such agents. Herein, we report a novel small molecule NIR-IIb dye IT-TQF with a D-A-D structure, which exhibited high fluorescence intensity in the NIR-IIb window. To further translate IT-TQF into an effective theranostic agent, IT-TQF was encapsulated into DSPE-PEG2000 to construct IT-TQF NPs. The physical and photochemical properties of the nanoprobe were investigated in vitro, and the in vivo NIR-IIb imaging and PTT performance were evaluated in normal, subcutaneous, orthotopic, and metastatic tumor mice models. IT-TQF NP-based NIR-IIb imaging demonstrated high spatial resolution and high tissue penetration depth, and small normal blood vessels (55.3 μm) were successfully imaged in the NIR-IIb window. Subcutaneous, orthotopic, and metastatic tumors were all clearly delineated. A high tumor signal-to-background ratio (SBR) of 9.42 was achieved for orthotopic osteosarcoma models, and the erosions of bone tissue caused by tumor cells were precisely visualized. Moreover, NIR-II image-guided surgery was successfully performed to completely remove the orthotopic tumor. Importantly, IT-TQF NPs displayed high PTT efficacy (photothermal conversion efficiency: 47%) for effective treatment of tumor mice. In conclusion, IT-TQF NPs are a novel and promising phototheranostic agent in the NIR-IIb window, and the nanoprobe has high potential for a broad range of biomedical applications.
    Keywords:  NIR-IIb; fluorophore; imaging guided surgery; osteosarcoma; photothermal therapy
    DOI:  https://doi.org/10.1021/acsami.2c11706
  48. Pharmaceutics. 2022 Jun 22. pii: 1319. [Epub ahead of print]14(7):
    Quaternized Chitosan Thiol Hydrogel-Thickened Nanoemulsion: A Multifunctional Platform for Upgrading the Topical Applications of Virgin Olive Oil.
    Ali M Nasr, Salama M Aboelenin, Mohammad Y Alfaifi, Ali A Shati, Serag Eldin I Elbehairi, Reda F M Elshaarawy, Nashwa H Abd Elwahab.
      (1) Background: Virgin olive oil (VOO) has attracted the attention of many researchers due to its nutritional and medicinal values. However, VOO's biological applications have been limited due to a lack of precise chemical profiling and approach to increase the physicochemical characteristics, bioactivity, and delivery of its bioactive components; (2) Methods: The current study intended to evaluate the chemical composition of VOO using the GC-MS technique and determine its major components. Furthermore, the effect of incorporating VOO into Tween 80-lecithin nanoemulsion (OONE) and a quaternized trimethyl chitosan-thiol (TMCT) hydrogel-thickened nanoemulsion system (OOHTN) on its physicochemical characteristics and biological potentials will be investigated; (3) Results: The VOO-based NEs' physicochemical properties (particle size and zeta potential) were steady during storage for four weeks owing to the inclusion of the protective TMCT hydrogel network to OONE. Excessive fine-tuning of olive oil nanoemulsion (OONE) and the TMCT protective network's persistent positive charge have contributed to the oil's improved antimicrobial, anti-biofilm, and antioxidant potentials; (4) Conclusions: The Tween 80-lecithin-TMCT nanosystem might provide a unique and multifunctional nanoplatform for efficient topical therapy as well as the transdermal delivery of lipophilic bioactive compounds.
    Keywords:  antimicrobial and anti-biofilm; antioxidant; hydrogel-thickened nanoemulsion; olive oil; quaternized chitosan thiol
    DOI:  https://doi.org/10.3390/pharmaceutics14071319
  49. Pharmaceutics. 2022 Jun 28. pii: 1365. [Epub ahead of print]14(7):
    Combined Photothermal and Photodynamic Therapy for Cancer Treatment Using a Multifunctional Graphene Oxide.
    Shi Guo, Zhengmei Song, Ding-Kun Ji, Giacomo Reina, Jean-Daniel Fauny, Yuta Nishina, Cécilia Ménard-Moyon, Alberto Bianco.
      Graphene oxide (GO) is one of the most studied nanomaterials in many fields, including the biomedical field. Most of the nanomaterials developed for drug delivery and phototherapies are based on noncovalent approaches that lead to an unspecific release of physisorbed molecules in complex biological environments. Therefore, preparing covalently functionalized GO using straightforward and versatile methods is highly valuable. Phototherapies, including photothermal therapy (PTT) and photodynamic therapy (PDT), have shown great potential as effective therapeutic approaches against cancer. To overcome the limits of a single method, the combination of PTT and PDT can lead to a combined effect with a higher therapeutic efficiency. In this work, we prepare a folic acid (FA) and chlorin e6 (Ce6) double-functionalized GO for combined targeted PTT/PDT. This conjugate can penetrate rapidly into cancer cells and macrophages. A combined effect of PTT and PDT is observed, leading to a higher killing efficiency toward different types of cells involved in cancer and other diseases. Our work provides a simple protocol to prepare multifunctional platforms for the treatment of various diseases.
    Keywords:  Carbon nanomaterials; chlorin e6; macrophages; phototherapy; targeting
    DOI:  https://doi.org/10.3390/pharmaceutics14071365
  50. J Int Med Res. 2022 Jul;50(7): 3000605221113800
    Vitamin D: an essential adjuvant therapeutic agent in breast cancer.
    Romany H Thabet, Adel A Gomaa, Laila M Matalqah, Erin M Shalaby.
      Low serum levels of vitamin D have been reported as a risk factor for breast cancer. This narrative review provides an update on the impact of vitamin D on hormone receptors, notably estrogen receptor subunits, and gives insights on possible therapeutic interventions to overcome breast cancer. In addition, evidence that supports the beneficial use of vitamin D as adjuvant treatment of breast cancer is summarized. Vitamin D deficiency is significantly widespread in patients with triple-negative tumors. Several studies have observed a possible modulatory effect of vitamin D or its analogues on the expression of different hormone receptors in breast cancer and increased sensitivity to tamoxifen. Vitamin D possesses anti-inflammatory and immunomodulatory effects in patients with breast cancer, and the mechanism of action of vitamin D in patients with breast cancer is discussed. In conclusion, vitamin D appears to have a beneficial role in the prevention and management of breast cancer, however, large-scale, randomized controlled trials are needed to confirm the effects of vitamin D in breast cancer prevention or treatment.
    Keywords:  Breast cancer; calcitriol; cancer prevention; estrogen receptor modulation; immunoregulatory activities; pro-inflammatory cytokines
    DOI:  https://doi.org/10.1177/03000605221113800
  51. ACS Nano. 2022 Jul 29.
    Platinum-Titania Schottky Junction as Nanosonosensitizer, Glucose Scavenger, and Tumor Microenvironment-Modulator for Promoted Cancer Treatment.
    Yinmin Zhao, Jiahui Liu, Mengting He, Qi Dong, Lei Zhang, Zhigang Xu, Yuejun Kang, Peng Xue.
      To date, the construction of heterogeneous interfaces between sonosensitizers and other semiconductors or noble metals has aroused increasing attention, owing to an enhanced interface charge transfer, augmented spin-flip, and attenuated activation energy of oxygen. Here, a smart therapeutic nanoplatform is constructed by surface immobilization of glucose oxidase (GOx) onto a TiO2@Pt Schottky junction. The sonodynamic therapy (SDT) and starvation therapy (ST) mediated by TiO2@Pt/GOx (TPG) promote systemic tumor suppression upon hypoxia alleviation in tumor microenvironment. The band gap of TiO2@Pt is outstandingly decreased to 2.9 eV, in contrast to that of pristine TiO2. The energy structure optimization enables a more rapid generation of singlet oxygen (1O2) and hydroxyl radicals (•OH) by TiO2@Pt under ultrasound irradiation, resulting from an enhanced separation of hole-electron pair for redox utilization. The tumorous reactive oxygen species (ROS) accumulation and GOx-mediated glucose depletion facilitate oxidative damage and energy exhaustion of cancer cells, both of which can be tremendously amplified by Pt-catalyzed oxygen self-supply. Importantly, the combinatorial therapy triggers intense immunogenetic cell death, which favors a follow-up suppression of distant tumor and metastasis by evoking antitumor immunity. Collectively, this proof-of-concept paradigm provides an insightful strategy for highly efficient SDT/ST, which possesses good clinical potential for tackling cancer.
    Keywords:  glucose oxidase; nanosonosensitizer; sonodynamic therapy; tumor microenvironment; tumor starvation
    DOI:  https://doi.org/10.1021/acsnano.2c02540
  52. Plants (Basel). 2022 Jul 20. pii: 1885. [Epub ahead of print]11(14):
    Anticancer Potential and Other Pharmacological Properties of Prunus armeniaca L.: An Updated Overview.
    Dusanka Kitic, Bojana Miladinovic, Milica Randjelovic, Agnieszka Szopa, Javad Sharifi-Rad, Daniela Calina, Veronique Seidel.
      Prunus armeniaca L. (Rosaceae)-syn. Amygdalus armeniaca (L.) Dumort., Armeniaca armeniaca (L.) Huth, Armeniaca vulgaris Lam is commonly known as the apricot tree. The plant is thought to originate from the northern, north-western, and north-eastern provinces of China, although some data show that it may also come from Korea or Japan. The apricot fruit is used medicinally to treat a variety of ailments, including use as an antipyretic, antiseptic, anti-inflammatory, emetic, and ophthalmic remedy. The Chinese and Korean pharmacopeias describe the apricot seed as an herbal medicinal product. Various parts of the apricot plant are used worldwide for their anticancer properties, either as a primary remedy in traditional medicine or as a complementary or alternative medicine. The purpose of this review was to provide comprehensive and up-to-date information on ethnobotanical data, bioactive phytochemicals, anticancer potential, pharmacological applications, and toxicology of the genus Prunus armeniaca, thus providing new perspectives on future research directions. Included data were obtained from online databases such as PubMed/Medline, Google Scholar, Science direct, and Wiley Online Library. Multiple anticancer mechanisms have been identified in in vitro and in vivo studies, the most important mechanisms being apoptosis, antiproliferation, and cytotoxicity. The anticancer properties are probably mediated by the contained bioactive compounds, which can activate various anticancer mechanisms and signaling pathways such as tumor suppressor proteins that reduce the proliferation of tumor cells. Other pharmacological properties resulting from the analysis of experimental studies include neuroprotective, cardioprotective, antioxidant, immunostimulatory, antihyperlipidemic, antibacterial, and antifungal effects. In addition, data were provided on the toxicity of amygdalin, a compound found in apricot kernel seeds, which limits the long-term use of complementary/alternative products derived from P. armeniaca. This updated review showed that bioactive compounds derived from P. armeniaca are promising compounds for future research due to their important pharmacological properties, especially anticancer. A detailed analysis of the chemical structure of these compounds and their cytotoxicity should be carried out in future research. In addition, translational pharmacological studies are required for the correct determination of pharmacologically active doses in humans.
    Keywords:  Prunus armeniaca; adjuvant therapy; amygdalin; anticancer mechanisms; toxicity
    DOI:  https://doi.org/10.3390/plants11141885
  53. Nutrients. 2022 Jul 19. pii: 2956. [Epub ahead of print]14(14):
    The Mediterranean Diet: An Update of the Clinical Trials.
    Mauro Finicelli, Anna Di Salle, Umberto Galderisi, Gianfranco Peluso.
      The Mediterranean Diet (MedDiet) is a term used to identify a dietary pattern originating from the unique multi-millennial interplay between natural food resources and the eating practices of people living in the Mediterranean basin. Scientific evidence has described the healthy properties of the MedDiet and its beneficial role in several pathological conditions. Nevertheless, current socio-economic trends have moved people away from this healthy lifestyle. Thus, clinical and biological evidence supporting the benefits of the MedDiet is needed to overcome these limitations. Clinical nutrition research examines the effects of dietary interventions on biological or health-related outcomes in a determined study population. The evidence produced by these studies is useful for dietary guidance and public health messaging. We provided an update of the clinical trials registered on the database clinicaltrials.gov evaluating the effects of the MedDiet on health and specific diseases. Our findings revealed an increased number of clinical trials in the last decade and found that most disease-related studies focused on cardiovascular diseases, metabolic diseases, and cancer. The majority of MedDiet's beneficial effects could be primarily related to its anti-inflammatory and anti-oxidant properties as well as the effectiveness of this dietary pattern in controlling waist circumference and obesity. Moreover, strict and long-lasting adherence to the MedDiet as well as the beneficial effects of specific components (e.g., olive oil or its polyphenols) seem to emerge as useful insights for interventional improvements. These findings present further insights into the MedDiet's resources and how it could strengthen overall public health.
    Keywords:  Mediterranean Diet; cancer; cardiovascular disease; clinical trials; diabetes; inflammation; metabolic diseases; oxidative stress
    DOI:  https://doi.org/10.3390/nu14142956
  54. J Clin Med. 2022 Jul 12. pii: 4039. [Epub ahead of print]11(14):
    An Updated Review on the Psychoactive, Toxic and Anticancer Properties of Kava.
    Rita B Soares, Ricardo Jorge Dinis-Oliveira, Nuno G Oliveira.
      Kava (Piper methysticum) has been widely consumed for many years in the South Pacific Islands and displays psychoactive properties, especially soothing and calming effects. This plant has been used in Western countries as a natural anxiolytic in recent decades. Kava has also been used to treat symptoms associated with depression, menopause, insomnia, and convulsions, among others. Along with its putative beneficial health effects, kava has been associated with liver injury and other toxic effects, including skin toxicity in heavy consumers, possibly related to its metabolic profile or interference in the metabolism of other xenobiotics. Kava extracts and kavalactones generally displayed negative results in genetic toxicology assays although there is sufficient evidence for carcinogenicity in experimental animals, most likely through a non-genotoxic mode of action. Nevertheless, the chemotherapeutic/chemopreventive potential of kava against cancer has also been suggested. Both in vitro and in vivo studies have evaluated the effects of flavokavains, kavalactones and/or kava extracts in different cancer models, showing the induction of apoptosis, cell cycle arrest and other antiproliferative effects in several types of cancer, including breast, prostate, bladder, and lung. Overall, in this scoping review, several aspects of kava efficacy and safety are discussed and some pertinent issues related to kava consumption are identified.
    Keywords:  anxiety; cancer; clinical uses; interactions; kava; toxicity; toxicokinetics
    DOI:  https://doi.org/10.3390/jcm11144039
  55. Molecules. 2022 Jul 14. pii: 4493. [Epub ahead of print]27(14):
    Biocompatibility Study of Curcumin-Loaded Pluronic F127 Nanoformulation (NanoCUR) against the Embryonic Development of Zebrafish (Danio rerio).
    Siti Nur Sharmila Abdullah, Kalai Arasu Subramaniam, Zahir Haizat Muhamad Zamani, Seri Narti Edayu Sarchio, Faizah Md Yasin, Suhaili Shamsi.
      Curcumin (CUR) has been studied for its biomedical applications due to its active biological properties. However, CUR has limitations such as poor solubility, low bioavailability, and rapid degradation. Thus, CUR was nanoformulated with the application of polymeric micelle. Previous studies of CUR-loaded Pluronic F127 nanoformulation (NanoCUR) were generally prioritized toward cancer cells and its therapeutic values. There are reports that emphasize the toxicity of CUR, but reports on the toxicity of NanoCUR on embryonic developmental stages is still scarce. The present study aims to investigate the toxicity effects of NanoCUR on the embryonic development of zebrafish (Danio rerio). NanoCUR was synthesized via thin film hydration method and then characterized using DLS, UV-Vis, FTIR, FESEM, and XRD. The toxicity assessment of NanoCUR was conducted using zebrafish embryos, in comparison to native CUR, as well as Pluronic F127 (PF) as the controls, and ROS assay was further carried out. It was revealed that NanoCUR showed an improved toxicity profile compared to native CUR. NanoCUR displayed a delayed toxicity response and showed a concentration- and time-dependent toxicity response. NanoCUR was also observed to generate a significantly low reactive oxygen species (ROS) compared to native CUR in ROS assay. Overall, the results obtained highlight the potential of NanoCUR to be developed in clinical settings due to its improved toxicity profile compared to CUR.
    Keywords:  NanoCUR; Pluronic; curcumin; toxicity; zebrafish embryo
    DOI:  https://doi.org/10.3390/molecules27144493
  56. Molecules. 2022 Jul 13. pii: 4470. [Epub ahead of print]27(14):
    Formulation and Optimization of Alogliptin-Loaded Polymeric Nanoparticles: In Vitro to In Vivo Assessment.
    Dibyalochan Mohanty, Sadaf Jamal Gilani, Ameeduzzafar Zafar, Syed Sarim Imam, Ladi Alik Kumar, Mohammed Muqtader Ahmed, Mohammed Asadullah Jahangir, Vasudha Bakshi, Wasim Ahmad, Eyman Mohamed Eltayib.
      The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box-Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p &lt; 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p &lt; 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity.
    Keywords:  Eudragit; alogliptin; antidiabetic activity; nanoparticle; pharmacokinetic study
    DOI:  https://doi.org/10.3390/molecules27144470
  57. Cell Mol Life Sci. 2022 Jul 25. 79(8): 445
    Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage.
    Haibin Deng, Yanyun Gao, Verdiana Trappetti, Damian Hertig, Darya Karatkevich, Tereza Losmanova, Christian Urzi, Huixiang Ge, Gerrit Adriaan Geest, Remy Bruggmann, Valentin Djonov, Jean-Marc Nuoffer, Peter Vermathen, Nicola Zamboni, Carsten Riether, Adrian Ochsenbein, Ren-Wang Peng, Gregor Jan Kocher, Ralph Alexander Schmid, Patrick Dorn, Thomas Michael Marti.
      Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate metabolism. We show that silencing of LDHB induces persistent mitochondrial DNA damage, decreases mitochondrial respiratory complex activity and OXPHOS, resulting in reduced levels of mitochondria-dependent metabolites, e.g., TCA intermediates, amino acids, and nucleotides. Inhibition of LDHB dramatically reduced the survival of tumor-initiating cells and sphere formation in vitro, which can be partially restored by nucleotide supplementation. In addition, LDHB silencing reduced tumor initiation and growth of xenograft tumors. Furthermore, we report for the first time that homozygous deletion of LDHB significantly reduced lung tumorigenesis upon the concomitant loss of Tp53 and expression of oncogenic KRAS without considerably affecting the animal's health status, thereby identifying LDHB as a potential target for NSCLC therapy. In conclusion, our study shows for the first time that LDHB is essential for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, demonstrating that LDHB is crucial for the survival and proliferation of NSCLC tumor-initiating cells and tumorigenesis.
    Keywords:  Cancer stem cells; Cellular plasticity; Lung cancer; Mitochondrial DNA; Mitochondrial metabolism; Nucleotide metabolism; Tumorigenicity
    DOI:  https://doi.org/10.1007/s00018-022-04453-5
  58. Food Sci Biotechnol. 2022 Jul;31(8): 1009-1026
    Applications and perspectives of polyphenol-loaded solid lipid nanoparticles and nanostructured lipid carriers for foods.
    Eunghee Kim, Choongjin Ban, Sang-Oh Kim, Seokwon Lim, Young Jin Choi.
      Imbalanced nutrition in modern society is one of the reasons for disorders, such as cancer, cardiovascular disease, and diabetes, which have attracted the interest in bioactives (particularly polyphenols) to assist in the balanced diet of modern people. Although stability can be maintained during preparation and storage, the ingested polyphenols undergo harsh gastrointestinal digestion processes, resulting in limited bioaccessibility and low gut-epithelial permeation and bioavailability. Several lipid-based formulations have been proposed to overcome these issues. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have also been highlighted as carrier systems for the oral delivery of lipophilic bioactives, including polyphenols. This paper summarizes the research on the ingredients, production methods, post-processing procedures, general characteristics, and advantages and disadvantages of SLNs and NLCs. Overall, this paper reviews the applications and perspectives of polyphenol-loaded SLNs and NLCs in foods, as well as their regulation, production, storage, and economic feasibility.
    Keywords:  Food system; Lipophilic polyphenol; Nanostructured lipid carriers (NLCs); Oral delivery; Solid lipid nanoparticles (SLNs)
    DOI:  https://doi.org/10.1007/s10068-022-01093-0
  59. Pharmaceuticals (Basel). 2022 Jun 30. pii: 816. [Epub ahead of print]15(7):
    Targeting Colorectal Cancer Cells with Niosomes Systems Loaded with Two Anticancer Drugs Models; Comparative In Vitro and Anticancer Studies.
    Shaymaa Wagdy El-Far, Hadel A Abo El-Enin, Ebtsam M Abdou, Ola Elsayed Nafea, Rehab Abdelmonem.
      Colorectal cancer (CRC) is considered one of the most commonly diagnosed malignant diseases. Recently, there has been an increased focus on using nanotechnology to resolve most of the limitations in conventional chemotherapy. Niosomes have great advantages that overcome the drawbacks associated with other lipid drug delivery systems. They are simple, cheap, and highly stable nanocarriers. This study investigated the effectiveness of using niosomes with their amphiphilic characteristics in the incorporation of both hydrophilic and hydrophobic anticancer drugs for CRC treatment.
    METHODS: Drug-free niosomes were formulated using a response surface D-optimal factorial design to study the cholesterol molar ratio, surfactant molar ratio and surfactant type effect on the particle size and Z-potential of the prepared niosomes. After numerical and statistical optimization, an optimized formulation having a particle size of 194.4 ± 15.5 nm and a Z-potential of 31.8 ± 1.9 mV was selected to be loaded with Oxaliplatin and Paclitaxel separately in different concentrations. The formulations with the highest entrapment efficiency (EE%) were evaluated for their drug release using the dialysis bag method, in vitro antitumor activity on HT-29 colon cancer cell line and apoptosis activity.
    RESULTS: Niosomes prepared using d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) at a molar ratio 4, cholesterol (2 molar ratio) and loaded with 1 molar ratio of either Oxaliplatin or Paclitaxel provided nanosized vesicles (278.5 ± 19.7 and 251.6 ± 18.1 nm) with a Z-potential value (32.7 ± 1.01 and 31.69 ± 0.98 mV) with the highest EE% (90.57 ± 2.05 and 93.51 ± 2.97) for Oxaliplatin and Paclitaxel, respectively. These formulations demonstrated up to 48 h drug release and increased the in vitro cytotoxicity and apoptosis efficiency of both drugs up to twice as much as free drugs.
    CONCLUSION: These findings suggest that different formulation composition parameters can be adjusted to obtain nanosized niosomal vesicles with an accepted Z-potential. These niosomes could be loaded with either hydrophilic drugs such as Oxaliplatin or hydrophobic drugs such as Paclitaxel. Drug-loaded niosomes, as a unique nanomicellar system, could enhance the cellular uptake of both drugs, resulting in enhanced cytotoxic and apoptosis effects against HT-29 colon cancer cells. Oxaliplatin-niosomes and Paclitaxel-niosomes can be considered promising alternative drug delivery systems with enhanced bioavailability of these two anticancer drugs for colorectal cancer treatment.
    Keywords:  Colorectal Cancer; Niosomes; Oxaliplatin; Paclitaxel; d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS)
    DOI:  https://doi.org/10.3390/ph15070816
  60. Antioxidants (Basel). 2022 Jun 21. pii: 1217. [Epub ahead of print]11(7):
    Protective Effects of Diets Rich in Polyphenols in Cigarette Smoke (CS)-Induced Oxidative Damages and Associated Health Implications.
    Mithun Rudrapal, Siddhartha Maji, Shiv Kumar Prajapati, Payal Kesharwani, Prashanta Kumar Deb, Johra Khan, Randa Mohamed Ismail, Rani S Kankate, Ranjan Kumar Sahoo, Shubham J Khairnar, Atul R Bendale.
      Cigarette smoking has been responsible for causing many life-threatening diseases such as pulmonary and cardiovascular diseases as well as lung cancer. One of the prominent health implications of cigarette smoking is the oxidative damage of cellular constituents, including proteins, lipids, and DNA. The oxidative damage is caused by reactive oxygen species (ROS, oxidants) present in the aqueous extract of cigarette smoke (CS). In recent years, there has been considerable interest in the potential health benefits of dietary polyphenols as natural antioxidant molecules. Epidemiological studies strongly suggest that long-term consumption of diets (fruits, vegetables, tea, and coffee) rich in polyphenols offer protective effects against the development of cancer, cardiovascular diseases, diabetes, osteoporosis, and neurodegenerative diseases. For instance, green tea has chemopreventive effects against CI-induced lung cancer. Tea might prevent CS-induced oxidative damages in diseases because tea polyphenols, such as catechin, EGCG, etc., have strong antioxidant properties. Moreover, apple polyphenols, including catechin and quercetin, provide protection against CS-induced acute lung injury such as chronic obstructive pulmonary disease (COPD). In CS-induced health problems, the antioxidant action is often accompanied by the anti-inflammatory effect of polyphenols. In this narrative review, the CS-induced oxidative damages and the associated health implications/pathological conditions (or diseases) and the role of diets rich in polyphenols and/or dietary polyphenolic compounds against various serious/chronic conditions of human health have been delineated.
    Keywords:  COPD; bioavailability; cardioprotective; cigarette smoke; dietary polyphenols; oxidative damage
    DOI:  https://doi.org/10.3390/antiox11071217
  61. Drug Deliv. 2022 Dec;29(1): 2414-2427
    A facile method for anti-cancer drug encapsulation into polymersomes with a core-satellite structure.
    Hongchao Xu, Weiwei Cui, Zhitao Zong, Yinqiu Tan, Congjun Xu, Jiahui Cao, Ting Lai, Qi Tang, Zhongjuan Wang, Xiaofeng Sui, Cuifeng Wang.
      Polymersomes possess the self-assembly vesicular structure similar to liposomes. Although a variety of comparisons between polymersomes and liposomes in the aspects of physical properties, preparation and applications have been elaborated in many studies, few focus on their differences in drug encapsulation, delivery and release in vitro and in vivo. In the present work, we have provided a modified direct hydration method to encapsulate anti-cancer drug paclitaxel (PTX) into PEG-b-PCL constituted polymersomes (PTX@PS). In addition to advantages including narrow particle size distribution, high colloid stability and moderate drug-loading efficiency, we find that the loaded drug aggregate in small clusters and reside through the polymersome membrane, representing a unique core-satellite structure which might facilitate the sustained drug release. Compared with commercial liposomal PTX formulation (Lipusu®), PTX@PS exhibited superb tumor cell killing ability underlain by multiple pro-apoptotic mechanisms. Moreover, endocytic process of PTX@PS significantly inhibits drug transporter P-gp expression which could be largely activated by free drug diffusion. In glioma mice models, it has also confirmed that PTX@PS remarkably eradicate tumors, which renders polymersomes as a promising alternative to liposomes as drug carriers in clinic.
    Keywords:  Polymersome; core-satellite drug encapsulation; direct hydration method; glioma; multidrug resistance
    DOI:  https://doi.org/10.1080/10717544.2022.2103209
  62. Angew Chem Int Ed Engl. 2022 Jul 28.
    Arene-Ruthenium(II)/Osmium(II) Complexes Potentiate the Anticancer Efficacy of Metformin via Glucose Metabolism Reprogramming.
    Qi-Yuan Yang, Rui Ma, Yun-Qiong Gu, Xiao-Fang Xu, Zhen-Feng Chen, Hong Liang.
      Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming.
    Keywords:  Glucose Metabolism; Intermittent Fasting; Metformin; Oxoaporphine Arene−Ruthenium(II)/Osmium(II); cancer
    DOI:  https://doi.org/10.1002/anie.202208570
  63. Biomedicines. 2022 Jun 22. pii: 1470. [Epub ahead of print]10(7):
    An Oral 3D Printed PLGA-Tocopherol PEG Succinate Nanocomposite Hydrogel for High-Dose Methotrexate Delivery in Maintenance Chemotherapy.
    Pierre P D Kondiah, Thankhoe A Rants'o, Sifiso S Makhathini, Sipho Mdanda, Yahya E Choonara.
      High-dose methotrexate (HDMTX) is one of the chemotherapeutic agents used to treat a variety of cancers in both adults and children. However, the toxicity associated with HDMTX has resulted in the spread of infections and treatment interruption. Further, poor bioavailability due to efflux pump activities mediated by P-glycoprotein has also been linked to poor therapeutic effects of methotrexate following oral administrations. D-α-Tocopheryl poly-ethylene glycol 1000 succinate (TPGS) is known to improve the bioavailability of poorly soluble drugs by inhibiting P-gp efflux activities, thus enhancing cellular uptake. Therefore, to achieve improved bioavailability for MTX, this study aimed to design and develop a novel drug delivery system employing TPGS and a biodegradable polymer, i.e., PLGA, to construct methotrexate-loaded nanoparticles fixated in alginate-gelatine 3D printable hydrogel ink to form a solid 3D printed tablet for oral delivery. The results indicated that high accuracy (&gt;95%) of the 3D printed tablets was achieved using a 25 G needle. In vitro, drug release profiles were investigated at pH 1.2 and pH 7.4 to simulate the gastrointestinal environment. The in vitro release profile displayed a controlled and prolonged release of methotrexate over 24 h. The in silico modeling study displayed P-gp ATPase inhibition, suggesting enhanced MTX absorption from the gastrointestinal site. The 3D-printed hydrogel-based tablet has the potential to overcome the chemotherapeutic challenges that are experienced with conventional therapies.
    Keywords:  3D printed systems; biodegradable; cancer therapy; drug delivery; methotrexate; nanocomposites
    DOI:  https://doi.org/10.3390/biomedicines10071470
  64. Polymers (Basel). 2022 Jul 24. pii: 2991. [Epub ahead of print]14(15):
    A Review on the Delivery of Plant-Based Antidiabetic Agents Using Nanocarriers: Current Status and Their Role in Combatting Hyperglycaemia.
    Husna Zolkepli, Riyanto Teguh Widodo, Syed Mahmood, Norazlinaliza Salim, Khalijah Awang, Noraini Ahmad, Rozana Othman.
      Diabetes mellitus is a prevalent metabolic syndrome that is associated with high blood glucose levels. The number of diabetic patients is increasing every year and the total number of cases is expected to reach more than 600 million worldwide by 2045. Modern antidiabetic drugs alleviate hyperglycaemia and complications that are caused by high blood glucose levels. However, due to the side effects of these drugs, plant extracts and bioactive compounds with antidiabetic properties have been gaining attention as alternative treatments for diabetes. Natural products are biocompatible, cheaper and expected to cause fewer side effects than the current antidiabetic drugs. In this review, various nanocarrier systems are discussed, such as liposomes, niosomes, polymeric nanoparticles, nanoemulsions, solid lipid nanoparticles and metallic nanoparticles. These systems have been applied to overcome the limitations of the current drugs and simultaneously improve the efficacy of plant-based antidiabetic drugs. The main challenges in the formulation of plant-based nanocarriers are the loading capacity of the plant extracts and the stability of the carriers. A brief review of lipid nanocarriers and the amphipathic properties of phospholipids and liposomes that encapsulate hydrophilic, hydrophobic and amphiphilic drugs is also described. A special emphasis is placed on metallic nanoparticles, with their advantages and associated complications being reported to highlight their effectiveness for treating hyperglycaemia. The present review could be an interesting paper for researchers who are working in the field of using plant extract-loaded nanoparticles as antidiabetic therapies.
    Keywords:  antidiabetic; lipid nanoparticles; metallic nanoparticles; nanocarriers; plant extract
    DOI:  https://doi.org/10.3390/polym14152991
  65. Int J Mol Sci. 2022 Jul 08. pii: 7565. [Epub ahead of print]23(14):
    A Broad-Based Characterization of a Cell-Penetrating, Single Domain Camelid Bi-Specific Antibody Monomer That Targets STAT3 and KRAS Dependent Cancers.
    Sunanda Singh, Genoveva Murillo, Justin Richner, Samara P Singh, Erica Berleth, Vijay Kumar, Rajendra Mehta, Vijay Ramiya, Ashutosh S Parihar.
      STAT3 and KRAS regulate cell proliferation, survival, apoptosis, cell migration, and angiogenesis. Aberrant expression of STAT3 and mutant active forms of KRAS have been well-established in the induction and maintenance of multiple cancers. STAT3 and KRAS mutant proteins have been considered anti-cancer targets; however, they are also considered to be clinically "undruggable" intracellular molecules, except for KRAS(G12C). Here we report a first-in-class molecule, a novel, single domain camelid VHH antibody (15 kDa), SBT-100, that binds to both STAT3 and KRAS and can penetrate the tumor cell membrane, and significantly inhibit cancer cell growth. Additionally, SBT-100 inhibits KRAS GTPase activity and downstream phosphorylation of ERK in vitro. In addition, SBT-100 inhibits the growth of multiple human cancers in vitro and in vivo. These results demonstrate the feasibility of targeting hard-to-reach aberrant intracellular transcription factors and signaling proteins simultaneously with one VHH to improve cancer therapies.
    Keywords:  KRAS; PD-L1; STAT3; VEGF; VHH; bi-specific; blood brain barrier
    DOI:  https://doi.org/10.3390/ijms23147565
  66. Molecules. 2022 Jul 17. pii: 4553. [Epub ahead of print]27(14):
    Hyaluronic Acid Modified Nanostructured Lipid Carrier for Targeting Delivery of Kaempferol to NSCLC: Preparation, Optimization, Characterization, and Performance Evaluation In Vitro.
    Yufei Ma, Jinli Liu, Xinyu Cui, Jiafu Hou, Fengbo Yu, Jinghua Wang, Xiaoxue Wang, Cong Chen, Lei Tong.
      Lung cancer seriously threatens the health of human beings, with non-small cell lung cancer (NSCLC) accounting for 80%. Nowadays, the potential position of nano-delivery in treating cancer has been the subject of continuous research. The present research aimed to prepare two molecular weight hyaluronic acid (HA)-modified kaempferol (KA)-loaded nanostructured lipid carriers (HA-KA-NLCs) by the method of melting ultrasonic and electrostatic adsorption, and to assess the antitumor effect of the preparations on A549 cells. The characterization and safety evaluation of the preparations illustrated that they are acceptable for drug delivery for cancer. Subsequently, differential scanning calorimetry (DSC) curve and transmission electron microscopy (TEM) images indicated that the drug was adequately incorporated in the carrier, and the particle appeared as a sphere. Moreover, HA-KA-NLC showed predominant in vitro antitumor effects, inhibiting proliferation, migration, and invasion, promoting apoptosis and increasing cellular uptake of A549 cells. Otherwise, the Western blot assay revealed that preparations could activate epithelial-mesenchymal transition (EMT)-related signaling pathways and modulate the expression of E-cadherin, N-cadherin, and Vimentin in A549 cells. Our present findings demonstrated that HA-KA-NLC could be considered as a secure and effective carrier for targeted tumor delivery and may have potential application prospects in future clinic therapy of NSCLC.
    Keywords:  kaempferol; nanostructured lipid carrier; non-small cell lung cancer
    DOI:  https://doi.org/10.3390/molecules27144553
  67. Toxicol Rep. 2022 ;9 961-969
    Fabrication of phenyl boronic acid modified pH-responsive zinc oxide nanoparticles as targeted delivery of chrysin on human A549 cells.
    Sushweta Mahalanobish, Mousumi Kundu, Sumit Ghosh, Joydeep Das, Parames C Sil.
      Recently, different natural bioactive compounds have been used as anticancer agents for their various therapeutic benefits and non-toxic nature to other organs. However, they have various restrictions in preclinical and clinical studies due to their non-targeting nature and insufficient bioavailability. As a result, a zinc oxide nanoparticle (ZnO) based drug delivery medium was constructed which has good bio-compatibility and bio-degradability. It also displays cancer cell-specific drug delivery in a targeted and controlled way. In the present study, phenylboronic acid (PBA) tagged ZnO nanoparticles (ZnO-PBA) was fabricated and in the next step, chrysin (a natural bio-active molecule) was loaded to it to form the nanoconjugate (ZnO-PBA-Chry). Different characterization techniques were used to confirm the successful fabrication of ZnO-PBA-Chry. PBA-tagging to the nanoparticle helps in targeted delivery of chrysin in lung cancer cells (A549) as PBA binds with sialic acid receptors which are over-expressed on the surface of A549 cells. As ZnO dissociates in acidic pH, it shows stimuli-responsive release of chrysin in tumor microenvironment. Application of ZnO-PBA-Chry nanohybrid in lung cancer cell line A549 caused oxidative stress mediated intrinsic cell death and cell cycle arrest. ZnO-PBA-Chry downregulated MMP-2 and VE-Cadherin, thereby inhibiting metastasis and the invasive property of A549 cells.
    Keywords:  Chrysin; Lung cancer; Nanoparticle; Reactive oxygen species; Zinc oxide
    DOI:  https://doi.org/10.1016/j.toxrep.2022.04.017
  68. Antioxidants (Basel). 2022 Jul 19. pii: 1402. [Epub ahead of print]11(7):
    Dietary Selenium and Its Antioxidant Properties Related to Growth, Lipid and Energy Metabolism.
    María Luisa Ojeda, Fátima Nogales.
      Selenium (Se) is an essential trace element mainly known for its antioxidant, anti-inflammatory and anti-apoptotic properties [...].
    DOI:  https://doi.org/10.3390/antiox11071402
  69. Mar Drugs. 2022 Jul 22. pii: 466. [Epub ahead of print]20(8):
    Therapeutic Potential of Marine Peptides in Prostate Cancer: Mechanistic Insights.
    Salman Ahmed, Waqas Alam, Philippe Jeandet, Michael Aschner, Khalaf F Alsharif, Luciano Saso, Haroon Khan.
      Prostate cancer (PCa) is the leading cause of cancer death in men, and its treatment is commonly associated with severe adverse effects. Thus, new treatment modalities are required. In this context, natural compounds have been widely explored for their anti-PCa properties. Aquatic organisms contain numerous potential medications. Anticancer peptides are less toxic to normal cells and provide an efficacious treatment approach via multiple mechanisms, including altered cell viability, apoptosis, cell migration/invasion, suppression of angiogenesis and microtubule balance disturbances. This review sheds light on marine peptides as efficacious and safe therapeutic agents for PCa.
    Keywords:  antiangiogenic; antimetastatic; antimitotic; apoptosis; cell cycle arrest; marine peptides
    DOI:  https://doi.org/10.3390/md20080466
  70. Pharmaceutics. 2022 Jul 12. pii: 1450. [Epub ahead of print]14(7):
    Glioblastoma Multiforme Selective Nanomedicines for Improved Anti-Cancer Treatments.
    Jason Thomas Duskey, Arianna Rinaldi, Ilaria Ottonelli, Riccardo Caraffi, Chiara Alessia De Benedictis, Ann Katrin Sauer, Giovanni Tosi, Maria Angela Vandelli, Barbara Ruozi, Andreas Martin Grabrucker.
      Glioblastoma Multiforme (GBM) is a devastating disease with a low survival rate and few efficacious treatment options. The fast growth, late diagnostics, and off-target toxicity of currently used drugs represent major barriers that need to be overcome to provide a viable cure. Nanomedicines (NMeds) offer a way to overcome these pitfalls by protecting and loading drugs, increasing blood half-life, and being targetable with specific ligands on their surface. In this study, the FDA-approved polymer poly (lactic-co-glycolic) acid was used to optimise NMeds that were surface modified with a series of potential GBM-specific ligands. The NMeds were fully characterised for their physical and chemical properties, and then in vitro testing was performed to evaluate cell uptake and GBM cell specificity. While all targeted NMeds showed improved uptake, only those decorated with the-cell surface vimentin antibody M08 showed specificity for GBM over healthy cells. Finally, the most promising targeted NMed candidate was loaded with the well-known chemotherapeutic, paclitaxel, to confirm targeting and therapeutic effects in C6 GBM cells. These results demonstrate the importance of using well-optimised NMeds targeted with novel ligands to advance delivery and pharmaceutical effects against diseased cells while minimising the risk for nearby healthy cells.
    Keywords:  NMeds; brain tumour; cancer; drug delivery; drug targeting; glioblastoma; improved chemotherapeutics; nanomedicine; nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics14071450
  71. Pharmaceutics. 2022 Jul 20. pii: 1506. [Epub ahead of print]14(7):
    Polymeric Nanosystems Applied for Metal-Based Drugs and Photosensitizers Delivery: The State of the Art and Recent Advancements.
    Kele Cristina Ferreira Dantas, Jânia Dos Santos Rosário, Priscila Pereira Silva-Caldeira.
      Nanotechnology-based approaches for targeting the delivery and controlled release of metal-based therapeutic agents have revealed significant potential as tools for enhancing the therapeutic effect of metal-based agents and minimizing their systemic toxicities. In this context, a series of polymer-based nanosized systems designed to physically load or covalently conjugate metal-based therapeutic agents have been remarkably improving their bioavailability and anticancer efficacy. Initially, the polymeric nanocarriers were applied for platinum-based chemotherapeutic agents resulting in some nanoformulations currently in clinical tests and even in medical applications. At present, these nanoassemblies have been slowly expanding for nonplatinum-containing metal-based chemotherapeutic agents. Interestingly, for metal-based photosensitizers (PS) applied in photodynamic therapy (PDT), especially for cancer treatment, strategies employing polymeric nanocarriers have been investigated for almost 30 years. In this review, we address the polymeric nanocarrier-assisted metal-based therapeutics agent delivery systems with a specific focus on non-platinum systems; we explore some biological and physicochemical aspects of the polymer-metallodrug assembly. Finally, we summarize some recent advances in polymeric nanosystems coupled with metal-based compounds that present potential for successful clinical applications as chemotherapeutic or photosensitizing agents. We hope this review can provide a fertile ground for the innovative design of polymeric nanosystems for targeting the delivery and controlled release of metal-containing therapeutic agents.
    Keywords:  drug delivery systems; metallodrugs; photosensitizers; polymer conjugate
    DOI:  https://doi.org/10.3390/pharmaceutics14071506
  72. Molecules. 2022 Jul 13. pii: 4469. [Epub ahead of print]27(14):
    Endophytes, a Potential Source of Bioactive Compounds to Curtail the Formation-Accumulation of Advanced Glycation End Products: A Review.
    Lory Sthephany Rochín-Hernández, Lory Jhenifer Rochín-Hernández, Luis Bernardo Flores-Cotera.
      Endophytes, microorganisms that live in the internal tissues and organs of the plants, are known to produce numerous bioactive compounds, including, at times, some phytochemicals of their host plant. For such reason, endophytes have been quoted as a potential source for discovering bioactive compounds, particularly, of medical interest. Currently, many non-communicable diseases are threatening global human health, noticeably: diabetes, neurodegenerative diseases, cancer, and other ailment related to chronic inflammation and ageing. Intriguingly, the pathogenesis and development of these diseases have been linked to an excessive formation and accumulation of advanced glycation end products (AGEs). AGEs are a heterogeneous group of compounds that can alter the conformation, function, and lifetime of proteins. Therefore, compounds that prevent the formation and consequent accumulation of AGEs (AntiAGEs compounds) could be useful to delay the progress of some chronic diseases, and/or harmful effects of undue AGEs accumulation. Despite the remarkable ability of endophytes to produce bioactive compounds, most of the natural antiAGEs compounds reported in the literature are derived from plants. Accordingly, this work covers 26 plant antiAGEs compounds and some derivatives that have been reported as endophytic metabolites, and discusses the importance, possible advantages, and challenges of using endophytes as a potential source of antiAGEs compounds.
    Keywords:  AGEs detoxification; RAGEs antagonists; carboxymethyl-lysine; diabetes; endophytic metabolites; methylglyoxal; protein glycation
    DOI:  https://doi.org/10.3390/molecules27144469
  73. Curr Oncol. 2022 Jul 07. 29(7): 4779-4790
    Does Molecular Profiling of KRAS-Mutant Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Help in Treatment Strategy Planning?
    Nagla Abdel Karim, Asad Ullah, Peterson Pathrose, Hassana Fathallah, Ashley Perry, John C Morris, Jiang Wang, Sandra L Starnes.
       BACKGROUND: Several studies suggest that patients with KRAS-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Most recently, KRAS 12c data suggest specific treatment for improving ORR and OS. There is a clear need for therapies specifically developed for these patients. Moreover, data that might be suggestive of a response to specific therapies, such as BRCA1, are needed, and two mutations that were studied in other malignancies show more response to PARP inhibitors. Molecular profiling has the potential to identify other potential targets that may provide better treatment and novel targeted therapy for KRAS-mutated NSCLC.
    METHODS: We purified RNA from archived tissues of patients with stage I and II NSCLC with wild-type (wt) and mutant (mt) KRAS tumors; paired normal tissue adjacent to the tumor from 20 and 17 patients, respectively, and assessed, using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), the expression of four genes involved in DNA synthesis and repair, including thymidylate synthase (TS), BRCA1, ECCR1, RAP80, and the proto-oncogene SRC. Additionally, we assessed the expression of PD-L1 in mt&amp;nbsp;KRAS tumors with immunohistochemistry using an antibody against PD-L1.
    RESULTS: Our results show that in mtKRAS tumors, the level of expression of ERCC1, TS, and SRC was significantly increased in comparison to paired normal lung tissue (p ≤ 0.04). The expression of BRCA1 and RAP80 was similar in both mt&amp;nbsp;KRAS tumors and paired normal tissue. Furthermore, the expression of BRCA1, TS, and SRC was significantly increased in wt&amp;nbsp;KRAS tumors relative to their expression in the normal lung tissue (p &lt; 0.044). The expression of ERCC1 and RAP80 was similar in wt&amp;nbsp;KRAS tumors and paired normal tissue. Interestingly, SRC expression in mtKRAS tumors was decreased in comparison to wt&amp;nbsp;KRAS tumors. Notably, there was an expression of PD-L1 in the tumor and stromal cells in a few (5 out of 20) mtKRAS tumors. Our results suggest that a greater ERCC1 expression in mt KRAS tumors might increase platinum resistance in this group of patients, whereas the greater expression of BRCA1 in wt&amp;nbsp;KRAS tumor might be suggestive of the sensitivity of taxanes. Our data also suggest that the combination of an SRC inhibitor with a TS inhibitor, such as pemetrexed, might improve the outcome of patients with NSCLC and in particular, patients with wt&amp;nbsp;KRAS tumors. PD-L1 expression in tumors, and especially stromal cells, suggests a better outcome.
    CONCLUSION: mt&amp;nbsp;KRAS NSCLC patients might benefit from a treatment strategy that targets KRAS in combination with therapeutic agents based on pharmacogenomic markers, such as SRC and BRCA1. mtKRAS tumors are likely to be platinum-, taxane-, and pemetrexed-resistant, as well as having a low level of PD-L1 expression; thus, they are less likely to receive single-agent immunotherapy, such as pembrolizumab, as the first-line therapy. wt&amp;nbsp;KRAS tumors with BRCA1 positivity tend to be sensitive to taxane therapy and, potentially, platinum. Our results suggest the need to develop targeted therapies for KRAS-mutant NSCLC or combine the targeting of oncogenic KRAS in addition to other therapeutic agents specific to the molecular profile of the tumor.
    Keywords:  molecular profiling; mutations; systemic therapy
    DOI:  https://doi.org/10.3390/curroncol29070379
  74. Pharmaceutics. 2022 Jun 27. pii: 1361. [Epub ahead of print]14(7):
    Glucose-Modified Zein Nanoparticles Enhance Oral Delivery of Docetaxel.
    Yabing Xing, Xiao Li, Weiwei Cui, Meng Xue, Yanan Quan, Xinhong Guo.
      Based on glucose (G) transporters (GLUTs), structuring nanoparticles with G as a target are an effective strategy to enhance oral bioavailability and anti-tumor effects of drugs. A novel drug delivery system using G-modified zein (GZ) nanoparticles loaded with docetaxel (DTX) (DTX-GNPs) was prepared and characterized in vitro and in vivo via assessment of cellular uptake, absorption site, pharmacokinetics, ex vivo distribution, and anti-tumor effects. The DTX-GNPs were approximately 120 nm in size. Compared with DTX-NPs, G modification significantly enhanced cellular uptake of DTX-GNPs by 1.22 times in CaCo-2 cells, which was related to GLUT mediation and the enhancement of endocytosis pathways via clathrin, micropinocytosis, and caveolin. Compared to DTX-NPs, G modification significantly enhanced DTX-NP absorption in the jejunum and ileum, delayed plasma concentration peak time, prolonged the average residence time in vivo, and increased oral bioavailability (from 43.82% to 96.04%). Cellular uptake and oral bioavailability of DTX were significantly affected by the G modification ratio. Compared with DTX-NPs, G modification significantly reduced drug distribution in the liver, lungs, and kidneys and increased tumor distribution and tumor growth inhibition rate without obvious systemic toxicity. This study demonstrated the potential of GZ-NPs as nanocarriers for DTX to enhance oral bioavailability and anti-tumor effects.
    Keywords:  anti-tumor effect; docetaxel; glucose transporter; nanocarriers; zein nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics14071361
  75. Adv Exp Med Biol. 2022 ;1370 121-128
    Taurine and Its Anticancer Functions: In Vivo and In Vitro Study.
    Ning Ma, Feng He, Jun Kawanokuchi, Guifeng Wang, Takenori Yamashita.
      Taurine (2-aminoethanesulfonic acid) is a natural amino acid that is found widely in all mammalian tissues. Several studies have demonstrated that taurine has anti-inflammatory, antioxidant, and hypoglycemic effects. Recently, taurine not only mitigates the side effects of chemotherapy in cancer but also possesses antitumor properties, including inhibiting cancer cell proliferation and inducing apoptosis in certain cancers by differential regulating proapoptotic and antiapoptotic proteins. Antitumor studies of taurine are still in their infancy, and the mechanism of its antitumor effect is not fully understood. In this regard, it is worthwhile to study the antitumor mechanism of taurine, which may provide clues to develop new synthetic therapeutic molecules. In this mini review, we summarize the main effects of taurine that have shown suppressing actions in the initiation and progression of cancers. The underlying molecular mechanism also suggested that taurine can be a potential clinical application in tumor therapy. In addition, with the in-depth study of different biological functions of taurine, we found that many systemic diseases are associated with taurine. In this review, the research progress of taurine's antitumor effect is briefly summarized including the in vivo and in vitro studies in our laboratory.
    Keywords:  Anticancer; Azomethane; Ki-67; PTEN; PUMA; Taurine
    DOI:  https://doi.org/10.1007/978-3-030-93337-1_11
  76. Polymers (Basel). 2022 Jul 26. pii: 3023. [Epub ahead of print]14(15):
    Novel Trends in Hydrogel Development for Biomedical Applications: A Review.
    Pablo Sánchez-Cid, Mercedes Jiménez-Rosado, Alberto Romero, Víctor Pérez-Puyana.
      Nowadays, there are still numerous challenges for well-known biomedical applications, such as tissue engineering (TE), wound healing and controlled drug delivery, which must be faced and solved. Hydrogels have been proposed as excellent candidates for these applications, as they have promising properties for the mentioned applications, including biocompatibility, biodegradability, great absorption capacity and tunable mechanical properties. However, depending on the material or the manufacturing method, the resulting hydrogel may not be up to the specific task for which it is designed, thus there are different approaches proposed to enhance hydrogel performance for the requirements of the application in question. The main purpose of this review article was to summarize the most recent trends of hydrogel technology, going through the most used polymeric materials and the most popular hydrogel synthesis methods in recent years, including different strategies of enhancing hydrogels' properties, such as cross-linking and the manufacture of composite hydrogels. In addition, the secondary objective of this review was to briefly discuss other novel applications of hydrogels that have been proposed in the past few years which have drawn a lot of attention.
    Keywords:  biomedical applications; biopolymers; chemical cross-linking; composite hydrogels; hydrogel; physical cross-linking; synthetic polymers
    DOI:  https://doi.org/10.3390/polym14153023
  77. Cytokine. 2022 Jul 26. pii: S1043-4666(22)00176-4. [Epub ahead of print]157 155967
    Epigenomic interplay in tumor heterogeneity: Potential of epidrugs as adjunct therapy.
    Suvasmita Rath, Diptesh Chakraborty, Jyotsnarani Pradhan, Mohammad Imran Khan, Jagneshwar Dandapat.
      "Heterogeneity" in tumor mass has immense importance in cancer progression and therapy. The impact of tumor heterogeneity is an emerging field and not yet fully explored. Tumor heterogeneity is mainly considered as intra-tumor heterogeneity and inter-tumor heterogeneity based on their origin. Intra-tumor heterogeneity refers to the discrepancy within the same cancer mass while inter-tumor heterogeneity refers to the discrepancy between different patients having the same tumor type. Both of these heterogeneity types lead to variation in the histopathological as well as clinical properties of the cancer mass which drives disease resistance towards therapeutic approaches. Cancer stem cells (CSCs) act as pinnacle progenitors for heterogeneity development along with various other genetic and epigenetic parameters that are regulating this process. In recent times epigenetic factors are one of the most studied parameters that drive oxidative stress pathways essential during cancer progression. These epigenetic changes are modulated by various epidrugs and have an impact on tumor heterogeneity. The present review summarizes various aspects of epigenetic regulation in the tumor microenvironment, oxidative stress, and progression towards tumor heterogeneity that creates complications during cancer treatment. This review also explores the possible role of epidrugs in regulating tumor heterogeneity and personalized therapy against drug resistance.
    Keywords:  Acetylation; Cancer stem cells; Epidrugs; Methylation; Reactive oxygen species; ncRNA
    DOI:  https://doi.org/10.1016/j.cyto.2022.155967
  78. Biochem Pharmacol. 2022 Jul 25. pii: S0006-2952(22)00279-9. [Epub ahead of print] 115185
    Recent advances in circadian-regulated pharmacokinetics and its implications for chronotherapy.
    Fangjun Yu, Yuanyuan Liu, Rong Zhang, Lijun Zhu, Tianpeng Zhang, Yafei Shi.
      Dependence of pharmacokinetics and drug effects (efficacy and toxicity) on dosing time has long been recognized. However, significant progress has only recently been made in our understanding of circadian rhythms and their regulation on drug pharmacokinetics, efficacy and toxicity. This review will cover the relevant literature and a series of publications from our work summarizing the effects of circadian rhythms on drug pharmacokinetics, and propose that the influence of circadian rhythms on pharmacokinetics are ultimately translated into therapeutic effects and side effects of drugs. Evidence suggests that daily rhythmicity in expression of drug-metabolizing enzymes and transporters necessary for drug ADME (absorption, distribution, metabolism and excretion) are key factors determining circadian pharmacokinetics. Newly discovered mechanisms for circadian control of the enzymes and transporters are covered. We also discuss how the rhythms of drug-processing proteins are translated into circadian pharmacokinetics and drug chronoefficacy/chronotoxicity, which has direct implications for chronotherapy. More importantly, we will present perspectives on the challenges that are still needed for a breakthrough in translational research. In addition, knowledge of the circadian influence on drug disposition has provided new possibilities for novel pharmacological strategies. Careful application of pharmacokinetics-based chronotherapy strategies can improve efficacy and reduce toxicity. Circadian rhythm-mediated metabolic and transport strategies can also be implemented to design drugs.
    Keywords:  Chronoefficacy; Chronopharmacokinetics; Chronotoxicity; Circadian rhythms; Drug-metabolizing enzymes; Transporters
    DOI:  https://doi.org/10.1016/j.bcp.2022.115185
  79. J Nanobiotechnology. 2022 Jul 26. 20(1): 344
    Aggregation-induced emission photosensitizer-based photodynamic therapy in cancer: from chemical to clinical.
    Zijuan Meng, Huiying Xue, Tingting Wang, Biao Chen, Xiyuan Dong, Lili Yang, Jun Dai, Xiaoding Lou, Fan Xia.
      Cancer remains a serious threat to human health owing to the lack of effective treatments. Photodynamic therapy (PDT) has emerged as a promising non-invasive cancer treatment that consists of three main elements: photosensitizers (PSs), light and oxygen. However, some traditional PSs are prone to aggregation-caused quenching (ACQ), leading to reduced reactive oxygen species (ROS) generation capacity. Aggregation-induced emission (AIE)-PSs, due to their distorted structure, suppress the strong molecular interactions, making them more photosensitive in the aggregated state instead. Activated by light, they can efficiently produce ROS and induce cell death. PS is one of the core factors of efficient PDT, so proceeding from the design and preparation of AIE-PSs, including how to manipulate the electron donor (D) and receptor (A) in the PSs configuration, introduce heavy atoms or metal complexes, design of Type I AIE-PSs, polymerization-enhanced photosensitization and nano-engineering approaches. Then, the preclinical experiments of AIE-PSs in treating different types of tumors, such as ovarian cancer, cervical cancer, lung cancer, breast cancer, and its great potential clinical applications are discussed. In addition, some perspectives on the further development of AIE-PSs are presented. This review hopes to stimulate the interest of researchers in different fields such as chemistry, materials science, biology, and medicine, and promote the clinical translation of AIE-PSs.
    Keywords:  Aggregation-induced emission; Cancer therapy; Clinical translation; Photodynamic therapy; Photosensitizers
    DOI:  https://doi.org/10.1186/s12951-022-01553-z
  80. Biomedicines. 2022 Jul 11. pii: 1662. [Epub ahead of print]10(7):
    Near-Infrared Photoimmunotherapy for Thoracic Cancers: A Translational Perspective.
    Kohei Matsuoka, Mizuki Yamada, Mitsuo Sato, Kazuhide Sato.
      The conventional treatment of thoracic tumors includes surgery, anticancer drugs, radiation, and cancer immunotherapy. Light therapy for thoracic tumors has long been used as an alternative; conventional light therapy also called photodynamic therapy (PDT) has been used mainly for early-stage lung cancer. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a completely different concept from conventional PDT, has been developed and approved in Japan for the treatment of recurrent and previously treated head and neck cancer because of its specificity and effectiveness. NIR-PIT can apply to any target by changing to different antigens. In recent years, it has become clear that various specific and promising targets are highly expressed in thoracic tumors. In combination with these various specific targets, NIR-PIT is expected to be an ideal therapeutic approach for thoracic tumors. Additionally, techniques are being developed to further develop NIR-PIT for clinical practice. In this review, NIR-PIT is introduced, and its potential therapeutic applications for thoracic cancers are described.
    Keywords:  NIR-PIT; lung cancer; near-infrared photoimmunotherapy; phototherapy; target antigens; thoracic tumor
    DOI:  https://doi.org/10.3390/biomedicines10071662
  81. Drug Deliv. 2022 Dec;29(1): 2403-2413
    Therapeutic potential of human serum albumin nanoparticles encapsulated actinonin in murine model of lung adenocarcinoma.
    Priyanca Ahlawat, Kanika Phutela, Amanjit Bal, Navneet Singh, Sadhna Sharma.
      Non-small cell lung cancer comprises 85% of the global lung cancer cases. Conventional chemotherapeutics possess certain limitations like systemic toxicity and drug resistance that requires the development of new therapeutic agents for successful treatment of lung cancer. Actinonin, a human peptide deformylase inhibitor, has demonstrated anti-cancerous properties in various leukemias and solid cancer types. However, it has limited therapeutic application because of its low bioavailability and systemic toxicity if administered in free form. This limitation can be overcome by using nano-delivery systems that will increase the therapeutic efficacy of actinonin. In the present study, human serum albumin actinonin nanoparticles were prepared using a desolvation technique and folic acid was conjugated to lysine residues of albumin for effective delivery to the lung. The lung adenocarcinoma model was established 24 weeks after intraperitoneal administration of urethane and chemotherapeutic efficacy of free as well as nanoencapsulated actinonin was evaluated. This study demonstrated anti-proliferative potential of folic acid conjugated human serum albumin nanoparticles encapsulating actinonin. The intraperitoneally administered nanoformulation exhibited sustain release profile of actinonin with longer half-life and mean retention time. The reduced dose frequency resulted in therapeutic efficacy comparable to free drug in vivo in terms of 100% survival and reduced tumor burden along with downregulation of epidermal growth factor receptor, folate receptor α and peptide deformylase expression in lung adenocarcinoma mice model. Therefore, actinonin encapsulated albumin nanoparticles-based therapy holds great potential as an alternative strategy to improve its anti-cancerous activity against lung adenocarcinoma.
    Keywords:  Non-small cell lung cancer; actinonin; adenocarcinoma; folate; human serum albumin; peptide deformylase
    DOI:  https://doi.org/10.1080/10717544.2022.2067600
  82. Emerg Med Int. 2022 ;2022 6449607
    Preparation of PCL Electrospun Fibers Loaded with Cisplatin and Their Potential Application for the Treatment of Prostate Cancer.
    Hilla Mills, Ronald Acquah, Nova Tang, Luke Cheung, Susanne Klenk, Ronald Glassen, Magali Pirson, Alain Albert, Duong Trinh Hoang, Thang Nguyen Van.
      Prostate cancer is a global fatal type of cancer. It is a type of cancer that affect men. Signs and symptoms of the disease include blood in the urine, pain when one micturates, and difficulties in penis erection. Cisplatin chemotherapy is a principal treatment normally given to the prostate cancer patients. Nonetheless, on its own, cisplatin loses efficacy once administered due to liver pass effects and other biochemical attacks. In this paper, we looked at preparation of PCL nanoparticles loaded with cisplatin and their potential for the treatment of prostate cancer. PCL nanoparticles protect cisplatin from biochemical attack, thus increasing drug efficacy. Incorporation of P-glycoprotein inhibitors in PCL nanoparticles (NPs) loaded with cisplatin could improve prostate cancer treatment even more.
    DOI:  https://doi.org/10.1155/2022/6449607
  83. ACS Appl Mater Interfaces. 2022 Jul 24.
    Multifunctional Magnetic CuS/Gd2O3 Nanoparticles for Fluorescence/Magnetic Resonance Bimodal Imaging-Guided Photothermal-Intensified Chemodynamic Synergetic Therapy of Targeted Tumors.
    Minchuan Luo, Hiroshi Yukawa, Kazuhide Sato, Makoto Tozawa, Masato Tokunaga, Tatsuya Kameyama, Tsukasa Torimoto, Yoshinobu Baba.
      Chemodynamic therapy (CDT), which consumes endogenous hydrogen peroxide (H2O2) to generate reactive oxygen species (ROS) and causes oxidative damage to tumor cells, shows tremendous promise for advanced cancer treatment. However, the rate of ROS generation based on the Fenton reaction is prone to being restricted by inadequate H2O2 and unattainable acidity in the hypoxic tumor microenvironment. We herein report a multifunctional nanoprobe (BCGCR) integrating bimodal imaging and photothermal-enhanced CDT of the targeted tumor, which is produced by covalent conjugation of bovine serum albumin-stabilized CuS/Gd2O3 nanoparticles (NPs) with the Cy5.5 fluorophore and the tumor-targeting ligand RGD. BCGCR exhibits intense near-infrared (NIR) fluorescence and acceptable r1 relaxivity (∼15.3 mM-1 s-1) for both sensitive fluorescence imaging and high-spatial-resolution magnetic resonance imaging of tumors in living mice. Moreover, owing to the strong NIR absorbance from the internal CuS NPs, BCGCR can generate localized heat and displays a high photothermal conversion efficiency (30.3%) under 980 nm laser irradiation, which enables photothermal therapy and further intensifies ROS generation arising from the Cu-induced Fenton-like reaction for enhanced CDT. This synergetic effect shows such an excellent therapeutic efficacy that it can ablate xenografted tumors in vivo. We believe that this strategy will be beneficial to exploring other advanced nanomaterials for the clinical application of multimodal imaging-guided synergetic cancer therapies.
    Keywords:  copper sulfide; enhanced chemodynamic therapy; fluorescence imaging; magnetic resonance imaging; photothermal therapy
    DOI:  https://doi.org/10.1021/acsami.2c06503
  84. Pharmacol Res. 2022 Jul 23. pii: S1043-6618(22)00306-1. [Epub ahead of print] 106361
    Progress in the treatment of drug-induced liver injury with natural products.
    Yuan-Kai Sun, Ya-Fei Zhang, Li Xie, Fan Rong, Xing-Yu Zhu, Jing Xie, Huan Zhou, Tao Xu.
      There are numerous prescription drugs and non-prescription drugs that cause drug-induced liver injury (DILI), which is the main cause of liver disease in humans around the globe. Its mechanism becomes clearer as the disease is studied further. For an instance, when acetaminophen (APAP) is taken in excess, it produces N-acetyl-p-benzoquinone imine (NAPQI) that binds to biomacromolecules in the liver causing liver injury. Treatment of DILI with traditional Chinese medicine (TCM) has shown to be effective. For example, activation of the Nrf2 signaling pathway as well as regulation of glutathione (GSH) synthesis, coupling, and excretion are the mechanisms by which ginsenoside Rg1 (Rg1) treats APAP-induced acute liver injury. Nevertheless, reducing the toxicity of TCM in treating DILI is still a problem to be overcome at present and in the future. Accumulated evidences show that hydrogel-based nanocomposite may be an excellent carrier for TCM. Therefore, we reviewed TCM with potential anti-DILI, focusing on the signaling pathway of these drugs' anti-DILI effect, as well as the possibility and prospect of treating DILI by TCM based on hydrogel materials in the future. In conclusion, this review provides new insights to further explore TCM in the treatment of DILI.
    Keywords:  Baicalin (PubChem CID: 64982); Crocetin (PubChem CID: 5281232); Curcumin (PubChem CID: 969516); DILI; Ginsenoside Rg1 (PubChem CID: 441923); Glycyrrhetinic acid (PubChem CID: 3230); Luteolin (PubChem CID: 5280445); Naringin (PubChem CID: 442428); Quercetin (PubChem CID: 5280343); Resveratrol (PubChem CID: 445154); Salvianolic acid C (PubChem CID: 13991590); TCM; hydrogel; natural products
    DOI:  https://doi.org/10.1016/j.phrs.2022.106361
  85. Adv Healthc Mater. 2022 Jul 25. e2201613
    Engineering H2 O2 and O2 self-supplying nanoreactor to conduct synergistic chemiexcited photodynamic and calcium-overloaded therapy in orthotopic hepatic tumors.
    Ying-Chi Chen, Yu-Ju Liu, Chin-Lai Lee, Khang-Yen Pham, Divinah Manoharan, Suresh Thangudu, Chia-Hao Su, Chen-Sheng Yeh.
      Photodynamic therapy (PDT) is traditionally ineffective for deeply embedded tumors due to the poor penetration depth of the excitation light. Chemiluminescence resonance energy transfer (CRET) has emerged as a promising mode of PDT without external light source. To date, related research has frequently used endogenous H2 O2 and O2 inside the solid tumor microenvironment to trigger CRET-mediated PDT. Unfortunately, this significantly restricts treatment efficacy and the development of further biomedical applications because of the limited amounts of endogenous H2 O2 and O2 in intracellular cells. Herein, a nanohybrid (mSiO2 /CaO2 /CPPO/Ce6: mSCCC) nanoparticles (NPs) is designed to achieve synergistic CRET-mediated PDT and calcium (Ca2+ )-overload-mediated therapy. The CaO2 formed inside mesoporous SiO2 (mSC) with the inclusion of the chemiluminescent agent (CPPO) and photosensitizer (Ce6) self-supplies H2 O2 , O2 , and Ca2+ allowing for the subsequent processes for treatments. The Ce6 in mSCCC NPs is excited by chemical energy in situ following the supply of H2 O2 and O2 to produce singlet oxygen (1 O2 ). The nanohybrid NPs are coated with stearic acid to avoid decomposition during blood circulation through contact with aqueous environment. This nanohybrid showed promising performance in the generation of 1 O2 for external light-free PDT and the release of calcium ions for calcium-overloaded therapy against orthotopic hepatocellular carcinoma. This article is protected by copyright. All rights reserved.
    Keywords:  calcium peroxide; calcium-overloaded; light-free CRET; reactive oxygen species; self-supplying hydrogen peroxide
    DOI:  https://doi.org/10.1002/adhm.202201613
  86. Molecules. 2022 Jul 08. pii: 4400. [Epub ahead of print]27(14):
    A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health.
    Siyu Liu, Jie Liu, Lan He, Liu Liu, Bo Cheng, Fangliang Zhou, Deliang Cao, Yingchun He.
      Curcumin is the most important active component in turmeric extracts. Curcumin, a natural monomer from plants has received a considerable attention as a dietary supplement, exhibiting evident activity in a wide range of human pathological conditions. In general, curcumin is beneficial to human health, demonstrating pharmacological activities of anti-inflammation and antioxidation, as well as antitumor and immune regulation activities. Curcumin also presents therapeutic potential in neurodegenerative, cardiovascular and cerebrovascular diseases. In this review article, we summarize the advancements made in recent years with respect to curcumin as a biologically active agent in malignant tumors, Alzheimer's disease (AD), hematological diseases and viral infectious diseases. We also focus on problems associated with curcumin from basic research to clinical translation, such as its low solubility, leading to poor bioavailability, as well as the controversy surrounding the association between curcumin purity and effect. Through a review and summary of the clinical research on curcumin and case reports of adverse effects, we found that the clinical transformation of curcumin is not successful, and excessive intake of curcumin may have adverse effects on the kidneys, heart, liver, blood and immune system, which leads us to warn that curcumin has a long way to go from basic research to application transformation.
    Keywords:  Alzheimer’s disease; blood diseases; curcumin; hurdles; malignant tumors; potentials and side effects; viral infectious diseases
    DOI:  https://doi.org/10.3390/molecules27144400
  87. Gels. 2022 Jul 21. pii: 456. [Epub ahead of print]8(7):
    Tamoxifen Citrate Containing Topical Nanoemulgel Prepared by Ultrasonication Technique: Formulation Design and In Vitro Evaluation.
    Mohammad H Alyami, Hamad S Alyami, Abdullah A Alshehri, Wijdan K Alsharif, Ibrahim Ahmed Shaikh, Thamer S Algahtani.
      The present study aims to design and develop a nanoemulgel formulation of Tamoxifen citrate (TAM), a water-insoluble, potent anticancer drug, using the spontaneous emulsification method to improve topical delivery, achieve high accumulation at the tumour site, and spare the healthy tissues. The oil-based selection was related to the TAM solubility, while the surfactant and co-surfactant were chosen based on the droplets' thermodynamic stability and size. Afterwards, a pseudo-ternary phase diagram was built for the most promising formulation using two oils, olive and sesame, with a varied mix of Tween 40 as the surfactant and Trascutol HP as the co-surfactant (Smix), by the optimisation of experiments. The nanoemulsion (NE) formulations that were prepared were found to have an average droplet size of 41.77 ± 1.23 nm and 188.37 ± 3.53 nm, with suitable thermodynamic stability and physicochemical properties. Both olive and sesame oils are natural food additives due to their associated antioxidant effects; therefore, they showed no toxicity profile on breast cell lines (MCF-7, ATCC number HTB-22). The TAM-NE preparations revealed a prolonged and doublings superior cumulative percentage of in vitro release of TAM compared to TAM plain gel suspension over 24 h. The release data suggested that the Higuchi model was the best fitting kinetical model for the developed formulations of NE1, NE9, and NE18. The extended release of the drug as well as an acceptable amount of the drug permeated TAM via nanogel preparations suggested that nanoemulgel (NEG) is suitable for the topical delivery of TAM in breast cancer management. Thus, this work suggests that a nanogel of TAM can improve anticancer properties and reduce systemic adverse effects compared to a suspension preparation of TAM when applied in the treatment of breast cancer.
    Keywords:  MTT assay; Tamoxifen citrate; nanoemulgel; nanoemulsion; surfactants; ultrasonic emulsification
    DOI:  https://doi.org/10.3390/gels8070456
  88. Materials (Basel). 2022 Jul 12. pii: 4838. [Epub ahead of print]15(14):
    Antioxidant Effect of Nanoparticles Composed of Zein and Orange (Citrus sinensis) Extract Obtained by Ultrasound-Assisted Extraction.
    Ana G Luque-Alcaraz, Miranda Velazquez-Antillón, Cynthia N Hernández-Téllez, Abril Z Graciano-Verdugo, Nadia García-Flores, Jorge L Iriqui-Razcón, María Irene Silvas-García, Aldo Zazueta-Raynaud, María J Moreno-Vásquez, Pedro A Hernández-Abril.
      In the present research, an orange extract (OE) was obtained and encapsulated in a zein matrix for its subsequent physicochemical characterization and evaluation of its antioxidant capacity. The OE consists of phenolic compounds and flavonoids extracted from orange peel (Citrus sinensis) by ultrasound-assisted extraction (UAE). The results obtained by dynamic light scattering (DLS) and scanning electron microscopy (SEM) indicated that zein nanoparticles with orange extract (NpZOE) presented a nanometric size and spherical shape, presenting a hydrodynamic diameter of 159.26 ± 5.96 nm. Furthermore, ζ-potential evolution and Fourier transform infrared spectroscopy (FTIR) techniques were used to evaluate the interaction between zein and OE. Regarding antioxidant activity, ABTS and DPPH assays indicated no significant differences at high concentrations of orange peel extract and NpZOE; however, NpZOE was more effective at low concentrations. Although this indicates that ultrasonication as an extraction method effectively obtains the phenolic compounds present in orange peels, the nanoprecipitation method under the conditions used allowed us to obtain particles in the nanometric range with positive ζ-potential. On the other hand, the antioxidant capacity analysis indicated a high antioxidant capacity of both OE and the NpZOE. This study presents the possibility of obtaining orange extracts by ultrasound and coupling them to zein-based nanoparticulate systems to be applied as biomedical materials functionalized with antioxidant substances of pharmaceutical utility.
    Keywords:  antioxidant capacity; ultrasound-assisted extraction; zein nanoparticles
    DOI:  https://doi.org/10.3390/ma15144838
  89. Biol Aujourdhui. 2022 ;216(1-2): 37-39
    [Intestinal gluconeogenesis: an insulin-mimetic function].
    Gilles Mithieux.
      Intestinal gluconeogenesis (IGN) is a regulatory function of energy homeostasis. IGN-produced glucose is sensed by the gastrointestinal nervous system and sends a signal to regions of the brain regulating food intake and glucose control. IGN is activated by dietary protein and dietary fibre, and by gastric bypass surgery of obesity. Glutamine, propionate and succinate are the main substrates used for glucose production by IGN. Activation of IGN accounts for the well-known satiety effect of protein-enriched diets and the anti-obesity and anti-diabetes effects associated with fibre feeding and gastric bypass surgery. Genetic activation of IGN in mice shows the same beneficial effects, independently of any nutritional manipulation, including a marked prevention of hepatic steatosis under hypercaloric feeding. The activation of IGN could thus be the basis for new approaches to prevent or correct metabolic diseases in humans.
    Keywords:  Intestinal gluconeogenesis; diabetes; diabète; gut-to-brain signaling; insulin sensitivity; néoglucogenèse intestinale; obesity; obésité; sensibilité à l’insuline; signalisation intestin-cerveau
    DOI:  https://doi.org/10.1051/jbio/2022003
  90. Pharmaceuticals (Basel). 2022 Jul 14. pii: 868. [Epub ahead of print]15(7):
    How Should the Worldwide Knowledge of Traditional Cancer Healing Be Integrated with Herbs and Mushrooms into Modern Molecular Pharmacology?
    Yulia Kirdeeva, Olga Fedorova, Alexandra Daks, Nikolai Barlev, Oleg Shuvalov.
      Traditional herbal medicine (THM) is a "core" from which modern medicine has evolved over time. Besides this, one third of people worldwide have no access to modern medicine and rely only on traditional medicine. To date, drugs of plant origin, or their derivates (paclitaxel, vinblastine, vincristine, vinorelbine, etoposide, camptothecin, topotecan, irinotecan, and omacetaxine), are very important in the therapy of malignancies and they are included in most chemotherapeutic regimes. To date, 391,000 plant and 14,000 mushroom species exist. Their medical and biochemical capabilities have not been studied in detail. In this review, we systematized the information about plants and mushrooms, as well as their active compounds with antitumor properties. Plants and mushrooms are divided based on the regions where they are used in ethnomedicine to treat malignancies. The majority of their active compounds with antineoplastic properties and mechanisms of action are described. Furthermore, on the basis of the available information, we divided them into two priority groups for research and for their potential of use in antitumor therapy. As there are many prerequisites and some examples how THM helps and strengthens modern medicine, finally, we discuss the positive points of THM and the management required to transform and integrate THM into the modern medicine practice.
    Keywords:  anti-neoplastic compounds; bioavailability; cancer; ethnomedicine; medical herbs; medical plants and mushrooms; pharmacology; safety; standardization; traditional medicine
    DOI:  https://doi.org/10.3390/ph15070868
  91. Pharmaceutics. 2022 Jun 23. pii: 1326. [Epub ahead of print]14(7):
    PLGA-Quercetin Nano-Formulation Inhibits Cancer Progression via Mitochondrial Dependent Caspase-3,7 and Independent FoxO1 Activation with Concomitant PI3K/AKT Suppression.
    Neera Yadav, Amit Kumar Tripathi, Amna Parveen.
      Quercetin is one of the most important plant flavanols, having several pharmacological and biological uses. Quercetin (Q) is an extremely hydrophobic phytochemical and has poor intracellular absorption, which makes its use limited. Present research demonstrates that quercetin-loaded PLGA nanoparticles (PLGA-QNPs) could overcome its low hydrophilicity and improve its anti-cancer potential. PLGA nanoparticles loaded with Q were prepared by the solvent evaporation technique and its anticancer activity was examined in vitro as well as in vivo. The cell viability was assessed through MTT assay and apoptosis was assayed through Hoechst-PI and EB/AO double staining followed by mitochondrial damage through Mito-tracker RMX-Ros. Gene expression was examined through RT-PCR. Cell cycle arrest in G2/M phase was analyzed through FACS. The results obtained revealed that PLGA-QNPs significantly reduced the viability of human cervical and breast cancer cell lines. PLGA-QNPs induced apoptosis in human cervical cancer cells in a dose dependent manner. The gene expression of PI3K/AKT was down-regulated and FoxO1 was upregulated in PLGA-QNP-treated cells, which showed a high expression level of active Caspase-3 and 7, which are responsible for apoptosis. In addition, PLGA-QNPs reduced the average number of tumors and prolonged the tumor latency period in DMBA-induced mammary adenocarcinoma SD rats. These findings suggest that PLGA-QNPs inhibit cervical and breast cancer progression via mitochondrial dependent Caspase-3 and 7 and mitochondrial independent FoxO1 activation with concomitant suppression of the PI3K/AKT pathway. For future studies, we suggest that potential druggability efficacy and clinical development of anticancer PLGA-QNPs need to be evaluated intensely for successful anticancer drug development.
    Keywords:  FoxO1; anti-cancer; drug delivery; phytochemical; quercetin
    DOI:  https://doi.org/10.3390/pharmaceutics14071326
  92. Pharmaceutics. 2022 Jul 22. pii: 1533. [Epub ahead of print]14(8):
    Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD).
    Jingxin Fu, Kunfeng Zhang, Likang Lu, Manzhen Li, Meihua Han, Yifei Guo, Xiangtao Wang.
      Cannabidiol (CBD), a nonpsychoactive major component derived from Cannabis sativa, widely used in neurodegenerative diseases, has now been proven to have growth inhibitory effects on many tumor cell lines, including breast tumors. Meanwhile CBD can effectively alleviate cancer-associated pain, anxiety, and depression, especially tumor cachexia, thus it is very promising as an anti-tumor drug with unique advantages. 20(S)-Protopanaxadiol (PPD) derived from the best-known tonic Chinese herbal medicine Ginseng was designed to be co-loaded with CBD into liposomes to examine their synergistic tumor-inhibitory effect. The CBD-PPD co-loading liposomes (CP-liposomes) presented a mean particle size of 138.8 nm. Further glycosyl-modified CP-liposomes (GMCP-liposomes) were prepared by the incorporation of n-Dodecyl β-D-maltoside (Mal) into the liposomal bilayer with glucose residue anchored on the surface to act as a ligand targeting the GLUT1 receptor highly expressed on tumor cells. In vivo studies on murine breast tumor (4T1 cells)-bearing BALB/c mice demonstrated good dose dependent anti-tumor efficacy of CP-liposomes. A high tumor inhibition rate (TIR) of 82.2% was achieved with good tolerance. However, glycosylation modification failed to significantly enhance TIR of CP-liposomes. In summary, combined therapy with PPD proved to be a promising strategy for CBD to be developed into a novel antitumor drug, with characteristics of effectiveness, good tolerance, and the potential to overcome tumor cachexia.
    Keywords:  20(S)-Protopanaxadiol (PPD); Cannabidiol (CBD); anti-tumor efficacy; breast cancer; liposomes
    DOI:  https://doi.org/10.3390/pharmaceutics14081533
  93. Adv Colloid Interface Sci. 2022 Jul 21. pii: S0001-8686(22)00146-4. [Epub ahead of print]307 102744
    Alginate-based nanocarriers for the delivery and controlled-release of bioactive compounds.
    Aiman Karim, Abdur Rehman, Jianguo Feng, Asia Noreen, Elham Assadpour, Mohammad Saeed Kharazmi, Zhang Lianfu, Seid Mahdi Jafari.
      Alginate-based nanocarriers are propitious vehicles used for the delivery of bioactive compounds (bioactives). In this area, calcium alginate and sodium alginate are the most promising wall materials because they are nontoxic, comparatively cheap, simple in production, biocompatible and biodegradable. In this review, we have highlighted different alginate-based nanocarriers such as nanoparticles, nanofibers, nanoemulsions, nanocomplexes, and nanohydrogels; also entrapment of different bioactives within alginate nanocarriers and their bioavailability in the gastric environment has been comprehensively discussed. Being biopolymers, alginates can be exploited as emulsifiers/ encapsulants for entrapment and delivery of different bioactives such as vitamins, minerals, essential fatty acids, peptides, essential oils, bioactive oils, polyphenols and carotenoids. Furthermore, the use of alginate-based nanocarriers in combination with other polysaccharides/ emulsifiers was recognized as the most effective and favorable approach for the protection, delivery and sustained release of bioactives.
    Keywords:  Bioavailability; Delivery systems; Nanoencapsulation; Nutraceuticals; Release
    DOI:  https://doi.org/10.1016/j.cis.2022.102744
  94. Polymers (Basel). 2022 Jul 26. pii: 3021. [Epub ahead of print]14(15):
    Development and Optimization of Nigella sativa Nanoemulsion Loaded with Pioglitazone for Hypoglycemic Effect.
    Tamer M Shehata, Mervt M Almostafa, Heba S Elsewedy.
      Diabetes mellitus (DM) is a metabolic disorder associated with an increased blood glucose level. The world health burden of DM has increased as a result of numerous causes that necessitates suitable treatment. Pioglitazone (PGZ) is a generally prescribed medication for managing type II diabetes. However, its low solubility creates complications for its formulation. Therefore, the aim of the current study was to incorporate PGZ into a nanoemulsion (NE) formulation prepared with Nigella sativa oil (NSO) to boost the action of PGZ. To our knowledge, no previous study has addressed the combination and synergistic effect of PGZ and NSO as a hypoglycemic NE formulation intended for oral administration. An experiment was designed to test several PGZ-loaded NE formulations, varying factors such as NSO, surfactant and co-surfactant concentrations. These factors were investigated for their influence on responses including particle size and in vitro release. An optimized PGZ-loaded NE was selected and examined for its morphology, kinetic activity and stability. Further, the anti-diabetic effect of the optimized formulation was evaluated using diabetically induced rats. The optimized formula exhibited a good particle size of 167.1 nm and in vitro release of 89.5%. A kinetic study revealed that the drug release followed the Korsmeyer-Peppas mechanism. Additionally, the PGZ-loaded NE formulation was found to be stable, showing non-significant variation in the evaluated parameters when stored at 4 and 25 °C for a period of 3 months. In vivo investigation of the PGZ-loaded NE formulation showed a significant reduction in blood glucose level, which appeared to be enhanced by the presence of NSO. In conclusion, NS-NE could be a promising nanocarrier for enhancing the hypoglycemic effect of PGZ.
    Keywords:  Nigella sativa; diabetes; hypoglycemia; nanoemulsion; optimization; pioglitazone
    DOI:  https://doi.org/10.3390/polym14153021
  95. Eur J Pharmacol. 2022 Jul 21. pii: S0014-2999(22)00392-2. [Epub ahead of print] 175131
    Folic acid-targeted pluronic F127 micelles improve oxidative stress and inhibit fibrosis for increasing AKI efficacy.
    Bin Du, Mengmeng Zhao, Yuehua Wang, Lili Yu, Qingqing Jiao, Yimeng Bai, Genyang Cheng.
      The oxidative stress and activation of the fibrosis pathway are essential pathological mechanisms of acute kidney injury (AKI). In this article, we designed a drug delivery system that could effectively improve oxidative stress and relieve fibrosis by the combination of precise targeting, solubilization, and reducing the toxicity of nano-transport system to strengthen the efficacy of AKI. Folic acid (FA) was used as the targeting molecule, and curcumin (Cur) and resveratrol (Res), which are Chinese medicine monomers with anti-inflammatory and antioxidant effects, were used as model drugs. Here, the targeting nanosystem (Cur/Res@FA-F127/TPGS) co-loaded with Cur and Res was successfully synthesized. Finally, the comprehensive therapeutic effect of the nanosystem was evaluated through the targeted and pharmacodynamic researches on the AKI models induced by cisplatin (CDDP) in vitro and in vivo. The studies in vitro proved that the nanosystem could not only specifically target HK-2 cells and promote the effective accumulation of Cur and Res in the kidney, but also effectively improve oxidative stress by eliminating reactive oxygen species (ROS), stabilizing mitochondrial membrane potential (MMP), and reducing the expression of apoptosis-related proteins. The studies in vivo showed that the nanosystem could effectively play the role of anti-oxidation, anti-inflammatory and alleviate fibrosis to reduce the apoptosis and necrosis of renal tubular cells. The nanosystem could coordinately repair damaged HK-2 cells by improving oxidative stress, inhibiting inflammation and tissue fibrosis, which provided a new idea for the treatment of AKI.
    Keywords:  Acute kidney injury; Fibrosis; Inflammatory factor; NF-κB; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175131
  96. Molecules. 2022 Jul 25. pii: 4750. [Epub ahead of print]27(15):
    Epithelial-Mesenchymal Transition-Mediated Tumor Therapeutic Resistance.
    Zhimin Xu, Yingxin Zhang, Huanyan Dai, Bing Han.
      Cancer is one of the world's most burdensome diseases, with increasing prevalence and a high mortality rate threat. Tumor recurrence and metastasis due to treatment resistance are two of the primary reasons that cancers have been so difficult to treat. The epithelial-mesenchymal transition (EMT) is essential for tumor drug resistance. EMT causes tumor cells to produce mesenchymal stem cells and quickly adapt to various injuries, showing a treatment-resistant phenotype. In addition, multiple signaling pathways and regulatory mechanisms are involved in the EMT, resulting in resistance to treatment and hard eradication of the tumors. The purpose of this study is to review the link between EMT, therapeutic resistance, and the molecular process, and to offer a theoretical framework for EMT-based tumor-sensitization therapy.
    Keywords:  EMT; chemoresistance; immunity therapy; radioresistance; targeted therapy
    DOI:  https://doi.org/10.3390/molecules27154750
  97. Mater Today Bio. 2022 Dec;16 100349
    Engineered hyaluronic acid-decorated niosomal nanoparticles for controlled and targeted delivery of epirubicin to treat breast cancer.
    Amirreza Mansoori-Kermani, Sadaf Khalighi, Iman Akbarzadeh, Fazeleh Ranjbar Niavol, Hamidreza Motasadizadeh, Athar Mahdieh, Vahid Jahed, Masoud Abdinezhad, Nikoo Rahbariasr, Mahshid Hosseini, Nima Ahmadkhani, Behnam Panahi, Yousef Fatahi, Masoud Mozafari, Alan Prem Kumar, Ebrahim Mostafavi.
      Targeted drug delivery systems using nanocarriers offer a versatile platform for breast cancer treatment; however, a robust, CD44-targeted niosomal formulation has not been developed and deeply studied (both in vitro and in vivo) yet. Here, an optimized system of epirubicin (Epi)-loaded niosomal nanoparticles (Nio) coated with hyaluronic acid (HA) has been engineered for targeting breast cancer cells. The nanoformulation was first optimized (based on size, polydispersity index, and entrapment efficiency); then, we characterized the morphology, stability, and release behavior of the nanoparticles. Epirubicin release from the HA-coated system (Epi-Nio-HA) showed a 21% (acidic buffer) and 20% (neutral buffer) reduction in comparison with the non-coated group (Epi-Nio). The cytotoxicity and apoptosis results of 4T1 and SkBr3 cells showed an approximately 2-fold increase in the Epi-Nio-HA system over Epi-Nio and free epirubicin, which confirms the superiority of the engineered nanocarriers. Moreover, real-time PCR data demonstrated the down-regulation of the MMP-2, MMP-9, cyclin D, and cyclin E genes expression while caspase-3 and caspase-9 gene expression were up-regulated. Confocal microscopy and flow cytometry studies uncovered the cellular uptake mechanism of the Epi-Nio-HA system, which was CD44-mediated. Furthermore, in vivo studies indicated Epi-Nio-HA decreased mice breast tumor volume by 28% (compared to epirubicin) without side effects on the liver and kidney. Conclusively, our results indicated that the HA-functionalized niosomes provide a promising nanoplatform for efficient and targeted delivery of epirubicin to potentially treat breast cancer.
    Keywords:  Active targeting; Breast cancer; CD44; Controlled drug delivery; Hyaluronic acid; Nanomedicine
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100349
  98. Molecules. 2022 Jul 15. pii: 4531. [Epub ahead of print]27(14):
    Curcumin Modifies the Activity of Plasmatic Antioxidant Enzymes and the Hippocampal Oxidative Profile in Rats upon Acute and Chronic Exposure to Ozone.
    Abraham Alberto Ramírez-Mendoza, Mario Alberto Ramírez-Herrera, Cesar Ricardo Cortez-Álvarez, Sendar Daniel Nery-Flores, Aldo Rafael Tejeda-Martínez, Marina María de Jesús Romero-Prado, María Luisa Mendoza-Magaña.
      Ozone (O3) is an oxidating tropospheric pollutant. When O3 interacts with biological substrates, reactive oxygen and nitrogen species (RONS) are formed. Severe oxidative damage exhausts the endogenous antioxidant system, which leads to the decreased activity of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Curcumin (CUR) is a natural polyphenol with well-documented antioxidant and anti-inflammatory properties. The aim of this work is to evaluate the effects of curcumin on CAT, GPx, and SOD activity and the inhibition of oxidative damage after the acute and chronic exposure to O3. Fifty male Wistar rats were divided into five experimental groups: the intact control, CUR-fed control, exposed-to-O3 control, CUR-fed (preventive), and CUR-fed (therapeutic) groups. These two last groups received a CUR-supplemented diet while exposed to O3. These experiments were performed during acute- and chronic-exposure phases. In the preventive and therapeutic groups, the activity of plasma CAT, GPx, and SOD was increased during both exposure phases, with slight differences; concomitantly, lipid peroxidation and protein carbonylation were inhibited. For this reason, we propose that CUR could be used to enhance the activity of the antioxidant system and to diminish the oxidative damage caused by exposure to O3.
    Keywords:  antioxidant properties; curcumin; ozone
    DOI:  https://doi.org/10.3390/molecules27144531
  99. J Food Biochem. 2022 Jul 27. e14325
    Date fruit as a promising source of functional carbohydrates and bioactive compounds: A review on its nutraceutical potential.
    Tayyaba Alvi, Muhammad Kashif Iqbal Khan, Abid Aslam Maan, Zafar Ullah Razzaq.
      From the past decade, consumption of ready-to-eat food and ease of access to fast food increased the onset of several diseases. Thus, there is a need to shift the trend from consumption of unhealthy food item to natural and healthy alternatives. In this context, fruits can be considered as functional food, which have ability to provide essential nutrients and bioactive compounds. These compounds when consume in adequate amount would have the potential to lower the onset of diseases. In this regard, Phoenix dactylifera or date fruit is an important source of functional carbohydrates and bioactive compounds for their use as functional foods. The major functional carbohydrate in date fruit are in the form of dietary fiber, such as β-glucan, cellulose and fructans along with other bioactive compounds. Additionally, it is also a good source of other important nutrients such as sugars, minerals, along with minor quantities of proteins and lipids. Due to these functional compounds, date fruit have shown a wide range of pharmaceutical properties such as antioxidant, anti-inflammatory, anti-diabetic, hepatoprotective and anticancer. This review provides latest information regarding functional and nutraceutical carbohydrates of date fruits along-with mechanism of action on different diseases reported in recent years. PRACTICAL APPLICATIONS: This will provide information to food industries for the development of innovative food products by using date fruit. Moreover, bioactive components from date fruit may prove to enhance global health and wellness. However, further research is needed on clinical trials for the development of functional food products by using date fruit for functional foods and pharmaceutical applications.
    Keywords:  bioactive compounds; date fruit; dietary fiber; health promoting; therapeutic potential
    DOI:  https://doi.org/10.1111/jfbc.14325
  100. Int J Mol Sci. 2022 Jul 26. pii: 8237. [Epub ahead of print]23(15):
    Digitoxin Affects Metabolism, ROS Production and Proliferation in Pancreatic Cancer Cells Differently Depending on the Cell Phenotype.
    Heléne Lindholm, Katarina Ejeskär, Ferenc Szekeres.
      Digitoxin has repeatedly shown to have negative effects on cancer cell viability; however, the actual mechanism is still unknown. In this study, we investigated the effects of digitoxin (1-100 nM) in four pancreatic cancer cell lines, BxPC-3, CFPAC-1, Panc-1, and AsPC-1. The cell lines differ in their KRAS/BRAF mutational status and primary tumor or metastasis origin. We could detect differences in the basal rates of cell proliferation, glycolysis, and ROS production, giving the cell lines different phenotypes. Digitoxin treatment induced apoptosis in all four cell lines, but to different degrees. Cells derived from primary tumors (Panc-1 and BxPC-3) were highly proliferating with a high proportion of cells in the S/G2 phase, and were more sensitive to digitoxin treatment than the cell lines derived from metastases (CFPAC-1 and AsPC-1), with a high proportion of cells in G0/G1. In addition, the effects of digitoxin on the rate of glycolysis, ROS production, and proliferation were dependent on the basal metabolism and origin of the cells. The KRAS downstream signaling pathways were not altered by digitoxin treatment, thus the effects exerted by digitoxin were probably disconnected from these signaling pathways. We conclude that digitoxin is a promising treatment in highly proliferating pancreatic tumors.
    Keywords:  KRAS; PDAC; ROS; cardiac glycosides; cell proliferation; digitoxin; metabolism; pancreatic cancer
    DOI:  https://doi.org/10.3390/ijms23158237
  101. Front Pharmacol. 2022 ;13 929161
    Natural Products from Actinobacteria as a Potential Source of New Therapies Against Colorectal Cancer: A Review.
    Yadollah Bahrami, Sasan Bouk, Elham Kakaei, Mohammad Taheri.
      Colorectal cancer (CRC) is a common, and deadly disease. Despite the improved knowledge on CRC heterogeneity and advances in the medical sciences, there is still an urgent need to cope with the challenges and side effects of common treatments for the disease. Natural products (NPs) have always been of interest for the development of new medicines. Actinobacteria are known to be prolific producers of a wide range of bioactive NPs, and scientific evidence highlights their important protective role against CRC. This review is a holistic picture on actinobacter-derived cytotoxic compounds against CRC that provides a good perspective for drug development and design in near future. This review also describes the chemical structure of 232 NPs presenting anti-CRC activity with the being majority of quinones, lactones, alkaloids, peptides, and glycosides. The study reveals that most of these NPs are derived from marine actinobacteria followed by terrestrial and endophytic actinobacteria, respectively. They are predominantly produced by Streptomyces, Micromonospors, Saliniospors and Actinomadura, respectively, in which Streptomyces, as the predominant contributor generating over 76% of compounds exclusively. Besides it provides a valuable snapshot of the chemical structure-activity relationship of compounds, highlighting the presence or absence of some specific atoms and chemical units in the structure of compounds can greatly influence their biological activities. To the best of our knowledge, this is the first comprehensive review on natural actinobacterial compounds affecting different types of CRC. Our study reveals that the high diversity of actinobacterial strains and their NPs derivatives, described here provides a new perspective and direction for the production of new anti-CRC drugs and paves the way to innovation for drugs discovery in the future. The knowledge obtain from this review can help us to understand the pivotal application of actinobacteria in future drugs development.
    Keywords:  actinobacteria; anti-cancer effects; bioactive compounds; colorectal cancer; endophytic actinobacteria; marine actinobacteria; natural products; secondary metabolites
    DOI:  https://doi.org/10.3389/fphar.2022.929161
  102. J Control Release. 2022 Jul 22. pii: S0168-3659(22)00442-4. [Epub ahead of print]
    Polymeric nanoparticles for drug delivery in glioblastoma: State of the art and future perspectives.
    Fatemeh Madani, Seyedeh Sara Esnaashari, Thomas J Webster, Masood Khosravani, Mahdi Adabi.
      Glioblastoma (GBM) is an aggressive, fatal and malignant primary brain tumor. Despite the current standard treatment for glioblastoma patients including neurosurgical resection, followed by concomitant radiation and chemotherapy, the median survival rate is about 15 months. An unresolved challenge for current therapies is related to getting drugs through the blood-brain barrier (BBB), which hinders many chemotherapeutic agents from reaching tumors cells. Although a large amount of research has been done to circumvent the BBB and deliver drugs to the brain, with nanoparticles (NPs) taking the lead, the challenge is still high. In this regard, the BBB and how to transfer drug pathways through the BBB, especially using NPs, are introduced here. Afterwards, the latest advances in drug delivery, co-drug delivery, and combination modality are described specifically for GBM treatment using natural and synthetic polymeric NPs and adjuvant therapies including hyperthermia, photodynamic therapy and also ketogenic regimens. In addition, receptor-mediated endocytosis agents that exist in endothelial capillary cells of the brain are explained. Lastly, future directions to finally deliver drugs through the BBB for GBM treatment are emphasized. It is the hope that this review can provide a number of practical pathways for the future development of BBB permeable nanochemotherapeutics against GBM.
    Keywords:  Blood-brain barrier; Drug delivery; Glioblastoma; Polymeric nanoparticles
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.023
  103. Cancers (Basel). 2022 Jul 09. pii: 3348. [Epub ahead of print]14(14):
    The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids.
    Mariarosaria Boccellino, Pasqualina Ambrosio, Andrea Ballini, Danila De Vito, Salvatore Scacco, Stefania Cantore, Antonia Feola, Marzia Di Donato, Lucio Quagliuolo, Antonella Sciarra, Giovanni Galasso, Felice Crocetto, Ciro Imbimbo, Silvia Boffo, Erika Di Zazzo, Marina Di Domenico.
      A major challenge in the clinical management of prostate cancer (PC) is to inhibit tumor growth and prevent metastatic spreading. In recent years, considerable efforts have been made to discover new compounds useful for PC therapy, and promising advances in this field were reached. Drugs currently used in PC therapy frequently induce resistance and PC progresses toward metastatic castration-resistant forms (mCRPC), making it virtually incurable. Curcumin, a commercially available nutritional supplement, represents an attractive therapeutic agent for mCRPC patients. In the present study, we compared the effects of chemotherapeutic drugs such as docetaxel, paclitaxel, and cisplatin, to curcumin, on two PC cell lines displaying a different metastatic potential: DU145 (moderate metastatic potential) and PC-3 (high metastatic potential). Our results revealed a dose-dependent reduction of DU145 and PC-3 cell viability upon treatment with curcumin similar to chemotherapeutic agents (paclitaxel, cisplatin, and docetaxel). Furthermore, we explored the EGFR-mediated signaling effects on ERK activation in DU145 and PC-3 cells. Our results showed that DU145 and PC-3 cells overexpress EGFR, and the treatment with chemotherapeutic agents or curcumin reduced EGFR expression levels and ERK activation. Finally, chemotherapeutic agents and curcumin reduced the size of DU145 and PC-3 spheroids and have the potential to induce apoptosis and also in Matrigel. In conclusion, despite different studies being carried out to identify the potential synergistic curcumin combinations with chemopreventive/therapeutic efficacy for inhibiting PC growth, the results show the ability of curcumin used alone, or in combinatorial approaches, to impair the size and the viability of PC-derived spheroids.
    Keywords:  3D cell culture; chemotherapeutic agents; curcumin; metastasis; prostate cancer; spheroids
    DOI:  https://doi.org/10.3390/cancers14143348
  104. J Pers Med. 2022 Jun 24. pii: 1039. [Epub ahead of print]12(7):
    Experience with Photodynamic Therapy Using Indocyanine Green Liposomes for Refractory Cancer.
    Kensho Yorozu, Masaki Kaibori, Shintarou Kimura, Misa Ichikawa, Kosuke Matsui, Soichiro Kaneshige, Masanori Kobayashi, Daiki Jimbo, Yusuke Torikai, Yoshitaka Fukuzawa, Yoshiharu Okamoto.
      We reported the development of an effective cancer treatment using a multidisciplinary treatment, including photodynamic therapy (PDT) with indocyanine green (ICG) liposomes and a combination of Lentinula edodes mycelia (LEM) and hydrogen gas inhalation therapy. ICG liposomes were prepared by adding 5 mg of ICG to 50 mL liposomes. Later, 25 mL of ICG liposomes were diluted with 250 mL of 5% glucose solution and administered intravenously to the patient. We selected the multi-laser delivery system (MLDS), a laser irradiator for performing PDT. Further, the patients received a combination of LEM and hydrogen gas inhalation therapy throughout the treatment. We reported two cases of PDT therapy, one with middle intrathoracic esophagus carcinoma and the other with hypopharyngeal cancer. In the first case, the MLDS laser was directly attached to the endoscope and directed to the cancer area with wavelengths of 810 nm. After the treatment, a biopsy demonstrated no tumor recurrence. In the second case, the patient was treated with endovascular PDT using ICG liposomes and MLDS fiber optics. Later, tumor shrinkage was demonstrated after the first round and disappeared after six months. In conclusion, the present findings suggest that the effect of PDT using ICG liposomes with LEM and hydrogen gas may eradicate cancer without burdening patients by enhancing tumor immunity.
    Keywords:  Lentinula edodes mycelia; esophagus carcinoma; hydrogen gas; hypopharyngeal cancer; indocyanine green liposomes; multi-laser delivery system; photodynamic therapy
    DOI:  https://doi.org/10.3390/jpm12071039
  105. ChemMedChem. 2022 Jul 28.
    Copper Nanocluster Enabled Simultaneous Photodynamic and Chemo Therapy for Effective Cancer Diagnosis and Treatment In Vitro.
    Merin Joseph, Muhammed Shafeeque Rahman Pathiripparambath, Hanas Tharayil, Ramapurath S Jayasree, Lakshmi V Nair.
      Metal nanocluster mediated cancer diagnosis and therapy have drawn considerable attention in recent years due to its unique optical and photophysical properties. Such kind of material is highly useful for diagnosis, treatment, and further follow-up of the disease. However, a single treatment modality is not sufficient for the complete cure of the same. Multiple therapeutic strategies are one of the most promising methods for effective treatment along with an early-stage diagnosis. To address the multiple therapeutic modalities in a single nanomaterial, a copper nanocluster is synthesized using glutathione having inherent singlet oxygen generation and emission at 674 nm. A tumor-targeting agent (folic acid) and an anti-cancer drug (doxorubicin) is conjugated to the copper cluster for cancer diagnosis via targeted imaging and further double therapy (photodynamic and chemotherapy) in vitro . 10.5 µg (18.1 nmoles) of drug conjugated copper cluster shows 56% cell death for a 30 s laser irradiation in Hela cells. Effective cancer cell imaging and therapeutic efficacy are demonstrated in vitro .
    Keywords:  Cancer diagnosis; Chemotherapy; Copper metal nanoclusters; Nano drug carriers; photodynamic therapy
    DOI:  https://doi.org/10.1002/cmdc.202200201
  106. ACS Biomater Sci Eng. 2022 Jul 27.
    Unfolding the Potency of Adenosine in Targeting Triple Negative Breast Cancer via Paclitaxel-Incorporated pH-Responsive Stealth Liposomes.
    Dasharath Chaudhari, Oly Katari, Rohan Ghadi, Kaushik Kuche, Tushar Date, Nallamothu Bhargavi, Sanyog Jain.
      Triple-negative breast cancer (TNBC) belongs to the category of the most destructive forms of breast cancer. Being a highly potent chemotherapeutic agent, paclitaxel (PTX) is extensively utilized in the management of various cancers. Commercially available PTX formulations contain non-targeted drug carriers that result in low antitumor activity because of non-specific tissue distribution. Thus, to resolve this issue, we designed PTX-loaded pH-sensitive liposomes (pH Lipos) in the present investigation and used adenosine (ADN) as a targeting ligand. Further, d-α-tocopheryl polyethylene glycol succinate (TPGS) was incorporated into the liposomes to impart a stealth effect to the system. For the development of these pH Lipos, different conjugates were synthesized (ADN-CHEMS and TPGS-ADN) and further utilized for the preparation of ADN-PEG-pH Lipo and ADN-pH Lipo by a thin-film hydration method. DOPE:HSPC:CHEMS:cholesterol at a molar ratio of 3:3:2:2 was selected for the preparation of pH-Lipo possessing 7.5% w/w drug loading. They showed a particle size below 140 nm, a PDI below 0.205, and a % EE greater than 60%. All of the pH Lipos displayed a biphasic pattern of PTX release at pH 7.4 and 5.5. However, the percent drug release at pH 5.5 was substantially greater because of the pH-sensitive nature of the liposomes. The MDA MB 231 and 4T1 cell lines depicted improvement in the qualitative as well as quantitative cellular uptake of PTX ADN-PEG-pH Lipo with a substantial decrease in the IC50 value. Moreover, a higher apoptotic index was observed with pH Lipo compared to free PTX. PTX ADN-PEG-pH Lipo revealed a 3.98- and 3.41-fold rise in the AUC and t1/2 values of PTX compared to Intaxel, respectively. Overall, characteristic decreases in tumor volume and serum toxicity marker levels were observed, which confirmed the development of an efficient and safe formulation.
    Keywords:  adenosine; pH-sensitive liposomes; paclitaxel; triple-negative breast cancer; vitamin E TPGS
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00594
  107. Front Genet. 2022 ;13 921051
    Intelligent Nanoparticles With pH-Sensitive Co-Delivery of Temozolomide and siEGFR to Ameliorate Glioma Therapy.
    Zhen Wang, Yuyang Liu, Yong Xiao, Yandong Xie, Ran Wang, Yiding Zhang, Qi Zhou, Liang Liu, Shuo Sun, Hong Xiao, Yuanjie Zou, Kun Yang, Xiang Li, Mengjie Zhao, Yifang Hu, Hongyi Liu.
      Glioblastoma (GBM) is one of the most lethal forms of human cancer, with very few long-term survivors. In addition to surgery, chemotherapy is still an important strategy. Unfortunately, GBM chemotherapy faces two main challenges: first, in GBM, epidermal growth factor receptor (EGFR) overexpression results in chemoresistance; second, temozolomide (TMZ) lacks target specificity, which can lead to a reduction in the concentration and side effects in GBM. Nowadays, with the development of nanomedicine systems for applications in tumor therapies, increasing anticancer efficacy and reducing side effects with multi-drug delivery are huge advantages. In this study, pH-sensitive and GBM-targeting nanovesicle (Tf-PEG-PAE(SS)) was fabricated. The chemotherapy drug (TMZ) and EGFR inhibitor (EGFR-siRNA) were co-encapsulated in the nanocarrier, and their anticancer outcomes were investigated in detail. In vitro experiments have shown that the nanocarrier transports TMZ and EGFR-siRNA efficiently into U87 cells, causing a vigorous apoptotic response by silencing the proliferative EGFR gene and increasing the drug concentration of TMZ simultaneously. An experimental study in mice bearing orthotropic glioma revealed that the accumulated nanocarriers in the tumor site could inhibit the tumor growth and prolong the mice survival remarkably through the intracranial injection of Tf-PEG-PAE(SS)/TMZ@siEGFR. The drug co-delivery system could extend the blood circulation time and offer a new strategy to treat glioblastoma.
    Keywords:  TMZ; glioma; pH-responsive polymeric nanocarrier; siEGFR; synergistic therapy
    DOI:  https://doi.org/10.3389/fgene.2022.921051
  108. Polymers (Basel). 2022 Jul 26. pii: 3027. [Epub ahead of print]14(15):
    Polymer-Based Hybrid Nanoarchitectures for Cancer Therapy Applications.
    Arun Kumar, Mirkomil Sharipov, Abbaskhan Turaev, Shavkatjon Azizov, Ismatdjan Azizov, Edwin Makhado, Abbas Rahdar, Deepak Kumar, Sadanand Pandey.
      Globally, cancer is affecting societies and is becoming an important cause of death. Chemotherapy can be highly effective, but it is associated with certain problems, such as undesired targeting and multidrug resistance. The other advanced therapies, such as gene therapy and peptide therapy, do not prove to be effective without a proper delivery medium. Polymer-based hybrid nanoarchitectures have enormous potential in drug delivery. The polymers used in these nanohybrids (NHs)provide them with their distinct properties and also enable the controlled release of the drugs. This review features the recent use of polymers in the preparation of different nanohybrids for cancer therapy published since 2015 in some reputed journals. The polymeric nanohybrids provide an advantage in drug delivery with the controlled and targeted delivery of a payload and the irradiation of cancer by chemotherapeutical and photodynamic therapy.
    Keywords:  cancer therapy; chitosan-based nanohybrids; drug delivery; pH-based targeting; polymeric nanohybrids
    DOI:  https://doi.org/10.3390/polym14153027
  109. Molecules. 2022 Jul 13. pii: 4475. [Epub ahead of print]27(14):
    The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: 'Talented' Taxa from the Amaryllidaceae.
    Cynthia Amaning Danquah, Prince Amankwah Baffour Minkah, Theresa A Agana, Phanankosi Moyo, Michael Ofori, Peace Doe, Sibusiso Rali, Isaiah Osei Duah Junior, Kofi Bonsu Amankwah, Samuel Owusu Somuah, Isaac Newton Nugbemado, Vinesh J Maharaj, Sanjib Bhakta, Simon Gibbons.
      Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer's disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications.
    Keywords:  Allium; Amaryllidaceae; Crinum; Cyrtanthus; Tulbaghia; alkaloids; drug discovery; natural products; pharmacological activity; phytochemicals
    DOI:  https://doi.org/10.3390/molecules27144475
  110. Polymers (Basel). 2022 Jul 07. pii: 2787. [Epub ahead of print]14(14):
    Daptomycin-Biomineralized Silver Nanoparticles for Enhanced Photothermal Therapy with Anti-Tumor Effect.
    Jie Zhang, Jing Wang, Guixiu Fan, Bingjie Zhang, Guanglong Ma, Haiyan Xiao, Longgang Wang.
      Silver nanoparticles as photothermal agents have the problems of low stability and low photothermal conversion efficiency. Amphiphilic daptomycin can improve the stability of silver nanoparticles, thereby improving their photothermal conversion efficiency. Herein, daptomycin-biomineralized silver nanoparticles (Dap-AgNPs) were prepared by reducing silver nitrate with sodium borohydride in the presence of daptomycin as a stabilizer and biomineralizer. The Dap-AgNPs had good solution stability and peroxidase-like activity. Furthermore, the photothermal conversion efficiency of the Dap-AgNPs was as high as 36.8%. The Dap-AgNPs displayed good photothermal stability under irradiation. More importantly, the Dap-AgNPs showed good cell compatibility with HeLa cells and HT-29 cells without irradiation by 808-nanometer near-infrared light at a concentration of 0.5 mM, and the cell viability was greater than 85.0%. However, the Dap-AgNPs displayed significant anti-tumor ability with irradiation by 808-nanometer near-infrared light, which was due to the increasing temperature of the culture medium caused by the Dap-AgNPs. In conclusion, Dap-AgNPs have potential applications as photothermal agents in the treatment of tumors.
    Keywords:  anti-tumor; biocompatibility; biomineralization; daptomycin; silver nanoparticle
    DOI:  https://doi.org/10.3390/polym14142787
  111. Biomedicines. 2022 Jul 13. pii: 1686. [Epub ahead of print]10(7):
    Naringin and Naringenin: Their Mechanisms of Action and the Potential Anticancer Activities.
    Jolita Stabrauskiene, Dalia M Kopustinskiene, Robertas Lazauskas, Jurga Bernatoniene.
      Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. Numerous studies have reported these substances' antioxidant and antiandrogenic properties, as well as their ability to protect from inflammation and cancer, in various in vitro and in vivo experimental models in animals and humans. Naringin and naringenin can suppress cancer development in various body parts, alleviating the conditions of cancer patients by acting as effective alternative supplementary remedies. Their anticancer activities are pleiotropic, and they can modulate different cellular signaling pathways, suppress cytokine and growth factor production and arrest the cell cycle. In this narrative review, we discuss the effects of naringin and naringenin on inflammation, apoptosis, proliferation, angiogenesis, metastasis and invasion processes and their potential to become innovative and safe anticancer drugs.
    Keywords:  cancer; cellular signaling pathways; flavonoids; naringenin; naringin
    DOI:  https://doi.org/10.3390/biomedicines10071686
  112. Mater Today Bio. 2022 Dec;16 100358
    Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy.
    Wenjing Xu, Chunping Ye, Xin Qing, Shengli Liu, Xinyi Lv, Wenjun Wang, Xiaochen Dong, Yewei Zhang.
      Multi-target Tyrosine Kinase Inhibitors (MTKIs) have drawn substantial attention in tumor therapy. MTKIs could inhibit tumor cell proliferation and induce apoptosis by blocking the activity of tyrosine kinase. However, the toxicity and drug resistance of MTKIs severely restrict their further clinical application. The nano pharmaceutical technology based on MTKIs has attracted ever-increasing attention in recent years. Researchers deliver MTKIs through various types of nanocarriers to overcome drug resistance and improve considerably therapeutic efficiency. This review intends to summarize comprehensive applications of MTKIs nanoparticles in malignant tumor treatment. Firstly, the mechanism and toxicity were introduced. Secondly, various nanocarriers for MTKIs delivery were outlined. Thirdly, the combination treatment schemes and drug resistance reversal strategies were emphasized to improve the outcomes of cancer therapy. Finally, conclusions and perspectives were summarized to guide future research.
    Keywords:  Cancer treatment; Combination therapy; Drug delivery; Drug resistance; Multi-target tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100358
  113. Pharmaceutics. 2022 Jul 05. pii: 1407. [Epub ahead of print]14(7):
    Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: Approaches with Natural Compounds from Traditional Eastern Medicine.
    Geehoon Chung, Sun Kwang Kim.
      Chemotherapy-induced peripheral neuropathy (CIPN) often develops in patients with cancer treated with commonly used anti-cancer drugs. The symptoms of CIPN can occur acutely during chemotherapy or emerge after cessation, and often accompany long-lasting intractable pain. This adverse side effect not only affects the quality of life but also limits the use of chemotherapy, leading to a reduction in the survival rate of patients with cancer. Currently, effective treatments for CIPN are limited, and various interventions are being applied by clinicians and patients because of the unmet clinical need. Potential approaches to ameliorate CIPN include traditional Eastern medicine-based methods. Medicinal substances from traditional Eastern medicine have well-established analgesic effects and are generally safe. Furthermore, many substances can also improve other comorbid symptoms in patients. This article aims to provide information regarding traditional Eastern medicine-based plant extracts and natural compounds for CIPN. In this regard, we briefly summarized the development, mechanisms, and changes in the nervous system related to CIPN, and reviewed the substances of traditional Eastern medicine that have been exploited to treat CIPN in preclinical and clinical settings.
    Keywords:  chemotherapy-induced peripheral neuropathy; neuropathic pain; traditional eastern medicine
    DOI:  https://doi.org/10.3390/pharmaceutics14071407
  114. Pharmaceutics. 2022 Jun 29. pii: 1375. [Epub ahead of print]14(7):
    Cyclodextrin-Based Nanoplatforms for Tumor Phototherapy: An Update.
    Xingjie Wu, Ying Chen, Qianqian Guo, Ling Tao, Yang Ding, Xianguang Ding, Xiangchun Shen.
      Tumor phototherapies are light-mediated tumor treatment modalities, which usually refer to tumor photothermal therapy (PTT) and photodynamic therapy (PDT). Due to the outstanding spatial-temporal control over treatment through light irradiation, tumor phototherapies display extremely low side effects during treatment and are believed to be a tumor treatment method with a clinical translation potential. However, current tumor phototherapy nanoplatforms face obstacles, including light irradiation-induced skin burning, tumor hypoxia microenvironments, limited light penetration depth, et al. Therefore, one important research direction is developing a tumor phototherapy nanoplatform with multifunctionality and enhanced pharmacological effects to overcome the complexity of tumor treatment. On the other hand, cyclodextrins (CDs) are starch-originated circular oligosaccharides with negligible toxicity and have been used to form supermolecular nanostructures through a host-guest interaction between the inner cavity of CDs and functional biomolecules. In the past few years, numerous studies have focused on CD-based multifunctional tumor phototherapy nanoplatforms with an enhanced photoeffect, responsive morphological transformation, and elevated drug bioavailability. This review focuses on the preparation methods of CD-based tumor phototherapy nanoplatforms and their unique physiochemical properties for improving anti-tumor pharmacological efficacy.
    Keywords:  cyclodextrin; photodynamic therapy; photothermal therapy; supermolecular assembly
    DOI:  https://doi.org/10.3390/pharmaceutics14071375
  115. Adv Sci (Weinh). 2022 Jul 27. e2202744
    Glutathione Pulse Therapy: Promote Spatiotemporal Delivery of Reduction-Sensitive Nanoparticles at the "Cellular Level" and Synergize PD-1 Blockade Therapy.
    Songtao Dong, Yuan Zhang, Xiangnan Guo, Chuang Zhang, Zhaomeng Wang, Jiang Yu, Yubo Liu, Chang Li, Yuting Hu, Bingjun Sun, Mengchi Sun, Haotian Zhang, Defang Ouyang, Zhonggui He, Yongjun Wang.
      Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer-associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction-sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD-1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level."
    Keywords:  MALDI-MSI; PD-1; glutathione; nanoparticles; spatiotemporal delivery
    DOI:  https://doi.org/10.1002/advs.202202744
  116. Nutrients. 2022 Jul 09. pii: 2824. [Epub ahead of print]14(14):
    Leucine Supplementation in Cancer Cachexia: Mechanisms and a Review of the Pre-Clinical Literature.
    Anna G Beaudry, Michelle L Law.
      Cancer cachexia (CC) is a complex syndrome of bodily wasting and progressive functional decline. Unlike starvation, cachexia cannot be reversed by increased energy intake alone. Nonetheless, targeted nutritional support is a necessary component in multimodal syndrome management. Due to the highly catabolic nature of cancer cachexia, amino acid supplementation has been proposed. Interestingly, leucine has been found to increase protein synthesis and decrease protein degradation via mTORC1 pathway activation. Multiple pre-clinical studies have explored the impact of leucine supplementation in cachectic tumor-bearing hosts. Here, we provide an overview of leucine's proposed modes of action to preserve lean mass in cachexia and review the current pre-clinical literature related to leucine supplementation during CC. Current research indicates that a leucine-rich diet may attenuate CC symptomology; however, these works are difficult to compare due to methodological differences. There is need for further pre-clinical work exploring leucine's potential ability to modulate protein turnover and immune response during CC, as well as the impact of additive leucine on tumor growth.
    Keywords:  amino acids; atrophy; inflammation; mTOR; pre-clinical; skeletal muscle
    DOI:  https://doi.org/10.3390/nu14142824
  117. Biomedicines. 2022 Jul 04. pii: 1589. [Epub ahead of print]10(7):
    Drug Repurposing: The Mechanisms and Signaling Pathways of Anti-Cancer Effects of Anesthetics.
    King-Chuen Wu, Kai-Sheng Liao, Li-Ren Yeh, Yang-Kao Wang.
      Cancer is one of the leading causes of death worldwide. There are only limited treatment strategies that can be applied to treat cancer, including surgical resection, chemotherapy, and radiotherapy, but these have only limited effectiveness. Developing a new drug for cancer therapy is protracted, costly, and inefficient. Recently, drug repurposing has become a rising research field to provide new meaning for an old drug. By searching a drug repurposing database ReDO_DB, a brief list of anesthetic/sedative drugs, such as haloperidol, ketamine, lidocaine, midazolam, propofol, and valproic acid, are shown to possess anti-cancer properties. Therefore, in the current review, we will provide a general overview of the anti-cancer mechanisms of these anesthetic/sedative drugs and explore the potential underlying signaling pathways and clinical application of these drugs applied individually or in combination with other anti-cancer agents.
    Keywords:  anesthetics; anti-cancer; anti-proliferation; apoptosis; re-purposing; signaling
    DOI:  https://doi.org/10.3390/biomedicines10071589
  118. Nutrients. 2022 Jul 07. pii: 2798. [Epub ahead of print]14(14):
    The Effect of Curcumin on Renal Ischemia/Reperfusion Injury in Diabetic Rats.
    Douglas Ikedo Machado, Eloiza de Oliveira Silva, Sara Ventura, Maria de Fatima Fernandes Vattimo.
      Chronic kidney disease (CKD) and acute kidney injury (AKI) are global health problems that affect over 850 million people, twice the number of diabetic individuals around the world. Diabetes mellitus (DM) is known to increase the susceptibility to AKI. Plants and foods, such as curcumin, are traditionally used as treatments for various diseases due to its wide range of bioactive compounds that exert antioxidative, anti-inflammatory, antimicrobial and anticancer properties. The aim of this study is to evaluate the effect of curcumin in diabetic rats with AKI. Adult male Wistar rats, weighing between 250 and 290 g, were randomized into four groups: Citrate (citrate buffer, i.v., single dose, on Day 1 of the protocol); DM (streptozotocin (STZ), 65 mg/k, single dose, i.v., on Day 1); DM + I/R (DM rats that, on Day 26, had the renal pedicle clamped for 30 min on both sides); DM + I/R + Curcumin (DM + I/R rats submitted to curcumin treatment). Results showed that IR worsened renal function and oxidative stress in DM rats, but the DM + IR + Curcumin group showed an increase in inulin clearance and a decrease in serum creatinine and in NGAL, in addition to an improvement in renal hemodynamics. These effects were accompanied by a reduction in oxidative and nitrosative metabolites and an increase in the thiol antioxidant reserve when curcumin was administered to the DM + IR group.
    Keywords:  curcumin; diabetes; ischemia/reperfusion
    DOI:  https://doi.org/10.3390/nu14142798
  119. Nature. 2022 Jul 27.
    Akt protein boosts cancer metabolism through a two-pronged attack.
    Philipp Poeller, Almut Schulze.
      
    Keywords:  Biochemistry; Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-022-01603-4
  120. Cells. 2022 Jul 11. pii: 2172. [Epub ahead of print]11(14):
    Improved Delivery Performance of n-Butylidenephthalide-Polyethylene Glycol-Gold Nanoparticles Efficient for Enhanced Anti-Cancer Activity in Brain Tumor.
    Ming-Tai Hsing, Hui-Ting Hsu, Chih-Hsuan Chang, Kai-Bo Chang, Chun-Yuan Cheng, Jae-Hwan Lee, Chien-Li Huang, Meng-Yin Yang, Yi-Chin Yang, Szu-Yuan Liu, Chun-Ming Yen, Shun-Fa Yang, Huey-Shan Hung.
      n-butylidenephthalide (BP) has been verified as having the superior characteristic of cancer cell toxicity. Furthermore, gold (Au) nanoparticles are biocompatible materials, as well as effective carriers for delivering bio-active molecules for cancer therapeutics. In the present research, Au nanoparticles were first conjugated with polyethylene glycol (PEG), and then cross-linked with BP to obtain PEG-Au-BP nanodrugs. The physicochemical properties were characterized through ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) to confirm the combination of PEG, Au, and BP. In addition, both the size and structure of Au nanoparticles were observed through scanning electron microscopy (SEM) and transmission electron microscopy (TEM), where the size of Au corresponded to the results of DLS assay. Through in vitro assessments, non-transformed BAEC and DBTRG human glioma cells were treated with PEG-Au-BP drugs to investigate the tumor-cell selective cytotoxicity, cell uptake efficiency, and mechanism of endocytic routes. According to the results of MTT assay, PEG-Au-BP was able to significantly inhibit DBTRG brain cancer cell proliferation. Additionally, cell uptake efficiency and potential cellular transportation in both BAEC and DBTRG cell lines were observed to be significantly higher at 2 and 24 h. Moreover, the mechanisms of endocytosis, clathrin-mediated endocytosis, and cell autophagy were explored and determined to be favorable routes for BAEC and DBTRG cells to absorb PEG-Au-BP nanodrugs. Next, the cell progression and apoptosis of DBTRG cells after PEG-Au-BP treatment was investigated by flow cytometry. The results show that PEG-Au-BP could remarkably regulate the DBTRG cell cycle at the Sub-G1 phase, as well as induce more apoptotic cells. The expression of apoptotic-related proteins in DBTRG cells was determined through Western blotting assay. After treatment with PEG-Au-BP, the apoptotic cascade proteins p21, Bax, and Act-caspase-3 were all significantly expressed in DBTRG brain cancer cells. Through in vivo assessments, the tissue morphology and particle distribution in a mouse model were examined after a retro-orbital sinus injection containing PEG-Au-BP nanodrugs. The results demonstrate tissue integrity in the brain (forebrain, cerebellum, and midbrain), heart, liver, spleen, lung, and kidney, as they did not show significant destruction due to PEG-Au-BP treatment. Simultaneously, the extended retention period for PEG-Au-BP nanodrugs was discovered, particularly in brain tissue. The above findings identify PEG-Au-BP as a potential nanodrug for brain cancer therapies.
    Keywords:  DBTRG human glioblastoma multiforme; anti-cancer capacity; gold nanoparticle; n-butylidenephthalide; polyethylene glycol
    DOI:  https://doi.org/10.3390/cells11142172
  121. Life (Basel). 2022 Jun 27. pii: 963. [Epub ahead of print]12(7):
    Iron Overload and Breast Cancer: Iron Chelation as a Potential Therapeutic Approach.
    Sufia Islam, Nazia Hoque, Nishat Nasrin, Mehnaz Hossain, Farhana Rizwan, Kushal Biswas, Muhammad Asaduzzaman, Sabera Rahman, David W Hoskin, Saki Sultana, Christian Lehmann.
      Breast cancer has historically been one of the leading causes of death for women worldwide. As of 2020, breast cancer was reported to have overtaken lung cancer as the most common type of cancer globally, representing an estimated 11.3% of all cancer diagnoses. A multidisciplinary approach is taken for the diagnosis and treatment of breast cancer that includes conventional and targeted treatments. However, current therapeutic approaches to treating breast cancer have limitations, necessitating the search for new treatment options. Cancer cells require adequate iron for their continuous and rapid proliferation. Excess iron saturates the iron-binding capacity of transferrin, resulting in non-transferrin-bound iron (NTBI) that can catalyze free-radical reactions and may lead to oxidant-mediated breast carcinogenesis. Moreover, excess iron and the disruption of iron metabolism by local estrogen in the breast leads to the generation of reactive oxygen species (ROS). Therefore, iron concentration reduction using an iron chelator can be a novel therapeutic strategy for countering breast cancer development and progression. This review focuses on the use of iron chelators to deplete iron levels in tumor cells, specifically in the breast, thereby preventing the generation of free radicals. The inhibition of DNA synthesis and promotion of cancer cell apoptosis are the targets of breast cancer treatment, which can be achieved by restricting the iron environment in the body. We hypothesize that the usage of iron chelators has the therapeutic potential to control intracellular iron levels and inhibit the breast tumor growth. In clinical settings, iron chelators can be used to reduce cancer cell growth and thus reduce the morbidity and mortality in breast cancer patients.
    Keywords:  breast cancer; estrogen; iron chelator; iron overload; oxidative stress
    DOI:  https://doi.org/10.3390/life12070963
  122. Gels. 2022 Jul 20. pii: 454. [Epub ahead of print]8(7):
    Poly(N-isopropylacrylamide)-Based Hydrogels for Biomedical Applications: A Review of the State-of-the-Art.
    Mohammad Javed Ansari, Rahul R Rajendran, Sourav Mohanto, Unnati Agarwal, Kingshuk Panda, Kishore Dhotre, Ravi Manne, A Deepak, Ameeduzzafar Zafar, Mohd Yasir, Sheersha Pramanik.
      A prominent research topic in contemporary advanced functional materials science is the production of smart materials based on polymers that may independently adjust their physical and/or chemical characteristics when subjected to external stimuli. Smart hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) demonstrate distinct thermoresponsive features close to a lower critical solution temperature (LCST) that enhance their capability in various biomedical applications such as drug delivery, tissue engineering, and wound dressings. Nevertheless, they have intrinsic shortcomings such as poor mechanical properties, limited loading capacity of actives, and poor biodegradability. Formulation of PNIPAM with diverse functional constituents to develop hydrogel composites is an efficient scheme to overcome these defects, which can significantly help for practicable application. This review reports on the latest developments in functional PNIPAM-based smart hydrogels for various biomedical applications. The first section describes the properties of PNIPAM-based hydrogels, followed by potential applications in diverse fields. Ultimately, this review summarizes the challenges and opportunities in this emerging area of research and development concerning this fascinating polymer-based system deep-rooted in chemistry and material science.
    Keywords:  PNIPAM; drug delivery; hydrogels; smart polymer; tissue engineering; wound healing
    DOI:  https://doi.org/10.3390/gels8070454
  123. Pharmaceutics. 2022 Jun 21. pii: 1314. [Epub ahead of print]14(7):
    Ultrasound-Responsive Liposomes for Targeted Drug Delivery Combined with Focused Ultrasound.
    Yoon-Seok Kim, Min Jung Ko, Hyungwon Moon, Wonchul Sim, Ae Shin Cho, Gio Gil, Hyun Ryoung Kim.
      Chemotherapeutic drugs are traditionally used for the treatment of cancer. However, chemodrugs generally induce side effects and decrease anticancer effects due to indiscriminate diffusion and poor drug delivery. To overcome these limitations of chemotherapy, in this study, ultrasound-responsive liposomes were fabricated and used as drug carriers for delivering the anticancer drug doxorubicin, which was able to induce cancer cell death. The ultrasound-sensitive liposome demonstrated a size distribution of 81.94 nm, and the entrapment efficiency of doxorubicin was 97.1 ± 1.44%. The release of doxorubicin under the ultrasound irradiation was 60% on continuous wave and 50% by optimizing the focused ultrasound conditions. In vivo fluorescence live imaging was used to visualize the doxorubicin release in the MDA-MB-231 xenografted mouse, and it was demonstrated that liposomal drugs were released in response to ultrasound irradiation of the tissue. The combination of ultrasound and liposomes suppressed tumor growth over 56% more than liposomes without ultrasound exposure and 98% more than the control group. In conclusion, this study provides a potential alternative for overcoming the previous limitations of chemotherapeutics.
    Keywords:  high-intensity focused ultrasound; liposomal doxorubicin; stimuli-triggered drug release; triple-negative breast cancer; ultrasound-responsive liposome
    DOI:  https://doi.org/10.3390/pharmaceutics14071314
  124. Biomedicines. 2022 Jul 14. pii: 1706. [Epub ahead of print]10(7):
    Micro- and Nanosized Carriers for Nose-to-Brain Drug Delivery in Neurodegenerative Disorders.
    Radka Boyuklieva, Bissera Pilicheva.
      Neurodegenerative disorders (NDs) have become a serious health problem worldwide due to the rapid increase in the number of people that are affected and the constantly aging population. Among all NDs, Alzheimer's and Parkinson's disease are the most common, and many efforts have been made in the development of effective and reliable therapeutic strategies. The intranasal route of drug administration offers numerous advantages, such as bypassing the blood-brain barrier and providing a direct entrance to the brain through the olfactory and trigeminal neurons. The present review summarizes the available information on recent advances in micro- and nanoscale nose-to-brain drug-delivery systems as a novel strategy for the treatment of Alzheimer's and Parkinson's disease. Specifically, polymer- and lipid-base micro- and nanoparticles have been studied as a feasible approach to increase the brain bioavailability of certain drugs. Furthermore, nanocomposites are discussed as a suitable formulation for administration into the nasal cavity.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; microparticles; nanoparticles; neurodegenerative disorders; nose-to-brain
    DOI:  https://doi.org/10.3390/biomedicines10071706
  125. Nanomaterials (Basel). 2022 Jul 21. pii: 2509. [Epub ahead of print]12(14):
    Self-Supply Oxygen ROS Reactor via Fenton-like Reaction and Modulating Glutathione for Amplified Cancer Therapy Effect.
    Huanli Zhang, Wei Ma, Zhiqiang Wang, Xiaodan Wu, Hui Zhang, Wen Fang, Rui Yan, Yingxue Jin.
      Reactive oxygen species (ROS) are highly reactive oxidant molecules that can kill cancer cells through irreversible damage to biomacromolecules. ROS-mediated cancer therapies, such as chemodynamic (CDT) and photodynamic therapy (PDT), are often limited by the hypoxia tumor microenvironment (TME) with high glutathione (GSH) level. This paper reported the preparation, characterization, in vitro and in vivo antitumor bioactivity of a meso-tetra(4-carboxyphenyl)porphine (TCPP)-based therapeutic nanoplatform (CMMFTP) to overcome the limitations of TME. Using Cu2+ as the central ion and TCPP as the ligand, the 2D metal-organic framework Cu-TCPP was synthesized by the solvothermal method, then CMMFTP was prepared by modifying MnO2, folic acid (FA), triphenylphosphine (TPP), and poly (allylamine hydrochloride) (PAH) on the surface of Cu-TCPP MOFs. CMMFTP was designed as a self-oxygenating ROS nanoreactor based on the PDT process of TCPP MOFs and the CDT process by Cu(II) and MnO2 components (mainly through Fenton-like reaction). The in vitro assay suggested CMMFTP caused a 96% lethality rate against Hela cells (MTT analysis) in specific response to TME stimulation. Moreover, the Cu(II) and MnO2 in CMMFTP efficiently depleted the glutathione (80%) in tumor cells and consequently amplified ROS levels to improve CDT/PDT effects. The FA-induced tumor targeting and TPP-induced mitochondria targeting further enhanced the antitumor activity. Therefore, the nanoreactor based on dual targeting and self-oxygenation-enhanced ROS mechanism provided a new strategy for cancer therapy.
    Keywords:  Fenton-like reaction; reactive oxygen species (ROS); self-supply oxygen; synergetic effect; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/nano12142509
  126. Pharmaceutics. 2022 Jul 06. pii: 1414. [Epub ahead of print]14(7):
    Targeting the Blood-Brain Tumor Barrier with Tumor Necrosis Factor-α.
    Angelo Corti, Teresa Calimeri, Flavio Curnis, Andres J M Ferreri.
      The blood-brain tumor barrier represents a major obstacle for anticancer drug delivery to brain tumors. Thus, novel strategies aimed at targeting and breaching this structure are of great experimental and clinical interest. This review is primarily focused on the development and use of a derivative of tumor necrosis factor-α (TNF) that can target and alter the blood-brain-tumor-barrier. This drug, called NGR-TNF, consists of a TNF molecule fused to the Cys-Asn-Gly-Arg-Cys-Gly (CNGRCG) peptide (called NGR), a ligand of aminopeptidase N (CD13)-positive tumor blood vessels. Results of preclinical studies suggest that this peptide-cytokine fusion product represents a valuable strategy for delivering TNF to tumor vessels in an amount sufficient to break the biological barriers that restrict drug penetration in cancer lesions. Moreover, clinical studies performed in patients with primary central nervous system lymphoma, have shown that an extremely low dose of NGR-TNF (0.8 µg/m2) is sufficient to promote selective blood-brain-tumor-barrier alteration, increase the efficacy of R-CHOP (a chemo-immunotherapy regimen) and improve patient survival. Besides reviewing these findings, we discuss the potential problems related to the instability and molecular heterogeneity of NGR-TNF and review the various approaches so far developed to obtain more robust and homogeneous TNF derivatives, as well as the pharmacological properties of other peptide/antibody-TNF fusion products, muteins and nanoparticles that are potentially useful for targeting the blood-brain tumor barrier. Compared to other TNF-related drugs, the administration of extremely low-doses of NGR-TNF or its derivatives appear as promising non-immunogenic approaches to overcome TNF counter-regulatory mechanism and systemic toxicity, thereby enabling safe breaking of the BBTB.
    Keywords:  CD13; NGR-TNF; TNF; TNF receptors; blood–brain tumor barrier; brain tumors; permeabilization; primary central nervous system lymphoma; targeted delivery; tumor necrosis factor-alpha; vascular targeting
    DOI:  https://doi.org/10.3390/pharmaceutics14071414
  127. Pharmaceutics. 2022 Jul 25. pii: 1542. [Epub ahead of print]14(8):
    Mesoporous Materials as Elements of Modern Drug Delivery Systems for Anti-Inflammatory Agents: A Review of Recent Achievements.
    Michał Moritz, Małgorzata Geszke-Moritz.
      Interest in the use of mesoporous materials as carriers of medicinal substances has been steadily increasing in the last two decades. Mesoporous carriers have application in the preparation of delivery systems for drugs from various therapeutic groups; however, their use as the carriers of anti-inflammatory agents is particularly marked. This review article, with about 170 references, summarizes the achievements in the application of mesoporous materials as the carriers of anti-inflammatory agents in recent years. This article will discuss a variety of mesoporous carriers as well as the characteristics of their porous structure that determine further use of these materials in the field of medical applications. Special attention will be paid to the progress observed in the construction of stimuli-responsive drug carriers and systems providing site-specific drug delivery. Subsequently, a review of the literature devoted to the use of mesoporous matrices as the carriers of anti-inflammatory drugs was carried out.
    Keywords:  anti-inflammatory drugs; controlled release; drug delivery systems; mesoporous materials; physicochemical properties
    DOI:  https://doi.org/10.3390/pharmaceutics14081542
  128. Medicina (Kaunas). 2022 Jul 14. pii: 932. [Epub ahead of print]58(7):
    The Role of Nut and Seed Consumption in Colorectal Cancer: A Narrative Review.
    Deiana Roman, Bogdan Timar, Vlad Avram, Adina Braha, Sorin Saftescu, Șerban Negru, Romulus Timar.
      Given the increased incidence of colorectal cancer worldwide, especially in developed and developing countries, is comes as no surprise that researchers are concentrating on methods to combat this public health issue, through investigating both lifestyle interventions and treatment options. Although treatment options are being constantly discovered and developed, researchers have also begun investigating the influence that nutrition and lifestyle have on CRC. Among the food categories, nuts and seeds boast numerous beneficial effects for cardiovascular health and metabolic balance and they contain a plethora of phytochemicals and antioxidants. The present narrative review aims to offer a broad perspective to date on the known effects of this consumption on colorectal cancer. For this purpose, articles were identified by conducting a search in the PubMed and Google Scholar databases, using search phrases such as ″nut intake and colorectal cancer″ and ″seed consumption and colorectal cancer", narrowing the search pool to those articles published between 2019 and 2022. The search returned eight relevant papers, all of which were validated by a second author. While the existing research is divided between those studies which have found no significant link between nut consumption and colorectal cancer protection and those which have, there is a consensus regarding the necessity for further research on this subject, as well as the possible mechanisms which might be involved in the protective effect observed by some researchers.
    Keywords:  clinical observations; colorectal cancer; dietary habits; nut consumption; nuts and seeds
    DOI:  https://doi.org/10.3390/medicina58070932
  129. Biomed Eng Lett. 2022 Aug;12(3): 317-329
    Margetuximab conjugated-PEG-PAMAM G4 nano-complex: a smart nano-device for suppression of breast cancer.
    Yasaman Khakinahad, Saeedeh Sohrabi, Shokufeh Razi, Asghar Narmani, Sepideh Khaleghi, Mahboubeh Asadiyun, Hanieh Jafari, Javad Mohammadnejad.
       Abstract: Breast cancer due to its high incidence and mortality is the second leading cause of death among females. On the other hand, nanoparticle-based drug delivery is one of the most promising approaches in cancer therapy, nowadays. Hence, margetuximab- and polyethylene glycol-conjugated PAMAM G4 dendrimers were efficiently synthesized for targeted delivery of quercetin (therapeutic agent) to MDA-MB-231 breast cancer cells. Synthesized nano-complexes were characterized using analytical devices such as FT-IR, TGA, DLS, Zeta potential analyzer, and TEM. The size less than 40 nm, - 18.8 mV surface charge, efficient drug loading capacity (21.48%), and controlled drug release (about 45% of drug release normal pH after 8 h) were determined for the nano-complex. In the biomedical test, the cell viability was obtained 14.67% at 24 h of post-treatment for 800 nM concentration, and IC50 was ascertained at 100 nM for the nano-complex. The expression of apoptotic Bax and Caspase9 genes was increased by more than eightfolds and more than fivefolds after treatment with an optimal concentration of nanocarrier. Also, more than threefolds of cell cycle arrest was observed at the optimal concentration synthetics, and 27.5% breast cancer cell apoptosis was detected after treatment with 100 nM nano-complex. These outputs have been indicating the potential capacity of synthesized nano-complex in inhibiting the growth of breast cancer cells.
    Graphic abstract:
    Keywords:  Breast cancer suppression; PAMAM G4 nanoparticle; PEG and Margetuximab; Quercetin; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s13534-022-00225-z
  130. Pharmaceuticals (Basel). 2022 Jun 24. pii: 790. [Epub ahead of print]15(7):
    Phytosomes as a Plausible Nano-Delivery System for Enhanced Oral Bioavailability and Improved Hepatoprotective Activity of Silymarin.
    Ravi Gundadka Shriram, Afrasim Moin, Hadil Faris Alotaibi, El-Sayed Khafagy, Ahmed Al Saqr, Amr Selim Abu Lila, Rompicherla Narayana Charyulu.
      Silymarin, a phyto-constituent derived from the plant Silybum marianum, has been widely acknowledged for its hepatoprotective activities. Nevertheless, its clinical utility is adversely hampered by its poor water-solubility and its limited oral bioavailability. The aim of this study was to investigate the efficacy of phospholipid-based phytosomes for enhancing the oral bioavailability of silymarin. The phytosomes were prepared using the solvent evaporation technique and were optimized using a full factorial design. The optimized silymarin phytosomal formulation was then characterized for particle size, surface morphology, aqueous solubility, and in vitro drug release. Furthermore, in vivo antioxidant activity, hepatoprotective activity and oral bioavailability of the optimized formula were investigated in a rat model. The prepared silymarin phytosomes were discrete particles with a porous, nearly smooth surface and were 218.4 ± 2.54 nm in diameter. In addition, the optimized silymarin phytosomal formulation showed a significant improvement in aqueous solubility (~360 µg/mL) compared to pure silymarin and manifested a higher rate and extent of silymarin release from the optimized formula in dissolution studies. The in vivo assessment studies revealed that the optimized silymarin phytosomal formulation efficiently exerted a hepatoprotective effect in a CCl4-induced hepatotoxicity rat model via restoring the normal levels of antioxidant enzymes and ameliorating cellular abnormalities caused by CCl4-intoxication. Most notably, as compared to pure silymarin, the optimized silymarin phytosomal formulation significantly improved silymarin oral bioavailability, as indicated by a 6-fold increase in the systemic bioavailability. Collectively, phytosomes might represent a plausible phospholipid-based nanocarrier for improving the oral bioavailability of phyto-constituents with poor aqueous solubility.
    Keywords:  Silymarin; anti-oxidant activity; hepatoprotective effect; phospholipid; phytosomes
    DOI:  https://doi.org/10.3390/ph15070790
  131. Front Pharmacol. 2022 ;13 920411
    Research and Development of Natural Product Tanshinone I: Pharmacology, Total Synthesis, and Structure Modifications.
    Xing Huang, Lili Jin, Hao Deng, Dan Wu, Qing-Kun Shen, Zhe-Shan Quan, Chang-Hao Zhang, Hong-Yan Guo.
      Salvia miltiorrhiza (S. miltiorrhiza), which has been used for thousands of years to treat cardiovascular diseases, is a well-known Chinese medicinal plant. The fat-soluble tanshinones in S. miltiorrhiza are important biologically active ingredients including tanshinone I, tanshinone IIA, dihydrotanshinone, and cryptotanshinone. Tanshinone I, a natural diterpenoid quinone compound widely used in traditional Chinese medicine, has a wide range of biological effects including anti-cancer, antioxidant, neuroprotective, and anti-inflammatory activities. To further improve its potency, water solubility, and bioavailability, tanshinone I can be used as a platform for drug discovery to generate high-quality drug candidates with unique targets and enhanced drug properties. Numerous derivatives of tanshinone I have been developed and have contributed to major advances in the identification of new drugs to treat human cancers and other diseases and in the study of related molecular mechanisms. This review focuses on the structural modification, total synthesis, and pharmacology of tanshinone I. We hope that this review will help understanding the research progress in this field and provide constructive suggestions for further research on tanshinone I.
    Keywords:  danshen; pharmacology; structure-modifications; tanshinone I; total synthesis
    DOI:  https://doi.org/10.3389/fphar.2022.920411
  132. Mar Drugs. 2022 Jun 21. pii: 406. [Epub ahead of print]20(7):
    A Comprehensive Update on the Bioactive Compounds from Seagrasses.
    Christina Mutiara Putri Gono, Peni Ahmadi, Triana Hertiani, Eris Septiana, Masteria Yunovilsa Putra, Giuseppina Chianese.
      Marine angiosperms produce a wide variety of secondary metabolites with unique structural features that have the potential to be developed as effective and potent drugs for various diseases. Recently, research trends in secondary metabolites have led to drug discovery with an emphasis on their pharmacological activity. Among marine angiosperms, seagrasses have been utilized for a variety of remedial purposes, such as treating fevers, mental disorders, wounds, skin diseases, muscle pain, and stomach problems. Hence, it is essential to study their bioactive metabolites, medical properties, and underlying mechanisms when considering their pharmacological activity. However, there is a scarcity of studies on the compilation of existing work on their pharmacological uses, pharmacological pathways, and bioactive compounds. This review aims to compile the pharmacological activities of numerous seagrass species, their secondary metabolites, pharmacological properties, and mechanism of action. In conclusion, this review highlights the potency of seagrasses as a promising source of natural therapeutical products for preventing or inhibiting human diseases.
    Keywords:  bioactive compound; marine angiosperm; medical properties; potential drug
    DOI:  https://doi.org/10.3390/md20070406
  133. Pharmaceuticals (Basel). 2022 Jul 22. pii: 907. [Epub ahead of print]15(8):
    Royal Jelly Components Encapsulation in a Controlled Release System-Skin Functionality, and Biochemical Activity for Skin Applications.
    Eleni Spanidi, Sophia Athanasopoulou, Angeliki Liakopoulou, Angeliki Chaidou, Sophia Hatziantoniou, Konstantinos Gardikis.
      Royal jelly is a yellowish-white substance with a gel texture that is secreted from the hypopharyngeal and mandibular glands of young worker bees. It consists mainly of water (50-56%), proteins (18%), carbohydrates (15%), lipids (3-6%), minerals (1.5%), and vitamins, and has many beneficial properties such as antimicrobial, anti-inflammatory, anticancer, antioxidant, antidiabetic, immunomodulatory, and anti-aging. Royal jelly has been used since ancient times in traditional medicine, cosmetics and as a functional food due to its high nutritional value. The main bioactive substances are royalactin, and 10-hydroxy-2-decenoic acid (10-HDA). Other important bioactive molecules with antioxidant and photoprotective skin activity are polyphenols. However, they present difficulties in extraction and in use as they are unstable physicochemically, and a higher temperature causes color change and component degradation. In the present study, a new encapsulation and delivery system consisting of liposomes and cyclodextrins incorporating royal jelly has been developed. The new delivery system aims to the elimination of the stability disadvantages of royal jelly's sensitive component 10-HDA, but also to the controlled release of its ingredients and, more particularly, 10-HDA, for an enhanced bioactivity in cosmeceutical applications.
    Keywords:  10-hydroxy-2-decenoic acid (10-HDA); controlled release; liposome; polyphenols; royal jelly
    DOI:  https://doi.org/10.3390/ph15080907
  134. Front Oncol. 2022 ;12 858480
    Pharmacological targets for the induction of ferroptosis: Focus on Neuroblastoma and Glioblastoma.
    Luciano Ferrada, María José Barahona, Katterine Salazar, Alejandro S Godoy, Matias Vera, Francisco Nualart.
      Neuroblastomas are the main extracranial tumors that affect children, while glioblastomas are the most lethal brain tumors, with a median survival time of less than 12 months, and the prognosis of these tumors is poor due to multidrug resistance. Thus, the development of new therapies for the treatment of these types of tumors is urgently needed. In this context, a new type of cell death with strong antitumor potential, called ferroptosis, has recently been described. Ferroptosis is molecularly, morphologically and biochemically different from the other types of cell death described to date because it continues in the absence of classical effectors of apoptosis and does not require the necroptotic machinery. In contrast, ferroptosis has been defined as an iron-dependent form of cell death that is inhibited by glutathione peroxidase 4 (GPX4) activity. Interestingly, ferroptosis can be induced pharmacologically, with potential antitumor activity in vivo and eventual application prospects in translational medicine. Here, we summarize the main pathways of pharmacological ferroptosis induction in tumor cells known to date, along with the limitations of, perspectives on and possible applications of this in the treatment of these tumors.
    Keywords:  GPX4; brain tumors; cancer cell; ferroptosis; iron; lipid ROS; system xc−
    DOI:  https://doi.org/10.3389/fonc.2022.858480
  135. Front Pharmacol. 2022 ;13 948610
    Therapeutic Implications of FABP4 in Cancer: An Emerging Target to Tackle Cancer.
    Naihui Sun, Xing Zhao.
      Metabolic reprogramming is an emerging hallmark of tumor cells. In order to survive in nutrient-deprived environment, tumor cells rewire their metabolic phenotype to provide sufficient energy and build biomass to sustain their transformed state and promote malignant behaviors. Fatty acid uptake and trafficking is an essential part of lipid metabolism within tumor cells. Fatty acid-binding proteins (FABPs), which belongs to a family of intracellular lipid-binding protein, can bind hydrophobic ligands to regulate lipid trafficking and metabolism. In particular, adipocyte fatty acid binding protein (FABP4), one of the most abundant members, has been found to be upregulated in many malignant solid tumors, and correlated with poor prognosis. In multiple tumor types, FABP4 is critical for tumor proliferation, metastasis and drug resistance. More importantly, FABP4 is a crucial driver of malignancy not only by activating the oncogenic signaling pathways, but also rewiring the metabolic phenotypes of tumor cells to satisfy their enhanced energy demand for tumor development. Thus, FABP4 serves as a tumor-promoting molecule in most cancer types, and may be a promising therapeutic target for cancer treatment.
    Keywords:  cancer; fatty acid; metabolic reprogramming; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2022.948610
  136. AAPS PharmSciTech. 2022 Jul 28. 23(6): 206
    Advanced Vesicular Systems for Antifungal Drug Delivery.
    Shaimaa Mosallam, Rofida Albash, Manar Adel Abdelbari.
      Fungal infections are considered one of the most serious conditions as their occurrence has increased lately. Fungi like Candida, Fusarium, and Aspergillus species mostly affect immunocompromised patients as they are considered opportunistic pathogens. These infections can be superficial, cutaneous, subcutaneous, or systemic fungal infections that require specific treatment. There is a wide variety of antifungal drugs that can be used to cure fungal infections; however, most of them have many systemic side effects due to their physicochemical characteristics and high toxicity profile. Hence, the current review focuses on various advanced vesicular carriers with high biocompatibility that can encapsulate the antifungal drugs owing to increase their efficacy and limit the undesirable side effects. These advanced systems can manage stability, solubility, bioavailability, safety, and effectiveness issues present in conventional systems.
    Keywords:  Advanced vesicular carriers; Antifungal drugs; Conventional systems; Fungal infections
    DOI:  https://doi.org/10.1208/s12249-022-02357-y
  137. Nanomedicine. 2022 Jul 26. pii: S1549-9634(22)00078-8. [Epub ahead of print] 102592
    Nano-drug delivery system with enhanced tumour penetration and layered anti-tumour efficacy.
    Nan Zhang, Nannan Feng, Xiangying Xin, Junwei Zhang, Deqiao Wu, Qianqian Jiang, Tong Yu, Ming Gao, Siyuan Zhao, Hui Yang, Qingfeng Tian.
      The low delivery efficiency of nano-drugs and limited tumour penetration are still huge challenges in treating solid tumours. Herein, we developed a pH-responsive nano-drug delivery system, CALS/PDMA@DOX, with a size conversion-layered delivery function. The system is composed of a pH-responsive cationic liposome loaded with DOX (CALS) and a polyamidoamine dendrimer loaded with DOX (PAMAM@DOX) modified with 2,3-dimethylmaleic anhydride (PDMA@DOX) using electrostatic adsorption. In the tumour microenvironment, the positively-charged large-size CALS and the positively-charged small-size PAMAM@DOX were dissociated to exert anti-tumour effects. CALS preferentially targeted tumour angiogenesis endothelial cells. Because of its small size and positive charge, PAMAM@DOX showed excellent tumour penetration. Significant tumour suppression by the system in vivo was confirmed in a 4T1 tumour xenograft mouse model. This pH-triggered size-switching layered delivery nanosystem is a safe and effective cancer treatment delivery platform that improves drug permeability and therapeutic efficacy.
    Keywords:  Cationic liposomes; PAMAM; Size changeable; Tumour penetration; pH-responsive
    DOI:  https://doi.org/10.1016/j.nano.2022.102592
  138. Front Oncol. 2022 ;12 859707
    CNN1 Represses Bladder Cancer Progression and Metabolic Reprogramming by Modulating HIF-1α Signaling Pathway.
    Zheng Zhang, Xiaoqing Li, Shaokun Ren, Wei Zhang.
      Bladder cancer (BC) is the second most common urinary system malignant tumor around the whole world. It has been reported that CNN1 was lowly expressed in BC tissues. However, the mechanisms of CNN1 on BC cells were unclear. Herein, we aimed to probe the specific influences of CNN1 on BC pathogenesis. First, the expression level and prognostic ability of CNN1 in BC patients were surveyed. Then, CNN1 overexpression was executed to exhibit the influences of CNN1 on BC cells. The real-time PCR and Western blotting were employed to detect by the mRNA and protein expression levels. CCK8 assay was utilized to examine cell proliferation, and transwell assay was executed to test cell invasion and migration. The corresponding kits were utilized to detect glucose absorption, lactate secretion, and ATP level. BC cells overexpressing CNN1 were utilized to establish a nude mouse xenograft tumor model, and the tumor volume and tumor weight were detected. Nude mouse tumor tissues were used for immunohistochemical experiments to test the expression levels of Ki-67 and CNN1. The outcomes indicated that CNN1 was significantly lowly expressed in BC tissues and cells. Besides, low expression of CNN1 might be concerned with poor prognosis. Moreover, overexpression of CNN1 repressed the proliferation, invasion, and migration of BC cells. Furthermore, CNN1 overexpression decreased the protein levels of glycolysis-related protein GLUT1 (glucose transporter 1), pyruvate kinase M2 (PKM2), and LDHA (lactate dehydrogenase A). Then, the decreased mRNA and protein levels of HIF-1α and PDK1 were identified after CNN1 overexpression. The in vivo assays verified the effects of aberrant expression of CNN1 in mice with BC. In conclusion, these findings suggested that CNN1 might modulate BC progression through activating HIF-1α pathway and CNN1 might be a promising marker for BC diagnosis.
    Keywords:  CNN1; HIF-1α; bladder cancer; glycolysis; overexpression
    DOI:  https://doi.org/10.3389/fonc.2022.859707
  139. Cancers (Basel). 2022 Jul 07. pii: 3320. [Epub ahead of print]14(14):
    Prognostic Value of KRAS Mutations in Colorectal Cancer Patients.
    Asimina Koulouridi, Michaela Karagianni, Ippokratis Messaritakis, Maria Sfakianaki, Alexandra Voutsina, Maria Trypaki, Maria Bachlitzanaki, Evangelos Koustas, Michalis V Karamouzis, Anastasios Ntavatzikos, Anna Koumarianou, Nikolaos Androulakis, Dimitrios Mavroudis, Maria Tzardi, John Souglakos.
      Colorectal cancer (CRC) remains a major public health issue. The detection of parameters that affect CRC prognosis is of great significance. KRAS mutations, play a crucial role in tumorigenesis with a strong predictive value. KRAS-mutated stage-IV CRC patients gain no benefit of the anti-EGFR therapy. The KRAS G12C mutation subtype is under investigation for treatment regimens. The present study aimed to detect various RAS mutations in a cohort of 578 RAS-mutated CRC patients; 49% of them had de novo metastatic disease; 60% were male; 71.4% had left-sided tumors; and 94.6% had a good performance status. KRAS mutations were detected in 93.2% of patients, with KRAS G12D being the most common subtype (30.1%). KRAS mutations presented shorter progression-free (PFS) and overall survival (OS), compared with NRAS mutations, although not significantly (PFS: 13.8 vs. 18.5 months; p = 0.552; OS: 53.1 vs. 60.9 months; p = 0.249). KRAS G12D mutations presented better OS rates (p = 0.04). KRAS G12C mutation, even though not significantly, presented worse PFS and OS rates. KRAS exon 3 and 4 mutations presented different PFS and OS rates, although these were not significant. Concluding, KRAS G12D and G12C mutations lead to better and worst prognosis, respectively. Further studies are warranted to validate such findings and their possible therapeutic implication.
    Keywords:  KRAS; colorectal cancer; mutations; prognosis
    DOI:  https://doi.org/10.3390/cancers14143320
  140. Sci China Life Sci. 2022 Jul 21.
    The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy.
    Han Yao, Wenbin Xu, Yajing Liu, Zhijie Cao, Jia Wen, Mi Zhang, Zhen Wu, Xiaojun Yan, Zishan Jiao, Zijing Zhang, Jianyuan Chen, Meng Zhang, Wei-Guo Zhu, Donglai Wang.
      The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms, including the hijacking of the tumor suppressors p53 and PP2A. Targeting aberrant SET represents a promising strategy for cancer intervention. However, the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown. Here, we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells. In addition, p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET, whereby SET-mediated inhibition of PP2A was alleviated. Moreover, targeting the interaction between SET and PP2A catalytic subunit (PP2Ac) with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55 (Thr55). Therefore, our findings uncovered a previously unknown p53-SET-PP2A regulatory feedback loop. To functionally potentiate this feedback loop, we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression. Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.
    Keywords:  FTY720; PP2A; SET; feedback loop; p53; tumor suppression
    DOI:  https://doi.org/10.1007/s11427-021-2123-8
  141. Nutrients. 2022 Jul 27. pii: 3075. [Epub ahead of print]14(15):
    Vitamin D and Visceral Obesity in Humans: What Should Clinicians Know?
    Prapimporn Chattranukulchai Shantavasinkul, Hataikarn Nimitphong.
      The extraskeletal effect of vitamin D on adipose tissue biology and modulation in human obesity is of great interest and has been extensively investigated. Current evidence from preclinical and clinical studies in human adipose tissue suggests that the anti-inflammatory effects of vitamin D are evident and consistent, whereas the effects of vitamin D on adipocyte differentiation, adipogenesis, and energy metabolism and the effects of vitamin D supplementation on adipokine levels are inconclusive. Interventional studies related to medical and surgical weight loss in humans have shown small or no improvement in vitamin D status. Additionally, the benefit of vitamin D supplementation for the reduction in visceral adipose tissue has only been demonstrated in a few studies. Overall, the findings on the relationship between vitamin D and visceral adipose tissue in humans are still inconclusive. Further studies are required to confirm the beneficial effects of vitamin D on ameliorating adipose tissue dysfunction.
    Keywords:  adipose tissue inflammation; bariatric surgery; caloric restriction; visceral obesity; vitamin D; weight loss
    DOI:  https://doi.org/10.3390/nu14153075
  142. Evid Based Complement Alternat Med. 2022 ;2022 2276094
    Anti-Diabesity Middle Eastern Medicinal Plants and Their Action Mechanisms.
    Bashar Saad, Abdalsalam Kmail, Sameena Z H Haq.
      Over the last four decades, the escalation in diabetes and obesity rates has become epidemic all over the world. Diabesity describes the strong link between T2D and obesity. It correlates deeper with the elevated risks of developing cardiovascular disease hypertension, stroke, and several malignancies. Therapeutic usage of medicinal plants and natural products in the treatment of diabetes and obesity has long been known to physicians of Greco-Arab and Islamic medicine. Improved versions of their abundant medicinal plant-based formulations are at present some of the most popular herbal treatments used. Preclinical and clinical data about medicinal plants along with their bioactive constituents are now available, justifying the traditionally known therapeutic uses of products derived from them for the prevention and cure of obesity-related T2D and other health problems. The aim of this review is to systematize published scientific data dealing with the efficiency of active ingredients or extracts from Middle Eastern medicinal plants and diet in the management of diabesity and its complications. Google Scholar, MEDLINE, and PubMed were searched for publications describing the medicinal plants and diet used in the management of T2D, obesity, and their complications. The used keywords were "medicinal plants" or "herbals" in combination with "obesity," "diabetes," "diabetes," or nephropathy. More than 130 medicinal plants were identified to target diabesity and its complications. The antidiabetic and anti-obesity effects and action mechanisms of these plants are discussed here. These include the regulation of appetite, thermogenesis, lipid absorption, and lipolysis; pancreatic lipase activity and adipogenesis; glucose absorption in the intestine, insulin secretion, glucose transporters, gluconeogenesis, and epigenetic mechanisms.
    DOI:  https://doi.org/10.1155/2022/2276094
  143. Anticancer Res. 2022 Aug;42(8): 3857-3861
    Long-term Stable Disease in a Rectal-cancer Patient Treated by Methionine Restriction With Oral Recombinant Methioninase and a Low-methionine Diet.
    Yutaro Kubota, Qinghong Han, Kazuyuki Hamada, Yusuke Aoki, Noriyuki Masaki, Koya Obara, Takuya Tsunoda, Robert M Hoffman.
       BACKGROUND/AIM: Rectal cancer is a recalcitrant disease with limited treatment options. Pre-clinical studies have shown the efficacy of methionine restriction with a low-methionine diet and oral recombinant methioninase (o-rMETase) for colorectal cancer. There are also clinical studies on methionine restriction with o-rMETase for other recalcitrant cancer types. The goal of the present study was to determine the efficacy of a low-methionine diet and o-rMETase on a rectal cancer patient.
    PATIENT AND METHODS: A 55-year-old man diagnosed with recurrent locally-advanced rectal-cancer was treated with o-rMETase and a low-methionine diet, during which time, he did not receive standard chemotherapy. Disease stability was monitored by carcinoembryonic antigen (CEA) levels, sigmoidoscopy, and computed tomography (CT).
    RESULTS: The patient was diagnosed with stage II rectal cancer (adenocarcinoma) in 2018. After neoadjuvant chemoradiotherapy, the patient received total mesorectal excision (TME) in 2018. Local recurrence was found by sigmoidoscopy one year later. The patient was given chemotherapy, the recurrent lesion shrunk, and was then removed endoscopically in December 2019, with positive margins. The tumor did not become apparent for about a year after that. An endoscopic examination performed in December 2020, revealed a local recurrence. Since that time, the patient had an elevated CEA. The patient went on o-rMETase and a low-methionine diet from January 2021. Since then, the patient's CEA level has remained stable for the next year and a half. He received sigmoidoscopy and CT regularly, and the tumor size has not changed.
    CONCLUSION: This patient's clinical course indicates that o-rMETase and a low-methionine diet may be effective for rectal cancer, for long-term disease stabilization. Further case studies and clinical trials are needed to determine the generality of the present result.
    Keywords:  Hoffman effect; Rectal cancer; low-methionine diet; methionine addiction; methionine restriction; oral recombinant methioninase; patient; stable disease
    DOI:  https://doi.org/10.21873/anticanres.15877
  144. Pharmaceuticals (Basel). 2022 Jun 21. pii: 769. [Epub ahead of print]15(7):
    Synthesis of Prussian Blue Nanoparticles and Their Antibacterial, Antiinflammation and Antitumor Applications.
    Danyang Li, Meng Liu, Wenyao Li, Qiang Fu, Liyang Wang, Enping Lai, Weixin Zhao, Kaile Zhang.
      In recent years, Prussian blue nanoparticles (PBNPs), also named Prussian blue nano-enzymes, have been shown to demonstrate excellent multi-enzyme simulation activity and anti-inflammatory properties, and can be used as reactive oxygen scavengers. Their good biocompatibility and biodegradability mean that they are ideal candidates for in vivo use. PBNPs are highly efficient electron transporters with oxidation and reduction activities. PBNPs also show considerable promise as nano-drug carriers and biological detection sensors owing to their huge specific surface area, good chemical characteristics, and changeable qualities, which might considerably increase the therapeutic impact. More crucially, PBNPs, as therapeutic and diagnostic agents, have made significant advances in biological nanomedicine. This review begins with a brief description of the synthesis methods of PBNPs, then focuses on the applications of PBNPs in tissue regeneration and inflammation according to the different properties of PBNPs. This article will provide a timely reference for further study of PBNPs as therapeutic agents.
    Keywords:  Prussian blue nanoparticles; anti-inflammatory effects; drug carrier; nano-enzyme; tissue repair
    DOI:  https://doi.org/10.3390/ph15070769
  145. Cancers (Basel). 2022 Jul 22. pii: 3560. [Epub ahead of print]14(15):
    Cancer Cell Metabolism Reprogramming and Its Potential Implications on Therapy in Squamous Cell Carcinoma of the Head and Neck: A Review.
    Francesco Perri, Giuseppina Della Vittoria Scarpati, Monica Pontone, Maria Luisa Marciano, Alessandro Ottaiano, Marco Cascella, Francesco Sabbatino, Agostino Guida, Mariachiara Santorsola, Piera Maiolino, Ernesta Cavalcanti, Giulia Togo, Franco Ionna, Francesco Caponigro.
      Carcinogenesis is a multistep process that consists of the transformation of healthy cells into cancer cells. Such an alteration goes through various stages and is closely linked to random mutations of genes that have a key role in the neoplastic phenotype. During carcinogenesis, cancer cells acquire and exhibit several characteristics including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, and expressing an immune phenotype, which allow them to evade recognition and destruction through cognate immune cells. In addition, cancer cells may acquire the ability to reprogram their metabolism in order to further promote growth, survival, and energy production. This phenomenon, termed metabolic reprogramming, is typical of all solid tumors, including squamous carcinomas of the head and neck (SCCHN). In this review, we analyze the genetic and biological mechanisms underlying metabolic reprogramming of SCCHN, focusing on potential therapeutic strategies that are able to counteract it.
    Keywords:  Akt; TP53; Warburg effect; head and neck squamous cell carcinoma; immunosurveillance; metabolic reprogramming
    DOI:  https://doi.org/10.3390/cancers14153560
  146. Molecules. 2022 Jul 11. pii: 4430. [Epub ahead of print]27(14):
    Formulation, Optimization, and Evaluation of Moringa oleifera Leaf Polyphenol-Loaded Phytosome Delivery System against Breast Cancer Cell Lines.
    Jecinta Wanjiru, Jeremiah Gathirwa, Elingarami Sauli, Hulda Shaid Swai.
      Moringa oleifera leaf polyphenols (Mopp) were encapsulated with phytosomes to enhance their efficacy on 4T1 cancer cell lines. The Mopp were extracted via microwave-assisted extraction. Moringa oleifera polyphenol-loaded phytosomes (MoP) were prepared with the nanoprecipitation method and characterized using the dynamic light scattering and dialysis membrane techniques. The in vitro cytotoxic and antiproliferative activity were investigated with the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazole) MTT assay. Acute toxicity was assessed using Swiss albino mice. An MoP particle size of 296 ± 0.29 nm, -40.1 ± 1.19 mV zeta potential, and polydispersity index of 0.106 ± 0.002 were obtained. The total phenolic content was 50.81 ± 0.02 mg GAE/g, while encapsulation efficiency was 90.32 ± 0.11%. The drug release profiles demonstrated biphasic and prolonged subsequent sustained release. In vitro assays indicated MoP had a low cytotoxicity effect of 98.84 ± 0.53 μg/mL, doxorubicin was 68.35 ± 3.508, and Mopp was 212.9 ± 1.30 μg/mL. Moreover, MoP exhibited the highest antiproliferative effect on 4T1 cancer cells with an inhibitory concentration of 7.73 ± 2.87 μg/mL and selectivity index &gt; 3. The results indicated a significant difference (p ≤ 0.001) in MoP when compared to Mopp and doxorubicin. The in vivo investigation showed the safety of MoP at a dose below 2000 mg/kg. The present findings suggest that MoP may serve as an effective and promising formulation for breast cancer drug delivery and therapy.
    Keywords:  Moringa oleifera; antiproliferation; breast cancer; natural nanoparticles; polyphenols
    DOI:  https://doi.org/10.3390/molecules27144430
  147. Anticancer Res. 2022 Aug;42(8): 3807-3814
    STAT3 Inactivation and Induction of Apoptosis Associate With Fluoxetine-inhibited Epithelial-mesenchymal Transition and Growth of Triple-negative Breast Cancer In Vivo.
    Pen-An Liao, Pei-Yi Chu, Zhao-Lin Tan, Fei-Ting Hsu, Yang-Cheng Lee, Hsing-Ju Wu.
       BACKGROUND/AIM: Breast cancer (BC) is the most common cancer and second leading cause of death in women worldwide. Triple-negative breast cancer (TNBC) is the most aggressive type of BC, while the treatment option is limited and has long been considered as a major unmet need. Meta-analysis indicated the anti-tumor potential of anti-depressants, especially selective serotonin-reuptake inhibitors (SSRIs). The SSRI fluoxetine has been shown to suppress BC and ovarian cancer cell growth; however, whether it suppresses tumor progression in vivo is unclear.
    MATERIALS AND METHODS: We established an 4T1 bearing animal model, an orthotopic TNBC model, to identify the mechanism and therapeutic efficacy of fluoxetine.
    RESULTS: Tumor growth evaluated by caliper and computed tomography scan demonstrated the inhibition effect by fluoxetine treatment. Immunohistochemistry showed that the expression of STAT3-mediated epithelial-to-mesenchymal transition (EMT) proteins and apoptosis-related proteins was decreased.
    CONCLUSION: Fluoxetine may induce an anti-TNBC effect via inactivating STAT3 signaling transduction and triggering the caspase-mediated apoptotic pathway.
    Keywords:  Fluoxetine; STAT3; apoptosis; epithelial-to-mesenchymal transition; triple-negative breast cancer
    DOI:  https://doi.org/10.21873/anticanres.15871
  148. Oxid Med Cell Longev. 2022 ;2022 4591134
    Quercetin Protects Ethanol-Induced Hepatocyte Pyroptosis via Scavenging Mitochondrial ROS and Promoting PGC-1α-Regulated Mitochondrial Homeostasis in L02 Cells.
    Xingtao Zhao, Cheng Wang, Shu Dai, Yanfang Liu, Fang Zhang, Cheng Peng, Yunxia Li.
      Alcoholic liver disease (ALD) is a multifaceted process that involves excessive lipid, reactive oxygen species (ROS) production, unbalanced mitochondrial homeostasis, and ultimate cell death. Quercetin is a dietary phytochemical presented in various fruits and vegetables, which has anti-inflammatory and antioxidant effects. According to recent advances in pharmanutritional management, the effects of quercetin on various mitochondrial processes have attracted attention. In the study, we explored whether quercetin could attenuate ethanol-induced hepatocyte pyroptosis by maintaining mitochondrial homeostasis and studied its hepatoprotective effect and the underlying mechanism. We chose L02 cells to establish an in vitro model with ethanol-induced hepatocyte pyroptosis. Then, the cells at approximately 80% confluence were treated with quercetin (80, 40, and 20 μM). The cell viability (CCK-8) was used to investigate the effect of quercetin on ethanol-induced L02 cell proliferation. Relative assay kits were used to measure oxidative stress index (OSI = TOS/TAS), lipid peroxidation (LPO) release, and mitochondrial membrane potential (δΨm). The morphology of mitochondria was characterized by transmission electron microscopy- (TEM-) based analysis. Mitochondrial dynamics (Mito Tracker Green), mitROS (MitoSOX Red Mitochondrial Superoxide) production, and nuclear DNA (nDNA) damage (γH2AX) markers were detected by immunofluorescence. The mRNA levels of mitochondrial function (including mitochondrial DNA (mtDNA) transcription genes TWNK, MTCO1, and MFND) and pyroptosis-related genes were detected by RT-qPCR, and the protein levels of NLRP3, ASC, caspase1, cleaved-caspase1, IL-18, IL-1β, and GSDMD-N were detected by western blot. The results showed that quercetin treatment downregulated redox status, lipid droplets, and LPO release, restored damaged mitochondrial membrane potential, and repaired mtDNA damage, PGC-1α nuclear transfer, and mitochondrial dynamics. The gene and protein expressions of NLRP3, ASC, cleaved-caspase1, IL-18, IL-1β, and GSDMD-N were decreased, which effectively inhibited cell pyroptosis. Therefore, the results indicated that quercetin protected ethanol-induced hepatocyte pyroptosis via scavenging mitROS and promoting PGC-1α-mediated mitochondrial homeostasis in L02 cells.
    DOI:  https://doi.org/10.1155/2022/4591134
  149. Molecules. 2022 Jul 20. pii: 4632. [Epub ahead of print]27(14):
    Maleimide-Functionalized Liposomes: Prolonged Retention and Enhanced Efficacy of Doxorubicin in Breast Cancer with Low Systemic Toxicity.
    Chuane Tang, Dan Yin, Tianya Liu, Rui Gou, Jiao Fu, Qi Tang, Yao Wang, Liang Zou, Hanmei Li.
      Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy.
    Keywords:  breast cancer; doxorubicin; liposome; maleimide; sustained release
    DOI:  https://doi.org/10.3390/molecules27144632
  150. Nanomaterials (Basel). 2022 Jul 26. pii: 2560. [Epub ahead of print]12(15):
    Recent Advances in Honey-Based Nanoparticles for Wound Dressing: A Review.
    Norfarina Bahari, Norhashila Hashim, Abdah Md Akim, Bernard Maringgal.
      Wounds with impaired healing, including delayed acute injuries and chronic injuries, generally fail to progress through normal healing stages. A deeper understanding of the biochemical processes involved in chronic wound cures is necessary to correct the microenvironmental imbalances in the wound treatment designs of products. The therapeutic benefits of honey, particularly its antimicrobial activity, make it a viable option for wound treatment in a variety of situations. Integration with nanotechnology has opened up new possibilities not only for wound healing but also for other medicinal applications. In this review, recent advances in honey-based nanoparticles for wound healing are discussed. This also covers the mechanism of the action of nanoparticles in the wound healing process and perspectives on the challenges and future trends of using honey-based nanoparticles. The underlying mechanisms of wound healing using honey are believed to be attributed to hydrogen peroxide, high osmolality, acidity, non-peroxide components, and phenols. Therefore, incorporating honey into various wound dressings has become a major trend due to the increasing demand for combination dressings in the global wound dressing market because these dressings contain two or more types of chemical and physical properties to ensure optimal functionality. At the same time, their multiple features (low cost, biocompatibility, and swelling index) and diverse fabrication methods (electrospun fibres, hydrogels, etc.) make them a popular choice among researchers.
    Keywords:  dressing; honey; nanoparticles; wound healing
    DOI:  https://doi.org/10.3390/nano12152560
  151. Front Oncol. 2022 ;12 925379
    Chemopreventive Potential of Dietary Nanonutraceuticals for Prostate Cancer: An Extensive Review.
    Hitesh Chopra, Shabana Bibi, Rajat Goyal, Rupesh K Gautam, Rashmi Trivedi, Tarun Kumar Upadhyay, Mohd Hasan Mujahid, Mohammad Ajmal Shah, Muhammad Haris, Kartik Bhairu Khot, Gopika Gopan, Inderbir Singh, Jin Kyu Kim, Jobin Jose, Mohamed M Abdel-Daim, Fahad A Alhumaydhi, Talha Bin Emran, Bonglee Kim.
      There are more than two hundred fifty different types of cancers, that are diagnosed around the world. Prostate cancer is one of the suspicious type of cancer spreading very fast around the world, it is reported that in 2018, 29430 patients died of prostate cancer in the United State of America (USA), and hence it is expected that one out of nine men diagnosed with this severe disease during their lives. Medical science has identified cancer at several stages and indicated genes mutations involved in the cancer cell progressions. Genetic implications have been studied extensively in cancer cell growth. So most efficacious drug for prostate cancer is highly required just like other severe diseases for men. So nutraceutical companies are playing major role to manage cancer disease by the recommendation of best natural products around the world, most of these natural products are isolated from plant and mushrooms because they contain several chemoprotective agents, which could reduce the chances of development of cancer and protect the cells for further progression. Some nutraceutical supplements might activate the cytotoxic chemotherapeutic effects by the mechanism of cell cycle arrest, cell differentiation procedures and changes in the redox states, but in other, it also elevate the levels of effectiveness of chemotherapeutic mechanism and in results, cancer cell becomes less reactive to chemotherapy. In this review, we have highlighted the prostate cancer and importance of nutraceuticals for the control and management of prostate cancer, and the significance of nutraceuticals to cancer patients during chemotherapy.
    Keywords:  cancer; chemotherapy; nanotechnology; nutraceutical; nutrition; prostate cancer; supplements
    DOI:  https://doi.org/10.3389/fonc.2022.925379
  152. Biomolecules. 2022 Jun 27. pii: 895. [Epub ahead of print]12(7):
    Silencing VDAC1 to Treat Mesothelioma Cancer: Tumor Reprograming and Altering Tumor Hallmarks.
    Swaroop Kumar Pandey, Renen Machlof-Cohen, Manikandan Santhanam, Anna Shteinfer-Kuzmine, Varda Shoshan-Barmatz.
      Mesothelioma, an aggressive cancer with a poor prognosis, is linked to asbestos exposure. However, carbon nanotubes found in materials we are exposed to daily can cause mesothelioma cancer. Cancer cells reprogram their metabolism to support increased biosynthetic and energy demands required for their growth and motility. Here, we examined the effects of silencing the expression of the voltage-dependent anion channel 1 (VDAC1), controlling the metabolic and energetic crosstalk between mitochondria and the rest of the cell. We demonstrate that VDAC1 is overexpressed in mesothelioma patients; its levels increase with disease stage and are associated with low survival rates. Silencing VDAC1 expression using a specific siRNA identifying both mouse and human VDAC1 (si-m/hVDAC1-B) inhibits cell proliferation of mesothelioma cancer cells. Treatment of xenografts of human-derived H226 cells or mouse-derived AB1 cells with si-m/hVDAC1-B inhibited tumor growth and caused metabolism reprogramming, as reflected in the decreased expression of metabolism-related proteins, including glycolytic and tricarboxylic acid (-)cycle enzymes and the ATP-synthesizing enzyme. In addition, tumors depleted of VDAC1 showed altered microenvironments and inflammation, both associated with cancer progression. Finally, tumor VDAC1 silencing also eliminated cancer stem cells and induced cell differentiation to normal-like cells. The results show that silencing VDAC1 expression leads to reprogrammed metabolism and to multiple effects from tumor growth inhibition to modulation of the tumor microenvironment and inflammation, inducing differentiation of malignant cells. Thus, silencing VDAC1 is a potential therapeutic approach to treating mesothelioma.
    Keywords:  VDAC1; mesothelioma; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/biom12070895
  153. Gels. 2022 Jun 23. pii: 397. [Epub ahead of print]8(7):
    Gelatinase Responsive Nanogel for Antibacterial Phototherapy and Wound Healing.
    Qianqian Han, Xuan Wang, Lin Qiu, Xinpei Zhou, Zexuan Hui, Xinye Ni, Yang Xuan, Xiaoling Lei, Jianhao Wang.
      The unique bactericidal mechanism of metal nanoparticles (MNPs) is considered to be an effective strategy to deal with antibiotic resistance, but the oxidative stress damage caused by excessive accumulation of MNPs to normal cells cannot be ignored. Achieving on-demand release of nano-drugs in specific infection environments is highly attractive. Herein, we constructed a "core-shell" nanogel (G@CuS) based on a copper sulfide (CuS) antimicrobial agent and gelatin for targeted drug release and bacterial clearance in a gelatinase infected microenvironment. G@CuS produced heat and reactive oxygen species (ROS) under the irradiation of a laser, which together with the released Cu2+ cause irreversible and efficient physical damage to the bacteria. Moreover, the encapsulation of gelatin not only limits the biotoxicity of CuS nanodots (NDs), but also effectively promotes the proliferation of mammalian cells. Under the synergy of multiple mechanisms, G@CuS eradicated the colonized bacteria in the wound of mice infected with Staphylococcus aureus (S. aureus) and accelerated wound healing. The proposed application strategy of nanogel is expected to provide a new idea for clinical transformation.
    Keywords:  CuS NDs; antibacterial activity; gelatin nanogel; targeted drug release; wound healing
    DOI:  https://doi.org/10.3390/gels8070397
  154. Mol Metab. 2022 Jul 20. pii: S2212-8778(22)00123-5. [Epub ahead of print] 101554
    A Glucokinase-linked Sensor in the Taste System Contributes to Glucose Appetite.
    Sandrine Chometton, A-Hyun Jung, Lilly Mai, Taylor Dal Bon, Alexa Osorio Ramirez, Dave W Pittman, Lindsey A Schier.
      Dietary glucose is a robust elicitor of central reward responses and ingestion, but the key peripheral sensors triggering these orexigenic mechanisms are not entirely known. Here, we provide the first evidence that glucokinase, an enzyme involved in glucose metabolism and glucosensing, in the taste bud cells, is regulated by metabolic state, dietary factors, and contributes to glucose appetite. These results expand our understanding of sensory inputs underlying nutrition, metabolism, and food reward.
    Keywords:  Sugar sensing; food reward; gustation; ingestive motivation; metabolism; nutrient assimilation
    DOI:  https://doi.org/10.1016/j.molmet.2022.101554
  155. Turk J Pediatr. 2022 ;pii: 2445. [Epub ahead of print]64(3): 435-445
    Evaluation of ketogenic diet therapy in children diagnosed with drug-resistant epilepsy: a single-center experience.
    Gonca Kılıç Yıldırım, Murat Yağcı, Anıl Çiğdem Uygur, Hülya Özen, Coşkun Yarar, Kürşat Bora Çarman.
       BACKGROUND: We evaluate here the effect of the ketogenic diet (KD) on children with drug-resistant epilepsy (DRE) in terms of clinical effectiveness, anthropometric measurements, and some electroencephalogram (EEG) and biochemical findings.
    METHODS: Included in the study were 18 children (median age 70 months, 61.1% female) who received the classical KD and modified Atkins diet (MAD) for at least one year due to DRE. The patients` demographic and laboratory data; weight, height and body mass index values; EEG and electrocardiographic findings; abdominal ultrasonography findings; and biochemical parameters were recorded at baseline and at 12 months after the initiation of the diet. A reduction of ≥50% in the number of seizures was accepted as a response to KD.
    RESULTS: Classic KD was chosen for 14 patients (77.8%), and MAD for four patients (22.2%). The response to KD therapy (≥50% reduction) was 55.5% (n = 10) (p = 0.008), and one patient even became seizure-free. By the 12th month of treatment, 10 patients had experienced a reduction of more than 50% in epileptiform discharges, as indicated by EEG findings. There was no difference in seizure reduction between the patients who received classical KD and MAD. A total of 11.1% of the children lost weight during KD treatment. The most common side effect was constipation (n = 10, 55.6%). At the end of one year of treatment, total cholesterol and low density lipoprotein cholesterol (LDL-C) LDL-C levels had increased dramatically, while fasting blood glucose levels had decreased significantly.
    CONCLUSIONS: Our study suggests that KD treatment provides good clinical efficacy in the treatment of pediatric DRE, and can significantly reduce the frequency of epileptic discharges. Also, total cholesterol and LDL-C levels increased significantly, and fasting blood glucose levels decreased significantly compared to the baseline levels.
    Keywords:  child; classical ketogenic diet; drug-resistant epilepsy; efficacy; modified Atkins diet
    DOI:  https://doi.org/10.24953/turkjped.2020.3091
  156. Metabolites. 2022 Jul 12. pii: 639. [Epub ahead of print]12(7):
    Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learnt and Future Directions.
    Bala Mohan Sivani, Mahmoud Azzeh, Rajashree Patnaik, Anca Pantea Stoian, Manfredi Rizzo, Yajnavalka Banerjee.
      Turmeric is a plant with a very long history of medicinal use across different cultures. Curcumin is the active part of turmeric, which has exhibited various beneficial physiological and pharmacological effects. This review aims to critically appraise the corpus of literature associated with the above pharmacological properties of curcumin, with a specific focus on antioxidant, anti-inflammatory, anticancer and antimicrobial properties. We have also reviewed the different extraction strategies currently in practice, highlighting the strengths and drawbacks of each technique. Further, our review also summarizes the clinical trials that have been conducted with curcumin, which will allow the reader to get a quick insight into the disease/patient population of interest with the outcome that was investigated. Lastly, we have also highlighted the research areas that need to be further scrutinized to better grasp curcumin's beneficial physiological and medicinal properties, which can then be translated to facilitate the design of better bioactive therapeutic leads.
    Keywords:  Curcuma longa; SARS-CoV-2; anticancer; antiinflammation; antimicrobial; antioxidant; antiviral; clinical trial; curcumin; functional food; nutraceutical; turmeric
    DOI:  https://doi.org/10.3390/metabo12070639
  157. Comb Chem High Throughput Screen. 2022 Jul 26.
    Naturally Occurring Compounds as Potential Inhibitors of Epidermal Growth Factor Receptors (EGFRs).
    Listiana Oktavia, Asrul Muhamad Fuad, Seni Kurnia Senjaya, Yuliawati.
      The Epidermal Growth Factor Receptor (EGFR) activation appears essential in tumor growth and progression. Targeting EGFR signaling pathway becomes an exciting area in cancer therapy. Synthetic chemotherapy drugs have been used to treat some EGFR signaling in various cancer cells. The utilization of naturally occurring compounds as EGFR inhibitors is exciting to be explored due to the urgent need to combat resistance over current EGFR inhibitors. In this review, we first summarize the schematic role of EGFR in cancer and the current EGFR inhibitor used, its advantage, and disadvantage. Next, we discuss the natural products that have been reported as the source of EGFR inhibitors. The discussion covers the natural products which are majorly reported from the year 2005-2020. A total of 21 groups of natural compounds and their derivatives were reported to have the potential to inhibit EGFR signaling pathways. We then discuss the advanced technologies and approaches that rapidly discover EGFR inhibitor-based natural products. Hopefully, this literature review could increase the excitement of finding an effective EGFR pathway inhibitor from natural products.
    Keywords:  Cancer; Chemotherapy; EGFR; Inhibitor; Natural Products
    DOI:  https://doi.org/10.2174/1386207325666220726164712
  158. Cells. 2022 Jul 18. pii: 2232. [Epub ahead of print]11(14):
    Emergence of Edible Plant-Derived Nanovesicles as Functional Food Components and Nanocarriers for Therapeutics Delivery: Potentials in Human Health and Disease.
    Sora Q Kim, Kee-Hong Kim.
      Extracellular vesicles (EVs) are a highly heterogeneous population of membranous particles that are secreted by almost all types of cells across different domains of life, including plants. In recent years, studies on plant-derived nanovesicles (PDNVs) showed that they could modulate metabolic reactions of the recipient cells, affecting (patho)physiology with health benefits in a trans-kingdom manner. In addition to its bioactivity, PDNV has advantages over conventional nanocarriers, making its application promising for therapeutics delivery. Here, we discuss the characteristics of PDNV and highlight up-to-date pre-clinical and clinical evidence, focusing on therapeutic application.
    Keywords:  exosomes; extracellular vesicles; food components; functional foods; phytochemicals; plant-derived nanovesicles; therapy; trans-kingdom interaction
    DOI:  https://doi.org/10.3390/cells11142232
  159. Biomedicines. 2022 Jul 05. pii: 1596. [Epub ahead of print]10(7):
    Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy.
    Veronica Angela Maria Vitto, Silvia Bianchin, Alicia Ann Zolondick, Giulia Pellielo, Alessandro Rimessi, Diego Chianese, Haining Yang, Michele Carbone, Paolo Pinton, Carlotta Giorgi, Simone Patergnani.
      Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer.
    Keywords:  anoikis; autophagy; cancer; therapy; tumor promotion; tumor suppression
    DOI:  https://doi.org/10.3390/biomedicines10071596
  160. Nanomaterials (Basel). 2022 Jul 16. pii: 2440. [Epub ahead of print]12(14):
    Nanosponges for Drug Delivery and Cancer Therapy: Recent Advances.
    Siavash Iravani, Rajender S Varma.
      Nanosponges with three-dimensional (3D) porous structures, narrow size distribution, and high entrapment efficiency are widely engineered for cancer therapy and drug delivery purposes. They protect the molecular agents from degradation and help to improve the solubility of lipophilic therapeutic agents/drugs with targeted delivery options in addition to being magnetized to attain suitable magnetic features. Nanosponge-based delivery systems have been applied for cancer therapy with high specificity, biocompatibility, degradability, and prolonged release behavior. In this context, the drug loading within nanosponges is influenced by the crystallization degree. Notably, 3D printing technologies can be applied for the development of novel nanosponge-based systems for biomedical applications. The impacts of polymers, cross-linkers, type of drugs, temperature, loading and mechanism of drug release, fabrication methods, and substitution degree ought to be analytically evaluated. Eco-friendly techniques for the manufacturing of nanosponges still need to be uncovered in addition to the existing methods, such as solvent techniques, ultrasound-assisted preparation, melting strategies, and emulsion solvent diffusion methods. Herein, the recent advancements associated with the drug delivery and cancer therapy potential of nanosponges (chiefly, cyclodextrin-based, DNAzyme, and ethylcellulose nanosponges) are deliberated, focusing on the important challenges and future perspectives.
    Keywords:  DNAzyme nanosponges; cancer therapy; cyclodextrin-based nanosponges; drug delivery; ethylcellulose nanosponges; nanosponges
    DOI:  https://doi.org/10.3390/nano12142440
  161. Pharmaceutics. 2022 Jul 25. pii: 1544. [Epub ahead of print]14(8):
    Design and Validation of Nanofibers Made of Self-Assembled Peptides to Become Multifunctional Stimuli-Sensitive Nanovectors of Anticancer Drug Doxorubicin.
    Valentina Del Genio, Annarita Falanga, Emilie Allard-Vannier, Katel Hervé-Aubert, Marilisa Leone, Rosa Bellavita, Rustem Uzbekov, Igor Chourpa, Stefania Galdiero.
      Self-assembled peptides possess remarkable potential as targeted drug delivery systems and key applications dwell anti-cancer therapy. Peptides can self-assemble into nanostructures of diverse sizes and shapes in response to changing environmental conditions (pH, temperature, ionic strength). Herein, we investigated the development of self-assembled peptide-based nanofibers (NFs) with the inclusion of a cell-penetrating peptide (namely gH625) and a matrix metalloproteinase-9 (MMP-9) responsive sequence, which proved to enhance respectively the penetration and tumor-triggered cleavage to release Doxorubicin in Triple Negative Breast Cancer cells where MMP-9 levels are elevated. The NFs formulation has been optimized via critical micelle concentration measurements, fluorescence, and circular dichroism. The final nanovectors were characterized for morphology (TEM), size (hydrodynamic diameter), and surface charge (zeta potential). The Doxo loading and release kinetics were studied in situ, by optical microspectroscopy (fluorescence and surface-enhanced Raman scattering-SERS). Confocal spectral imaging of the Doxo fluorescence was used to study the TNBC models in vitro, in cells with various MMP-9 levels, the drug delivery to cells as well as the resulting cytotoxicity profiles. The results confirm that these NFs are a promising platform to develop novel nanovectors of Doxo, namely in the framework of TNBC treatment.
    Keywords:  cell-penetrating peptides; magnetic nanoparticles; self-assembling peptides; triple negative breast cancer
    DOI:  https://doi.org/10.3390/pharmaceutics14081544
  162. Molecules. 2022 Jul 08. pii: 4382. [Epub ahead of print]27(14):
    Anti-Colon Cancer Activity of Dietary Phytochemical Soyasaponin I and the Induction of Metabolic Shifts in HCT116.
    Xuewei Xia, Qianmin Lin, Ning Zhao, Jinzi Zeng, Jiajia Yang, Zhiyuan Liu, Riming Huang.
      Dietary phytochemicals play an important role in the prevention and treatment of colon cancer. It is reported that group B of soyasaponin, derived from dietary pulses, has anti-colonic effects on some colon cancer cell lines. However, it is uncertain which specific soybean saponins play a role. In our study, as one of the group B soyasaponin, the anti-colon cancer activity of soyasaponins I (SsI) was screened, and we found that it had the inhibitory effect of proliferation on colon cancer cell lines HCT116 (IC50 = 161.4 μM) and LoVo (IC50 = 180.5 μM), but no effect on HT29 between 0-200 μM. Then, nine potential targets of SsI on colon cancer were obtained by network pharmacology analysis. A total of 45 differential metabolites were identified by metabolomics analysis, and the KEGG pathway was mainly enriched in the pathways related to the absorption and metabolism of amino acids. Finally, molecular docking analysis predicted that SsI might dock with the protein of DNMT1, ERK1. The results indicated that the effect of SsI on HCT116 might be exerted by influencing amino acid metabolism and the estrogen signaling pathway. This study may provide the possibility for the application of SsI against colon cancer.
    Keywords:  anti-colon cancer; dietary phytochemicals; metabolomic analysis; molecular docking; network pharmacology; soyasaponin I
    DOI:  https://doi.org/10.3390/molecules27144382
  163. Biosensors (Basel). 2022 Jul 26. pii: 568. [Epub ahead of print]12(8):
    3D and 4D Printing in the Fight against Breast Cancer.
    Sofia Moroni, Luca Casettari, Dimitrios A Lamprou.
      Breast cancer is the second most common cancer worldwide, characterized by a high incidence and mortality rate. Despite the advances achieved in cancer management, improvements in the quality of life of breast cancer survivors are urgent. Moreover, considering the heterogeneity that characterizes tumors and patients, focusing on individuality is fundamental. In this context, 3D printing (3DP) and 4D printing (4DP) techniques allow for a patient-centered approach. At present, 3DP applications against breast cancer are focused on three main aspects: treatment, tissue regeneration, and recovery of the physical appearance. Scaffolds, drug-loaded implants, and prosthetics have been successfully manufactured; however, some challenges must be overcome to shift to clinical practice. The introduction of the fourth dimension has led to an increase in the degree of complexity and customization possibilities. However, 4DP is still in the early stages; thus, research is needed to prove its feasibility in healthcare applications. This review article provides an overview of current approaches for breast cancer management, including standard treatments and breast reconstruction strategies. The benefits and limitations of 3DP and 4DP technologies are discussed, as well as their application in the fight against breast cancer. Future perspectives and challenges are outlined to encourage and promote AM technologies in real-world practice.
    Keywords:  3D printing; 4D printing; additive manufacturing; breast cancer; drug delivery
    DOI:  https://doi.org/10.3390/bios12080568
  164. Int J Pharm. 2022 Jul 22. pii: S0378-5173(22)00604-4. [Epub ahead of print]624 122049
    Biotin receptor-targeting nanogels loaded with methotrexate for enhanced antitumor efficacy in triple-negative breast cancer in vitro and in vivo models.
    Samira Sadat Abolmaali, Sepideh Zarenejad, Younes Mohebi, Haniyeh Najafi, Sanaz Javanmardi, Mehdi Abedi, Ali Mohammad Tamaddon.
      High-dose methotrexate (MTX) chemotherapeutic applications confront drug specificity and pharmacokinetic challenges, which can be overcome by utilizing targeted drug delivery systems. In the present study, biotin-PEG conjugated nanogels of carboxymethyl polyethyleneimine (Biotin-PEG-CMPEI) were developed for active targeted delivery of MTX in triple negative breast cancer (TNBC). TEM and DLS analyses revealed uniform, discrete, and spherical particles with a mean hydrodynamic diameter of about 100 nm and ζ-potential of + 15 mV (pH = 7.4). Biotin-PEG-CMPEI nanogels exhibited a zero-order MTX release kinetics at pH = 7.5 and a swelling-controlled release at pH = 5.5. In 4 T1 cells treated with the MTX-loaded Biotin-PEG-CMPEI, the IC50 was reduced by about 10 folds compared to the free drug, while the unloaded nanogels showed no significant toxicity. In the model mice, the group treated with the MTX-loaded Biotin-PEG-CMPEI had a lower tumor volume and mortality rate animal model when compared to free drug. Additionally, histopathological analyses showed that the group treated with the MTX-loaded nanogels had less lung metastasis and glomerular damage caused by MTX. Overall, the MTX-loaded Biotin-PEG-CMPEI targeted directly against overexpressed biotin receptors in TNBC have been shown to improve the MTX safety and therapeutic efficacy.
    Keywords:  Allograft animal model; Biotin; Methotrexate; Nanogels; Targeted delivery; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122049
  165. Am J Physiol Cell Physiol. 2022 Jul 25.
    Rapid nutrient depletion to below the physiological range by cancer cells cultured in Plasmax.
    Georgina Gardner, Feresteh Moradi, Christopher Moffatt, Meagan Cliche, Bianca Garlisi, John Gratton, Fatima Mehmood, Jeffrey A Stuart.
      Mammalian cell culture is a fundamental tool used to study living cells. Presently, the standard protocol for performing cell culture involves the use of commercial media that contain an excess of nutrients. While this reduces the likelihood of cell starvation, it creates non-physiologic culture conditions that have been shown to 're-wire' cellular metabolism. Recently, researchers have developed new media like Plasmax, formulated to approximate the nutrient composition of human blood plasma. Although this represents an improvement in cell culture practice, physiologic media may be vulnerable to nutrient depletion. In this study we directly addressed this concern by measuring the rates of glucose and amino acid depletion from Plasmax in several cancer cell lines (PC-3, LNCaP, MCF-7, SH-SY5Y) over 48 hours. In all cell lines, depletion of glucose from Plasmax was rapid such that, by 48h, cells were hypoglycemic (<2mM glucose). Most amino acids were similarly rapidly depleted to sub-physiological levels by 48h. In contrast, glucose and most amino acids remained within the physiological range at 24h. When the experiment was done at physiological oxygen (5%) versus standard (18%)with LNCaP cells, no effect on glucose or amino acid consumption was observed. Using RNA sequencing, we show that this nutrient depletion is associated with enrichment of starvation responses, apoptotic signalling, and endoplasmic reticulum stress. A shift from glycolytic metabolism to mitochondrial respiration at 5% O2 was also measured using Seahorse analysis. Taken together, these results exemplify the metabolic considerations for Plasmax, highlighting that cell culture in Plasmax requires daily media exchange.
    Keywords:  amino acids; metabolism; metabolomics; physiologic cell culture; physioxia
    DOI:  https://doi.org/10.1152/ajpcell.00403.2021
  166. Polymers (Basel). 2022 Jul 06. pii: 2774. [Epub ahead of print]14(14):
    Relationship between the Antifungal Activity of Chitosan-Capsaicin Nanoparticles and the Oxidative Stress Response on Aspergillus parasiticus.
    Cynthia Nazareth Hernández-Téllez, Ana Guadalupe Luque-Alcaraz, Sahily Alejandra Núñez-Mexía, Mario Onofre Cortez-Rocha, Jaime Lizardi-Mendoza, Ema Carina Rosas-Burgos, Aarón de Jesús Rosas-Durazo, Norma Violeta Parra-Vergara, Maribel Plascencia-Jatomea.
      The fungus Aspergillus parasiticus is a contaminant in agricultural crops and its eradication involves the indiscriminate use of harmful synthetic pesticides. In the search for antifungal agents of natural origin, chitosan (Q) and capsaicin (C) are coupled in the form of nanoparticles (Np), which can possess a direct application under specific conditions. Due to their small size, Np can cross through the cell wall, taking the cells into a pro-oxidant environment known as "oxidative stress", which presents when the reactive oxygen species (ROS) surpass the number of antioxidants in the cell. In the present investigation, nanoparticles of chitosan (Np Q) and nanoparticles of chitosan-capsaicin (Np QC) with an average diameter of 44.8 ± 20.6 nm and 111.1 ± 14.1 nm, respectively, were synthesized, and there was a zeta potential of + 25.6 ± 0.7 mV and + 26.8 ± 6.1 mV, respectively. The effect of the concentration of Np Q (A, B, C, and D), of Np QC (A, B, C, and D), and capsaicin in a solution (control) was evaluated on the viability of the spores, the accumulation of intracellular ROS, and the morphometric changes of A. parasiticus. Acute toxicity of the Np was determined utilizing bioassays with Artemia salina, and acute phytotoxicity was evaluated in lettuce seeds (Lactuca sativa). According to ROS results, capsaicin (control) did not induce oxidative stress in the cell; otherwise, it was observed to have an elevated (p &lt; 0.05) accumulation of ROS when the concentration of Np Q increased. For both, Np Q and Np QC, an inverse physiological pattern relating spore viability and ROS accumulation in the fungus was found; the viability of spores decreased as the ROS accumulation increased. The spore viability of A. parasiticus diminished upon increasing the concentration of chitosan (0.3-0.4 mg/mL) in the Np, while the intracellular accumulation of ROS increased proportionally to the concentration of the nanomaterials in the treatments of Np Q and Np QC. On the other hand, Np QC presented a lower (p &lt; 0.05) toxicological effect in comparison with Np Q, which indicates that the incorporation of bioactive compounds, such as capsaicin, into nanoparticles of chitosan is a strategy that permits the reduction of the toxicity associated with nanostructured materials.
    Keywords:  acute toxicity; bioactive compounds; biopolymer; nanomaterials; phytopathogenic fungi
    DOI:  https://doi.org/10.3390/polym14142774
  167. Nanomaterials (Basel). 2022 Jul 18. pii: 2462. [Epub ahead of print]12(14):
    Microenvironmental Behaviour of Nanotheranostic Systems for Controlled Oxidative Stress and Cancer Treatment.
    Yaser Rehman, Hamzeh Qutaish, Jung Ho Kim, Xu-Feng Huang, Sadia Alvi, Konstantin Konstantinov.
      The development of smart, efficient and multifunctional material systems for diseases treatment are imperative to meet current and future health challenges. Nanomaterials with theranostic properties have offered a cost effective and efficient solution for disease treatment, particularly, metal/oxide based nanotheranostic systems already offering therapeutic and imaging capabilities for cancer treatment. Nanoparticles can selectively generate/scavenge ROS through intrinsic or external stimuli to augment/diminish oxidative stress. An efficient treatment requires higher oxidative stress/toxicity in malignant disease, with a minimal level in surrounding normal cells. The size, shape and surface properties of nanoparticles are critical parameters for achieving a theranostic function in the microenvironment. In the last decade, different strategies for the synthesis of biocompatible theranostic nanostructures have been introduced. The exhibition of therapeutics properties such as selective reactive oxygen species (ROS) scavenging, hyperthermia, antibacterial, antiviral, and imaging capabilities such as MRI, CT and fluorescence activity have been reported in a variety of developed nanosystems to combat cancer, neurodegenerative and emerging infectious diseases. In this review article, theranostic in vitro behaviour in relation to the size, shape and synthesis methods of widely researched and developed nanosystems (Au, Ag, MnOx, iron oxide, maghemite quantum flakes, La2O3-x, TaOx, cerium nanodots, ITO, MgO1-x) are presented. In particular, ROS-based properties of the nanostructures in the microenvironment for cancer therapy are discussed. The provided overview of the biological behaviour of reported metal-based nanostructures will help to conceptualise novel designs and synthesis strategies for the development of advanced nanotheranostic systems.
    Keywords:  ROS; apoptosis; cancer; cellular internalisation; nanotheranostics; oxidative stress; oxide nanoparticles
    DOI:  https://doi.org/10.3390/nano12142462
  168. Evid Based Complement Alternat Med. 2022 ;2022 3827933
    Simvastatin in the Treatment of Colorectal Cancer: A Review.
    Hongliang Zang, Wei Yang, Xiaofeng Tian.
      Drug repositioning and drug reuse are the heated topics in the field of oncology in recent years. These two concepts refer to seeking effective drugs for cancer that are not originally intended to treat cancer. The survival benefits are then analyzed by combining the re-positioned drugs with conventional cancer treatment methods. Simvastatin is a clinically commonly used hyperlipidemia drug and exerts the effect of preventing cardiovascular diseases. Recent studies have found that simvastatin has great potential in the treatment of colorectal cancer, and a large number of clinical studies have used simvastatin as an adjuvant drug to help treat metastatic colorectal cancer.
    DOI:  https://doi.org/10.1155/2022/3827933
  169. Mol Pharm. 2022 Jul 25.
    Emerging Nanotechnologies and Microbiome Engineering for the Treatment of Inflammatory Bowel Disease.
    Omar A Abed, Younes Attlassy, Jin Xu, Kai Han, James J Moon.
      Inflammatory bowel disease (IBD) is characterized by the chronic inflammation of the gastrointestinal tract and impacts almost 7 million people across the globe. Current therapeutics are effective in treating the symptoms, but they often do not address the root cause or selectively target areas of inflammation. Notably, self-assembled nanoparticles show great promise as drug delivery systems for the treatment of IBD. Nanoparticles can be designed to survive the harsh gastric conditions and reach inflamed areas of the gastrointestinal tract. Oral drug delivery with nanoparticles can localize drugs to the impacted inflamed region using active and/or passive targeting and promote a high rate of drug dispersion in local tissues, thus reducing potential off-target toxicities. Since a dysregulated gut microbiome is implicated in the development and progression of IBD, it is also important to develop nanoparticles and biomaterials that can restore symbiotic microbes while reducing the proliferation of harmful microbes. In this review, we highlight recent advances in self-assembled nanosystems designed for addressing inflammation and dysregulated gut microbiomes as potential treatments for IBD. Nanoparticles have a promising future in improving the delivery of current therapeutics, increasing patient compliance by providing an oral method of medication, and reducing side effects. However, remaining challenges include scale-up synthesis of nanoparticles, potential side effects, and financial obstacles of clinical trials. It would be in the patients' best interest to continue research on nanoparticles in the pursuit of more effective therapeutics for the treatment of IBD.
    Keywords:  Drug delivery; Gut microbiome; Inflammatory bowel disease; Nanoparticles; Reactive oxygen species; Self-assembly
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00222
  170. Biomed Res Int. 2022 ;2022 4931368
    The Molecular Mechanism of Traditional Chinese Medicine Prescription: Gu-tong Formula in Relieving Osteolytic Bone Destruction.
    Jinyuan Chang, Zhenglong Jiang, Wei Jin, Yaohan Wang, Jie Li, Jiayang Chen, Hao Li, Li Feng.
      Bone metastasis is a common complication in patients with advanced tumors, causing pain and bone destruction and affecting their quality of life. Typically, complementary and alternative medicine (CAM), with unique theoretical guidance, has played key roles in the treatment of tumor-related diseases. Gu-tong formula (GTF), as a representative prescription of traditional Chinese medicine, has been demonstrated to be an effective clinical medication for the relief of cancer pain. However, the molecular mechanism of GTF in the treatment of osteolytic metastasis is still unclear. Herein, we employ network pharmacology and molecular dynamics methods to uncover the potential treatment mechanism, indicating that GTF can reduce the levels of serum IL6 and TGFB1 and thus limit the scope of bone cortical damage. Among the active compounds, sesamin and deltoin can bind stably with IL6 and TGFB1, respectively, and have the potential to become anti-inflammatory and anticancer drugs. Although the reasons for the therapeutic effect of GTF are complex and comprehensive, this work provides biological plausibility in the treatment of osteolytic metastases, which has a guiding significance for the treatment of cancer pain with CAM.
    DOI:  https://doi.org/10.1155/2022/4931368
  171. Int J Mol Sci. 2022 Jul 19. pii: 7972. [Epub ahead of print]23(14):
    Therapeutic Benefits of Selenium in Hematological Malignancies.
    Melanie A Ehudin, Upendarrao Golla, Devnah Trivedi, Shobha D Potlakayala, Sairam V Rudrabhatla, Dhimant Desai, Sinisa Dovat, David Claxton, Arati Sharma.
      Supplementing chemotherapy and radiotherapy with selenium has been shown to have benefits against various cancers. This approach has also been shown to alleviate the side effects associated with standard cancer therapies and improve the quality of life in patients. In addition, selenium levels in patients have been correlated with various cancers and have served as a diagnostic marker to track the efficiency of treatments or to determine whether these selenium levels cause or are a result of the disease. This concise review presents a survey of the selenium-based literature, with a focus on hematological malignancies, to demonstrate the significant impact of selenium in different cancers. The anti-cancer mechanisms and signaling pathways regulated by selenium, which impart its efficacious properties, are discussed. An outlook into the relationship between selenium and cancer is highlighted to guide future cancer therapy development.
    Keywords:  cancer; chemoprevention; chemotherapeutic; hematologic malignancies; leukemia; murine disease model; radiotherapy; selenium; selenoprotein
    DOI:  https://doi.org/10.3390/ijms23147972
  172. Front Pharmacol. 2022 ;13 847702
    Therapeutic Potential of Polyphenol and Nanoparticles Mediated Delivery in Periodontal Inflammation: A Review of Current Trends and Future Perspectives.
    Putri Ayu Jayusman, Nurrul Shaqinah Nasruddin, Nurul Inaas Mahamad Apandi, Norliwati Ibrahim, Siti Balkis Budin.
      Periodontitis is an oral inflammatory process involving the periodontium, which is mainly caused by the invasion of periodontopathogenic microorganisms that results in gingival connective tissue and alveolar bone destruction. Metabolic products of the oral pathogens and the associated host immune and inflammatory responses triggered are responsible for the local tissue destruction. Numerous studies in the past decades have demonstrated that natural polyphenols are capable of modulating the host inflammatory responses by targeting multiple inflammatory components. The proposed mechanism by which polyphenolic compounds exert their great potential is by regulating the immune cell, proinflammatory cytokines synthesis and gene expression. However, due to its low absorption and bioavailability, the beneficial effects of these substances are very limited and it hampers their use as a therapeutic agent. To address these limitations, targeted delivery systems by nanoencapsulation techniques have been explored in recent years. Nanoencapsulation of polyphenolic compounds with different carriers is an efficient and promising approach to boost their bioavailability, increase the efficiency and reduce the degradability of natural polyphenols. In this review, we focus on the effects of different polyphenolic substances in periodontal inflammation and to explore the pharmaceutical significance of polyphenol-loaded nanoparticles in controlling periodontitis, which may be useful for further enhancement of their efficacy as therapeutic agents for periodontal disease.
    Keywords:  inflammation; nanoencapsulation; nanotechnolody; periodonditis; polyphenol
    DOI:  https://doi.org/10.3389/fphar.2022.847702
  173. Pharm Res. 2022 Jul 29.
    Novel Self-Assembled Micelles With Increased Tumor Penetration and Anti-Tumor Efficiency Against Breast Cancer.
    Yani Yang, Yuezhu Zhao, Jie Liu, Chen Ge, Weiwei Zhang, Yue Zhang, Junji Wang, Guohao Sun, Xiujun Lin, Xiaohong Lu, Xiang Tang, Jun He, Weigen Lu, Jing Qin.
       PURPOSE: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency.
    METHODS: Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively.
    RESULTS: The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects.
    CONCLUSIONS: The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.
    Keywords:  Acitretin; Amphiphilic surfactant; Docetaxel; Micelles; Tumor-targeting
    DOI:  https://doi.org/10.1007/s11095-022-03338-3
  174. Drug Deliv Transl Res. 2022 Jul 25.
    Development, characterisation, and in vitro anti-tumor effect of self-microemulsifying drug delivery system containing polyphyllin I.
    Xin Wang, Rui Zhang, Shu Wang, Minju Gu, Yuan Li, Xiuping Zhuang, Chao Chen, Peimin Yang, Gongling Guo, Ping Sun.
      Polyphyllin I (PPI), an effective active ingredient in Paris polyphylla, has a diverse set of pharmacological properties. However, due to its poor solubility and oral absorption, its application and development are limited. In the study, we were committed to improving the solubility of PPI by developing a self-microemulsifying drug delivery system of PPI (PPI-SMEDDS), screening the best preparation process, and evaluating the quality and the in vivo pharmacokinetics of PPI, and PPI-SMEDDS following oral administration to rats were also studied. In addition, the pharmacological activities against human lung adenocarcinoma cell A549 in vitro were assessed. The best formulation had 15.89% ethyl oleate, 47.38% Cremophor RH40, and 36.73% 1,2 propylene glycol. The produced PPI-SMEDDS was clear and transparent, with an average particle size of 24.51 nm and a zeta potential of -17.54 ± 0.51 mV. In vitro, the cumulative release rate of PPI-SMEDDS was nearly 80% within 2 h. PPI-SMEDDS had a substantially greater area under the curve than PPI following oral treatment in rats, and the relative bioavailability of PPI in rats was 278.99%. More importantly, the anti-tumor effect of PPI-SMEDDS in vitro was significantly greater than that of PPI. These findings suggested that PPI-SMEDDS has the potential to improve the solubility, oral bioavailability of PPI, and anti-tumor effect, laying the groundwork for future research on the new PPI dosage form.
    Keywords:  Formulation optimization; In vitro anti-tumor effect; Pharmacokinetics; Polyphyllin I; Quality evaluation; Self-microemulsifying drug delivery system (SMEDDS); Stability
    DOI:  https://doi.org/10.1007/s13346-022-01212-8
  175. Int J Mol Sci. 2022 Jul 19. pii: 7974. [Epub ahead of print]23(14):
    A Recap of Heme Metabolism towards Understanding Protoporphyrin IX Selectivity in Cancer Cells.
    Martin Kiening, Norbert Lange.
      Mitochondria are essential organelles of mammalian cells, often emphasized for their function in energy production, iron metabolism and apoptosis as well as heme synthesis. The heme is an iron-loaded porphyrin behaving as a prosthetic group by its interactions with a wide variety of proteins. These complexes are termed hemoproteins and are usually vital to the whole cell comportment, such as the proteins hemoglobin, myoglobin or cytochromes, but also enzymes such as catalase and peroxidases. The building block of porphyrins is the 5-aminolevulinic acid, whose exogenous administration is able to stimulate the entire heme biosynthesis route. In neoplastic cells, this methodology repeatedly demonstrated an accumulation of the ultimate heme precursor, the fluorescent protoporphyrin IX photosensitizer, rather than in healthy tissues. While manifold players have been proposed, numerous discrepancies between research studies still dispute the mechanisms underlying this selective phenomenon that yet requires intensive investigations. In particular, we wonder what are the respective involvements of enzymes and transporters in protoporphyrin IX accretion. Is this mainly due to a boost in protoporphyrin IX anabolism along with a drop of its catabolism, or are its transporters deregulated? Additionally, can we truly expect to find a universal model to explain this selectivity? In this report, we aim to provide our peers with an overview of the currently known mitochondrial heme metabolism and approaches that could explain, at least partly, the mechanism of protoporphyrin IX selectivity towards cancer cells.
    Keywords:  aminolevulinic acid; cancer; photochemotherapy; photodynamic diagnosis; protoporphyrin IX; theranostics
    DOI:  https://doi.org/10.3390/ijms23147974
  176. Prog Biomater. 2022 Jul 25.
    Slow release curcumin-containing soy protein nanoparticles as anticancer agents for osteosarcoma: synthesis and characterization.
    Hadi Zare-Zardini, Hossein Soltaninejad, Adel Ghorani-Azam, Reza Nafisi-Moghadam, Navid Haddadzadegan, Mojtaba Ansari, Seyed Houssein Saeed-Banadaki, Mohammad Reza Sobhan, Sima Mozafari, Mahlagha Zahedi.
      Curcumin-containing soy protein nanoparticles (curcumin-SPNs) were synthesized by desolvation (coacervation) method and characterized by SEM, DLS, FTIR, and XRD. For anticancer evaluation, osteogenic sarcoma (SAOS2) cell lines were incubated with different concentrations of nanostructures. The dialysis method was used for assessment of drug release. Intracellular reactive oxygen species (ROS) were evaluated in IC50 dose after 24 h of exposure to free curcumin and curcumin-SPNs. Characterization data showed that the size of drug-free SPNs and curcumin-SPNs were 278.2 and 294.7 nm, respectively. The zeta potential of drug-free SPNs and curcumin-SPNs were - 37.1 and - 36.51 mv, respectively. There was no significant difference between the control and drug-free SPNs groups in terms of cell viability (p > 0.05). The viability of cells in different concentrations of the designed curcumin-SPNs in Saos2 cell line was significantly higher than free drug (p < 0.05). The release of curcumin showed that more than 50% of the drug was released in the first 2 h of incubation. After this time, the slow release of drug was continued to 62-83% of drug. IC50 values of free curcumin and curcumin-SPNs (1/10) were 156.8 and 65.9 µg/mL, respectively (a free curcumin IC50 was 2.4 times more than curcumin-SPNs). Slow-release of the curcumin causes the cell to be exposed to the anticancer drug for a longer period of time. The intracellular ROS levels significantly increased in an IC50 dose after 24 h of exposure to both free curcumin and curcumin-SPNs compared with controls (p < 0.05).
    Keywords:  Curcumin; Nanoparticle; Saos2 cell lines; Soy protein
    DOI:  https://doi.org/10.1007/s40204-022-00197-4
  177. Cell Mol Biol Lett. 2022 Jul 26. 27(1): 60
    Quercetin as a JAK-STAT inhibitor: a potential role in solid tumors and neurodegenerative diseases.
    Hamidreza Zalpoor, Mohsen Nabi-Afjadi, Razieh Forghaniesfidvajani, Chanour Tavakol, Faranak Farahighasreaboonasr, Farid Pakizeh, Vahid Ghobadi Dana, Farhad Seif.
      The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is involved in many immunological processes, including cell growth, proliferation, differentiation, apoptosis, and inflammatory responses. Some of these processes can contribute to cancer progression and neurodegeneration. Owing to the complexity of this pathway and its potential crosstalk with alternative pathways, monotherapy as targeted therapy has usually limited long-term efficacy. Currently, the majority of JAK-STAT-targeting drugs are still at preclinical stages. Meanwhile, a variety of plant polyphenols, especially quercetin, exert their inhibitory effects on the JAK-STAT pathway through known and unknown mechanisms. Quercetin has shown prominent inhibitory effects on the JAK-STAT pathway in terms of anti-inflammatory and antitumor activity, as well as control of neurodegenerative diseases. This review discusses the pharmacological effects of quercetin on the JAK-STAT signaling pathway in solid tumors and neurodegenerative diseases.
    Keywords:  Cancers; JAK–STAT inhibitor; Neurodegenerative diseases; Quercetin; Solid tumors
    DOI:  https://doi.org/10.1186/s11658-022-00355-3
  178. Pharmaceutics. 2022 Jul 23. pii: 1534. [Epub ahead of print]14(8):
    Mitochondria-Targeted Delivery of Camptothecin Based on HPMA Copolymer for Metastasis Suppression.
    Xiaoli Yi, Yue Yan, Xinran Shen, Lian Li, Yuan Huang.
      Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment.
    Keywords:  2-(dimethylamino) ethyl methacrylate; camptothecin; metastasis; mitochondria
    DOI:  https://doi.org/10.3390/pharmaceutics14081534
  179. Int J Biol Macromol. 2022 Jul 25. pii: S0141-8130(22)01600-2. [Epub ahead of print]
    Preparation, properties, and applications of gelatin-based hydrogels (GHs) in the environmental, technological, and biomedical sectors.
    Farwa Mushtaq, Zulfiqar Ali Raza, Syeda Rubab Batool, Muhammad Zahid, Ozgun Can Onder, Ammara Rafique, Muhammad Anwaar Nazeer.
      Gelatin's versatile functionalization offers prospects of facile and effective crosslinking as well as combining with other materials (e.g., metal nanoparticles, carbonaceous, minerals, and polymeric materials exhibiting desired functional properties) to form hybrid materials of improved thermo-mechanical, physio-chemical and biological characteristics. Gelatin-based hydrogels (GHs) and (nano)composite hydrogels possess unique functional features that make them appropriate for a wide range of environmental, technical, and biomedical applications. The properties of GHs could be balanced by optimizing the hydrogel design. The current review explores the various crosslinking techniques of GHs, their properties, composite types, and ultimately their end-use applications. GH's ability to absorb a large volume of water within the gel network via hydrogen bonding is frequently used for water retention (e.g., agricultural additives), and absorbency towards targeted chemicals from the environment (e.g., as wound dressings for absorbing exudates and in water treatment for absorbing pollutants). GH's controllable porosity makes its way to be used to restrict access to chemicals entrapped within the gel phase (e.g., cell encapsulation), regulate the release of encapsulated cargoes within the GH (e.g., drug delivery, agrochemicals release). GH's soft mechanics closely resembling biological tissues, make its use in tissue engineering to deliver suitable mechanical signals to neighboring cells. This review discussed the GHs as potential materials for the creation of biosensors, drug delivery systems, antimicrobials, modified electrodes, water adsorbents, fertilizers and packaging systems, among many others. The future research outlooks are also highlighted.
    Keywords:  Composite hydrogels; Crosslinking; Functionalization; Gelatin-based hydrogels; Structure-property relationship
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.168
  180. Molecules. 2022 Jul 23. pii: 4707. [Epub ahead of print]27(15):
    Biological Evaluation, Phytochemical Screening, and Fabrication of Indigofera Linifolia Leaves Extract-Loaded Nanoparticles.
    Muhammad Talha, Noor Ul Islam, Muhammad Zahoor, Abdul Sadiq, Asif Nawaz, Farhat Ali Khan, Naila Gulfam, Saleh A Alshamrani, Mohammed H Nahari, Mohammed Abdulrahman Alshahrani, Mater H Mahnashi, Syed Shams Ul Hassan.
      Indigofera linifolia is a medicinally important plant, and by virtue of its rich phytochemical composition, this plant is widely used as essential component in traditional medication systems. Due to its wide range of medicinal applications, the extract-loaded chitosan (Ext+Ch), extract-loaded PEG (Ext+PEG), and extract-loaded locust bean gum (Ext+LGB) nanoparticles (NPs) were prepared in the present study. The prepared NPs were then evaluated for their antibacterial, antioxidant, and antidiabetic potentials. Antibacterial activities of the crude extract and the synthesized NPs were performed following standard procedures reported in the literature. The antioxidant capabilities of extract and NPs were evaluated using DPPH free radical scavenging assay. The antidiabetic potential of the samples was evaluated against α-amylase and α-glucosidase. Ext+PEG NPs showed more potent antibacterial activity against the selected strains of bacteria with the highest activity against Escherichia coli. The lowest antibacterial potential was observed for Ext+LGB NPs. The Ext+LGB NPs IC50 value of 39 μg/mL was found to be the most potent inhibitor of DPPH free radicals. Ext+LGB NPs showed a greater extent of inhibition against α-glucosidase and α-amylase with an IC50 of 83 and 78 μg/mL, whereas for the standard acarbose the IC50 values recorded against the mentioned enzymes were 69 and 74 μg/mL, respectively. A high concentration of phenolics and flavonoids in the crude extract was confirmed through TPC and TFC tests, HPLC profiling, and GC-MS analysis. It was considered that the observed antibacterial, antidiabetic, and antioxidant potential might be due the presence of these phenolics and flavonoids detected. The plant could thus be considered as a potential candidate to be used as a remedy of the mentioned health complications. However, further research in this regard is needed to isolate the exact responsible compounds of the observed biological potentials exhibited by the crude extract. Further, toxicity and pharmacological evaluations in animal models are also needed to establish the safety or toxicity profile of the plant.
    Keywords:  Indigofera linifolia; antidiabetic; antioxidant; nanoparticles
    DOI:  https://doi.org/10.3390/molecules27154707
  181. Biomater Adv. 2022 Jun 08. pii: S2772-9508(22)00256-4. [Epub ahead of print]139 212979
    Multifunctional hydrogel loaded with 4-octyl itaconate exerts antibacterial, antioxidant and angiogenic properties for diabetic wound repair.
    Qiuyue Ding, Xirui Jing, Sheng Yao, Weijie Su, Bing Ye, Yanzhen Qu, Fei Gao, Tingfang Sun, Xiaodong Guo.
      Cutaneous wound healing, especially diabetic wound healing, is a common clinical problem. Reactive oxygen species (ROS) and bacterial infection are two major factors in the induction of oxidative stress and inflammation, leading to impeded angiogenesis and wound healing. However, it is still very difficult to reverse the harsh microenvironment of chronic inflammation and excessive oxidative stress on diabetic wound. Itaconate, an endogenous metabolite, has recently attracted extensive attention as a critical immune-regulator. In this study, we used 4-octyl itaconate (4OI), a cell-permeable itaconate derivative, to have antioxidative and anti-inflammatory functions for diabetic wound regeneration. Simultaneously, an injectable, self-healing, and antibacterial dynamic coordinative hydrogel was manufactured by binding the 4-arm polyethylene glycol (PEG) with silver nitrate to deliver the bioactive molecule. In vitro experiments confirmed that 4OI@PEG hydrogel could inhibit bacterial growth, protect human umbilical vein endothelial cells from ROS damage and enhance neovascularization. In addition, the hydrogel increased mitochondrial polarization and reduced mitochondrial fragmentation by activating the Keap1-Nrf2 antioxidant defense system. In vivo experiments proved that this multifunctional hydrogel facilitated diabetic wound healing by inhibiting local inflammation and promoting angiogenesis. Collectively, 4OI-loaded multifunctional materials could reverse various unfavorable microenvironments, such as excessive oxidative stress, inflammation, and infection, and can promote neovascularization; thus, such materials show great promise for the treatment of diabetic ulcers.
    Keywords:  4-octyl itaconate; Diabetic wound healing; Oxidative stress; Self-healing hydrogel; Vascularization
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212979
  182. Cell Biol Int. 2022 Jul 23.
    Diosgenin promotes cisplatin-induced apoptosis through oxidative DNA damage in A549 non-small cell lung cells.
    Qing Wang, Liqiong Zhang, Youchuan Xiao, Asghar Ghaemnezhad.
      The efficacy of cisplatin-based chemotherapy in malignancy is limited by the occurrence of innate and acquired drug resistance. Clinical observations suggest that targeting phytopharmaceuticals is the right choice to enhance the effectiveness of conventional chemotherapy. We aimed to evaluate the effects of diosgenin (DG) combined with cisplatin on apoptosis and its underlying mechanisms in the A549 non-small cell lung cells. Cell viability was measured using an MTT assay. Western blot was used for the measurement of γ-H2AX and 8-Hydroxy-2'-deoxyguanosine expression level. DCFH-DA fluorescence dye was used to detect reactive oxygen species (ROS) in cells. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase were also assessed. For evaluation of apoptosis, TUNEL assay was used. DG significantly increases the cytotoxic effects of cisplatin. Besides, DG considerably increased the expression levels of γ-H2AX in cells. Upon melatonin treatment, ROS levels were increased, and antioxidant enzymes expression levels were significantly decreased. Co-treatment of DG and cisplatin resulted in increased cellular cytotoxicity through increasing ROS levels, inducing oxidative DNA damage, and decreasing cellular antioxidant defense, hence led to potent induction of apoptosis in tumor cells.
    Keywords:  DNA damage; apoptosis; cancer; chemotherapy; cisplatin; diosgenin
    DOI:  https://doi.org/10.1002/cbin.11862
  183. Int J Mol Sci. 2022 Jul 22. pii: 8083. [Epub ahead of print]23(15):
    Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma.
    Sumit Siddharth, Panjamurthy Kuppusamy, Qitong Wu, Arumugam Nagalingam, Neeraj K Saxena, Dipali Sharma.
      Hepatocellular carcinoma (HCC) incidence, as well as related mortality, has been steadily increasing in the USA and across the globe, partly due to the lack of effective therapeutic options for advanced HCC. Though sorafenib is considered standard-of-care for advanced HCC, it only improves median survival by a few months when compared to placebo. Sorafenib is also associated with several unpleasant side effects that often lead to early abatement of therapy. Here, we investigate whether a combination regimen including low-dose sorafenib and a non-toxic dose of anti-diabetic drug metformin can achieve effective inhibition of HCC. Indeed, combining metformin with low-dose sorafenib inhibited growth, proliferation, migration, and invasion potential of HCC cells. We observed a 5.3- and 1.9-fold increase in sub-G1 population in the combination treatment compared to sorafenib alone. We found that the combination of metformin enhanced the efficacy of sorafenib and inhibited the MAPK/ERK/Stat3 axis. Our in vivo studies corroborated the in vitro findings, and mice harboring HepG2-derived tumors showed effective tumor reduction upon treatment with low-dose sorafenib and metformin combination. This work sheds light on a therapeutic strategy aiming to augment sorafenib efficacy or dose-de-escalation that may prove beneficial in circumventing sorafenib resistance as well as minimizing related side effects.
    Keywords:  ERK; MAPK; Stat3; combination treatment; hepatocellular carcinoma; metformin; sorafenib
    DOI:  https://doi.org/10.3390/ijms23158083
  184. Pharmaceuticals (Basel). 2022 Jun 23. pii: 780. [Epub ahead of print]15(7):
    Pharmacological Potential of Lathyrane-Type Diterpenoids from Phytochemical Sources.
    Fátima Vela, Abdellah Ezzanad, Alan Christy Hunter, Antonio José Macías-Sánchez, Rosario Hernández-Galán.
      Lathyrane diterpenoids are one of the primary types of secondary metabolites present in the genus Euphorbia and one of the largest groups of diterpenes. They are characterized by having a highly oxygenated tricyclic system of 5, 11 and 3 members. These natural products and some synthetic derivatives have shown numerous interesting biological activities with clinical potential against various diseases, such as cytotoxic activity against cancer cell lines, multi-drug resistance reversal, antiviral properties, anti-inflammatory activity and their capability to induce proliferation or differentiation into neurons of neural progenitor cells. The structure of the lathyrane skeleton could be considered privileged because its framework is able to direct functional groups in a well-defined space. The favorable arrangement of these makes interaction possible with more than one target. This review aims to highlight the evidence of lathyranes as privileged structures in medicinal chemistry. Chemical structures of bioactive compounds, the evaluation of biological properties of natural and semisynthetic derivatives, and the exploration of the mechanisms of action as well as target identification and some aspects of their targeted delivery are discussed.
    Keywords:  Euphorbia; biological activity; diterpene; lathyrane
    DOI:  https://doi.org/10.3390/ph15070780
  185. Biomater Adv. 2022 Jul 09. pii: S2772-9508(22)00298-9. [Epub ahead of print]139 213021
    Tailoring nanoparticles design for enhanced heating efficiency and improved magneto-chemo therapy for glioblastoma.
    Ruby Gupta, Tashmeen Kaur, Anjali Chauhan, Ravi Kumar, Bijoy K Kuanr, Deepika Sharma.
      Development of multifunctional magnetic nanomaterials (MNPs) with improved heat-generating capabilities and effective combination with localized chemotherapy has emerged as a promising therapeutic regime for solid tumors like glioblastoma. In this regard, the shape-dependent hyperthermic and chemo-therapeutic potential of nanomaterials, has not been extensively explored. Here we present, development of various morphological designs of MNPs including spherical, clusters, rods and cubic; to compare the effect of shape on tuning the properties of MNPs that are relevant to many potential biomedical applications like drug delivery, cellular uptake and heat generation. The study includes extensive comparison of morpho-structural characteristics, size distributions, chemical composition, surface area measurements and magnetic properties of the variable shaped MNPs. Further the heating efficiencies in aqueous and cellular environments and heat triggered drug release profiles for successful magneto-chemotherapy were compared among all in-house synthesized MNPs. Under biosafety limit considerations given by Hergt's limit (H*f value <5 × 109 Am-1 s-1), cuboidal shaped MNPs demonstrated highest heating efficiency owing to magnetosome-like chain formation along with sustained drug release profile as compared to other synthesized MNPs. The mechanism of cancer cell death mediated via magneto-chemotherapy was elucidated to be the oxidative stress-mediated apoptotic cell death pathway. In vivo studies further demonstrated complete tumor regression only in the magneto-chemotherapy treated group. These findings suggest the potential of combinatorial therapy to overcome the clinical limitations of the independent therapies for advanced thermotherapy of glioblastoma.
    Keywords:  Anisotropy; Doxorubicin; Magnetic hyperthermia; Nanomaterials; Triggered release
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213021
  186. Molecules. 2022 Jul 07. pii: 4364. [Epub ahead of print]27(14):
    Cecropin-Loaded Zeolitic Imidazolate Framework Nanoparticles with High Biocompatibility and Cervical Cancer Cell Toxicity.
    Jingwen Jiang, Yanzhu Pan, Jinyao Li, Lijie Xia.
      Cecropins (CECs) are insect venom-derived amphiphilic peptides with numerous pharmacological effects, including anti-inflammatory, antibacterial, antiviral, and anti-tumor activities. Cecropins induce tumor cell death by disrupting phospholipid membrane integrity. However, non-specific cytotoxicity and in vivo rapid degradation limit clinical application. Nanotechnologies provide novel strategies for tumor eradication, including nanocarriers that can precisely target drugs to tumor tissue. We report the fabrication of CEC-encapsulated zeolitic imidazolate framework 8 (ZIF-8) nanoparticles (CEC@ZIF-8 NPs) via the preparation of CEC@ZIF-8 NPs in pure water by one-pot stirring. This method yielded morphologically uniform NPs with 20 wt% drug loading capacity and 9% loading efficiency. The NP formulation protected CECs from proteasome degradation, enhanced peptide bioavailability, promoted HeLa tumor cell uptake, and increased antitumor efficacy compared to free CECs. In conclusion, this ZIF-8 encapsulation strategy may enhance the clinical applicability of CECs and other antitumor peptides.
    Keywords:  antitumor; cecropins; nanoparticles; zeolitic imidazolate framework
    DOI:  https://doi.org/10.3390/molecules27144364
  187. Int J Mol Sci. 2022 Jul 19. pii: 7971. [Epub ahead of print]23(14):
    Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma.
    Jin Hong Lim, Keunwan Park, Kyung Hwa Choi, Chan Wung Kim, Jae Ha Lee, Raymond Weicker, Cheol-Ho Pan, Seok-Mo Kim, Ki Cheong Park.
      Drug resistance causes therapeutic failure in refractory cancer. Cancer drug resistance stems from various factors, such as patient heterogeneity and genetic alterations in somatic cancer cells, including those from identical tissues. Generally, resistance is intrinsic for cancers; however, cancer resistance becomes common owing to an increased drug treatment. Unfortunately, overcoming this issue is not yet possible. The present study aimed to evaluate a clinical approach using candidate compounds 19 and 23, which are sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitors, discovered using the evolutionary chemical binding similarity method. mRNA sequencing indicated SERCA as the dominant marker of patient-derived anti-cancer drug-resistant hepatocellular carcinoma (HCC), but not of patient-derived anti-cancer drug-sensitive HCC. Candidate compounds 19 and 23 led to significant tumor shrinkage in a tumor xenograft model of anti-cancer drug-resistant patient-derived HCC cells. Our results might be clinically significant for the development of novel combinatorial strategies that selectively and efficiently target highly malignant cells such as drug-resistant and cancer stem-like cells.
    Keywords:  cancer stem cells; candidate 19; candidate 23; endoplasmic reticulum stress; patient-derived anti-cancer drug-resistant hepatocellular carcinoma; sarcoplasmic/endoplasmic reticulum calcium ATPase; thapsigargin
    DOI:  https://doi.org/10.3390/ijms23147971
  188. Food Funct. 2022 Jul 25.
    Addition of grapes to both a standard and a high-fat Western pattern diet modifies hepatic and urinary metabolite profiles in the mouse.
    Diren Beyoğlu, Eun-Jung Park, Adolfo Quiñones-Lombraña, Asim Dave, Falguni Parande, John M Pezzuto, Jeffrey R Idle.
      The benefits of fruit and vegetable dietary consumption are largely defined in epidemiological terms. Relatively little is known about the discrete effects on metabolic pathways elicited by individual dietary fruits and vegetables. To address this, grape powder was added to both a standard and a high-fat Western pattern diet given to 10-week-old female C57BL/6J mice for a period of 91 days, whereupon 24 h urines were collected and the mice euthanized after a 12 h fast for the collection of liver tissue. Alterations in hepatic and urinary metabolite patterns were determined by gas chromatography-mass spectrometry-based metabolomics. Urinary excretion of the gut microbiota metabolites 4-hydroxyphenylacetic acid, 5-hydroxyindole, glyceric acid, gluconic acid and myo-inositol was attenuated when grape was added to the standard diet but the gut microbiota metabolites gluconic acid, scyllo-inositol, mannitol, xylitol, 5-hydroxyindole and 2-deoxyribonic acid were increased in urine when grape was added to the high-fat diet. Increased hepatic ascorbic acid and 5-oxoproline levels indicated the anti-oxidant effect of grape powder on the liver. Pathway enrichment analysis demonstrated that for both standard and high-fat diets, grape addition significantly upregulated the malate-aspartate shuttle indicating enhanced hepatic utilization of glucose via cytosolic glycolysis for mitochondrial ATP production. It is concluded that a grape diet reprogrammes gut microbiota metabolism, attenuates the hepatic oxidative stress of a high-fat diet and increases the efficiency of glucose utilization by the liver for energy production.
    DOI:  https://doi.org/10.1039/d2fo00961g
  189. Polymers (Basel). 2022 Jul 06. pii: 2764. [Epub ahead of print]14(14):
    Current Advances in the Development of Hydrogel-Based Wound Dressings for Diabetic Foot Ulcer Treatment.
    Viviana R Güiza-Argüello, Víctor A Solarte-David, Angie V Pinzón-Mora, Jhair E Ávila-Quiroga, Silvia M Becerra-Bayona.
      Diabetic foot ulcers (DFUs) are one of the most prevalent complications associated with diabetes mellitus. DFUs are chronic injuries that often lead to non-traumatic lower extremity amputations, due to persistent infection and other ulcer-related side effects. Moreover, these complications represent a significant economic burden for the healthcare system, as expensive medical interventions are required. In addition to this, the clinical treatments that are currently available have only proven moderately effective, evidencing a great need to develop novel strategies for the improved treatment of DFUs. Hydrogels are three-dimensional systems that can be fabricated from natural and/or synthetic polymers. Due to their unique versatility, tunability, and hydrophilic properties, these materials have been extensively studied for different types of biomedical applications, including drug delivery and tissue engineering applications. Therefore, this review paper addresses the most recent advances in hydrogel wound dressings for effective DFU treatment, providing an overview of current perspectives and challenges in this research field.
    Keywords:  diabetic foot; hydrogel; tissue engineering; wound dressing
    DOI:  https://doi.org/10.3390/polym14142764
  190. Molecules. 2022 Jul 13. pii: 4468. [Epub ahead of print]27(14):
    Development and Optimization of Ciprofloxacin HCl-Loaded Chitosan Nanoparticles Using Box-Behnken Experimental Design.
    Noha M Soliman, Faiyaz Shakeel, Nazrul Haq, Fars K Alanazi, Sultan Alshehri, Mohsen Bayomi, Ahmed S M Alenazi, Ibrahim A Alsarra.
      Various chitosan (CS)-based nanoparticles (CS-NPs) of ciprofloxacin hydrochloride (CHCl) have been investigated for therapeutic delivery and to enhance antimicrobial efficacy. However, the Box-Behnken design (BBD)-supported statistical optimization of NPs of CHCl has not been performed in the literature. As a result, the goal of this study was to look into the key interactions and quadratic impacts of formulation variables on the performance of CHCl-CS-NPs in a systematic way. To optimize CHCl-loaded CS-NPs generated by the ionic gelation process, the response surface methodology (RSM) was used. The BBD was used with three factors on three levels and three replicas at the central point. Tripolyphosphate, CS concentrations, and ultrasonication energy were chosen as independent variables after preliminary screening. Particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), and in vitro release were the dependent factors (responses). Prepared NPs were found in the PS range of 198-304 nm with a ZP of 27-42 mV. EE and drug release were in the range of 23-45% and 36-61%, respectively. All of the responses were optimized at the same time using a desirability function based on Design Expert® modeling and a desirability factor of 95%. The minimum inhibitory concentration (MIC) of the improved formula against two bacterial strains, Pseudomonas aeruginosa and Staphylococcus aureus, was determined. The MIC of the optimized NPs was found to be decreased 4-fold compared with pure CHCl. The predicted and observed values for the optimized formulation were nearly identical. The BBD aided in a better understanding of the intrinsic relationship between formulation variables and responses, as well as the optimization of CHCl-loaded CS-NPs in a time- and labor-efficient manner.
    Keywords:  Box–Behnken design; antibacterial effects; chitosan nanoparticles; ciprofloxacin HCl; desirability function; response surface methodology
    DOI:  https://doi.org/10.3390/molecules27144468
  191. Drug Deliv. 2022 Dec;29(1): 2498-2512
    Chitosan-modified hollow manganese dioxide nanoparticles loaded with resveratrol for the treatment of spinal cord injury.
    Yingqiao Li, Zhiru Zou, Jinyu An, Qian Wu, Le Tong, Xifan Mei, He Tian, Chao Wu.
      Spinal cord injury (SCI) is a serious central nervous system disease, and secondary injury, including oxidative stress, the inflammatory response and accompanying neuronal apoptosis, will aggravate the condition. Due to the existence of the blood-spinal cord barrier (BSCB), the existing drugs for SCI treatment are difficulty to reach the injury site and thus their efficacy is limited. In this study, we designed chitosan-modified hollow manganese dioxide nanoparticles (CM) for the delivery of resveratrol to help it pass through the BSCB. Resveratrol (Res), a poorly soluble drug, was adsorbed into CM with a particle size of approximately 130 nm via the adsorption method, and the drug loading reached 21.39 ± 2.53%. In vitro dissolution experiment, the Res release of the loaded sample (CMR) showed slowly release behavior and reached about 87% at 36 h. In vitro at the cellular level and in vivo at the animal level experiments demonstrated that CMR could alleviate significantly oxidative stress by reducing level of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and increasing glutathione peroxidase (GSH) level. Additionally, immunofluorescence (iNOS, IL-1β, and Cl caspase-3) and western blot (iNOS, cox-2, IL-1β, IL-10, Cl caspase-3, bax, and bcl-2) were used to detect the expression of related factors, which verified that CMR could also reduce inflammation and neuronal apoptosis. These results indicated that CM, as a potential central nervous system drug delivery material, was suitable for SCI treatment.
    Keywords:  Oxidative stress; apoptosis; blood–spinal cord barrier; inflammation
    DOI:  https://doi.org/10.1080/10717544.2022.2104957
  192. Bioengineering (Basel). 2022 Jul 15. pii: 320. [Epub ahead of print]9(7):
    Nano-Based Theranostic Platforms for Breast Cancer: A Review of Latest Advancements.
    Rabia Arshad, Maria Hassan Kiani, Abbas Rahdar, Saman Sargazi, Mahmood Barani, Shirin Shojaei, Muhammad Bilal, Deepak Kumar, Sadanand Pandey.
      Breast cancer (BC) is a highly metastatic multifactorial disease with various histological and molecular subtypes. Due to recent advancements, the mortality rate in BC has improved over the past five decades. Detection and treatment of many cancers are now possible due to the application of nanomedicine in clinical practice. Nanomedicine products such as Doxil® and Abraxane® have already been extensively used for BC adjuvant therapy with favorable clinical outcomes. However, these products were designed initially for generic anticancer purposes and not specifically for BC treatment. With a better understanding of the molecular biology of BC, several novel and promising nanotherapeutic strategies and devices have been developed in recent years. In this context, multi-functionalized nanostructures are becoming potential carriers for enhanced chemotherapy in BC patients. To design these nanostructures, a wide range of materials, such as proteins, lipids, polymers, and hybrid materials, can be used and tailored for specific purposes against BC. Selective targeting of BC cells results in the activation of programmed cell death in BC cells and can be considered a promising strategy for managing triple-negative BC. Currently, conventional BC screening methods such as mammography, digital breast tomosynthesis (DBT), ultrasonography, and magnetic resonance imaging (MRI) are either costly or expose the user to hazardous radiation that could harm them. Therefore, there is a need for such analytical techniques for detecting BC that are highly selective and sensitive, have a very low detection limit, are durable, biocompatible, and reproducible. In detecting BC biomarkers, nanostructures are used alone or in conjunction with numerous molecules. This review intends to highlight the recent advances in nanomedicine in BC treatment and diagnosis, emphasizing the targeting of BC cells that overexpress receptors of epidermal growth factors. Researchers may gain insight from these strategies to design and develop more tailored nanomedicine for BC to achieve further improvements in cancer specificity, antitumorigenic effects, anti-metastasis effects, and drug resistance reversal effects.
    Keywords:  breast cancer; cancer imaging; nanoparticles; nanotechnology; theranostics
    DOI:  https://doi.org/10.3390/bioengineering9070320
  193. Molecules. 2022 Jul 19. pii: 4615. [Epub ahead of print]27(14):
    Peptide-Mediated Targeted Delivery of Aloe-Emodin as Anticancer Drug.
    Annarita Stringaro, Stefano Serra, Alessandro Gori, Annarica Calcabrini, Marisa Colone, Maria Luisa Dupuis, Francesca Spadaro, Serena Cecchetti, Alberto Vitali.
      Breast cancer is one of the most diffuse cancers in the world and despite the availability of the different drugs employed against it, the need for new and particularly more specific molecules is ever growing. In this framework, natural products are increasingly assuming an important role as new anticancer drugs. Aloe-emodin (AE) is one of the best characterized molecules in this field. The functionalization of bioactive natural products with selected peptide sequences to enhance their bioavailability and specificity of action is a powerful and promising strategy. In this study, we analyzed the cell specificity, cell viability effects, intracellular distribution, and immune cell response of a new peptide conjugate of Aloe-emodin in SKBR3 and A549 cell lines by means of viability tests, flow cytometry, and confocal microscopy. The conjugate proved to be more effective at reducing cell viability than AE in both cell lines. Furthermore, the results showed that it was mainly internalized within the SKBR3 cells, showing a nuclear localization, while A459 cells displayed mainly a cytoplasmic distribution. A preserving effect of the conjugate on NKs' cell function was also observed. The designed conjugate showed a promising specific activity towards HER2-expressing cells coupled with an enhanced water solubility and a higher cytotoxicity; thus, the resulting proof-of-concept molecule can be further improved as an anticancer compound.
    Keywords:  Aloe-emodin; HER2; SKBR3; bioconjugate; breast cancer; drug delivery
    DOI:  https://doi.org/10.3390/molecules27144615
  194. Pharmaceuticals (Basel). 2022 Jul 17. pii: 881. [Epub ahead of print]15(7):
    Co-Delivery of 5-Fluorouracil and Paclitaxel in Mitochondria-Targeted KLA-Modified Liposomes to Improve Triple-Negative Breast Cancer Treatment.
    Tianyu Chen, Hui Chen, Yichun Jiang, Qi Yan, Shuling Zheng, Min Wu.
      In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against triple-negative breast cancer (TNBC) was evaluated. KLA-5-FU/PTX Lps were prepared using the thin-film dispersion method, and their in vitro anticancer efficacy was assessed in human breast cancer cells (MDA-MB-231). An MDA-MB-231 tumor-bearing mouse model was also established to evaluate their antitumor efficacy in vivo. KLA-5-FU/PTX Lps showed enhanced cytotoxicity against MDA-MB-231 cells, improved drug delivery to mitochondria, and induced mitochondria-mediated apoptosis. The modified liposomes also showed favorable antitumor activity in vivo due to their strong ability to target tumors and mitochondria. The liposomes showed no obvious systemic toxicity. Our results suggest that KLA-5-FU/PTX Lps are a promising system with which to target the delivery of antitumor drugs to mitochondria as a treatment for TNBC.
    Keywords:  5-fluorouracil; TNBC; liposomes; mitochondrial targeting; paclitaxel
    DOI:  https://doi.org/10.3390/ph15070881
  195. Metabolites. 2022 Jul 15. pii: 652. [Epub ahead of print]12(7):
    Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma.
    Yuchan Li, Omar Elakad, Sha Yao, Alexander von Hammerstein-Equord, Marc Hinterthaner, Bernhard C Danner, Carmelo Ferrai, Philipp Ströbel, Stefan Küffer, Hanibal Bohnenberger.
      Activating KRAS mutations occur in about 30% of pulmonary adenocarcinoma (AC) cases and the discovery of specific inhibitors of G12C-mutated KRAS has considerably improved the prognosis for a subgroup of about 14% of non-small cell lung cancer (NSCLC) patients. However, even in patients with a KRAS G12C mutation, the overall response rate only reaches about 40% and mutations other than G12C still cannot be targeted. Despite the fact that one-carbon metabolism (1CM) and epigenetic regulation are known to be dysregulated by aberrant KRAS activity, we still lack evidence that co-treatment with drugs that regulate these factors might ameliorate response rates and patient prognosis. In this study, we show a direct dependency of Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and Enhancer of Zeste Homolog 2 (EZH2) expression on mutationally activated KRAS and their prognostic relevance in KRAS-mutated AC. We show that aberrant KRAS activity generates a vulnerability of AC cancer cell lines to both MTHFD2 and EZH2 inhibitors. Importantly, co-inhibition of both factors was synergistically effective and comparable to KRASG12C inhibition alone, paving the way for their use in a therapeutic approach for NSCLC cancer patients.
    Keywords:  EZH2; KRAS; MTHFD2; one-carbon metabolism; pulmonary adenocarcinoma
    DOI:  https://doi.org/10.3390/metabo12070652
  196. Molecules. 2022 Jul 22. pii: 4697. [Epub ahead of print]27(15):
    Atheroprotective Effects of Glycyrrhiza glabra L.
    Yuliya V Markina, Tatiana V Kirichenko, Alexander M Markin, Irina Y Yudina, Antonina V Starodubova, Igor A Sobenin, Alexander N Orekhov.
      Cardiovascular diseases associated with atherosclerosis are the major cause of death in developed countries. Early prevention and treatment of atherosclerosis are considered to be an important aspect of the therapy of cardiovascular disease. Preparations based on natural products affect the main pathogenetic steps of atherogenesis, and so represent a perspective for the long-term prevention of atherosclerosis development. Numerous experimental and clinical studies have demonstrated the multiple beneficial effects of licorice and its bioactive compounds-anti-inflammatory, anti-cytokine, antioxidant, anti-atherogenic, and anti-platelet action-which allow us to consider licorice as a promising atheroprotective agent. In this review, we summarized the current knowledge on the licorice anti-atherosclerotic mechanisms of action based on the results of experimental studies, including the results of the in vitro study demonstrating licorice effect on the ability of blood serum to reduce intracellular cholesterol accumulation in cultured macrophages, and presented the results of clinical studies confirming the ameliorating activity of licorice in regard to traditional cardiovascular risk factors as well as the direct anti-atherosclerotic effect of licorice.
    Keywords:  atherosclerosis; cholesterol accumulation; cytokines; glabridin; inflammation; licorice
    DOI:  https://doi.org/10.3390/molecules27154697
  197. Nanomaterials (Basel). 2022 Jul 07. pii: 2337. [Epub ahead of print]12(14):
    Inorganic Nanomaterials versus Polymer-Based Nanoparticles for Overcoming Neurodegeneration.
    Simona Martano, Valeria De Matteis, Mariafrancesca Cascione, Rosaria Rinaldi.
      Neurodegenerative disorders (NDs) affect a great number of people worldwide and also have a significant socio-economic impact on the aging population. In this context, nanomedicine applied to neurological disorders provides several biotechnological strategies and nanoformulations that improve life expectancy and the quality of life of patients affected by brain disorders. However, available treatments are limited by the presence of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (B-CSFB). In this regard, nanotechnological approaches could overcome these obstacles by updating various aspects (e.g., enhanced drug-delivery efficiency and bioavailability, BBB permeation and targeting the brain parenchyma, minimizing side effects). The aim of this review is to carefully explore the key elements of different neurological disorders and summarize the available nanomaterials applied for neurodegeneration therapy looking at several types of nanocarriers. Moreover, nutraceutical-loaded nanoparticles (NPs) and synthesized NPs using green approaches are also discussed underling the need to adopt eco-friendly procedures with a low environmental impact. The proven antioxidant properties related to several natural products provide an interesting starting point for developing efficient and green nanotools useful for neuroprotection.
    Keywords:  antioxidants; blood–brain barrier; brain-targeting; drug-delivery; nanocarriers; neurodegeneration; neuroprotection
    DOI:  https://doi.org/10.3390/nano12142337
  198. J Nanobiotechnology. 2022 Jul 26. 20(1): 345
    Self-adjuvanting cancer nanovaccines.
    Zhiyun Liao, Jing Huang, Pui-Chi Lo, Jonathan F Lovell, Honglin Jin, Kunyu Yang.
      Nanovaccines, a new generation of vaccines that use nanoparticles as carriers and/or adjuvants, have been widely used in the prevention and treatment of various diseases, including cancer. Nanovaccines have sparked considerable interest in cancer therapy due to a variety of advantages, including improved access to lymph nodes (LN), optimal packing and presentation of antigens, and induction of a persistent anti-tumor immune response. As a delivery system for cancer vaccines, various types of nanoparticles have been designed to facilitate the delivery of antigens and adjuvants to lymphoid organs and antigen-presenting cells (APCs). Particularly, some types of nanoparticles are able to confer an immune-enhancing capability and can themselves be utilized for adjuvant-like effect for vaccines, suggesting a direction for a better use of nanomaterials and the optimization of cancer vaccines. However, this role of nanoparticles in vaccines has not been well studied. To further elucidate the role of self-adjuvanting nanovaccines in cancer therapy, we review the mechanisms of antitumor vaccine adjuvants with respect to nanovaccines with self-adjuvanting properties, including enhancing cross-presentation, targeting signaling pathways, biomimicking of the natural invasion process of pathogens, and further unknown mechanisms. We surveyed self-adjuvanting cancer nanovaccines in clinical research and discussed their advantages and challenges. In this review, we classified self-adjuvanting cancer nanovaccines according to the underlying immunomodulatory mechanism, which may provide mechanistic insights into the design of nanovaccines in the future.
    Keywords:  Antigen presentation; Cancer immunotherapy; Lymph node; Nanovaccine; Self-adjuvanting
    DOI:  https://doi.org/10.1186/s12951-022-01545-z
  199. Pharmaceuticals (Basel). 2022 Jun 28. pii: 808. [Epub ahead of print]15(7):
    Phytochemicals as Regulators of Tumor Glycolysis and Hypoxia Signaling Pathways: Evidence from In Vitro Studies.
    Ioana-Ecaterina Pralea, Alina-Maria Petrache, Adrian Bogdan Tigu, Diana Gulei, Radu-Cristian Moldovan, Maria Ilieș, Raul Nicoară, Simona-Codruța Hegheș, Alina Uifălean, Cristina-Adela Iuga.
      The full understanding of the complex nature of cancer still faces many challenges, as cancers arise not as a result of a single target disruption but rather involving successive genetic and epigenetic alterations leading to multiple altered metabolic pathways. In this light, the need for a multitargeted, safe and effective therapy becomes essential. Substantial experimental evidence upholds the potential of plant-derived compounds to interfere in several important pathways, such as tumor glycolysis and the upstream regulating mechanisms of hypoxia. Herein, we present a comprehensive overview of the natural compounds which demonstrated, in vitro studies, an effective anticancer activity by affecting key regulators of the glycolytic pathway such as glucose transporters, hexokinases, phosphofructokinase, pyruvate kinase or lactate dehydrogenase. Moreover, we assessed how phytochemicals could interfere in HIF-1 synthesis, stabilization, accumulation, and transactivation, emphasizing PI3K/Akt/mTOR and MAPK/ERK pathways as important signaling cascades in HIF-1 activation. Special consideration was given to cell culture-based metabolomics as one of the most sensitive, accurate, and comprising approaches for understanding the response of cancer cell metabolome to phytochemicals.
    Keywords:  HIF-1 signaling pathway; Warburg effect; metabolomics; phytochemicals; tumor glycolysis; tumor hypoxia
    DOI:  https://doi.org/10.3390/ph15070808
  200. Toxins (Basel). 2022 Jul 05. pii: 460. [Epub ahead of print]14(7):
    Anticancer Activity of Bee Venom Components against Breast Cancer.
    Na-Yoen Kwon, Soo-Hyun Sung, Hyun-Kyung Sung, Jang-Kyung Park.
      While the survival rate has increased due to treatments for breast cancer, the quality of life has decreased because of the side effects of chemotherapy. Various toxins are being developed as alternative breast cancer treatments, and bee venom is drawing attention as one of them. We analyzed the effect of bee venom and its components on breast cancer cells and reviewed the mechanism underlying the anticancer effects of bee venom. Data up to March 2022 were searched from PubMed, EMBASE, OASIS, KISS, and Science Direct online databases, and studies that met the inclusion criteria were reviewed. Among 612 studies, 11 were selected for this research. Diverse drugs were administered, including crude bee venom, melittin, phospholipase A2, and their complexes. All drugs reduced the number of breast cancer cells in proportion to the dose and time. The mechanisms of anticancer effects included cytotoxicity, apoptosis, cell targeting, gene expression regulation, and cell lysis. Summarily, bee venom and its components exert anticancer effects on human breast cancer cells. Depending on the mechanisms of anticancer effects, side effects are expected to be reduced by using various vehicles. Bee venom and its components have the potential to prevent and treat breast cancer in the future.
    Keywords:  bee venom; breast cancer; melittin; phospholipase A2
    DOI:  https://doi.org/10.3390/toxins14070460
  201. Int J Mol Sci. 2022 Jul 23. pii: 8108. [Epub ahead of print]23(15):
    Role of Diet in Stem and Cancer Stem Cells.
    Francesca Puca, Monica Fedele, Debora Rasio, Sabrina Battista.
      Diet and lifestyle factors greatly affect health and susceptibility to diseases, including cancer. Stem cells' functions, including their ability to divide asymmetrically, set the rules for tissue homeostasis, contribute to health maintenance, and represent the entry point of cancer occurrence. Stem cell properties result from the complex integration of intrinsic, extrinsic, and systemic factors. In this context, diet-induced metabolic changes can have a profound impact on stem cell fate determination, lineage specification and differentiation. The purpose of this review is to provide a comprehensive description of the multiple "non-metabolic" effects of diet on stem cell functions, including little-known effects such as those on liquid-liquid phase separation and on non-random chromosome segregation (asymmetric division). A deep understanding of the specific dietetic requirements of normal and cancer stem cells may pave the way for the development of nutrition-based targeted therapeutic approaches to improve regenerative and anticancer therapies.
    Keywords:  SIRT1; asymmetric division; autophagy; caloric restriction; cancer stem cells; diet; mTOR; nutrients; stem cells
    DOI:  https://doi.org/10.3390/ijms23158108
  202. Prog Biomater. 2022 Jul 29.
    Therapeutic applications of curcumin nanomedicine formulations in cystic fibrosis.
    Cristina Quispe, Jesús Herrera-Bravo, Khushbukhat Khan, Zeeshan Javed, Prabhakar Semwal, Sakshi Painuli, Senem Kamiloglu, Miquel Martorell, Daniela Calina, Javad Sharifi-Rad.
      Medicinal applications of turmeric-derived curcumin have been known to mankind for long ages. Its potential in managing "cystic fibrosis" has also been evaluated. This autosomal recessive genetic disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which involves an impaired secretion of chloride ions and leads to hypersecretion of thick and sticky mucus and serious complications including airway obstruction, chronic lung infection, and inflammatory reactions. This narrative review aims to highlight the available evidence for the efficacy of curcumin nanoformulations in its potential treatment of cystic fibrosis. Recent research has shown that curcumin acts on the localized mutant CFTR ion channel at the plasma membrane. Preclinical studies have also shown that curcumin nanoformulations have promising effects in the treatment of cystic fibrosis. In this context, the purpose of this narrative review is to highlight the general bioactivity of curcumin, the types of formulations and related studies, thus opening new therapeutic perspectives for CF.
    Keywords:  Bioavailability; Curcumin nanoparticles; Cystic fibrosis; Molecular mechanisms; Signalling pathways
    DOI:  https://doi.org/10.1007/s40204-022-00198-3
  203. Sichuan Da Xue Xue Bao Yi Xue Ban. 2022 Jul;53(4): 564-572
    [Targeted Drug Therapy for Intracranial Tumors].
    Han Wang, Yue-Long Wang, Zhi-Yong Liu, Jian-Guo Xu.
      Intracranial tumors seriously affect the physical and mental health of humans. Due to variations in the nature and the growth site of tumors, individualized and specific treatment of patients with intracranial tumor has become a hotspot topic of research, and targeted drug therapy of intracranial tumors, an important subspecialty of precision medicine, has become a key issue that scientists are working hard to tackle. At present, the rapid development in molecular biology and genomics has provided corresponding targets for precision therapies of tumors. However, the blood-brain barrier and blood-tumor barrier prevent drugs from reaching intracranial targets. Therefore, finding effective ways to elevate the concentration of intracranial drugs has become the key issue concerning existing targeted therapies for intracranial tumors. Herein, we reviewed the current status of targeted drug therapy for different intracranial tumors and discussed their efficacy, intending to provide new perspectives for the treatment of intracranial tumors with targeted drugs in the future.
    Keywords:  Craniopharyngioma; Glioma; Meningioma; Pituitary adenoma; Schwannoma; Targeted drug therapy
    DOI:  https://doi.org/10.12182/20220760102
  204. Am J Chin Med. 2022 Jul 23. 1-53
    Angelica gigas: Signature Compounds, In Vivo Anticancer, Analgesic, Neuroprotective and Other Activities, and the Clinical Translation Challenges.
    Junxuan Lü, Cheng Jiang, Todd D Schell, Monika Joshi, Jay D Raman, Chengguo Xing.
      Angelica gigas Nakai (AGN) root is a medicinal herbal widely used in traditional medicine in Korea. AGN root ethanolic extract dietary supplements are marketed in the United States for memory health and pain management. We comprehensively reviewed the anticancer, analgesic, pro-memory and other bio-activities of AGN extract and its signature phytochemicals decursin, decursinol angelate, and decursinol a decade ago in 2012 and updated their anticancer activities in 2015. In the last decade, significant progress has been made for understanding the pharmacokinetics (PK) and metabolism of these compounds in animal models and single dose human PK studies have been published by us and others. In addition to increased knowledge of the known bioactivities, new bioactivities with potential novel health benefits have been reported in animal models of cerebral ischemia/stroke, anxiety, sleep disorder, epilepsy, inflammatory bowel disease, sepsis, metabolic disorders, osteoporosis, osteoarthritis, and even male infertility. Herein, we will update PK and metabolism of pyranocoumarins, review in vivo bioactivities from animal models and human studies, and critically appraise the relevant active compounds, the cellular and molecular pharmacodynamic targets, and pertinent mechanisms of action. Knowledge gaps include whether human pyranocoumarin PK metrics are AGN dose dependent and subjected to metabolic ceiling, or metabolic adaptation after repeated use. Critical clinical translation challenges include sourcing of AGN extracts, product consistency and quality control, and AGN dose optimization for different health conditions and disease indications. Future research directions are articulated to fill knowledge gaps and address these challenges.
    Keywords:  Angelica gigas; Decursin; Decursinol; In Vivo Bioactivities; Pyranocoumarins; Review
    DOI:  https://doi.org/10.1142/S0192415X2250063X
  205. Nutrients. 2022 Jul 21. pii: 2998. [Epub ahead of print]14(14):
    Mediterranean Diet on Sleep: A Health Alliance.
    Egeria Scoditti, Maria Rosaria Tumolo, Sergio Garbarino.
      The Mediterranean diet is a plant-based, antioxidant-rich, unsaturated fat dietary pattern that has been consistently associated with lower rates of noncommunicable diseases and total mortality, so that it is considered one of the healthiest dietary patterns. Clinical trials and mechanistic studies have demonstrated that the Mediterranean diet and its peculiar foods and nutrients exert beneficial effects against inflammation, oxidative stress, dysmetabolism, vascular dysfunction, adiposity, senescence, cognitive decline, neurodegeneration, and tumorigenesis, thus preventing age-associated chronic diseases and improving wellbeing and health. Nocturnal sleep is an essential physiological function, whose alteration is associated with health outcomes and chronic diseases. Scientific evidence suggests that diet and sleep are related in a bidirectional relationship, and the understanding of this association is important given their role in disease prevention. In this review, we surveyed the literature concerning the current state of evidence from epidemiological studies on the impact of the Mediterranean diet on nighttime sleep quantity and quality. The available studies indicate that greater adherence to the Mediterranean diet is associated with adequate sleep duration and with several indicators of better sleep quality. Potential mechanisms mediating the effect of the Mediterranean diet and its foods and nutrients on sleep are described, and gap-in-knowledge and new research agenda to corroborate findings are discussed.
    Keywords:  Mediterranean diet; inflammation; melatonin; mental health; metabolism; microbiota; sleep quality; sleep quantity; vasculoprotection
    DOI:  https://doi.org/10.3390/nu14142998
  206. Comp Biochem Physiol A Mol Integr Physiol. 2022 Jul 25. pii: S1095-6433(22)00137-4. [Epub ahead of print] 111279
    Effect of macronutrient and micronutrient manipulation on avian blood glucose concentration: A systematic review.
    Anthony J Basile, Kavita C Singh, Deborah F Watson, Karen L Sweazea.
      Animals with natural protections against diabetes complications may provide clues to improve human health. Birds are unique in their ability to avoid hyperglycemia-associated complications (e.g., glycation and oxidative stress) despite having naturally high blood glucose (BG) concentrations. This makes them useful models to elucidate strategies to prevent and/or treat diabetes-related complications in mammals. As diet plays a key role in BG concentration and diabetes risk, this systematic review aimed to summarize the effects of macro and micronutrient manipulation on avian BG. Three databases were searched (PubMed, SCOPUS, and Web of Science) for articles that met inclusion criteria: altered at least one nutrient and measured BG in at least one avian species. The search yielded 91 articles that produced 128 datasets (i.e., one nutrient manipulation in one sample). Across all macronutrient manipulations (n = 69 datasets), 62% reported no change in BG and 23% measured an increase (p < 0.001). Within the macronutrient groups (carbohydrate, lipid, protein, and mixed) most datasets showed no change in BG (67%, 62%, 52%, and 86%, respectively). Across micronutrient manipulations (n = 59 datasets), 51% demonstrated no change and 41% decreased BG (p < 0.001). While manipulations that altered vitamin intake largely produced no change in BG (62%), 48% of datasets examining altered mineral intake found no change and 46% decreased BG. Chromium was the most studied micronutrient (n = 24 datasets), where 67% of datasets reported a decrease in BG. These results suggest birds are largely able to maintain blood glucose homeostasis in response to altered nutrient intake indicative of dietary flexibility.
    Keywords:  Avian; Bird; Diet; Glucose; Macronutrient; Micronutrient; Nutrients
    DOI:  https://doi.org/10.1016/j.cbpa.2022.111279
  207. Nutrients. 2022 Jul 13. pii: 2867. [Epub ahead of print]14(14):
    Investigation of the Renal Protective Effect of Combined Dietary Polyphenols in Streptozotocin-Induced Diabetic Aged Rats.
    Yassine Chtourou, Maram Morjen, Rahma Ammar, Rania Mhiri, Mohamed Jemaà, Ines ELBini-Dhouib, Hamadi Fetoui, Najet Srairi-Abid, Naziha Marrakchi, Jed Jebali.
      Natural polyphenols are widely reported to have a large range of pharmacological properties, especially antioxidant activities and free radical scavenging capacities. In this study, we investigate the effects of naringin, chlorogenic acid, and quercetin mixtures (NCQ) on renal fibrosis in streptozotocin (STZ)-induced diabetic aged rats and its underlying mechanisms for ten consecutive weeks. The oxidative defense system in the kidneys of treated rats was found to be improved. Several biomarkers were investigated including the blood urea nitrogen, creatinine, and uric acid. Moreover, antioxidant parameters were evaluated and we found that superoxide dismutase, catalase, glutathione peroxidase, Na+-K+-ATPase activities, the nitric oxide production, the protein carbonyl, the advanced oxidation protein products, lipid peroxidation, and reduced glutathione levels were all significantly balanced and close to control values. In addition, NCQ restored renal injuries and fibrosis as assessed by histological method and molecular biology investigation of the matrix metalloproteinase, the transforming growth factor-beta TGF-β, the tumor necrosis factor TNFα, and p53 expression. Our study proposes the NCQ combination as potential plant-derived bioactive compounds to prevent diabetic nephropathy.
    Keywords:  natural polyphenols; pharmacological properties; renal fibrosis; streptozotocin-induced diabetic aged rats (STZ)
    DOI:  https://doi.org/10.3390/nu14142867
  208. Molecules. 2022 Jul 26. pii: 4774. [Epub ahead of print]27(15):
    Timeline of the Development of Skin-Lightening Active Ingredients in Japan.
    Kazuhisa Maeda.
      Japanese pharmaceutical cosmetics, often referred to as quasi-drugs, contain skin-lightening active ingredients formulated to prevent sun-induced pigment spots and freckles. Their mechanisms of action include suppressing melanin production in melanocytes and promoting epidermal growth to eliminate melanin more rapidly. For example, arbutin and rucinol are representative skin-lightening active ingredients that inhibit melanin production, and disodium adenosine monophosphate and dexpanthenol are skin-lightening active ingredients that inhibit melanin accumulation in the epidermis. In contrast, oral administration of vitamin C and tranexamic acid in pharmaceutical products can lighten freckles and melasma, and these products are more effective than quasi-drugs. On the basis of their clinical effectiveness, skin-lightening active ingredients can be divided into four categories according to their effectiveness and adverse effects. This review discusses academic research and development regarding skin-lightening ingredients in Japan.
    Keywords:  ingredient; melasma: pigment spots; pharmaceutical cosmetics; quasi-drug; skin-lightening
    DOI:  https://doi.org/10.3390/molecules27154774
  209. Pharmaceutics. 2022 Jul 18. pii: 1487. [Epub ahead of print]14(7):
    Self-Emulsifying Drug Delivery Systems: An Alternative Approach to Improve Brain Bioavailability of Poorly Water-Soluble Drugs through Intranasal Administration.
    Sara Meirinho, Márcio Rodrigues, Adriana O Santos, Amílcar Falcão, Gilberto Alves.
      Efforts in discovering new and effective neurotherapeutics are made daily, although most fail to reach clinical trials. The main reason is their poor bioavailability, related to poor aqueous solubility, limited permeability through biological membranes, and the hepatic first-pass metabolism. Nevertheless, crossing the blood-brain barrier is the major drawback associated with brain drug delivery. To overcome it, intranasal administration has become more attractive, in some cases even surpassing the oral route. The unique anatomical features of the nasal cavity allow partial direct drug delivery to the brain, circumventing the blood-brain barrier. Systemic absorption through the nasal cavity also avoids the hepatic first-pass metabolism, increasing the systemic bioavailability of highly metabolized entities. Nevertheless, most neurotherapeutics present physicochemical characteristics that require them to be formulated in lipidic nanosystems as self-emulsifying drug delivery systems (SEDDS). These are isotropic mixtures of oils, surfactants, and co-surfactants that, after aqueous dilution, generate micro or nanoemulsions loading high concentrations of lipophilic drugs. SEDDS should overcome drug precipitation in absorption sites, increase their permeation through absorptive membranes, and enhance the stability of labile drugs against enzymatic activity. Thus, combining the advantages of SEDDS and those of the intranasal route for brain delivery, an increase in drugs' brain targeting and bioavailability could be expected. This review deeply characterizes SEDDS as a lipidic nanosystem, gathering important information regarding the mechanisms associated with the intranasal delivery of drugs loaded in SEDDS. In the end, in vivo results after SEDDS intranasal or oral administration are discussed, globally revealing their efficacy in comparison with common solutions or suspensions.
    Keywords:  bioavailability; brain; intranasal; neurotherapeutics; self-emulsifying drug delivery systems
    DOI:  https://doi.org/10.3390/pharmaceutics14071487
  210. Biomolecules. 2022 Jun 23. pii: 875. [Epub ahead of print]12(7):
    Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties.
    Marco Fabbrini, Federica D'Amico, Monica Barone, Gabriele Conti, Mariachiara Mengoli, Patrizia Brigidi, Silvia Turroni.
      Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, and it is generally reported that a substantial elevation of their plasma concentration can only be achieved when they are consumed at pharmacological levels. Even so, positive effects have been reported associated with an average dietary consumption of several nutraceutical classes, meaning that the primary compound might not be solely responsible for all the biological effects. The in vivo activities of such biomolecules might be carried out by metabolites derived from gut microbiota fermentative transformation. This review discusses the structure and properties of phenolic nutraceuticals (i.e., polyphenols and tannins) and the putative role of the human gut microbiota in influencing the beneficial effects of such compounds.
    Keywords:  metabolites; microbiota; nutraceutical; polyphenol; tannin
    DOI:  https://doi.org/10.3390/biom12070875
  211. Cells. 2022 Jul 12. pii: 2178. [Epub ahead of print]11(14):
    Effects of Toxic AGEs (TAGE) on Human Health.
    Masayoshi Takeuchi, Akiko Sakasai-Sakai, Takanobu Takata, Jun-Ichi Takino, Yoshiki Koriyama.
      The habitual and excessive consumption of sugar (i.e., sucrose and high-fructose corn syrup, HFCS) is associated with the onset and progression of lifestyle-related diseases (LSRD). Advanced glycation end-products (AGEs) have recently been the focus of research on the factors contributing to LSRD. Approaches that inhibit the effects of AGEs may be used to prevent and/or treat LSRD; however, since the structures of AGEs vary depending on the type of reducing sugars or carbonyl compounds to which they respond, difficulties are associated with verifying that AGEs are an etiological factor. Cytotoxic AGEs derived from glyceraldehyde, a triose intermediate in the metabolism of glucose and fructose, have been implicated in LSRD and are called toxic AGEs (TAGE). A dietary imbalance (the habitual and excessive intake of sucrose, HFCS, or dietary AGEs) promotes the generation/accumulation of TAGE in vivo. Elevated circulating levels of TAGE have been detected in non-diabetics and diabetics, indicating a strong relationship between the generation/accumulation of TAGE in vivo and the onset and progression of LSRD. We herein outline current findings on "TAGE as a new target" for human health.
    Keywords:  advanced glycation end-products (AGEs); healthy life expectancy; human health; lifestyle-related diseases (LSRD); toxic AGEs (TAGE)
    DOI:  https://doi.org/10.3390/cells11142178
  212. Cancers (Basel). 2022 Jul 18. pii: 3487. [Epub ahead of print]14(14):
    Present Status, Challenges, and Prospects of Dihydromyricetin in the Battle against Cancer.
    Jiajun Wu, Zuowei Xiao, Hongfang Li, Neng Zhu, Jia Gu, Wenmao Wang, Chao Liu, Wei Wang, Li Qin.
      Dihydromyricetin (DHM) is a natural flavonoid compound extracted from Ampelopsis grossedentata that has been used for centuries in traditional Chinese medicine. DHM has attracted intensive attention due to its numerous beneficial activities, such as hepatoprotection, cardioprotection, antioxidant, and anti-inflammation. In addition, DHM inhibits the progression of cancers such as lung cancer, hepatocellular cancer, breast cancer, melanoma, and malignant reproductive systems through multiple mechanisms, including antiangiogenesis, antiproliferation, apoptosis, and inhibition of invasion and migration. Notably, DHM also activates autophagy at different levels, exerting a dual-regulatory effect on cancers. Mechanistically, DHM can effectively regulate mammalian target of rapamycin (mTOR), noncoding RNA-mediated signaling, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, nuclear factor-κB (NF-κB), p53, and endoplasmic reticulum stress (ER stress)-driven signaling in different types of cancers. DHM has also been shown to have inhibitory effects on various regulators that trigger epithelial-mesenchymal transition (EMT). Furthermore, DHM exhibits a remarkable anticancer reversal ability when used in combination with drugs such as adriamycin, nedaplatin, and other drugs. However, the low bioavailability of DHM limits its potential applications, which are improved through structural modification and the exploration of novel dosage forms. Therefore, DHM may become a promising candidate for treating malignancies alone or combined with conventional anticancer strategies used in clinical practice.
    Keywords:  anticancer activity; dihydromyricetin; multidrug resistance
    DOI:  https://doi.org/10.3390/cancers14143487
  213. Front Genet. 2022 ;13 812077
    Insights Into the Role of Epigenetic Factors Determining the Estrogen Response in Estrogen-Positive Ovarian Cancer and Prospects of Combining Epi-Drugs With Endocrine Therapy.
    Sadia Sarwar, Abir Alamro, Fazlul Huq, Amani Alghamdi.
      Ovarian cancer is one of the most lethal malignancies. The population at the risk is continually on the rise due to the acquired drug resistance, high relapse rate, incomplete knowledge of the etiology, cross-talk with other gynecological malignancies, and diagnosis at an advanced stage. Most ovarian tumors are thought to arise in surface epithelium somehow in response to changes in the hormonal environment. Prolonged treatment with hormone replacement therapy (HRT) is also considered a contributing factor. Estrogens influence the etiology and progression of the endocrine/hormone-responsive cancers in a patient-specific manner. The concept of hormonal manipulations got attention during the last half of the 20th century when tamoxifen was approved by the FDA as the first selective estrogen receptor modulator (SERM). Endocrine therapy that has been found to be effective against breast cancer can be an option for ovarian cancer. It is now established that global changes in the epigenetic landscape are not only the hallmark of tumor development but also contribute to the development of resistance to hormone therapy. A set of functionally related genes involved in epigenetic reprogramming are controlled by specific transcription factors (TFs). Thus, the activities of TFs mediate important mechanisms through which epigenetic enzymes and co-factors modify chromatin for the worst outcome in a site-specific manner. Furthermore, the role of epigenetic aberrations involving histone modifications is established in ovarian cancer pathogenesis. This review aims to provide insights on the role of key epigenetic determinants of response as well as resistance to the hormone therapy, the current status of research along with its limitations, and future prospects of epigenetic agents as biomarkers in early diagnosis, prognosis, and personalized treatment strategies. Finally, the possibility of small phytoestrogenic molecules in combination with immunotherapy and epi-drugs targeting ovarian cancer has been discussed.
    Keywords:  antiestrogens; biomarkers; chemohormonal; combination therapy; epi-drugs; estrogen receptor; hormone therapy; ovarian cancer
    DOI:  https://doi.org/10.3389/fgene.2022.812077
  214. Pharmaceutics. 2022 Jul 14. pii: 1465. [Epub ahead of print]14(7):
    Chalcones as Anti-Glioblastoma Stem Cell Agent Alone or as Nanoparticle Formulation Using Carbon Dots as Nanocarrier.
    Eduardo A Veliz, Anastasiia Kaplina, Sajini D Hettiarachchi, Athina L Yoham, Carolina Matta, Sabrin Safar, Meghana Sankaran, Esther L Abadi, Emel Kirbas Cilingir, Frederic A Vallejo, Winston M Walters, Steven Vanni, Roger M Leblanc, Regina M Graham.
      The current prognosis for glioblastoma is dismal. Treatment-resistant glioblastoma stem cells (GSCs) and the failure of most drugs to reach therapeutic levels within the tumor remain formidable obstacles to successful treatment. Chalcones are aromatic ketones demonstrated to reduce malignant properties in cancers including glioblastoma. Nanomedicines can increase drug accumulation and tumor cell death. Carbon-dots are promising nanocarriers that can be easily functionalized with tumor-targeting ligands and anti-cancer drugs. Therefore, we synthesized a series of 4'-amino chalcones with the rationale that the amino group would serve as a "handle" to facilitate covalent attachment to carbon-dots and tested their cytotoxicity toward GSCs. We generated 31 chalcones (22 4'-amino and 9 4' derivatives) including 5 novel chalcones, and found that 13 had an IC50 below 10 µM in all GSC lines. After confirming that the 4-amino group was not part of the active pharmacophore, chalcones were attached to transferrin-conjugated carbon-dots. These conjugates were significantly more cytotoxic than the free chalcones, with the C-dot-transferrin-2,5, dimethoxy chalcone conjugate inducing up to 100-fold more GSC death. Several of the tested chalcones represent promising lead compounds for the development of novel anti-GSC drugs. Furthermore, designing amino chalcones for carbon-dot mediated drug delivery is a rational and effective methodology.
    Keywords:  GSC; carbon dot; chalcone; drug delivery system; glioblastoma; glioblastoma stem cell; nanocarrier
    DOI:  https://doi.org/10.3390/pharmaceutics14071465
  215. Int J Biol Macromol. 2022 Jul 25. pii: S0141-8130(22)01597-5. [Epub ahead of print]
    Efficient epidermal delivery of antibiotics by self-assembled lecithin/chitosan nanoparticles for enhanced therapy on epidermal bacterial infections.
    Lijun Liu, Qingming Ma, Suning Wang, Yang Gao, Chunrong Zhu, Wenbin Zhao, Wentao Sun, Haifeng Ma, Yong Sun.
      The treatment for epidermal bacterial infections has become a primary healthy concern, producing a significant therapeutic challenge. Here we present a facile strategy to fabricate lecithin/chitosan nanoparticles (LCNPs) for efficient epidermal drug delivery over epidermal bacterial infections. The central rotatable composite design method was used for the optimization of the preparation, and that the optimal size (212.63 ± 1.95 nm) was obtained via analysis of variance (ANOVA). The prepared CIP-LCNPs show an average diameter of 325.9 ± 7.4 nm and a zeta potential of 26.6 ± 1.2 mV. Antibiotics can be well encapsulated in LCNPs and its release kinetics is studied with cumulative release of 93.81 ± 2.05 % for 48 h. The hemolytic activity, cytotoxicity, and skin irritation are further investigated. The zones of inhibition are 2.16 ± 0.04 cm and 2.92 ± 0.03 cm for Escherichia coli and Staphylococcus aureus, respectively. Moreover, in vitro permeation studies demonstrate that LCNPs can increase the accumulation of antibiotics in the epidermis with retention ratio 2-3 fold higher than commercial formulations. The in vivo result over epidermal-infected wound demonstrates the superior therapeutic effects of LCNPs. The developed LCNPs represent an important advance in fabricating therapeutic materials for enhanced therapy over epidermal bacterial infections.
    Keywords:  Chitosan; Epidermal bacterial infections; Lecithin; Self-assembly; Targeted delivery
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.165
  216. Front Bioeng Biotechnol. 2022 ;10 945148
    Dual Drug Loaded, pH-Sensitive Metal-Organic Particles for Synergistic Cancer Therapy.
    Shichao Wu, Shuo Hu, Xiangrui Yang.
      The strategy for dual drug-loaded nanomedicine with targeting properties was always complex. Herein, a novel strategy for the preparation of metal-organic particle-based nanomedicine has been developed, and combretastatin A4 (CA4) and mitoxantrone (MIT) loaded MOPs (CMMOPs) have been obtained. In this system, using merely Cu(II) as a bridge to connect and coordinate with the dual drugs has resulted in the CMMOPs possessing a fairly high drug load of almost 90%. Moreover, the coordination between Cu(II) and the drugs was stable at physiological pH but easily cleavable in the tumor acidic microenvironment, which would provide a good targeting property for CMMOPs. The in vivo experiments indicated that CMMOPs possessed a significantly enhanced antitumor efficiency with negligible side effects. The results suggest that CMMOPs could be a potential anticancer formulation for tumor-targeted drug delivery.
    Keywords:  combretastatin A4 (CA4); metal-organic particles (MOPs); mitoxantrone (MIT); pH sensitive; synergistic effect
    DOI:  https://doi.org/10.3389/fbioe.2022.945148
  217. Nat Prod Commun. 2022 Jul;17(7):
    Phytochemical characterization and bioactivity toward breast cancer cells of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica.
    Cristobal L Miranda, Yadano Kumbi, Wenbin Wu, Hyi-Seung Lee, Ralph L Reed, Jan F Stevens.
      Phytochemicals from the genus, Fagonia, have been attracting increasing attention due to their potential beneficial effects on human health. Fagonia species contain various types of phytochemicals such as flavonoids, alkaloids, saponins, terpenoids, coumarins and tannins. In this study, we investigated the phytochemical composition of unhydrolyzed and acid-hydrolyzed extracts of Fagonia indica and their bioactivity toward breast cancer MCF-7 cells in vitro. The results revealed that F. indica contains phytochemicals consistent with the reported phytochemical composition of this Fagonia species, with greater amounts of aglycones detected in the hydrolyzed extract. The crude extract of F. indica without acid hydrolysis was found to be ineffective in inhibiting the growth of MCF-7 cells at doses below 1000 μg/mL. However, after acid hydrolysis (to mimic gastro-intestinal hydrolysis), the F. indica extract became growth-inhibitory to MCF-7 cells as low as 10 μg/mL and the cytotoxicity increased with increasing dose and time of treatment. The results suggest that F. indica extracts contain phytochemicals in glycosidic forms whose aglycones are active as anti-proliferative agents toward breast cancer cells in vitro.
    Keywords:  Fagonia indica; Zygophyllum indicum; aglycones; bioactivity; breast cancer; flavonoids; triterpenoids
    DOI:  https://doi.org/10.1177/1934578x221109426
  218. Nutr Cancer. 2022 ;74(8): 2671-2685
    Cellular Calcium Signals in Cancer Chemoprevention and Chemotherapy by Phytochemicals.
    Xue Li, Shuhan Miao, Feng Li, Fen Ye, Guang Yue, Rongzhu Lu, Haijun Shen, Yang Ye.
      Identifying novel agents for cancer treatment is critical because of obstacles with anticancer drug resistance and lack of drug effectiveness. Intracellular calcium ion (Ca2+), a common second messenger, regulates various cellular pathophysiological processes including cell proliferation, differentiation and apoptosis. Recent studies have shown that the remodeling of Ca2+ signals is associated with cancer occurrence, progression and metastasis. Ca2+ channels, transporter and pumps regulate calcium movement, and alteration of Ca2+ signal component expression/activity is associated with numerous cancer cell activities. Therefore, targeting Ca2+ signals is an attractive research focus in cancer treatment. Phytochemicals, secondary metabolites in plants, exhibit multifaceted effective anticancer activities in various cancers. Although the mechanisms of the anticancer effects of phytochemicals remain unclarified, studies have indicated that many phytochemicals inhibit cancer progression through modulating calcium signals. In this review, we summarize the phytochemicals with demonstrated anticancer effects through their influence on calcium signaling, which may provide new ideas and directions in cancer research.
    DOI:  https://doi.org/10.1080/01635581.2021.2020305
  219. Int J Mol Sci. 2022 Jul 14. pii: 7774. [Epub ahead of print]23(14):
    Efficacy of Combined Use of Everolimus and Second-Generation Pan-EGRF Inhibitors in KRAS Mutant Non-Small Cell Lung Cancer Cell Lines.
    Renato José da Silva-Oliveira, Izabela Natalia Faria Gomes, Luciane Sussuchi da Silva, André van Helvoort Lengert, Ana Carolina Laus, Matias Eliseo Melendez, Carla Carolina Munari, Fernanda de Paula Cury, Giovanna Barbarini Longato, Rui Manuel Reis.
       BACKGROUND: EGFR mutations are present in approximately 15-50% of non-small cell lung cancer (NSCLC), which are predictive of anti-EGFR therapies. At variance, NSCLC patients harboring KRAS mutations are resistant to those anti-EGFR approaches. Afatinib and allitinib are second-generation pan-EGFR drugs, yet no predictive biomarkers are known in the NSCLC context. In the present study, we evaluated the efficacy of pan-EGFR inhibitors in a panel of 15 lung cancer cell lines associated with the KRAS mutations phenotype.
    METHODS: KRAS wild-type sensitive NCI-H292 cell line was further transfected with KRAS mutations (p.G12D and p.G12S). The pan-EGFR inhibitors' activity and biologic effect of KRAS mutations were evaluated by cytotoxicity, MAPK phospho-protein array, colony formation, migration, invasion, and adhesion. In addition, in vivo chicken chorioallantoic membrane assay was performed in KRAS mutant cell lines. The gene expression profile was evaluated by NanoString. Lastly, everolimus and pan-EGFR combinations were performed to determine the combination index.
    RESULTS: The GI50 score classified two cell lines treated with afatinib and seven treated with allitinib as high-sensitive phenotypes. All KRAS mutant cell lines demonstrated a resistant profile for both therapies (GI50 &lt; 30%). The protein array of KRAS edited cells indicated a significant increase in AKT, CREB, HSP27, JNK, and, importantly, mTOR protein levels compared with KRAS wild-type cells. The colony formation, migration, invasion, adhesion, tumor perimeter, and mesenchymal phenotype were increased in the H292 KRAS mutated cells. Gene expression analysis showed 18 dysregulated genes associated with the focal adhesion-PI3K-Akt-mTOR-signaling correlated in KRAS mutant cell lines. Moreover, mTOR overexpression in KRAS mutant H292 cells was inhibited after everolimus exposure, and sensitivity to afatinib and allitinib was restored.
    CONCLUSIONS: Our results indicate that allitinib was more effective than afatinib in NSCLC cell lines. KRAS mutations increased aggressive behavior through upregulation of the focal adhesion-PI3K-Akt-mTOR-signaling in NSCLC cells. Significantly, everolimus restored sensibility and improved cytotoxicity of EGFR inhibitors in the KRAS mutant NSCLC cell lines.
    Keywords:  KRAS mutations; NSCLC; afatinib; allitinib; everolimus; mTOR; pan-EGFR
    DOI:  https://doi.org/10.3390/ijms23147774
  220. Langmuir. 2022 Jul 26.
    Construction of Folate-Conjugated and pH-Responsive Cell Membrane Mimetic Mixed Micelles for Desirable DOX Release and Enhanced Tumor-Cellular Target.
    Haimei Cao, Meijun Yi, Henan Wei, Shiping Zhang.
      Smart multifunctional polymeric micelles are in urgent demand for future cancer diagnosis and therapy. In this paper, doxorubicin (DOX)-loaded folic acid (FA)-targeting and pH-responsive cell membrane mimetic mixed micelles of P(DMAEMA-co-MaPCL) (PCD) and FA-P(MPC-co-MaPCL) (PMCF) (mass ratio 5/5) were prepared by a dialysis method. The micelle size, morphology, X-ray powder diffraction (XRD), pH responsiveness, in vitro DOX release, cytotoxicity, and cellular uptake were studied in detail. The results indicated that DOX could be efficiently loaded into mixed micelles (PDMCF micelles), and the DOX-loaded mixed micelles (DOX@PDMCF micelles) exhibited a size of 150 nm and pH-responsive DOX release in an extended period. Furthermore, the DOX@PDMCF micelles could efficiently suppress the proliferation of tumor cells, HeLa and MCF-7 cells. Our data suggest that the DOX@PDMCF micelles have the potential to be applied in tumor therapy, especially for treating various folate receptor overexpressed tumors.
    DOI:  https://doi.org/10.1021/acs.langmuir.2c00905
  221. Front Nutr. 2022 ;9 920413
    Modulation of Gut Microbiota by Essential Oils and Inorganic Nanoparticles: Impact in Nutrition and Health.
    Veronica Lazar, Alina-Maria Holban, Carmen Curutiu, Lia Mara Ditu.
      Microbiota plays a crucial role in human health and disease; therefore, the modulation of this complex and yet widely unexplored ecosystem is a biomedical priority. Numerous antibacterial alternatives have been developed in recent years, imposed by the huge problem of antibioresistance, but also by the people demand for natural therapeutical products without side effects, as dysbiosis, cyto/hepatotoxicity. Current studies are focusing mainly in the development of nanoparticles (NPs) functionalized with herbal and fruit essential oils (EOs) to fight resistant pathogens. This is due to their increased efficiency against susceptible, multidrug resistant and biofilm embedded microorganisms. They are also studied because of their versatile properties, size and possibility to ensure a targeted administration and a controlled release of bioactive substances. Accordingly, an increasing number of studies addressing the effects of functional nanoparticles and plant products on microbial pathogens has been observed. Regardless the beneficial role of EOs and NPs in the treatment of infectious diseases, concerns regarding their potential activity against human microbiota raised constantly in recent years. The main focus of current research is on gut microbiota (GM) due to well documented metabolic and immunological functions of gut microbes. Moreover, GM is constantly exposed to micro- and nano-particles, but also plant products (including EOs). Because of the great diversity of both microbiota and chemical antimicrobial alternatives (i.e., nanomaterials and EOs), here we limit our discussion on the interactions of gut microbiota, inorganic NPs and EOs. Impact of accidental exposure caused by ingestion of day care products, foods, atmospheric particles and drugs containing nanoparticles and/or fruit EOs on gut dysbiosis and associated diseases is also dissected in this paper. Current models developed to investigate mechanisms of dysbiosis after exposure to NPs/EOs and perspectives for identifying factors driving EOs functionalized NPs dysbiosis are reviewed.
    Keywords:  bioactive nanoparticles; biofilms; dysbiosis; essential oils; microbiota interference
    DOI:  https://doi.org/10.3389/fnut.2022.920413
  222. Pharmaceutics. 2022 Jun 28. pii: 1369. [Epub ahead of print]14(7):
    Co-Delivery of Repurposing Itraconazole and VEGF siRNA by Composite Nanoparticulate System for Collaborative Anti-Angiogenesis and Anti-Tumor Efficacy against Breast Cancer.
    Mingji Jin, Bowen Zeng, Yanhong Liu, Lili Jin, Yan Hou, Chao Liu, Wei Liu, Hao Wu, Liqing Chen, Zhonggao Gao, Wei Huang.
      Combinations of two different therapeutic modalities of VEGF inhibitors against angiogenesis can cooperatively impede breast cancer tumor growth and enhance therapeutic efficacy. Itraconazole (ITZ) is a conventional antifungal drug with high safety; however, it has been repurposed to be a multi target anti-angiogenesis agent for cancer therapy in recent years. In the present study, composite nanoparticles co-loaded with ITZ and VEGF siRNA were prepared in order to investigate their anti-angiogenesis efficacy and synergistic anticancer effect against breast cancer. The nanoparticles had a suitable particle size (117.9 ± 10.3 nm) and weak positive surface charge (6.69 ± 2.46 mV), as well as good stability and drug release profile in vitro. Moreover, the nanoparticles successfully escaped from endosomes and realized cell apoptosis and cell proliferation inhibition in vitro. In vitro and in vivo experiments showed that the nanoparticles could induce the silencing of VEGF-related expressions as well as anti-angiogenesis efficacy, and the co-loaded ITZ-VEGF siRNA NPs could inhibit tumor growth effectively with low toxicity and side effects. Taken together, the as-prepared delivery vehicles are a simple and safe nano-platform that improves the antitumor efficacy of VEGF siRNA and ITZ, which allows the repositioning of the generic drug ITZ as a great candidate for antitumor therapy.
    Keywords:  VEGF siRNA; breast cancer; co-inhibition; itraconazole; siRNA delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14071369
  223. Molecules. 2022 Jul 13. pii: 4491. [Epub ahead of print]27(14):
    Prenylated Flavonoids in Topical Infections and Wound Healing.
    Alice Sychrová, Gabriela Škovranová, Marie Čulenová, Silvia Bittner Fialová.
      The review presents prenylated flavonoids as potential therapeutic agents for the treatment of topical skin infections and wounds, as they can restore the balance in the wound microenvironment. A thorough two-stage search of scientific papers published between 2000 and 2022 was conducted, with independent assessment of results by two reviewers. The main criteria were an MIC (minimum inhibitory concentration) of up to 32 µg/mL, a microdilution/macrodilution broth method according to CLSI (Clinical and Laboratory Standards Institute) or EUCAST (European Committee on Antimicrobial Susceptibility Testing), pathogens responsible for skin infections, and additional antioxidant, anti-inflammatory, and low cytotoxic effects. A total of 127 structurally diverse flavonoids showed promising antimicrobial activity against pathogens affecting wound healing, predominantly Staphylococcus aureus strains, but only artocarpin, diplacone, isobavachalcone, licochalcone A, sophoraflavanone G, and xanthohumol showed multiple activity, including antimicrobial, antioxidant, and anti-inflammatory along with low cytotoxicity important for wound healing. Although prenylated flavonoids appear to be promising in wound therapy of humans, and also animals, their activity was measured only in vitro and in vivo. Future studies are, therefore, needed to establish rational dosing according to MIC and MBC (minimum bactericidal concentration) values, test potential toxicity to human cells, measure healing kinetics, and consider formulation in smart drug release systems and/or delivery technologies to increase their bioavailability.
    Keywords:  MRSA; S. aureus; anti-inflammatory; antibacterial; antioxidant; cytotoxicity; mastitis; nanotechnology; prenylated flavonoids; skin; wound healing
    DOI:  https://doi.org/10.3390/molecules27144491
  224. Antioxidants (Basel). 2022 Jul 17. pii: 1383. [Epub ahead of print]11(7):
    Main Bioactive Components and Their Biological Activities from Natural and Processed Rhizomes of Polygonum sibiricum.
    Shih-Chi Chen, Chang-Syun Yang, Jih-Jung Chen.
      Polygonatum sibiricum (Asparagaceae) is often used as an herbal drug in the traditional medicine of Southeast Asia. Its rhizome, called "Huang Jing", is used in traditional Chinese medicine as an immune system stimulant, hypolipidemic agent, anti-aging agent, anti-fatigue agent, and cardiovascular protectant. We investigated the antioxidant, anti-acetylcholinesterase (AChE), anti-inflammatory, and anti-α-glucosidase effects of various solvent extracts and major bioactive components of Polygonatum sibiricum (PS) and processed Polygonatum sibiricum (PPS). Dichloromethane extract of PS showed stronger antioxidant effects by DPPH, ABTS, and FRAP assays, and EtOAc extract displayed relatively high antioxidant activity by a superoxide radical scavenging test. Moreover, acetone, EtOAc, and dichloromethane extracts displayed a significant anti-α-glucosidase effect. EtOH and CH2Cl2 extracts showed effective AChE inhibitory activity. In addition, dichloromethane extract showed the best inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) accumulation in RAW264.7 macrophages. HPLC analysis was used to investigate and compare the content of major active components of various solvent extracts of PS and PPS. Rutin showed the most effective scavenging of DPPH and ABTS free radicals, while scopoletin and isoquercetin displayed the strongest anti-α-glucosidase and anti-AChE effect, respectively. Rutin showed the best inhibition against LPS-induced NO production and also inhibited inducible nitric oxide synthase (iNOS) expression in Western blot. The molecular docking of AChE and iNOS revealed that active components could have a better antagonistic effect than positive controls (common inhibitors). This study shows that the active extracts and components of Polygonatum sibiricum have the potential to be further developed as a natural anti-AChE, anti-α-glucosidase, antioxidant and anti-inflammatory agent.
    Keywords:  Polygonatum sibiricum; anti-acetylcholinesterase effect; anti-inflammatory activity; anti-α-glucosidase effect; antioxidant effect; bioactive components; coumarin; flavone glycosides; molecular docking
    DOI:  https://doi.org/10.3390/antiox11071383
  225. Biochem J. 2022 Jul 29. 479(14): 1581-1608
    The cross-talk of autophagy and apoptosis in breast carcinoma: implications for novel therapies?
    Kamil Seyrek, Fabian Wohlfromm, Johannes Espe, Inna N Lavrik.
      Breast cancer is still the most common cancer in women worldwide. Resistance to drugs and recurrence of the disease are two leading causes of failure in treatment. For a more efficient treatment of patients, the development of novel therapeutic regimes is needed. Recent studies indicate that modulation of autophagy in concert with apoptosis induction may provide a promising novel strategy in breast cancer treatment. Apoptosis and autophagy are two tightly regulated distinct cellular processes. To maintain tissue homeostasis abnormal cells are disposed largely by means of apoptosis. Autophagy, however, contributes to tissue homeostasis and cell fitness by scavenging of damaged organelles, lipids, proteins, and DNA. Defects in autophagy promote tumorigenesis, whereas upon tumor formation rapidly proliferating cancer cells may rely on autophagy to survive. Given that evasion of apoptosis is one of the characteristic hallmarks of cancer cells, inhibiting autophagy and promoting apoptosis can negatively influence cancer cell survival and increase cell death. Hence, combination of antiautophagic agents with the enhancement of apoptosis may restore apoptosis and provide a therapeutic advantage against breast cancer. In this review, we discuss the cross-talk of autophagy and apoptosis and the diverse facets of autophagy in breast cancer cells leading to novel models for more effective therapeutic strategies.
    Keywords:  apoptosis; autophagy; breast cancer
    DOI:  https://doi.org/10.1042/BCJ20210676
  226. Nutrients. 2022 Jul 27. pii: 3076. [Epub ahead of print]14(15):
    The Potential of Spirulina platensis to Ameliorate the Adverse Effects of Highly Active Antiretroviral Therapy (HAART).
    Thabani Sibiya, Terisha Ghazi, Anil Chuturgoon.
      The human immunodeficiency virus (HIV) is one of the most prevalent diseases globally. It is estimated that 37.7 million people are infected with HIV globally, and 8.2 million persons are infected with the virus in South Africa. The highly active antiretroviral therapy (HAART) involves combining various types of antiretroviral drugs that are dependent on the infected person's viral load. HAART helps regulate the viral load and prevents its associated symptoms from progressing into acquired immune deficiency syndrome (AIDS). Despite its success in prolonging HIV-infected patients' lifespans, the use of HAART promotes metabolic syndrome (MetS) through an inflammatory pathway, excess production of reactive oxygen species (ROS), and mitochondrial dysfunction. Interestingly, Spirulina platensis (SP), a blue-green microalgae commonly used as a traditional food by Mexican and African people, has been demonstrated to mitigate MetS by regulating oxidative and inflammatory pathways. SP is also a potent antioxidant that has been shown to exhibit immunological, anticancer, anti-inflammatory, anti-aging, antidiabetic, antibacterial, and antiviral properties. This review is aimed at highlighting the biochemical mechanism of SP with a focus on studies linking SP to the inhibition of HIV, inflammation, and oxidative stress. Further, we propose SP as a potential supplement for HIV-infected persons on lifelong HAART.
    Keywords:  HAART toxicity; HAART/ARVs; HIV; MetS; Spirulina platensis; antioxidant; inflammation; oxidative stress
    DOI:  https://doi.org/10.3390/nu14153076
  227. Molecules. 2022 Jul 07. pii: 4350. [Epub ahead of print]27(14):
    Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation.
    Maira Smaniotto Cucielo, Roberta Carvalho Cesário, Henrique Spaulonci Silveira, Letícia Barbosa Gaiotte, Sérgio Alexandre Alcantara Dos Santos, Debora Aparecida Pires de Campos Zuccari, Fábio Rodrigues Ferreira Seiva, Russel J Reiter, Luiz Gustavo de Almeida Chuffa.
      Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.
    Keywords:  SKOV-3 cells; Warburg effect; glucose; melatonin; mitochondrial metabolism; ovarian cancer
    DOI:  https://doi.org/10.3390/molecules27144350
  228. Cancers (Basel). 2022 Jul 07. pii: 3309. [Epub ahead of print]14(14):
    Non-Canonical Programmed Cell Death in Colon Cancer.
    Bingchen Pan, Bowen Zheng, Chengzhong Xing, Jingwei Liu.
      Programmed cell death (PCD) is an evolutionarily conserved process of cell suicide that is regulated by various genes and the interaction of multiple signal pathways. Non-canonical programmed cell death (PCD) represents different signaling excluding apoptosis. Colon cancer is the third most incident and the fourth most mortal worldwide. Multiple factors such as alcohol, obesity, and genetic and epigenetic alternations contribute to the carcinogenesis of colon cancer. In recent years, emerging evidence has suggested that diverse types of non-canonical programmed cell death are involved in the initiation and development of colon cancer, including mitotic catastrophe, ferroptosis, pyroptosis, necroptosis, parthanatos, oxeiptosis, NETosis, PANoptosis, and entosis. In this review, we summarized the association of different types of non-canonical PCD with tumorigenesis, progression, prevention, treatments, and prognosis of colon cancer. In addition, the prospect of drug-resistant colon cancer therapy related to non-canonical PCD, and the interaction between different types of non-canonical PCD, was systemically reviewed.
    Keywords:  carcinogenesis; cell death; colon cancer
    DOI:  https://doi.org/10.3390/cancers14143309
  229. Pharmaceutics. 2022 Jul 25. pii: 1546. [Epub ahead of print]14(8):
    Localized Controlled Release of Kynurenic Acid Encapsulated in Synthetic Polymer Reduces Implant-Induced Dermal Fibrosis.
    Layla Nabai, Aziz Ghahary, John Jackson.
      Excessive fibrosis following surgical procedures is a challenging condition with serious consequences and no effective preventive or therapeutic option. Our group has previously shown the anti-fibrotic effect of kynurenic acid (KynA) in vitro and as topical cream formulations or nanofiber dressings in open wounds. Here, we hypothesized that the implantation of a controlled release drug delivery system loaded with KynA in a wound bed can prevent fibrosis in a closed wound. Poly (lactic-co-glycolic acid) (PLGA), and a diblock copolymer, methoxy polyethylene glycol-block-poly (D, L-lactide) (MePEG-b-PDLLA), were used for the fabrication of microspheres which were evaluated for their characteristics, encapsulation efficiency, in vitro release profile, and in vivo efficacy for reduction of fibrosis. The optimized formulation exhibited high encapsulation efficiency (&gt;80%), low initial burst release (~10%), and a delayed, gradual release of KynA. In vivo evaluation of the fabricated microspheres in the PVA model of wound healing revealed that KynA microspheres effectively reduced collagen deposition inside and around PVA sponges and α-smooth muscle actin expression after 66 days. Our results showed that KynA can be efficiently encapsulated in PLGA microspheres and its controlled release in vivo reduces fibrotic tissue formation, suggesting a novel therapeutic option for the prevention or treatment of post-surgical fibrosis.
    Keywords:  PLGA; fibrosis; kynurenic acid; microsphere
    DOI:  https://doi.org/10.3390/pharmaceutics14081546
  230. Biomater Sci. 2022 Jul 21.
    Advances in hybrid peptide-based self-assembly systems and their applications.
    Alpana Boruah, Arup Roy.
      Self-assembly of peptides demonstrates a great potential for designing highly ordered, finely tailored supramolecular arrangements enriched with high specificity, improved efficacy and biological activity. Along with natural peptides, hybrid peptide systems composed of natural and chemically diverse unnatural amino acids have been used in various fields, including drug delivery, wound healing, potent inhibition of diseases, and prevention of biomaterial related diseases to name a few. In this review, we provide a brief outline of various methods that have been utilized for obtaining fascinating structures that create an avenue to reproduce a range of functions resulting from these folds. An overview of different self-assembled structures as well as their applications will also be provided. We believe that this review is very relevant to the current scenario and will cover conformations of hybrid peptides and resulting self-assemblies from the late 20th century through 2022. This review aims to be a comprehensive and reliable account of the hybrid peptide-based self-assembly owing to its enormous influence in understanding and mimicking biological processes.
    DOI:  https://doi.org/10.1039/d2bm00775d
  231. Molecules. 2022 Jul 09. pii: 4408. [Epub ahead of print]27(14):
    Mechanism Study on Nanoparticle Negative Surface Charge Modification by Ascorbyl Palmitate and Its Improvement of Tumor Targeting Ability.
    Lin Li, Hongliang Wang, Jun Ye, Yankun Chen, Renyun Wang, Dujia Jin, Yuling Liu.
      Surface charge polarity and density influence the immune clearance and cellular uptake of intravenously administered lipid nanoparticles (LNPs), thus determining the efficiency of their delivery to the target. Here, we modified the surface charge with ascorbyl palmitate (AsP) used as a negatively charged lipid. AsP-PC-LNPs were prepared by dispersion and ultrasonication of AsP and phosphatidylcholine (PC) composite films at various ratios. AsP inserted into the PC film with its polar head outward. The pKa for AsP was 4.34, and its ion form conferred the LNPs with negative surface charge. Zeta potentials were correlated with the amount and distribution of AsP on the LNPs surface. DSC, Raman and FTIR spectra, and molecular dynamics simulations disclosed that AsP distributed homogeneously in PC at 1-8% (w/w), and there were strong hydrogen bonds between the polar heads of AsP and PC (PO2-), which favored LNPs' stability. But at AsP:PC &gt; 8% (w/w), the excessive AsP changed the interaction modes between AsP and PC. The AsP-PC composite films became inhomogeneous, and their phase transition behaviors and Raman and FTIR spectra were altered. Our results clarified the mechanism of surface charge modification by AsP and provided a rational use of AsP as a charged lipid to modify LNP surface properties in targeted drug delivery systems. Furthermore, AsP-PC composites were used as phospholipid-based biological membranes to prepare paclitaxel-loaded LNPs, which had stable surface negative charge, better tumor targeting and tumor inhibitory effects.
    Keywords:  ascorbyl palmitate; lipid nanoparticles; molecular dynamics simulation; physicochemical characteristic; surface charge; tumor targeting
    DOI:  https://doi.org/10.3390/molecules27144408
  232. Cell Biol Int. 2022 Jul 28.
    Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets.
    Sayan Chakraborty, Poulomi Khamaru, Arindam Bhattacharyya.
      Metabolism is a dynamic process and keeps changing from time to time according to the demand of a particular cell to meet its bio-energetic requirement. Different immune cells rely on distinct metabolic programs which allow the cell to balance its requirements for energy, molecular biosynthesis, and effector activity. In the aspect of infection and cancer immunology, effector T and B cells get exhausted and help tumor cells to evade immunosurveillance. On the other hand, T cells become hyperresponsive in the scenario of autoimmune diseases. In this article, we have explored the uniqueness and distinct metabolic features of key CD4+ T and B helper cell subsets, CD4+ T, B regulatory cell subsets and CD8+ T cells regarding health and disease. Th1 cells rely on glycolysis and glutaminolysis; inhibition of these metabolic pathways promotes Th1 cells in Treg population. However, Th2 cells are also dependent on glycolysis but an abundance of lactate within TME shifts their metabolic dependency to fatty acid metabolism. Th17 cells depend on HIF-1α mediated glycolysis, ablation of HIF-1α reduces Th17 cells but enhance Treg population. In contrast to effector T cells which are largely dependent on glycolysis for their differentiation and function, Treg cells mainly rely on FAO for their function. Therefore, it is of utmost importance to understand the metabolic fates of immune cells and how it facilitates their differentiation and function for different disease models. Targeting metabolic pathways to restore the functionality of immune cells in diseased conditions can lead to potent therapeutic measures.
    Keywords:  autoimmune disorders; cancer; germinal center; immune cell regulation; infectious diseases; metabolic reprogramming
    DOI:  https://doi.org/10.1002/cbin.11867
  233. Food Sci Biotechnol. 2022 Jul;31(8): 905-934
    Protective effects of polyphenols against endocrine disrupting chemicals.
    Matthew P Madore, Junichi R Sakaki, Ock K Chun.
      Endocrine disrupting chemicals (EDCs) are a heterogenous group of compounds dispersed throughout the environment that possess the ability to alter endocrine system function. While there are numerous routes of exposure to EDCs, the predominant source of many of these compounds is diet, largely due to their widespread use in food contact materials. In recent years, there has been a surge of research aimed at assessing exposure to EDCs, identifying their health implications, and developing approaches to minimize the risks they may entail. Due to their antioxidant and anti-inflammatory potential, polyphenols have been purported to confer protection against EDC-induced health detriments. This review discusses the evidence pertaining to dietary exposure to the two predominant EDCs, bisphenol A and phthalates, in the United States, their associations with diabetes, cancer, and cardiovascular disease outcomes, the potential for polyphenols to mitigate their disease-promoting effects, gaps in knowledge, and recommendations for future research.
    Keywords:  Bisphenol A or BPA; Chronic disease; Endocrine disrupting chemicals or EDCs; Phthalates; Polyphenols
    DOI:  https://doi.org/10.1007/s10068-022-01105-z
  234. Zhongguo Fei Ai Za Zhi. 2022 Jul 20. 25(7): 452-459
    [MUC16: The Novel Target for Tumor Therapy].
    Ruyun Gao, Ning Lou, Xiaohong Han, Yuankai Shi.
      Mucin16 (MUC16), also known as carbohydrate antigen 125 (CA125), is a glycoprotein antigen that can be recognized by the monoclonal antibody OC125 detected from epithelial ovarian carcinoma antigen by Bast et al in 1981. CA125 is not present in normal ovarian tissue but is usually elevated in the serum of epithelial ovarian carcinoma patients. CA125 is the most commonly used serologic biomarker for the diagnosis and recurrence monitoring of epithelial ovarian carcinoma. MUC16 is highly expressed in varieties of tumors. MUC16 can interact with galectin-1/3, mesothelin, sialic acid-binding immunoglobulin-type lectins-9 (Siglec-9), and other ligands. MUC16 plays an important role in tumor genesis, proliferation, migration, invasion, and tumor immunity through various signaling pathways. Besides, therapies targeting MUC16 have some significant achievements. Related preclinical studies and clinical trials are in progress. MUC16 may be a potential novel target for tumor therapy. This article will review the mechanism of MUC16 in tumor genesis and progression, and focus on the research actuality of MUC16 in tumor therapy. This article also provides references for subsequent tumor therapy studies targeting MUC16.
.
    Keywords:  Immunotherapy; MUC16; Mucin; Targeted therapy; Tumor therapy
    DOI:  https://doi.org/10.3779/j.issn.1009-3419.2022.101.31
  235. Nat Rev Drug Discov. 2022 Jul 29.
    A route to rational anticancer combinations.
    M Teresa Villanueva.
      
    Keywords:  Biotechnology; Cancer; Drug discovery; Personalized medicine; Therapeutics
    DOI:  https://doi.org/10.1038/d41573-022-00133-y
  236. Pharmaceutics. 2022 Jun 30. pii: 1393. [Epub ahead of print]14(7):
    Preparation of Terbinafin-Encapsulated Solid Lipid Nanoparticles Containing Antifungal Carbopol® Hydrogel with Improved Efficacy: In Vitro, Ex Vivo and In Vivo Study.
    Nilesh R Rarokar, Sunil S Menghani, Deweshri R Kerzare, Pramod B Khedekar, Ashish P Bharne, Abdulhakeem S Alamri, Walaa F Alsanie, Majid Alhomrani, Nagaraja Sreeharsha, Syed Mohammed Basheeruddin Asdaq.
      The present research was aimed to develop a terbinafin hydrochloride (TH)-encapsulated solid lipid nanoparticles (SLNs) hydrogel for improved antifungal efficacy. TH-loaded SLNs were obtained from glyceryl monostearate (lipid) and Pluronic® F68 (surfactant) employing high-pressure homogenization. The ratio of drug with respect to lipid was optimized, considering factors such as desired particle size and highest percent encapsulation efficiency. Lyophilized SLNs were then incorporated in the hydrogel prepared from 0.2-1.0% w/v carbopol 934P and further evaluated for rheological parameters. The z-average, zeta potential and polydispersity index were found to be 241.3 nm, -15.2 mV and 0.415, respectively. The SLNs show a higher entrapment efficiency of about 98.36%, with 2.12 to 6.3602% drug loading. SEM images, XRD and the results of the DSC, FTIR show successful preparation of SLNs after freeze drying. The TH-loaded SLNs hydrogel showed sustained drug release (95.47 ± 1.45%) over a period of 24 h. The results reported in this study show a significant effect on the zone of inhibition than the marketed formulation and pure drug in Candida albicans cultures, with better physical stability at cooler temperatures. It helped to enhance skin deposition inthe ex vivostudy and improved, in vitro and in vivo, the antifungal activity.
    Keywords:  Candida albicans; antifungal; hydrogel; solid lipid nanoparticles; terbinafin
    DOI:  https://doi.org/10.3390/pharmaceutics14071393
  237. Molecules. 2022 Jul 25. pii: 4736. [Epub ahead of print]27(15):
    Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy.
    Jac A Nickoloff.
      Proliferating cells regularly experience replication stress caused by spontaneous DNA damage that results from endogenous reactive oxygen species (ROS), DNA sequences that can assume secondary and tertiary structures, and collisions between opposing transcription and replication machineries. Cancer cells face additional replication stress, including oncogenic stress that results from the dysregulation of fork progression and origin firing, and from DNA damage induced by radiotherapy and most cancer chemotherapeutic agents. Cells respond to such stress by activating a complex network of sensor, signaling and effector pathways that protect genome integrity. These responses include slowing or stopping active replication forks, protecting stalled replication forks from collapse, preventing late origin replication firing, stimulating DNA repair pathways that promote the repair and restart of stalled or collapsed replication forks, and activating dormant origins to rescue adjacent stressed forks. Currently, most cancer patients are treated with genotoxic chemotherapeutics and/or ionizing radiation, and cancer cells can gain resistance to the resulting replication stress by activating pro-survival replication stress pathways. Thus, there has been substantial effort to develop small molecule inhibitors of key replication stress proteins to enhance tumor cell killing by these agents. Replication stress targets include ATR, the master kinase that regulates both normal replication and replication stress responses; the downstream signaling kinase Chk1; nucleases that process stressed replication forks (MUS81, EEPD1, Metnase); the homologous recombination catalyst RAD51; and other factors including ATM, DNA-PKcs, and PARP1. This review provides an overview of replication stress response pathways and discusses recent pre-clinical studies and clinical trials aimed at improving cancer therapy by targeting replication stress response factors.
    Keywords:  DNA damage response; DNA replication stress; genotoxic cancer therapy; oncogenic stress; targeted therapy
    DOI:  https://doi.org/10.3390/molecules27154736
  238. Front Pharmacol. 2022 ;13 934156
    Nanostructured Lipid Carrier-Based Delivery of Pioglitazone for Treatment of Type 2 Diabetes.
    Umair Ilyas, Muhammad Asif, Minglian Wang, Reem Altaf, Hajra Zafar, Mirza Muhammad Faran Ashraf Baig, Ana Cláudia Paiva-Santos, Muhammad Abbas.
      Pioglitazone (PGZ) is utilized as a therapeutic agent in the management of (type 2) diabetes to control blood glucose levels. The existing research work was intended to make and optimize PGZ-containing NLCs (nanostructured lipid carriers). The fabricated nanostructured lipid carrier preparation was optimized by using different concentrations of the surfactants (Tween 80 and Span 80) and solid lipid (Compritol® 888 ATO) and liquid lipid (Labrasol®) while keeping the concentration of drug (PGZ), and co-surfactants (poloxamer 188) the same. The optimized NLC formulation (PGZ-NLCs) was further assessed for physical and chemical characterization, in vitro PGZ release, and stability studies. The optimized PGZ-NLCs have shown an average diameter of 150.4 nm, EE of 92.53%, PDI value of 0.076, and zeta-potential of -29.1 mV, correspondingly. The DSC thermal analysis and XRD diffractograms had not presented the spectrum of PGZ, confirming the comprehensive encapsulation of PGZ in the lipid core. PGZ-NLCs showed significantly extended release (51% in 24 h) compared to the unformulated PGZ. Our study findings confirmed that PGZ-NLCs can be a promising drug delivery system for the treatment of type 2 diabetes.
    Keywords:  NLCs; diabetes; nanoparticles; pioglitazone; poor aqueous solubility
    DOI:  https://doi.org/10.3389/fphar.2022.934156
  239. J Mater Chem B. 2022 Jul 26.
    Tannic acid: a versatile polyphenol for design of biomedical hydrogels.
    Hafez Jafari, Pejman Ghaffari-Bohlouli, Seyyed Vahid Niknezhad, Ali Abedi, Zohreh Izadifar, Reza Mohammadinejad, Rajender S Varma, Amin Shavandi.
      Tannic acid (TA), a natural polyphenol, is a hydrolysable amphiphilic tannin derivative of gallic acid with several galloyl groups in its structure. Tannic acid interacts with various organic, inorganic, hydrophilic, and hydrophobic materials such as proteins and polysaccharides via hydrogen bonding, electrostatic, coordinative bonding, and hydrophobic interactions. Tannic acid has been studied for various biomedical applications as a natural crosslinker with anti-inflammatory, antibacterial, and anticancer activities. In this review, we focus on TA-based hydrogels for biomaterials engineering to help biomaterials scientists and engineers better realize TA's potential in the design and fabrication of novel hydrogel biomaterials. The interactions of TA with various natural or synthetic compounds are deliberated, discussing parameters that affect TA-material interactions thus providing a fundamental set of criteria for utilizing TA in hydrogels for tissue healing and regeneration. The review also discusses the merits and demerits of using TA in developing hydrogels either through direct incorporation in the hydrogel formulation or indirectly via immersing the final product in a TA solution. In general, TA is a natural bioactive molecule with diverse potential for engineering biomedical hydrogels.
    DOI:  https://doi.org/10.1039/d2tb01056a
  240. Cancer Res. 2022 Jul 27. pii: CAN-22-0042. [Epub ahead of print]
    GOT2 Silencing Promotes Reprogramming of Glutamine Metabolism and Sensitizes Hepatocellular Carcinoma to Glutaminase Inhibitors.
    Yunzheng Li, Binghua Li, Yanchao Xu, Liyuan Qian, Tiancheng Xu, Gang Meng, Huan Li, Ye Wang, Laizhu Zhang, Xiang Jiang, Qi Liu, Yuanyuan Xie, Chunxiao Cheng, Beicheng Sun, Decai Yu.
      Hepatocellular carcinoma (HCC) is one of the primary liver malignancies with a poor prognosis. Glutamic-oxaloacetic transaminase 2 (GOT2) is a highly tissue-specific gene in the liver, but the roles GOT2 plays in the progression of HCC remain unclear. Here, we report that GOT2 is downregulated in HCC tumor tissues and that low expression of GOT2 is associated with advanced progression and poor prognosis. In HCC cells, knockdown of GOT2 promoted proliferation, migration, and invasion. In mouse models of HCC, loss of GOT2 promoted tumor growth as well as hematogenous and intrahepatic metastasis. Mechanistically, silencing of GOT2 enhanced glutaminolysis, nucleotide synthesis, and GSH synthesis by reprogramming glutamine metabolism to support the cellular antioxidant system, which activated the PI3K/AKT/mTOR pathway to contribute to HCC progression. Furthermore, HCC with low expression of GOT2 was highly dependent on glutamine metabolism and sensitive to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, GOT2 is involved in glutamine metabolic reprogramming to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0042
  241. Gels. 2022 Jul 04. pii: 418. [Epub ahead of print]8(7):
    Formulation and Evaluation of Moxifloxacin Loaded Bilosomes In-Situ Gel: Optimization to Antibacterial Evaluation.
    Ameeduzzafar Zafar, Omar Awad Alsaidan, Syed Sarim Imam, Mohd Yasir, Khalid Saad Alharbi, Mohammad Khalid.
      In this study, moxifloxacin (MX)-loaded bilosome (BS) in situ gel was prepared to improve ocular residence time. MX-BSs were prepared using the thin-film hydration method. They were optimized using a Box-Behnken design (BBD) with bile salt (A, sodium deoxycholate), an edge activator (B, Cremophor EL), and a surfactant (C, Span 60) as process variables. Their effects were assessed based on hydrodynamic diameter (Y1), entrapment efficacy (Y2), and polydispersity index (Y3). The optimized formulation (MX-BSop) depicted a low hydrodynamic diameter (192 ± 4 nm) and high entrapment efficiency (76 ± 1%). Further, MX-BSop was successfully transformed into an in situ gel using chitosan and sodium alginate as carriers. The optimized MX-BSop in situ gel (MX-BSop-Ig4) was further evaluated for gelling capacity, clarity, pH, viscosity, in vitro release, bio-adhesiveness, ex vivo permeation, toxicity, and antimicrobial properties. MX-BSop-Ig4 exhibited an optimum viscosity of 65.4 ± 5.3 cps in sol and 287.5 ± 10.5 cps in gel states. The sustained release profile (82 ± 4% in 24 h) was achieved with a Korsmeyer-Peppas kinetic release model (R2 = 0.9466). Significant bio-adhesion (967.9 dyne/cm2) was achieved in tear film. It also exhibited 1.2-fold and 2.8-fold higher permeation than MX-Ig and a pure MX solution, respectively. It did not show any toxicity to the tested tissue, confirmed by corneal hydration (77.3%), cornea histopathology (no internal changes), and a HET-CAM test (zero score). MX-BSop-Ig4 exhibited a significantly (p &lt; 0.05) higher antimicrobial effect than pure MX against Staphylococcus aureus and Escherichia coli. The findings suggest that bilosome in situ gel is a good alternative to increase corneal residence time, as well as to improve therapeutic activity.
    Keywords:  antimicrobial activity; bilosomes; moxifloxacin; ocular delivery; toxicity study
    DOI:  https://doi.org/10.3390/gels8070418
  242. Cancer Treat Rev. 2022 Jun 30. pii: S0305-7372(22)00102-5. [Epub ahead of print]109 102433
    Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer.
    Jorien B E Janssen, Jan Paul Medema, Elske C Gootjes, Daniele V F Tauriello, Henk M W Verheul.
      RAS genes are the most frequently mutated oncogenes in cancer. These mutations occur in roughly half of the patients with colorectal cancer (CRC). RAS mutant tumors are resistant to therapy with anti-EGFR monoclonal antibodies. Therefore, patients with RAS mutant CRC currently have few effective therapy options. RAS mutations lead to constitutively active RAS GTPases, involved in multiple downstream signaling pathways. These alterations are associated with a tumor microenvironment (TME) that drives immune evasion and disease progression by mechanisms that remain incompletely understood. In this review, we focus on the available evidence in the literature explaining the potential effects of RAS mutations on the CRC microenvironment. Ongoing efforts to influence the TME by targeting mutant RAS and thereby sensitizing these tumors to immunotherapy will be discussed as well.
    Keywords:  Colorectal cancer; Immunotherapy; RAS mutations; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ctrv.2022.102433
  243. Sci Rep. 2022 Jul 25. 12(1): 12670
    Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden.
    Maria Araceli Diaz Cruz, Benjamin Ulfenborg, Peter Blomstrand, Maria Faresjö, Fredrik Ståhl, Sandra Karlsson.
      Numerous studies have shown that lifestyle factors, such as regular physical activity and vitamin D intake, may remarkably improve overall health and mental wellbeing. This is especially important in older adults whose vitamin D deficiency occurs with a high prevalence. This study aimed to examine the influence of lifestyle and vitamin D on global DNA methylation patterns in an elderly cohort in Southwest of Sweden. We also sought to examine the methylation levels of specific genes involved in vitamin D's molecular and metabolic activated pathways. We performed a genome wide methylation analysis, using Illumina Infinium DNA Methylation EPIC 850kBeadChip array, on 277 healthy individuals from Southwest Sweden at the age of 70-95. The study participants also answered queries on lifestyle, vitamin intake, heart medication, and estimated health. Vitamin D intake did not in general affect methylation patterns, which is in concert with other studies. However, when comparing the group of individuals taking vitamin supplements, including vitamin D, with those not taking supplements, a difference in methylation in the solute carrier family 25 (SCL25A24) gene was found. This confirms a previous finding, where changes in expression of SLC25A24 were associated with vitamin D treatment in human monocytes. The combination of vitamin D intake and high physical activity increased methylation of genes linked to regulation of vitamin D receptor pathway, the Wnt pathway and general cancer processes. To our knowledge, this is the first study detecting epigenetic markers associated with the combined effects of vitamin D supplementation and high physical activity. These results deserve to be further investigated in an extended, interventional study cohort, where also the levels of 25(OH)D3 can be monitored.
    DOI:  https://doi.org/10.1038/s41598-022-15924-x
  244. Mar Drugs. 2022 Jul 11. pii: 452. [Epub ahead of print]20(7):
    Dual Role of Chitin as the Double Edged Sword in Controlling the NLRP3 Inflammasome Driven Gastrointestinal and Gynaecological Tumours.
    Chetan Roger Dhanjal, Rathnamegha Lingamsetty, Anooshka Pareddy, Se-Kwon Kim, Ritu Raval.
      The role of NLRP3 in the tumour microenvironment is elusive. In some cancers, the activation of NLRP3 causes a worse prognosis and in some cancers, NLRP3 increases chances of survivability. However, in many cases where NLRP3 has a protumorigenic role, inhibition of NLRP3 would be a crucial step in therapy. Consequently, activation of NLRP3 would be of essence when inflammation is required. Although many ways of inhibiting and activating NLRP3 in cancers have been discussed before, not a lot of focus has been given to chitin and chitosan in this context. The availability of these marine compounds and their versatility in dealing with inflammation needs to be investigated further in relation with cancers, along with other natural extracts. In this review, the effects of NLRP3 on gastrointestinal and gynaecological cancers and the impact of different natural extracts on NLRP3s with special emphasis on chitin and chitosan is discussed. A research gap in using chitin derivatives as anti/pro-inflammatory agents in cancer treatment has been highlighted.
    Keywords:  NLRP3; chitin derivatives; chito-oligosaccharides; chitosan; gastric cancers; gynaecological cancers
    DOI:  https://doi.org/10.3390/md20070452
  245. Front Pharmacol. 2022 ;13 934534
    Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies.
    Daniel L Pouliquen, Alice Boissard, Cécile Henry, Olivier Coqueret, Catherine Guette.
      Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host's immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.
    Keywords:  EMT cancer; biomarkers; cancer invasiveness; curcuminoids cancer; malignant mesothelioma; molecular targets; signaling pathway; tumor micro environment
    DOI:  https://doi.org/10.3389/fphar.2022.934534
  246. Mar Drugs. 2022 Jul 01. pii: 441. [Epub ahead of print]20(7):
    Antioxidant Efficacy of a Spirulina Liquid Extract on Oxidative Stress Status and Metabolic Disturbances in Subjects with Metabolic Syndrome.
    N'Deye Lallah Nina Koite, N'gouro Issa Sanogo, Olivier Lépine, Jean-Marie Bard, Khadija Ouguerram.
      Lipid peroxidation is associated with the development of some pathologies, such as cardiovascular diseases. Reduction in oxidative stress by antioxidants, such as Arthrospira (formely Spirulina), helps improving this redox imbalance. The aim of the study was to evaluate the effect of the Arthrospira liquid extract "Spirulysat®" on oxidative markers-in particular, oxidized LDL (oxLDL)/total LDL cholesterol-and isoprostanes and to investigate its impact on lipid and glucose metabolism in the metabolic syndrome subject. A controlled, randomised, double-blind design was conducted in 40 subjects aged 18 to 65 years with metabolic syndrome after a daily intake of Spirulysat® or placebo for twelve weeks. Blood and urinary samples were collected at three visits (V1, V2, V3) in the two groups for parameters determination. Although the Spirulysat® group showed a decrease at all visits of the oxLDL/total cholesterol ratio, there was no significant difference compared to the placebo (p = 0.36). The urinary isoprostanes concentration in the Spirulysat® group was reduced (p = 0.014) at V3. Plasma triglycerides decreased at V3 (p = 0.003) and HDL-cholesterol increased (p = 0.031) at all visits with Spirulysat®. In conclusion, Spirulysat® did not change the oxidized LDL (oxLDL)/LDL ratio but decreased the urinary isoprostanes, plasma triglycerides and increased HDL cholesterol, suggesting a beneficial effect on metabolic syndrome.
    Keywords:  Arthrospira liquid extract; dyslipidemia; isoprostanes; metabolic syndrome; oxLDL/LDL cholesterol
    DOI:  https://doi.org/10.3390/md20070441
  247. Pharmaceutics. 2022 Jun 27. pii: 1362. [Epub ahead of print]14(7):
    Doxorubicin-Loaded Lipid Nanoparticles Coated with Calcium Phosphate as a Potential Tool in Human and Canine Osteosarcoma Therapy.
    Daniela Chirio, Simona Sapino, Giulia Chindamo, Elena Peira, Cristina Vercelli, Chiara Riganti, Maela Manzoli, Graziana Gambino, Giovanni Re, Marina Gallarate.
      Osteosarcoma (OSA) is the most frequently diagnosed primary malignant bone tumor in humans and dogs. In both species, standard chemotherapy can be limited by multidrug resistance of neoplastic cells, which prevents intracellular accumulation of cytotoxic drugs, resulting in chemotherapy failure. In this study, a lipophilic ester of doxorubicin (C12DOXO) was loaded into nanoparticles (NPs) using the "cold microemulsion dilution" method. The resulting NPs were then coated with calcium phosphate (CaP) in two different ways to have calcium or phosphate ions externally exposed on the surface. These systems were characterized by determining mean diameter, zeta potential, and drug entrapment efficiency; afterward, they were tested on human and canine OSA cells to study the role that the coating might play in increasing both drug uptake into tumor cells and cytotoxicity. Mean diameter of the developed NPs was in the 200-300 nm range, zeta potential depended on the coating type, and C12DOXO entrapment efficiency was in the 60-75% range. Results of studies on human and canine OSA cells were very similar and showed an increase in drug uptake and cytotoxicity for CaP-coated NPs, especially when calcium ions were externally exposed. Therefore, applications in both human and veterinary medicine can be planned in the near future.
    Keywords:  calcium phosphate coating; canine osteosarcoma; cytotoxicity; doxorubicin; human osteosarcoma; microemulsion; nanoparticles; uptake
    DOI:  https://doi.org/10.3390/pharmaceutics14071362
  248. Front Pharmacol. 2022 ;13 917787
    Natural Compounds: A Hopeful Promise as an Antibiofilm Agent Against Candida Species.
    Aref Shariati, Mojtaba Didehdar, Shabnam Razavi, Mohsen Heidary, Fatemeh Soroush, Zahra Chegini.
      The biofilm communities of Candida are resistant to various antifungal treatments. The ability of Candida to form biofilms on abiotic and biotic surfaces is considered one of the most important virulence factors of these fungi. Extracellular DNA and exopolysaccharides can lower the antifungal penetration to the deeper layers of the biofilms, which is a serious concern supported by the emergence of azole-resistant isolates and Candida strains with decreased antifungal susceptibility. Since the biofilms' resistance to common antifungal drugs has become more widespread in recent years, more investigations should be performed to develop novel, inexpensive, non-toxic, and effective treatment approaches for controlling biofilm-associated infections. Scientists have used various natural compounds for inhibiting and degrading Candida biofilms. Curcumin, cinnamaldehyde, eugenol, carvacrol, thymol, terpinen-4-ol, linalool, geraniol, cineole, saponin, camphor, borneol, camphene, carnosol, citronellol, coumarin, epigallocatechin gallate, eucalyptol, limonene, menthol, piperine, saponin, α-terpineol, β-pinene, and citral are the major natural compounds that have been used widely for the inhibition and destruction of Candida biofilms. These compounds suppress not only fungal adhesion and biofilm formation but also destroy mature biofilm communities of Candida. Additionally, these natural compounds interact with various cellular processes of Candida, such as ABC-transported mediated drug transport, cell cycle progression, mitochondrial activity, and ergosterol, chitin, and glucan biosynthesis. The use of various drug delivery platforms can enhance the antibiofilm efficacy of natural compounds. Therefore, these drug delivery platforms should be considered as potential candidates for coating catheters and other medical material surfaces. A future goal will be to develop natural compounds as antibiofilm agents that can be used to treat infections by multi-drug-resistant Candida biofilms. Since exact interactions of natural compounds and biofilm structures have not been elucidated, further in vitro toxicology and animal experiments are required. In this article, we have discussed various aspects of natural compound usage for inhibition and destruction of Candida biofilms, along with the methods and procedures that have been used for improving the efficacy of these compounds.
    Keywords:  Candida biofilm; antibiobilm; essential oil; natural compounds; new treatment
    DOI:  https://doi.org/10.3389/fphar.2022.917787
  249. Front Bioeng Biotechnol. 2022 ;10 911455
    Magnetic-Driven Hydrogel Microrobots Selectively Enhance Synthetic Lethality in MTAP-Deleted Osteosarcoma.
    Haoran Mu, Chenlu Liu, Qi Zhang, Huanliang Meng, Shimin Yu, Ke Zeng, Jing Han, Xinmeng Jin, Shi Shi, Peiyao Yu, Tianlong Li, Jing Xu, Yingqi Hua.
      Background: Drugs based on synthetic lethality have advantages such as inhibiting tumor growth and affecting normal tissue in vivo. However, specific targets for osteosarcoma have not been acknowledged yet. In this study, a non-targeted but controllable drug delivery system has been applied to selectively enhance synthetic lethality in osteosarcoma in vitro, using the magnetic-driven hydrogel microrobots. Methods: In this study, EPZ015666, a PRMT5 inhibitor, was selected as the synthetic lethality drug. Then, the drug was carried by hydrogel microrobots containing Fe3O4. Morphological characteristics of the microrobots were detected using electron microscopy. In vitro drug effect was detected by the CCK-8 assay kit, Western blotting, etc. Swimming of microrobots was observed by a timing microscope. Selective inhibition was verified by cultured tumors in an increasing magnetic field. Results: Genomic mutation of MTAP deletion occurred commonly in pan-cancer in the TCGA database (nearly 10.00%) and in osteosarcoma in the TARGET database (23.86%). HOS and its derivatives, 143B and HOS/MNNG, were detected by MTAP deletion according to the CCLE database and RT-PCR. EPZ015666, the PRMT5 inhibitor, could reduce the SDMA modification and inhibition of tumor growth of 143B and HOS/MNNG. The hydrogel microrobot drug delivery system was synthesized, and the drug was stained by rhodamine. The microrobots were powered actively by a magnetic field. A simulation of the selected inhibition of microrobots was performed and lower cell viability of tumor cells was detected by adding a high dose of microrobots. Conclusion: Our magnetic-driven drug delivery system could carry synthetic lethality drugs. Meanwhile, the selective inhibition of this system could be easily controlled by programming the strength of the magnetic field.
    Keywords:  MTAP deletion; PRMT5; drug delivery system; microrobots; osteosarcoma
    DOI:  https://doi.org/10.3389/fbioe.2022.911455
  250. Molecules. 2022 Jul 22. pii: 4679. [Epub ahead of print]27(15):
    A Review on the Extraction, Bioactivity, and Application of Tea Polysaccharides.
    Jianmei Yao, Huifang Liu, Chiyu Ma, Lulu Pu, Wen Yang, Zhiwei Lei.
      Tea is a non-alcoholic drink containing various active ingredients, including tea polysaccharides (TPSs). TPSs have various biological activities, such as antioxidant, anti-tumor, hypoglycemic, and anti-cancer activities. However, TPSs have a complex composition, which significantly limits the extraction and isolation methods, thus limiting their application. This paper provides insight into the composition, methodological techniques for isolation and extraction of the components, biological activities, and functions of TPSs, as well as their application prospects.
    Keywords:  Tea Polysaccharides; antioxidant activity; bioactivity; extraction
    DOI:  https://doi.org/10.3390/molecules27154679
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