bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–08–14
224 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Fundamentals and applications of metal nanoparticle- enhanced singlet oxygen generation for improved cancer photodynamic therapy.
  2. Nano-delivery systems for food bioactive compounds in cancer: prevention, therapy, and clinical applications.
  3. Bee venom-loaded EGFR-targeting peptide-coupled chitosan nanoparticles for effective therapy of hepatocellular carcinoma by inhibiting EGFR-mediated MEK/ERK pathway.
  4. Traditional Medicinal Plants as a Source of Inspiration for Osteosarcoma Therapy.
  5. Bioactive compounds, bio-functional properties, and food applications of Garcinia indica: A review.
  6. Platinum-based nanocomposites loaded with MTH1 inhibitor amplify oxidative damage for cancer therapy.
  7. The metabolic addiction of cancer stem cells.
  8. Intelligent triggering of nanomicelles based on a ROS-activated anticancer prodrug and photodynamic therapy (PDT)-synergistic therapy for lung cancers.
  9. Development of nanocubosomes co-loaded with dual anticancer agents curcumin and temozolomide for effective Colon cancer therapy.
  10. Oxidation and Reduction Dual-Responsive Polymeric Prodrug Micelles Co-delivery Precisely Prescribed Paclitaxel and Honokiol for Laryngeal Carcinoma Combination Therapy.
  11. Combination of Probiotics and Natural Compounds to Treat Multiple Sclerosis via Warburg Effect.
  12. NIR-Active Porphyrin-Decorated Lipid Microbubbles for Enhanced Therapeutic Activity Enabled by Photodynamic Effect and Ultrasound in 3D Tumor Models of Breast Cancer Cell Line and Zebrafish Larvae.
  13. Engineering nanosystems to overcome barriers to cancer diagnosis and treatment.
  14. Fabrication of protein nanomaterials as delivery systems.
  15. The Anti-Leukemia Effect of Ascorbic Acid: From the Pro-Oxidant Potential to the Epigenetic Role in Acute Myeloid Leukemia.
  16. Mechanism of glycometabolism regulation by bioactive compounds from the fruits of Lycium barbarum: A review.
  17. Nutraceuticals and Food-Grade Lipid Nanoparticles: From Natural Sources to a Circular Bioeconomy Approach.
  18. Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation: Maternal soybean prevention on obesity-related breast cancer.
  19. Enhancing Tumor Therapy of Fe(III)-Shikonin Supramolecular Nanomedicine via Triple Ferroptosis Amplification.
  20. 5-aminolevulinic acid and sodium ferrous citrate decreased cell viability of gastric cancer cells by enhanced ROS generation through improving COX activity.
  21. Antioxidant, antibacterial, antitumor, antifungal, antiviral, anti-inflammatory, and nevro-protective activity of Ganoderma lucidum: An overview.
  22. Design Principles of Hybrid Nanomaterials for Radiotherapy Enhanced by Photodynamic Therapy.
  23. Hyaluronic acid coated spinel ferrite for combination of chemo and photodynamic therapy: Green synthesis, characterization, and in vitro and in vivo biocompatibility study.
  24. Protective Effect of Resveratrol on Knee Osteoarthritis and its Molecular Mechanisms: A Recent Review in Preclinical and Clinical Trials.
  25. Updated design strategies for oral delivery systems: maximized bioefficacy of dietary bioactive compounds achieved by inducing proper digestive fate and sensory attributes.
  26. Vitamin D Supplementation Could Enhance the Effectiveness of Glibenclamide in Treating Diabetes and Preventing Diabetic Nephropathy: A Biochemical, Histological and Immunohistochemical Study.
  27. Therapeutic Potential of Quercetin and its Derivatives in Epilepsy: Evidence from Preclinical Studies.
  28. A Review on Nanocarrier Mediated Treatment and Management of Triple Negative Breast Cancer: A Saudi Arabian Scenario.
  29. Synthesis, characterization, and evaluation of in vitro cytotoxicity and in vivo antitumor activity of asiatic acid-loaded poly lactic-co-glycolic acid nanoparticles: A strategy of treating breast cancer.
  30. Membrane-wrapped nanoparticles for photothermal cancer therapy.
  31. Microneedle-assisted transdermal delivery of amlodipine besylate loaded nanoparticles.
  32. Mitochondria-targeting polydopamine-coated nanodrugs for effective photothermal- and chemo-synergistic therapies against lung cancer.
  33. Endocytosis-mediated triple-activable prodrug nanotherapeutics potentiating therapeutic efficacy and security towards solid tumors.
  34. Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.
  35. Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.
  36. Heterogeneity in RAS mutations: One size does not fit all.
  37. Nature's Gold (Moringa Oleifera): Miracle Properties.
  38. Nisin and nisin-loaded nanoparticles: a cytotoxicity investigation.
  39. Cubosomes: Design, Development, and Tumor-Targeted Drug Delivery Applications.
  40. Iron oxide@chlorophyll clustered nanoparticles eliminate bladder cancer by photodynamic immunotherapy-initiated ferroptosis and immunostimulation.
  41. The Effect of the Ketogenic Diet on the Therapy of Neurodegenerative Diseases and Its Impact on Improving Cognitive Functions.
  42. A systematic review on potential anticancer activities of Ficus carica L. with focus on cellular and molecular mechanisms.
  43. Pulmonary delivery of size-transformable nanoparticles improves tumor accumulation and penetration for chemo-sonodynamic combination therapy.
  44. Recent Advances in Nanoparticle-Based Co-Delivery Systems for Cancer Therapy.
  45. Glucose Deprivation Induced by Acarbose and Oncolytic Newcastle Disease Virus Promote Metabolic Oxidative Stress and Cell Death in a Breast Cancer Model.
  46. The therapeutic role of nutraceuticals targeting the Nrf2/HO-1 signaling pathway in liver cancer.
  47. Ligand conjugated lipid-based nanocarriers for cancer theranostics.
  48. Mesoporous polydopamine nanoparticles for sustained release of rapamycin and reactive oxygen species scavenging to synergistically accelerate neurogenesis after spinal cord injury.
  49. Why Should Pistachio Be a Regular Food in Our Diet?
  50. Oncolytic Impediment/Promotion Balance Disruption by Sonosensitizer-Free Nanoplatforms Unfreezes Autophagy-Induced Resistance to Sonocatalytic Therapy.
  51. Black phosphorous nanomaterials as a new paradigm for postoperative tumor treatment regimens.
  52. Drug Delivery Systems with a "Tumor-Triggered" Targeting or Intracellular Drug Release Property Based on DePEGylation.
  53. The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment.
  54. Lower vitamin D levels and VDR variants are risk factors for breast cancer: an updated meta-analysis.
  55. A Promising Review on Cyclodextrin Conjugated Paclitaxel Nanoparticles for Cancer Treatment.
  56. Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma.
  57. A multi-responsive targeting drug delivery system for combination photothermal/chemotherapy of tumor.
  58. Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems.
  59. Roles of exosomes as drug delivery systems in cancer immunotherapy: a mini-review.
  60. Food protein-derived bioactive peptides for the management of nutrition related chronic diseases.
  61. A review on the latest developments of mesoporous silica nanoparticles as a promising platform for diagnosis and treatment of cancer.
  62. Defect Engineering Triggers Exceptional Sonodynamic Activity of Manganese Oxide Nanoparticles for Cancer Therapy.
  63. The potential application of natural products in cutaneous wound healing: A review of preclinical evidence.
  64. Injectable and reactive oxygen species-scavenging gelatin hydrogel promotes neural repair in experimental traumatic brain injury.
  65. Dihydroartemesinin and Curcumin Based Self-Microemulsifying Drug Delivery System for Antimalarial Activity.
  66. Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation.
  67. Effect of Different Proportions of Phenolics on Antioxidant Potential: Pointers for Bioactive Synergy/Antagonism in Foods and Nutraceuticals.
  68. Purvalanol A induces apoptosis and reverses cisplatin resistance in ovarian cancer.
  69. Intelligent poly(l-histidine)-based nanovehicles for controlled drug delivery.
  70. The effects of ginger and its constituents in the prevention of metabolic syndrome: A review.
  71. Self-healing pectin/cellulose hydrogel loaded with limonin as TMEM16A inhibitor for lung adenocarcinoma treatment.
  72. Advancements in redox-sensitive micelles as nanotheranostics: A new horizon in cancer management.
  73. Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.
  74. B Vitamins: Functions and Uses in Medicine.
  75. Metabolomics and integrated network pharmacology analysis reveal that ginkgolides act as potential active anticancer components by regulating one-carbon metabolism.
  76. Development and Challenges of Synthetic Retinoid Formulations in Cancer.
  77. Effect of Medicinal Plants and Natural Products on Liver Enzymes in Non-alcoholic Fatty Liver Patients in Iran: A Systematic Review and Meta-Analysis.
  78. Folic acid-decorated PEGylated magnetite nanoparticles as efficient drug carriers to tumor cells overexpressing folic acid receptor.
  79. VITAL Findings - A Decisive Verdict on Vitamin D Supplementation.
  80. Drug repurposing: re-inventing therapies for cancer without re-entering the development pipeline-a review.
  81. The potential interplay between G-quadruplex and p53: their roles in regulation of ferroptosis in cancer.
  82. Enzyme-triggered- and tumor-targeted delivery with tunable, methacrylated poly(ethylene glycols) and hyaluronic acid hybrid nanogels.
  83. Tumor-derived extracellular vesicles for the active targeting and effective treatment of colorectal tumors in vivo.
  84. Lipid-based solubilization technology via hot melt extrusion: promises and challenges.
  85. Advances in aptamer-based drug delivery vehicles for cancer therapy.
  86. A cell-mimicking platelet-based drug delivery system as a potential carrier of dimethyl fumarate for multiple sclerosis.
  87. An update on molecular mechanisms of curcumin effect on diabetes.
  88. Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.
  89. Vitamin D, Th17 Lymphocytes, and Breast Cancer.
  90. A phthalocyanine-based photosensitizer for effectively combating triple negative breast cancer with enhanced photodynamic anticancer activity and immune response.
  91. The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease.
  92. The use of traditional Chinese medicines in relieving exercise-induced fatigue.
  93. The application of photodynamic therapy in plastic and reconstructive surgery.
  94. Encapsulation of Essential Oils in Nanocarriers for Active Food Packaging.
  95. The beneficial therapeutic effects of plant-derived natural products for the treatment of sarcopenia.
  96. Tumor-targeting cell-penetrating peptide, p28, for glioblastoma imaging and therapy.
  97. Ethanolic extract of Coleus aromaticus leaves impedes the proliferation and instigates apoptotic cell death in liver cancer HepG2 cells through repressing JAK/STAT cascade.
  98. Cyclodextrins as an encapsulation molecular strategy for volatile organic compounds- Pharmaceutical applications.
  99. Epigenome Modulation Induced by Ketogenic Diets.
  100. Nanotechnology meets glioblastoma multiforme: Emerging therapeutic strategies.
  101. Xanthorrhizol, a potential anticancer agent, from Curcuma xanthorrhiza Roxb.
  102. Can dietary flavonoids be useful in the personalized treatment of colorectal cancer?
  103. AMPKα2/HNF4A/BORIS/GLUT4 pathway promotes hepatocellular carcinoma cell invasion and metastasis in low glucose microenviroment.
  104. Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression.
  105. Vilazodone-phospholipid mixed micelles for enhancing oral bioavailability and reducing pharmacokinetic variability between fed and fasted states.
  106. Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases.
  107. Vitamin D and colorectal cancer - A practical review of the literature.
  108. Stimuli-responsive liposomal nanoformulations in cancer therapy: Pre-clinical & clinical approaches.
  109. Resveratrol attenuates autophagy and inflammation after traumatic brain injury by activation of PI3K/Akt/mTOR pathway in rats.
  110. The effect of hypoxia on photodynamic therapy with 5-aminolevulinic acid in malignant gliomas.
  111. Advances in delivery methods of Arthrospira platensis (spirulina) for enhanced therapeutic outcomes.
  112. Enhancement of the c ytotoxic effect of dihydroartemisinin in high-riskhuman papillomavirus-infected cells by aminolevulinic acid via the Bax/Bcl-2-caspase pathway.
  113. Natural Polysaccharide-Based Nanodrug Delivery Systems for Treatment of Diabetes.
  114. In-Vitro Use of Verteporfin for Photodynamic Therapy in Glioblastoma.
  115. Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells.
  116. Recent Advances in Garcinia cambogia Nutraceuticals in Relation to Its Hydroxy Citric Acid Level. A Comprehensive Review of Its Bioactive Production, Formulation, and Analysis with Future Perspectives.
  117. Synthesis of ciprofloxacin-capped gold nanoparticles conjugates with enhanced sonodynamic antimicrobial activity in vitro.
  118. 1α,25-dihydroxyvitamin D reduction of MCF10A-ras cell viability in extracellular matrix detached conditions is dependent on regulation of pyruvate carboxylase.
  119. Expanding Arsenal against Neurodegenerative Diseases using Quercetin based Nanoformulations: Breakthroughs and Bottlenecks.
  120. Amplified Drug Delivery System with a Pair of Master Keys Triggering Precise Drug Release for Chemo-Photothermal Therapy.
  121. Effect of exercise on tumor markers - Is exercise anti-tumorigenic in humans?: A scoping review of preliminary clinical investigations.
  122. Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.
  123. Effect of epigallocatechin gallate on the fermentative and physicochemical properties of fermented milk.
  124. Calluna vulgaris as a Valuable Source of Bioactive Compounds: Exploring Its Phytochemical Profile, Biological Activities and Apitherapeutic Potential.
  125. What is the role of phenolic compounds of yerba mate (Ilex paraguariensis) in gut microbiota?
  126. Impact of ultrasonication applications on color profile of foods.
  127. Oral sorafenib-loaded microemulsion for breast cancer: evidences from the in-vitro evaluations and pharmacokinetic studies.
  128. An injectable thermosensitive hydrogel for dual delivery of diclofenac and Avastin® to effectively suppress inflammatory corneal neovascularization.
  129. Anticancer Effect of Puerarin on Ovarian Cancer Progression Contributes to the Tumor Suppressor Gene Expression and Gut Microbiota Modulation.
  130. Nanobodies; new molecular instruments with special specifications for targeting, diagnosis and treatment of triple-negative breast cancer.
  131. Plant lectin: A promising future anti-tumor drug.
  132. Selective delivery of pentamidine toward cancer cells by self-assembled nanoparticles.
  133. Potential targets and treatments affect oxidative stress in gliomas: An overview of molecular mechanisms.
  134. Antibacterial Properties and Mechanisms of Action of Sonoenzymatically Synthesized Lignin-Based Nanoparticles.
  135. Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes.
  136. Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis.
  137. Curcumin activates autophagy and attenuates high glucose-induced apoptosis in HUVECs through the ROS/NF-κB signaling pathway.
  138. Bilayer Hydrogels for Wound Dressing and Tissue Engineering.
  139. Inhibition of hypoxia-inducible factor 1 by acriflavine renders glioblastoma sensitive for photodynamic therapy.
  140. Antioxidant Capacity, Vitamin C and Polyphenol Profile Evaluation of a Capsicum chinense By-Product Extract Obtained by Ultrasound Using Eutectic Solvent.
  141. Shilajit potentiates the effect of chemotherapeutic drugs and mitigates metastasis induced liver and kidney damages in osteosarcoma rats.
  142. Combinations of chemo-, immuno-, and gene therapies using nanocarriers as a multifunctional drug platform.
  143. Efficacy and Safety of Curcumin and Curcuma longa Extract in the Treatment of Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trial.
  144. Size-Controllable DNA Origami-Stacked Gold Nanoparticles for Deep Tumor-Penetrating Therapy.
  145. Mechanism of Enhanced Oral Absorption of a Nano-Drug Delivery System Loaded with Trimethyl Chitosan Derivatives.
  146. Modulatory effect of berberine on plasma lipoprotein (or lipid) profile: a review.
  147. BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.
  148. Defibrotide suppresses brain metastasis by activating the adenosine A2A receptors.
  149. In Vitro Evaluation of Kaempferol-Loaded Hydrogel as pH-Sensitive Drug Delivery Systems.
  150. Linoleic Acid-Glucosamine Hybrid for Endogenous Iron-Activated Ferroptosis Therapy in High-Grade Serous Ovarian Cancer.
  151. Licorice: Resources, applications in ancient and modern times.
  152. Recent Advance in Tumor Microenvironment-Based Stimuli-Responsive Nanoscale Drug Delivery and Imaging Platform.
  153. Nano-embedded medical devices and delivery systems in interventional radiology.
  154. Injectable pH-responsive hydrogel for combinatorial chemoimmunotherapy tailored to the tumor microenvironment.
  155. Study on the Action Mechanism of the Yifei Jianpi Tongfu Formula in Treatment of Colorectal Cancer Lung Metastasis Based on Network Analysis, Molecular Docking, and Experimental Validation.
  156. Emerging roles of platelets in cancer biology and their potential as therapeutic targets.
  157. Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
  158. Nanotechnology based drug delivery systems: Does shape really matter?
  159. Melanoma Cancer Therapy Using PEGylated Nanoparticles and Semiconductor Laser.
  160. Kidney-Targeted Drug Delivery System Based on Metformin-Grafted Chitosan for Renal Fibrosis Therapy.
  161. KRAS-targeted therapy in the treatment of non-small cell lung cancer.
  162. Fabrication of nanoemulsion delivery system with high bioaccessibility of carotenoids from Lycium barbarum by spontaneous emulsification.
  163. Functional Thermoresponsive Hydrogel Molecule to Material Design for Biomedical Applications.
  164. Association between Vitamin D Supplementation and Cancer Mortality: A Systematic Review and Meta-Analysis.
  165. Nanoparticles in clinical trials of COVID-19: An update.
  166. Anti-melanoma effect and action mechanism of a novel chitosan-based composite hydrogel containing hydroxyapatite nanoparticles.
  167. Polymeric Hydrogel Scaffolds: Skin Tissue Engineering and Regeneration.
  168. Advances on nanoformulation approaches for delivering plant-derived antioxidants: A case of quercetin.
  169. The Effects of Chitosan-PEG Nanoparticles Based on Channa striata Protein Hydrolyzate on Decreasing Diabetes Mellitus in Diabetic Rats.
  170. Nanotechnology Approaches for Enhanced CNS Drug Delivery in the Management of Schizophrenia.
  171. Natural Dietary Compounds in the Treatment of Arsenic Toxicity.
  172. Targeted Nanotherapies For The Posterior Segment Of The Eye: An Integrative Review On Recent Advancements And Challenges.
  173. Targeting mucus barrier in respiratory diseases by chemically modified advanced delivery systems.
  174. Ferroptosis as ultimate target of cancer therapy.
  175. Chinese Medicine in the Treatment of Ulcerative Colitis: The Mechanisms of Signaling Pathway Regulations.
  176. The association of maternal dietary quality and the antioxidant-proxidant balance of human milk.
  177. Biodegradable Silk Fibroin Nanocarriers to Modulate Hypoxia Tumor Microenvironment Favoring Enhanced Chemotherapy.
  178. Spray drying and nano spray drying as manufacturing methods of drug-loaded polymeric particles.
  179. Mesoporous Silica Nanoparticles Incorporated with Ir(III) complexes: From Photophysics to Photodynamic Therapy.
  180. Phytochemical and biological diversity of triterpenoid saponins from family Sapotaceae: A comprehensive review.
  181. Application of Elastin-like Polypeptide in Tumor Therapy.
  182. Advancements and Applications in the Composites of Silk Fibroin and Graphene-Based Materials.
  183. Propolis Contra Pharmacological Interventions in Bees.
  184. Arsenic exposure increases susceptibility to Ptpn11-induced malignancy in mouse embryonic fibroblasts through mitochondrial hypermetabolism.
  185. An enzyme-particle hybrid ink for one step screen-printing and long-term metabolism monitoring.
  186. Author Correction: Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer.
  187. Modulation of autophagy by melatonin via sirtuins in stroke: From mechanisms to therapies.
  188. How can we use the endocytosis pathways to design nanoparticle drug-delivery vehicles to target cancer cells over healthy cells?
  189. Therapeutic Effects and Metabolic Spectrum of Traditional Chinese Medicine Hengqing II Prescription on Alzheimer's Disease.
  190. A Preliminary Assessment of the Nutraceutical Potential of Acai Berry (Euterpe sp.) as a Potential Natural Treatment for Alzheimer's Disease.
  191. Annexin A5 as a targeting agent for cancer treatment.
  192. Pump proton inhibitors display anti-tumour potential in glioma.
  193. Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer.
  194. Reactive Oxygen Species Responsive Cleavable Hierarchical Metallic Supra-Nanostructure.
  195. The anti-inflammatory properties of the methanolic extract of Cucumis melo Linn. against prostate enlargement in Wistar rats.
  196. Metabolic Reprogramming Helps to Define Different Metastatic Tropisms in Colorectal Cancer.
  197. Evaluation of Microwave-Assisted Extraction as a Potential Green Technology for the Isolation of Bioactive Compounds from Saffron (Crocus sativus L.) Floral By-Products.
  198. Health functions and related molecular mechanisms of ellagitannin-derived urolithins.
  199. Carotenoids in Palliative Care-Is There Any Benefit from Carotenoid Supplementation in the Adjuvant Treatment of Cancer-Related Symptoms?
  200. Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects.
  201. Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview.
  202. Emerging Roles of the Nervous System in Gastrointestinal Cancer Development.
  203. Blend of secondary metabolites from mesquite to improve nutrient digestibility, microbial protein, efficient use of nitrogen, ruminal parameters, and blood metabolites in sheep.
  204. Chitosan/PLGA shell nanoparticles as Tylotoin delivery platform for advanced wound healing.
  205. Big Data Analysis of Manufacturing and Preclinical Studies of Nanodrug-Targeted Delivery Systems: A Literature Review.
  206. Computational Metabolomics Reveals the Potential Mechanism of Matrine Mediated Metabolic Network Against Hepatocellular Carcinoma.
  207. A Carbon-Carbon Bond Cleavage-Based Prodrug Activation Strategy Applied to β-Lapachone for Cancer-Specific Targeting.
  208. Zwitterionic meso-silica/polypeptide hybrid nanoparticles for efficient azithromycin delivery and photodynamic therapy for synergistic treatment of drug-resistant bacterial infection.
  209. Biological and neurological activities of astaxanthin (Review).
  210. Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases.
  211. A Comparison of the Impact of Restrictive Diets on the Gastrointestinal Tract of Mice.
  212. Multifunctional nanolocks with GSH as the key for synergistic ferroptosis and anti-chemotherapeutic resistance.
  213. A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma.
  214. Lipid droplets promote efficient mitophagy.
  215. Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells.
  216. Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer's Disease.
  217. A literature review of the studies concerning selected plant-derived adaptogens and their general function in body with a focus on animal studies.
  218. Tumoral Oxygenation and Biodistribution of Lonidamine Oxygen Microbubbles Following Localized Ultrasound-Triggered Delivery.
  219. Extracts Rich in Nutrients as Novel Food Ingredients to Be Used in Food Supplements: A Proposal Classification.
  220. Editorial: Natural products as sources of innovative approaches in psychiatry.
  221. Plant-based diets and long-term health: findings from the EPIC-Oxford study.
  222. Nitrite lowers the oxygen cost of ATP supply in cultured skeletal muscle cells by stimulating the rate of glycolytic ATP synthesis.
  223. c-kit inhibitor masitinib induces reactive oxygen species-dependent apoptosis in c-kit-negative HepG2 cells.
  224. Beneficial Effects of Flaxseed and/or Mulberry Extracts Supplementation in Ovariectomized Wistar Rats.
  1. Front Chem. 2022 ;10 964674
    Fundamentals and applications of metal nanoparticle- enhanced singlet oxygen generation for improved cancer photodynamic therapy.
    Blassan P George, Alexander Chota, Paromita Sarbadhikary, Heidi Abrahamse.
      The introduction of nanotechnology in the field of Photodynamic Therapy (PDT) has proven to have great potential to overcome some of the challenges associated with traditional organic photosensitizers (PS) with respect to their solubility, drug delivery, distribution and site-specific targeting. Other focused areas in PDT involve high singlet oxygen production capability and excitability of PS by deep tissue penetrating light wavelengths. Owing to their very promising optical and surface plasmon resonance properties, combination of traditional PSs with plasmonic metallic nanoparticles like gold and silver nanoparticles results in remarkably high singlet oxygen production and extended excitation property from visible and near-infrared lights. This review summarizes the importance, fundamentals and applications of on plasmonic metallic nanoparticles in PDT. Lastly, we highlight the future prospects of these plasmonic nanoengineering strategies with or without PS combination, to have a significant impact in improving the therapeutic efficacy of cancer PDT.
    Keywords:  cancer; metallic nanoparticles; nanotechnology; photodynamic therapy; photosensitizers; photothermal therapy; singlet oxygen; surface plasmon resonance
    DOI:  https://doi.org/10.3389/fchem.2022.964674
  2. Crit Rev Food Sci Nutr. 2022 Aug 08. 1-26
    Nano-delivery systems for food bioactive compounds in cancer: prevention, therapy, and clinical applications.
    Italo Rennan Sousa Vieira, Carlos Adam Conte-Junior.
      Bioactive compounds represent a broad class of dietary metabolites derived from fruits and vegetables, such as polyphenols, carotenoids and glucosinolates with potential for cancer prevention. Curcumin, resveratrol, quercetin, and β-carotene have been the most widely applied bioactive compounds in chemoprevention. Lately, many approaches to encapsulating bioactive components in nano-delivery systems have improved biomolecules' stability and targeted delivery. In this review, we critically analyze nano-delivery systems for bioactive compounds, including polymeric nanoparticles (NPs), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes, niosomes, and nanoemulsions (NEs) for potential use in cancer therapy. Efficacy studies of the nanoformulations using cancer cell lines and in vivo models and updated human clinical trials are also discussed. Nano-delivery systems were found to improve the therapeutic efficacy of bioactive molecules against various types of cancer (e.g., breast, prostate, colorectal and lung cancer) mainly due to the antiproliferation and pro-apoptotic effects of tumor cells. Furthermore, some bioactive compounds have promised combination therapy with standard chemotherapeutic agents, with increased tumor efficiency and fewer side effects. These opportunities were identified and developed to ensure more excellent safety and efficacy of novel herbal medicines enabling novel insights for designing nano-delivery systems for bioactive compounds applied in clinical cancer therapy.
    Keywords:  Antioxidant; encapsulate; herbal medicine; nanoparticle; phenolics; tumor
    DOI:  https://doi.org/10.1080/10408398.2022.2106471
  3. PLoS One. 2022 ;17(8): e0272776
    Bee venom-loaded EGFR-targeting peptide-coupled chitosan nanoparticles for effective therapy of hepatocellular carcinoma by inhibiting EGFR-mediated MEK/ERK pathway.
    Shaymaa Abdulmalek, Nouf Mostafa, Marwa Gomaa, Mohamed El-Kersh, Ayman I Elkady, Mahmoud Balbaa.
      Hepatocellular carcinoma (HCC) is one of the world's most risky diseases due to the lack of clear and cost-effective therapeutic targets. Currently, the toxicity of conventional chemotherapeutic medications and the development of multidrug resistance is driving research into targeted therapies. The nano-biomedical field's potential for developing an effective therapeutic nano-sized drug delivery system is viewed as a significant pharmaceutical trend for the encapsulation and release of numerous anticancer therapies. In this regard, current research is centered on the creation of biodegradable chitosan nanoparticles (CSNPs) for the selective and sustained release of bee venom into liver cancer cells. Furthermore, surface modification with polyethylene glycol (PEG) and GE11 peptide-conjugated bee venom-CSNPs allows for the targeting of EGFR-overexpressed liver cancer cells. A series of in vitro and in vivo cellular analyses were used to investigate the antitumor effects and mechanisms of targeted bee venom-CSNPs. Targeted bee venom-CSNPs, in particular, were found to have higher cytotoxicity against HepG2 cells than SMMC-7721 cells, as well as stronger cellular uptake and a substantial reduction in cell migration, leading to improved cancer suppression. It also promotes cancer cell death in EGFR overexpressed HepG2 cells by boosting reactive oxygen species, activating mitochondria-dependent pathways, inhibiting EGFR-stimulated MEK/ERK pathway, and elevating p38-MAPK in comparison to native bee venom. In hepatocellular carcinoma (HCC)-induced mice, it has anti-cancer properties against tumor tissue. It also improved liver function and architecture without causing any noticeable toxic side effects, as well as inhibiting tumor growth by activating the apoptotic pathway. The design of this cancer-targeted nanoparticle establishes GE11-bee venom-CSNPs as a potential chemotherapeutic treatment for EGFR over-expressed malignancies. Finally, our work elucidates the molecular mechanism underlying the anticancer selectivity of targeted bee venom-CSNPs and outlines therapeutic strategies to target liver cancer.
    DOI:  https://doi.org/10.1371/journal.pone.0272776
  4. Molecules. 2022 Aug 06. pii: 5008. [Epub ahead of print]27(15):
    Traditional Medicinal Plants as a Source of Inspiration for Osteosarcoma Therapy.
    Liliya Kazantseva, José Becerra, Leonor Santos-Ruiz.
      Osteosarcoma is one of the most common types of bone cancers among paediatric patients. Despite the advances made in surgery, chemo-, and radiotherapy, the mortality rate of metastatic osteosarcoma remains unchangeably high. The standard drug combination used to treat this bone cancer has remained the same for the last 20 years, and it produces many dangerous side effects. Through history, from ancient to modern times, nature has been a remarkable source of chemical diversity, used to alleviate human disease. The application of modern scientific technology to the study of natural products has identified many specific molecules with anti-cancer properties. This review describes the latest discovered anti-cancer compounds extracted from traditional medicinal plants, with a focus on osteosarcoma research, and on their cellular and molecular mechanisms of action. The presented compounds have proven to kill osteosarcoma cells by interfering with different pathways: apoptosis induction, stimulation of autophagy, generation of reactive oxygen species, etc. This wide variety of cellular targets confer natural products the potential to be used as chemotherapeutic drugs, and also the ability to act as sensitizers in drug combination treatments. The major hindrance for these molecules is low bioavailability. A problem that may be solved by chemical modification or nano-encapsulation.
    Keywords:  combination therapy; drug discovery; natural products; osteosarcoma; signaling pathway; traditional medicinal plants
    DOI:  https://doi.org/10.3390/molecules27155008
  5. J Food Biochem. 2022 Aug 07. e14344
    Bioactive compounds, bio-functional properties, and food applications of Garcinia indica: A review.
    Sahil Desai, Poorva Sharma, Piyush Kashyap, Bharti Choudhary, Jasleen Kaur.
      Garcinia indica Choisy (kokum), a plant from Clusiaceae family, is an underexplored fruit tree in the Western Ghats region. Kokum has been studied for its health benefits, associated with numerous bioactive compounds, including phenolic acids, flavonoids, citric acids, and others. Among all, garcinol, hydroxycitric acid, and anthocyanins (cyanidin-3-glucoside and cyanidin-3-sambubioside) are major bioactive compounds. G. indica fruit and fruit rinds have been reported to possess numerous therapeutic applications in various health conditions such as cancer, inflammation, diabetes, obesity, cardiovascular disease, and neurologic disorders. In this review, information has been provided on the bioactive compounds present in kokum and their significant health benefits. In vitro and In vivo studies of bioactive components on various diseases have also been reported. The limited information about human studies and G. indica fruit and fruit rinds is also presented. PRACTICAL APPLICATIONS: Bioactive compounds present in Garcinia indica can be utilized for nutraceutical preparations. G. indica can be added to food products to make them functional foods. Extraction of bioactive compounds can be done on an industrial scale. Bioactive compounds can be extracted and used to commercialize lifesaving drugs.
    Keywords:   Garcinia indica ; CVDs; bioactive compounds; cancer; diabetes; neurologic disorders; obesity
    DOI:  https://doi.org/10.1111/jfbc.14344
  6. Colloids Surf B Biointerfaces. 2022 Aug 02. pii: S0927-7765(22)00398-8. [Epub ahead of print]218 112715
    Platinum-based nanocomposites loaded with MTH1 inhibitor amplify oxidative damage for cancer therapy.
    Qingcheng Song, Wenbo Yang, Xiangtian Deng, Yiran Zhang, Junyong Li, Xin Xing, Wei Chen, Weijian Liu, Hongzhi Hu, Yingze Zhang.
      Photodynamic therapy (PDT) is a promising therapeutic strategy for tumor ablation by generating highly toxic reactive oxygen species (ROS) to damage DNA and other biomacromolecules. However, the local hypoxic microenvironment of the tumor and the presence of ROS-defensing system, such as the mobilization of mutt homolog 1 (MTH1) to sanitize ROS-oxidized nucleotide pool, severely limit the efficiency of PDT. Therefore, a novel tumor ablation strategy was developed that not only focused on the enhancement of ROS generation but also weakened the ROS-defensing system by inhibiting MTH1 enzyme activity. In our work, a simple one-step reduction approach was applied to enable platinum nanoparticles (Pt NPs) with catalase activity to grow in situ in the nanochannels of mesoporous silica nanoparticles (MSNs). After physical encapsulation of photosensitizer chlorin e6 (Ce6) and MTH1 inhibitor TH588, the drug loading nanoplatform was modified with an arginine-glycine-aspartic acid (RGD) functionalized liposome shell, resulting in the fabrication of amplified oxidative damage nanoplatform MSN-Pt@Ce6/TH588 @Liposome-RGD (MPCT@Li-R). The prepared MPCT@Li-R NPs could continuously catalyze the decomposition of hydrogen peroxide (H2O2) into oxygen (O2) in tumor, thus promoting the generation of singlet oxygen during PDT process for improved oxidative damage of bases. Simultaneously, acid responsive released TH588 hindered MTH1-mediated scavenging of oxidative bases, further aggravating DNA oxidative damage. Consequently, this cascade therapy strategy exhibited excellent tumor suppression efficiency both in vitro and in vivo.
    Keywords:  Hypoxia; MTH1; Oxidative damage; Photodynamic therapy; Platinum nanoparticle
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112715
  7. Front Oncol. 2022 ;12 955892
    The metabolic addiction of cancer stem cells.
    Om Saswat Sahoo, Karthikeyan Pethusamy, Tryambak P Srivastava, Joyeeta Talukdar, Mohammed S Alqahtani, Mohamed Abbas, Ruby Dhar, Subhradip Karmakar.
      Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.
    Keywords:  cancer stem cells; cross talks; epigenetics; metabolism; oncometabolites
    DOI:  https://doi.org/10.3389/fonc.2022.955892
  8. Eur J Med Chem. 2022 Aug 03. pii: S0223-5234(22)00524-4. [Epub ahead of print]241 114622
    Intelligent triggering of nanomicelles based on a ROS-activated anticancer prodrug and photodynamic therapy (PDT)-synergistic therapy for lung cancers.
    Lixue Chen, Ruping Xu, Yanfang Ding, Changyuan Wang, Sitong Zhang, Zhenya Sun, Yali Chen, Yunfeng Mi, Meng Gao, Xiaodong Ma, Lei Li.
      The intelligent triggering of drug release at targeted sites is essential for the safety and efficacy of cancer therapies. This study aimed to design and synthesize a novel prodrug (DHA-S-CA) using a reactive oxygen species (ROS)-responsive moiety, thioacetal, to bridge cinnamaldehyde (CA) and dihydroartemisinin (DHA). As ROS are highly expressed in tumor tissues, the design uses the ROS-responsive moiety as an effective target for the nanodrug delivery system. Furthermore, the near-infrared dye IR808 and the prodrug were adopted to prepare co-loaded Soluplus®/TPGS nanomicelles (IR808/DHA-S-CA NMs). The photosensitized agent IR808 exhibited both tumor accumulation and cancer imaging properties while generating ROS during laser irradiation. Intracellular ROS detection indicated that the prodrug DHA-S-CA could degrade via the high concentration of ROS in cancer cells induced by laser irradiation, and the released CA stimulated mitochondria to regenerate additional ROS to further improve the antitumor effect of DHA. Combined with photodynamic therapy (PDT), IR808/DHA-S-CA (+) NMs outperformed free DHA, DHA NMs, and IR808/DHA-S-CA (-) in a comparison of their pharmacokinetic profiles because it had a longer circulation time and a greater area under the curve (AUC). Compared with other DHA groups, the ROS-responsive IR808/DHA-S-CA (+) micelles had comparable cytotoxic activity. Furthermore, the ROS-responsive IR808/DHA-S-CA (+) micelles exhibited markedly higher anticancer efficiency on lung cancer cells than the other DHA groups. Overall, these results indicated that the therapeutic strategy of our novel small-molecule prodrug combined with PDT has great potential for the treatment of tumors.
    Keywords:  Cinnamaldehyde; Dihydroartemisinin; Photodynamic therapy; Prodrug; ROS sensitive
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114622
  9. Drug Deliv. 2022 Dec;29(1): 2633-2643
    Development of nanocubosomes co-loaded with dual anticancer agents curcumin and temozolomide for effective Colon cancer therapy.
    Yosif Almoshari, Haroon Iqbal, Anam Razzaq, Khalil Ali Ahmad, Muhammad Khalid Khan, Saad Saeed Alqahtani, Muhammad Hadi Sultan, Barkat Ali Khan.
      Current research aimed to develop nanocubosomes co-loaded with dual anticancer drugs curcumin and temozolomide for effective colon cancer therapy. Drugs co-loaded nanocubosomal dispersion was prepared by modified emulsification method using glyceryl monooleate (GMO), pluronic F127 and bovine serum albumin (BSA) as a lipid phase, surfactant, and stabilizer, respectively. The resulting nanocubosomes were characterized by measuring hydrodynamic particle size, particle size distribution (PSD), drug loading capacity (DL), encapsulation efficiency (EE), colloidal stability and drug release profile. We also physiochemically characterized the nanocubosomes by transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and x-rays diffraction (XRD) for their morphology, polymer drug interaction and its nature, respectively. Further, the in-vitro cell-uptake, mechanism of cell-uptake, in-vitro anti-tumor efficacy and apoptosis level were evaluated using HCT-116 colon cancer cells. The prepared nanocubosomes exhibited a small hydrodynamic particle size (PS of 150 ± 10 nm in diameter) with nearly cubic shape and appropriate polydispersity index (PDI), enhanced drug loading capacity (LC of 6.82 ± 2.03% (Cur) and 9.65 ± 1.53% (TMZ), high entrapment efficiency (EE of 67.43 ± 2.16% (Cur) and 75.55 ± 3.25% (TMZ), pH-triggered drug release profile and higher colloidal stability in various physiological medium. Moreover, the nanocubosomes showed higher cellular uptake, in-vitro cytotoxicity and apoptosis compared to free drugs, curcumin and temozolomide, most likely because its small particle size. In addition, BSA-stabilized nanocubosomes were actively taken by aggressive colon cancer cells that over-expressed the albumin receptors and utilized BSA as nutrient source for their growth. In short, this study provides a new and simple strategy to improve the efficacy and simultaneously overawed the adaptive treatment tolerance in colon cancer.
    Keywords:  Nanocubosomes; colon cancer; curcumin; temozolomide; therapy
    DOI:  https://doi.org/10.1080/10717544.2022.2108938
  10. Front Pharmacol. 2022 ;13 934632
    Oxidation and Reduction Dual-Responsive Polymeric Prodrug Micelles Co-delivery Precisely Prescribed Paclitaxel and Honokiol for Laryngeal Carcinoma Combination Therapy.
    Lanzhu Zhou, Jun Wu, Zhe Sun, Wenzhong Wang.
      Laryngeal carcinoma is the most common head and neck malignancy globally, and chemotherapy is still the most common treatment for this type of carcinoma. Monotherapy has become powerless because of the lack of drugs in the anticancer agent library, the difficult process of new drug discovery, and the widespread drug resistance. Combination therapy with two agents, in particular Chinese herbal medicines with chemotherapy drugs, is a potential alternative to chemotherapy alone. However, combination therapy faces difficulties in delivering multiple drugs to tumor tissue in a precise ratio. Here, a cocktail polymeric prodrug micelle (PHPPM) was developed using an oxidation and reduction dual-responsive polymeric paclitaxel (PTX) and polymeric honokiol (HK) prodrugs. Both of them were obtained by covalently conjugating the drug to dextran via diselenium bonds. Following optimization and characterization, the PHPPM with the precise mass ratio of PTX and HK was obtained, enabling ratiometric drug loading, synchronized drug release in response to tumor high-level reactive oxygen species and glutathione environment, long blood circulation, and high tumor accumulation. This co-delivery system can effectively inhibit laryngeal carcinoma growth in vitro and in vivo. Codelivery of chemotherapy agents and Chinese herbal medicine with a precise ratio and controlled release of the two drugs at the tumor site provides an effective approach to clinical therapy for other laryngeal carcinomas.
    Keywords:  dextran; diselenium bond; glutathione; honokiol; paclitaxel; polymeric prodrug; reactive oxygen species; stimuli-responsive
    DOI:  https://doi.org/10.3389/fphar.2022.934632
  11. Adv Pharm Bull. 2022 May;12(3): 515-523
    Combination of Probiotics and Natural Compounds to Treat Multiple Sclerosis via Warburg Effect.
    Anjali Kandiruthi Ravi, Saradhadevi Kuppusami Muthukrishnan.
      Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). It is an auto-immune disorder. Its usual symptoms are unique to each person. In MS lesions vast fractions of pyruvate molecules are instantly transformed into lactate. This reprogramming mechanism of glycolysis is known as the Warburg effect. MS has no efficient treatment yet. Hence, there is a requirement for profitable immunomodulatory agents in MS. Probiotics perform as an immunomodulator because they regulate the host's immune responses. Its efficacy gets enhanced for an extended period when it combines with prebiotics. In this review, we focus on the metabolic alterations behind the MS lesions via the Warburg effect, and also suggesting, the combined efficacy of prebiotics and probiotics for the effective treatment of MS without side effects. The Warburg effect mechanism intensifies the infiltration of activated T-cells and B-cells into the CNS. It provokes the inflammation process on the myelin sheath. The infiltration of immune cells can be inhibited by the combination therapy of probiotics and prebiotics. By this review, we can recommend that the idea of this combinational therapy can do miracles in the treatment of MS in the future.
    Keywords:  Medicinal plants; Multiple sclerosis; Prebiotics; Probiotics; Warburg effect
    DOI:  https://doi.org/10.34172/apb.2022.057
  12. ACS Appl Bio Mater. 2022 Aug 12.
    NIR-Active Porphyrin-Decorated Lipid Microbubbles for Enhanced Therapeutic Activity Enabled by Photodynamic Effect and Ultrasound in 3D Tumor Models of Breast Cancer Cell Line and Zebrafish Larvae.
    Aditya Teja K V V N S K Guduru, Neha Manav, Abdulkhalik Mansuri, Iti Gupta, Dhiraj Bhatia, Ashutosh Kumar, Sameer V Dalvi.
      Porphyrin is known to enable the photodynamic effect during cancer drug delivery and molecular imaging. However, its hydrophobicity and tendency to aggregate in an aqueous medium create a significant hurdle for its use as an anticancer drug. Loading porphyrin onto biocompatible delivery vehicles can enhance its efficacy. This can be achieved by using gas-filled microbubbles that can be administered intravenously. This study aimed at developing near-infrared (NIR)-active porphyrin-loaded lipid microbubbles with anticancer activity enhanced by sonodynamic and photodynamic effects. The porphyrin-loaded microbubbles were studied for their cell toxicity, cellular uptake of porphyrin, and effect on cellular three-dimensional (3D) invasion of breast cancer cells (MDA-MB-231) in cellulo. Toxicity studies in zebrafish larvae (Danio rerio) in the presence and absence of photodynamic and sonodynamic therapy were also conducted. The results suggest that with a higher concentration of porphyrin loaded on microbubbles, the porphyrin-loaded microbubbles display a higher therapeutic effect facilitated by photodynamic and sonodynamic therapy, which results in enhanced cellular uptake and cellular toxicity. A lower concentration of loaded porphyrin microbubbles exhibits high cellular viability and good fluorescence intensity in the NIR region, which can be exploited for bioimaging applications.
    Keywords:  3D spheroid models; microbubbles; photodynamic therapy; porphyrin; sonodynamic therapy; zebrafish
    DOI:  https://doi.org/10.1021/acsabm.2c00483
  13. Adv Drug Deliv Rev. 2022 Aug 06. pii: S0169-409X(22)00372-6. [Epub ahead of print] 114482
    Engineering nanosystems to overcome barriers to cancer diagnosis and treatment.
    Suhaila O Alhaj-Suliman, Emad I Wafa, Aliasger K Salem.
      Over the past two decades, multidisciplinary investigations into the development of nanoparticles for medical applications have continually increased. However, nanoparticles are still subject to biological barriers and biodistribution challenges, which limit their overall clinical potential. This has motivated the implementation of innovational modifications to a range of nanoparticle formulations designed for cancer imaging and/or cancer treatment, to overcome specific barriers and shift the accumulation of payloads toward the diseased tissues. In recent years, novel technological and chemical approaches have been employed to modify or functionalize the surface of nanoparticles or manipulate the characteristics of nanoparticles. Combining these approaches with the identification of critical biomarkers provides new strategies for enhancing nanoparticle specificity for both cancer diagnostic and therapeutic applications. This review discusses the most recent advances in the design and engineering of nanoparticles as well as future directions for developing the next generation of nanomedicines.
    Keywords:  Engineered nanoparticles; cancer imaging and diagnosis; cancer therapy; drug delivery and targeting; nanomedicine; surface chemistry; surface engineering; surface-functionalization; surface-modification; tumor-targeted nanoparticles
    DOI:  https://doi.org/10.1016/j.addr.2022.114482
  14. Adv Food Nutr Res. 2022 ;pii: S1043-4526(22)00035-3. [Epub ahead of print]101 237-275
    Fabrication of protein nanomaterials as delivery systems.
    Weijuan Huang, Lingyun Chen.
      Bioactive compounds in foods, nutraceuticals and pharmaceutical have been gaining interest due to health benefits, which can help to reduce the risk of certain chronic diseases. Recently, nanoencapsulation have attract attention because it is an efficient and promising approach for protection of bioactive compounds, and delivery them to the target physiological sites for controlled release and improvement absorption. Food proteins are promising materials to be fabricated into a variety of nanostructured delivery systems because of their high nutritional value, good functional properties, and health-benefiting effects. Various techniques and approaches are utilized to prepare nanostructured food protein. This chapter introduces the major techniques for the fabrication of nanoparticles and nanoemulsions from food proteins. The basic principles, advantages, and limitations of the techniques are discussed. The encapsulation and release of bioactive compounds in different nanostructured food proteins are illustrated in specific case studies. Due to the fast growing interest of bioactive encapsulation in various sectors, this chapter is of importance for guiding the development of nanostructured food protein loaded with bioactive ingredients for food, nutraceutical and pharmaceutical applications.
    Keywords:  Bioactive compounds; Encapsulation; Food protein; Nanoemulsion; Nanoparticles
    DOI:  https://doi.org/10.1016/bs.afnr.2022.05.003
  15. Front Cell Dev Biol. 2022 ;10 930205
    The Anti-Leukemia Effect of Ascorbic Acid: From the Pro-Oxidant Potential to the Epigenetic Role in Acute Myeloid Leukemia.
    S Travaglini, C Gurnari, S Antonelli, G Silvestrini, N I Noguera, T Ottone, M T Voso.
      Data derived from high-throughput sequencing technologies have allowed a deeper understanding of the molecular landscape of Acute Myeloid Leukemia (AML), paving the way for the development of novel therapeutic options, with a higher efficacy and a lower toxicity than conventional chemotherapy. In the antileukemia drug development scenario, ascorbic acid, a natural compound also known as Vitamin C, has emerged for its potential anti-proliferative and pro-apoptotic activities on leukemic cells. However, the role of ascorbic acid (vitamin C) in the treatment of AML has been debated for decades. Mechanistic insight into its role in many biological processes and, especially, in epigenetic regulation has provided the rationale for the use of this agent as a novel anti-leukemia therapy in AML. Acting as a co-factor for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), ascorbic acid is involved in the epigenetic regulations through the control of TET (ten-eleven translocation) enzymes, epigenetic master regulators with a critical role in aberrant hematopoiesis and leukemogenesis. In line with this discovery, great interest has been emerging for the clinical testing of this drug targeting leukemia epigenome. Besides its role in epigenetics, ascorbic acid is also a pivotal regulator of many physiological processes in human, particularly in the antioxidant cellular response, being able to scavenge reactive oxygen species (ROS) to prevent DNA damage and other effects involved in cancer transformation. Thus, for this wide spectrum of biological activities, ascorbic acid possesses some pharmacologic properties attractive for anti-leukemia therapy. The present review outlines the evidence and mechanism of ascorbic acid in leukemogenesis and its therapeutic potential in AML. With the growing evidence derived from the literature on situations in which the use of ascorbate may be beneficial in vitro and in vivo, we will finally discuss how these insights could be included into the rational design of future clinical trials.
    Keywords:  acute myeloid leukemia; ascorbic acid; epigenetic regulation; oxidative stress; vitamin C
    DOI:  https://doi.org/10.3389/fcell.2022.930205
  16. Food Res Int. 2022 Sep;pii: S0963-9969(22)00465-3. [Epub ahead of print]159 111408
    Mechanism of glycometabolism regulation by bioactive compounds from the fruits of Lycium barbarum: A review.
    Hao Liu, Bo Cui, Zheng Zhang.
      Diabetes is a major public health concern with a high risk of onset. It can lead to glycometabolism disorders. Improvement in diet is an effective way to regulate metabolic disorders. The fruits of Lycium barbarum, an ancient tonic and a traditional Chinese medicine, have shown beneficial effects against chronic metabolic diseases. Lycium barbarum polysaccharides, polyphenols, carotenoids and amino acids are the major natural bioactive compounds in the fruits of Lycium barbarum. They have many physiological activities and medicinal value and have shown significant anti-diabetic effects. This article reviews the effective actions of the main bioactive compounds in Lycium barbarum fruits in reducing blood glucose, intestinal and renal inflammation, retinal damage and other complications, discusses the possible metabolism of these bioactive compounds in the pathogenesis of diabetes, and explains the basic mechanism of regulation of blood glucose. Although the current research is limited to animal experiments and in vitro cell experiments, we have provided reliable evidence for our reports based on previous studies. Lycium barbarum fruits is a beneficial food that can interfere with carbohydrate metabolism in vivo, a significant direction for the development of Lycium barbarum, and can be used as a potential target for treating diabetes.
    Keywords:  Bioactive compounds; Diabetes; Glycometabolism; Lycium barbarum fruits
    DOI:  https://doi.org/10.1016/j.foodres.2022.111408
  17. Foods. 2022 Aug 03. pii: 2318. [Epub ahead of print]11(15):
    Nutraceuticals and Food-Grade Lipid Nanoparticles: From Natural Sources to a Circular Bioeconomy Approach.
    Cristina Blanco-Llamero, Joel Fonseca, Alessandra Durazzo, Massimo Lucarini, Antonello Santini, Francisco J Señoráns, Eliana B Souto.
      Nutraceuticals have gained increasing attention over the last years due to their potential value as therapeutic compounds formulated from natural sources. For instance, there is a wide range of literature about the cardioprotective properties of omega-3 lipids and the antioxidant value of some phenolic compounds, which are related to antitumoral activity. However, the value of nutraceuticals can be limited by their instability under gastric pH and intestinal fluids, their low solubility and absorption. That is why encapsulation is a crucial step in nutraceutical design. In fact, pharmaceutical nanotechnology improves nutraceutical stability and bioavailability through the design and production of efficient nanoparticles (NPs). Lipid nanoparticles protect the bioactive compounds from light and external damage, including the gastric and intestinal conditions, providing a retarded delivery in the target area and guaranteeing the expected therapeutic effect of the nutraceutical. This review will focus on the key aspects of the encapsulation of bioactive compounds into lipid nanoparticles, exploring the pharmaceutical production methods available for the synthesis of NPs containing nutraceuticals. Moreover, the most common nutraceuticals will be discussed, considering the bioactive compounds, their natural source and the described biological properties.
    Keywords:  food-grade ingredients; lipids; nanostructured lipid carriers; nutraceuticals; solid lipid nanoparticles
    DOI:  https://doi.org/10.3390/foods11152318
  18. J Nutr Biochem. 2022 Aug 03. pii: S0955-2863(22)00187-5. [Epub ahead of print] 109119
    Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation: Maternal soybean prevention on obesity-related breast cancer.
    Min Chen, Shizhao Li, Itika Arora, Nengjun Yi, Manvi Sharma, Zhenhai Li, Trygve O Tollefsbol, Yuanyuan Li.
      Overnutrition-induced obesity and metabolic dysregulation are considered major risk factors contributing to breast cancer. The origin of both obesity and breast cancer can retrospect to early development in the human lifespan. Genistein (GE), a natural isoflavone enriched in soybean products, has been proposed to associate with a lower risk of breast cancer and various metabolic disorders. Our study aimed to determine the effects of maternal exposure to soybean dietary GE on prevention of overnutrition-induced breast cancer later in life and explore potential mechanisms in different mouse models. Our results showed that maternal dietary GE treatment improved offspring metabolic functions by significantly attenuating high-fat diet (HFD)-induced body fat accumulation, lipid panel abnormalities and glucose intolerance in mice offspring. Importantly, maternal dietary GE exposure effectively delayed HFD-simulated mammary tumor development in female offspring. Mechanistically, we found that maternal dietary GE may exert its chemopreventive effects through affecting essential regulatory gene expression in control of metabolism, inflammation and tumor development via, at least in part, regulation of offspring gut microbiome, bacterial metabolites and epigenetic profiles. Altogether, our findings indicate that maternal GE consumption is an effective intervention approach leading to early-life prevention of obesity-related metabolic disorders and breast cancer later in life through dynamically influencing the interplay between early-life gut microbiota, key microbial metabolite profiles and offspring epigenome.
    Keywords:  Breast cancer; epigenetics; gut microbiome; maternal prevention; obesity; soybean genistein
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109119
  19. ACS Appl Mater Interfaces. 2022 Aug 09.
    Enhancing Tumor Therapy of Fe(III)-Shikonin Supramolecular Nanomedicine via Triple Ferroptosis Amplification.
    Wenjie Feng, Wanrui Shi, Ze Wang, Yanqi Cui, Xinxin Shao, Shuwei Liu, Li Rong, Yi Liu, Hao Zhang.
      Ferroptosis has been considered as a promising pathway to overcome apoptosis-induced tumor chemoresistance. However, the antitumor efficacy of ferroptosis-inducing agents is still limited because of the complexity and diversity of tumor microenvironments. Herein, we demonstrate a triple ferroptosis amplification strategy for tumor therapy by associating iron-based nanocarriers, ferroptosis molecular drugs, and H2O2-producing enzymes. Fe(III)-Shikonin (FeShik) metal-polyphenol-coordinated networks are employed to load a ferroptosis inducer of sorafenib (SRF) inside and glucose oxidase (GOx) outside, thus producing SRF@FeShik-GOx supramolecular nanomedicines (SNs). After delivering into glutathione (GSH)-overexpressed tumor cells, FeShik will disassemble and release Fe2+ to induce cell death via ferroptosis. At the same time, GOx executes its catalytic activity to produce an acid environment and plenty of H2O2 for stimulating •OH generation via the Fenton reaction. Moreover, SRF will suppress the biosynthesis of GSH by inhibiting system Xc-, further deactivating the enzymatic activity of glutathione peroxidase 4 (GPX4). Up-regulation of the oxidative stress level and down-regulation of GPX4 expression can dramatically accelerate the accumulation of lethal lipid peroxides, leading to ferroptosis amplification of tumor cells. The current strategy that utilizes ferroptosis-inducing agents as both nanocarriers and cargoes provides a pathway to enhance the efficacy of ferroptosis-based tumor therapy.
    Keywords:  Shikonin; ferroptosis; glucose oxidase; sorafenib; supramolecular nanomedicine
    DOI:  https://doi.org/10.1021/acsami.2c11130
  20. Photodiagnosis Photodyn Ther. 2022 Aug 04. pii: S1572-1000(22)00341-6. [Epub ahead of print] 103055
    5-aminolevulinic acid and sodium ferrous citrate decreased cell viability of gastric cancer cells by enhanced ROS generation through improving COX activity.
    Arif Suprihadi, Anantya Pustimbara, Shun-Ichiro Ogura.
       BACKGROUND: Mitochondrial dysfunctions, particularly cancer still primarily challenging to cure. 5-aminolevulinic acid (ALA) is used for photodynamic therapy (PDT). In this PDT, protoporphyrin IX (PpIX), which is converted from ALA, can generate reactive oxygen species (ROS) that kill the cancer cell. ALA is also reported to promote cytochrome c oxidase (COX) activity, which can generate ROS itself. Therefore, this study focused on the effect of ALA during PDT. In addition, in the previous study, sodium ferrous citrate (SFC) is reported to increase COX activity. So, this study also aims to improve the COX activity by the addition of SFC that can promote ROS generation, which has a cytotoxic effect.
    METHODS: In this study, we used ALA and SFC, then evaluated the effects of the treatment on the human gastric cancer cell line MKN45, including the induction of cell death.
    RESULTS: This study showed that treatment with ALA and SFC increases intracellular heme and heme proteins. Moreover, COX activity was promoted, resulting in the production of intracellular reactive oxygen species (ROS), which eventually reduced the cell viability in human gastric cancer cell line MKN45.
    CONCLUSION: Our study can detect ROS generation with ALA and SFC. Furthermore, we found this generation of ROS has a cytotoxic effect. Therefore, this phenomenon contributes to the effect of PDT.
    Keywords:  ALA; COX; Mitochondria; PDT; SFC; gastric cancer
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103055
  21. Front Pharmacol. 2022 ;13 934982
    Antioxidant, antibacterial, antitumor, antifungal, antiviral, anti-inflammatory, and nevro-protective activity of Ganoderma lucidum: An overview.
    Darija Cör Andrejč, Željko Knez, Maša Knez Marevci.
      Ganoderma lucidum is a very medicinal mushroom that has been utilized in Oriental medicine for many years. It has a wide range of pharmacological and therapeutic properties, and has been used for many years as a health promoter. It contains various biologically active compounds that improve the immune system and have antioxidant, antitumor, anti-inflammatory, antifungal, and antimicrobial properties. Active compounds include triterpenoids and polysaccharides, as well as proteins, lipids, phenolics, sterols, etc. In the following review, we summarize briefly their biological activities, such as antioxidant, anti-bacterial, anti-fungal, antitumor, anti-viral, and anti-inflammatory activity. Although Ganoderma has a number of medicinal effects that have been confirmed by the in vitro and in vivo studies summarised in this review, there are some limitations. Clinical trials face mainly a lack of pure constituents. Accurate identification of the compounds obtained is also problematic. In addition, most of the included studies were small, and there were concerns about the methodological quality of each study. Studies have shown that Ganoderma has valuable potential for the prevention and treatment of cancer. In any case, G. lucidum cannot be used as first-line therapy for cancer.
    Keywords:  Ganoderma lucidum; active compounds; bioactive function; polysaccharides; triterpenoids
    DOI:  https://doi.org/10.3389/fphar.2022.934982
  22. Int J Mol Sci. 2022 Aug 05. pii: 8736. [Epub ahead of print]23(15):
    Design Principles of Hybrid Nanomaterials for Radiotherapy Enhanced by Photodynamic Therapy.
    Valeria Secchi, Angelo Monguzzi, Irene Villa.
      Radiation (RT) remains the most frequently used treatment against cancer. The main limitation of RT is its lack of specificity for cancer tissues and the limited maximum radiation dose that can be safely delivered without damaging the surrounding healthy tissues. A step forward in the development of better RT is achieved by coupling it with other treatments, such as photodynamic therapy (PDT). PDT is an anti-cancer therapy that relies on the light activation of non-toxic molecules-called photosensitizers-to generate ROS such as singlet oxygen. By conjugating photosensitizers to dense nanoscintillators in hybrid architectures, the PDT could be activated during RT, leading to cell death through an additional pathway with respect to the one activated by RT alone. Therefore, combining RT and PDT can lead to a synergistic enhancement of the overall efficacy of RT. However, the involvement of hybrids in combination with ionizing radiation is not trivial: the comprehension of the relationship among RT, scintillation emission of the nanoscintillator, and therapeutic effects of the locally excited photosensitizers is desirable to optimize the design of the hybrid nanoparticles for improved effects in radio-oncology. Here, we discuss the working principles of the PDT-activated RT methods, pointing out the guidelines for the development of effective coadjutants to be tested in clinics.
    Keywords:  energy sharing; nanoparticles; nanoscintillators; photodynamic therapy; radiotherapy; singlet oxygen
    DOI:  https://doi.org/10.3390/ijms23158736
  23. Int J Biol Macromol. 2022 Aug 09. pii: S0141-8130(22)01731-7. [Epub ahead of print]
    Hyaluronic acid coated spinel ferrite for combination of chemo and photodynamic therapy: Green synthesis, characterization, and in vitro and in vivo biocompatibility study.
    Mostafa Zamani, Mozhgan Aghajanzadeh, Setare Jashnani, S Shirin Shahangian, Farhad Shirini.
      In this project, different photosensitizers were prepared using different ratios of nickel, manganese, and iron. Then, multiple analysis were performed to evaluate their efficiency, and the most suitable one was used to be coated by hyaluronic acid to improve the nano-platform's biocompatibility and target ability. Moreover, another chemical targeting agent (riboflavin) was used to further improve the target ability of the prepared nano-platform. Different spectroscopies and thermal analysis were used to determine the physical and chemical characteristics of the prepared nano-platform. Also, in order to determine the biocompatibility of the nano-platform, in vitro and in vivo tests such as blood hemolysis, blood aggregation and lethal dose were performed. Then, an anti-cancer agent (curcumin) was loaded on the selected nano-platform to makes us able utilizing the synergistic effect of chemotherapy and photodynamic therapy simultaneously. Finally, the cell cytotoxicity results showed that the prepared nano-platform had a great anti-cancer potential which can make it a great candidate as a dual photo and chemo therapy agent for treatment of breast cancers.
    Keywords:  Chemo therapy; Curcumin; Photodynamic therapy; Spinel ferrite, hyaluronic acid
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.08.036
  24. Front Pharmacol. 2022 ;13 921003
    Protective Effect of Resveratrol on Knee Osteoarthritis and its Molecular Mechanisms: A Recent Review in Preclinical and Clinical Trials.
    Shenglei Yang, Mingli Sun, Xinan Zhang.
      Osteoarthritis (OA) is one of the progressing chronic joint associated with by many complex factors such as age, obesity, and trauma. Knee osteoarthritis (KOA) is the most common type of OA. KOA is characterized by articular cartilage destruction and degeneration, synovial inflammation, and abnormal subchondral bone changes. To date, no practical clinical approach has been able to modify the pathological progression of KOA. Drug therapy is limited to pain control and may lead to serious side effects when taken for a long time. Therefore, searching for safer and more reliable treatments has become necessary. Interestingly, more and more research has focused on natural products, and monomeric compounds derived from natural products have received much attention as drug candidates for KOA treatment. Resveratrol (RES), a natural phenolic compound, has various pharmacological and biological activities, including anti-cancer, anti-apoptotic, and anti-decay. Recently, studies on the effects of RES on maintaining the normal homeostasis of chondrocytes in KOA have received increasing attention, which seems to be attributed to the multi-targeted effects of RES on chondrocyte function. This review summarizes preclinical trials, clinical trials, and emerging tissue engineering studies of RES for KOA and discusses the specific mechanisms by which RES alleviates KOA. A better understanding of the pharmacological role of RES in KOA could provide clinical implications for intervention in the development of KOA.
    Keywords:  apoptosis; chondrocytes; inflammation; knee; osteoarthritis; resveratrol; tissue engineering
    DOI:  https://doi.org/10.3389/fphar.2022.921003
  25. Crit Rev Food Sci Nutr. 2022 Aug 12. 1-20
    Updated design strategies for oral delivery systems: maximized bioefficacy of dietary bioactive compounds achieved by inducing proper digestive fate and sensory attributes.
    Jie Xiao, Wenni Tian, Abdullah, Haonan Wang, Meimiao Chen, Qingrong Huang, Man Zhang, Muwen Lu, Mingyue Song, Yong Cao.
      Interest in the application of dietary bioactive compounds (DBC) in healthcare and pharmaceutical industries has motivated researchers to develop functional delivery systems (FDS) aiming to maximize their bioefficacy. As the direct and indirect health benefiting effects of DBC are acknowledged, traditional design principle of FDS aiming at improving the bioavailability of intact DBC is challenged by the updated one, where the maximized bioefficacy of DBC delivered by FDS will be achieved via rationally absorbed at target sites with proper metabolism pathways. This article briefly summarized the absorption and metabolic fates of orally digested DBC along with their direct and indirect mechanisms to perform health benefiting effects. Current strategies in designing the next generation FDS with an emphasis on their modulation effects on the distribution portion between the upper and lower digestive tract, portal vein and lymphatic absorption, human digestive and gut microbiota enzymatic mediated metabolism were highlighted. Updated research progresses of FDS in adjusting sensory attributes of food end products and inducing synergistic effects rooting from matrix materials and co-delivered cargos were also discussed. Challenges as well as future perspectives concerning the precise nutrition and the critical role of delivery systems in dietary intervention were proposed.
    Keywords:  Dietary bioactive compounds; absorption and metabolism; bioefficacy; functional delivery systems; modulation effects; sensory control; synergistic effects
    DOI:  https://doi.org/10.1080/10408398.2022.2109583
  26. J Evid Based Integr Med. 2022 Jan-Dec;27:27 2515690X221116403
    Vitamin D Supplementation Could Enhance the Effectiveness of Glibenclamide in Treating Diabetes and Preventing Diabetic Nephropathy: A Biochemical, Histological and Immunohistochemical Study.
    Tarek Atia, Mohammad Zahidul Iqbal, Hassan Fathy Ahmed, Hader I Sakr, M H Abdelzaher, Deaa Fekri Morsi, Mostafa E Metawee.
      Diabetes mellitus is an oxidative stress-related disease characterized by hyperglycemia and a variety of complications, including nephropathy. Vitamin D has variable functions extending beyond the calcium metabolism to prevent oxidative tissue damage. We aimed to investigate whether vitamin D supplements could enhance Glibenclamide's effectiveness in treating diabetes and minimize the risk of associated pathology. Wistar rats were divided into normal control (n = 10) and diabetic (n = 30), where animals received two low doses of Streptozotocin 30 mg/kg/BW intraperitoneally to develop diabetes. The diabetic rats were then randomly divided into three equal groups: untreated, treated with Glibenclamide (0.6 mg/kg), and treated with Glibenclamide and Vitamin D3 (500 IU/kg). After eight weeks, the animals were sacrificed, and blood samples and kidney tissues were collected to evaluate biochemical, anti-oxidant, and pro-inflammatory cytokine levels and histological and immunohistochemical changes. Diabetic animals had significantly increased fasting blood glucose, lipid profile, blood urea, serum creatinine, and Malondialdehyde levels, whereas serum insulin, albumin, and the anti-oxidant enzymes superoxide dismutase and catalase were significantly decreased compared to normal control (p < 0.01). Furthermore, some renal histological changes were observed together with significantly increased immunoreactivity of anti-p53, anti-TNF-α, and anti-IL-6 antibodies when compared to the normal control. All abnormal parameters improved significantly with Glibenclamide therapy (p < 0.01), but combination therapy with vitamin D produced a much better result. In conclusion, vitamin D supplementation along with anti-diabetic medication can help prevent or reduce the severity of diabetic nephropathy due to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties.
    Keywords:  Antioxidant; Diabetic Nephropathy; Glibenclamide; Inflammatory cytokines; Vitamin D
    DOI:  https://doi.org/10.1177/2515690X221116403
  27. Neuromolecular Med. 2022 Aug 11.
    Therapeutic Potential of Quercetin and its Derivatives in Epilepsy: Evidence from Preclinical Studies.
    Chandra Prakash, Jyoti Tyagi, Shyam Sunder Rabidas, Vijay Kumar, Deepak Sharma.
      Quercetin is a polyphenolic bioactive compound highly enriched in dietary fruits, vegetables, nuts, and berries. Quercetin and its derivatives like rutin and hyperoside are known for their beneficial effects in various neurological conditions including epilepsy. The clinical studies of quercetin and its derivatives in relation to epilepsy are limited. This review provides the evidence of most recent knowledge of anticonvulsant properties of quercetin and its derivatives on preclinical studies. Additionally, the studies demonstrating antiseizure potential of various plants extracts enriched with quercetin and its derivatives has been included in this review. Herein, we have also discussed neuroprotective effect of these bioactive compound and presented underlying mechanisms responsible for anticonvulsant properties in brief. Finally, limitations of quercetin and its derivatives as antiseizure compounds as well as possible strategies to enhance efficacy have also been discussed.
    Keywords:  Anticonvulsant properties; Antiseizure effect; Epileptic seizures; Plant extracts; Quercetin; Quercetin derivatives
    DOI:  https://doi.org/10.1007/s12017-022-08724-z
  28. Front Oncol. 2022 ;12 953865
    A Review on Nanocarrier Mediated Treatment and Management of Triple Negative Breast Cancer: A Saudi Arabian Scenario.
    Insha Nahvi, Sana Belkahla, Supratim Biswas, Suparna Chakraborty.
      People have continued to be petrified by the devastating effects of cancer for decades and thus a pursuit for developing anticancer agents have seen an ever-increasing trend in the past few decades. Globally, breast cancer is the most common malignancy in women and the second most common cause of cancer-related deaths. In Saudi Arabia, breast cancer is the most common type of cancer among women, constituting almost 14.2% of the total cancer burden. Triple-negative breast cancer (TNBC) is a subtype of breast cancer, which is a pathologically diverse disease of higher grade characterized by the absence of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) expressions. Despite the considerable advancements achieved in the therapeutic management of cancer, TNBC remains an unbeatable challenge, which requires immediate attention as it lacks conventional targets for treatment, leading to a poor clinical prognosis. The present research goals are directed toward the development and implementation of treatment regimens with enhanced bioavailability, targetability, minimized systemic toxicity, and improved outcomes of treatment options. The present treatment and management scenario of TNBC continues to provoke oncologists as well as nanomedical scientists to develop novel and efficient nanotherapies. Lately, scientific endeavors have addressed the importance of enhanced availability and targeted cellular uptake with minimal toxicity, which are achieved by the application of nano drug-carriers. This review intends to summarize the incidence rates of TNBC patients, the importance of nanotherapeutic options for patients suffering from TNBC, the identification of promising molecular targets, and challenges associated with the development of targeted nanotherapeutics with special reference to the Saudi Arabian context.
    Keywords:  TNBC; breast cancer; nano carrier and bioavailability; nanomedications; nanoparticles; targetability; triple negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2022.953865
  29. Life Sci. 2022 Aug 09. pii: S0024-3205(22)00576-8. [Epub ahead of print] 120876
    Synthesis, characterization, and evaluation of in vitro cytotoxicity and in vivo antitumor activity of asiatic acid-loaded poly lactic-co-glycolic acid nanoparticles: A strategy of treating breast cancer.
    Sayanta Dutta, Pratik Chakraborty, Susmita Basak, Sumit Ghosh, Noyel Ghosh, Sharmistha Chatterjee, Saikat Dewanjee, Parames C Sil.
      Asiatic acid (AA), an aglycone of pentacyclic triterpene glycoside, obtained from the leaves of Centella asiatica exerts anticancer effects by inhibiting cellular proliferation and inducing apoptosis in a wide range of carcinogenic distresses. However, its chemotherapeutic efficacy is dampened by its low bioavailability. Polymeric nanoparticles (NPs) exhibit therapeutic efficacy and compliance by improving tissue penetration and lowering toxicity. Thus, to increase the therapeutic effectiveness of AA in the treatment of breast cancer, AA-loaded poly lactic-co-glycolic acid (PLGA) NPs (AA-PLGA NPs) have been formulated. The AA-PLGA NPs were characterized on the basis of their average particle size, zeta potential, electron microscopic imaging, drug loading, and entrapment efficiency. The NPs exhibited sustained drug release profile in vitro. Developed NPs exerted dose-dependent cytotoxicity to MCF-7 and MDA-MB-231 cells without damaging normal cells. The pro-oxidant and pro-apoptotic properties of AA-PLGA NPs were determined by the study of the cellular levels of SOD, CAT, GSH-GSSG, MDA, protein carbonylation, ROS, mitochondrial membrane potential, and FACS analyses on MCF-7 cells. Immunoblotting showed that AA-PLGA NPs elicited an intrinsic pathway of apoptosis in MCF-7 cells. In vivo studies on female BALB/c mice exhibited reduced volume of mammary pad tumor tissues and augmented expression of caspase-3 when administered with AA-PLGA NPs. No systemic adverse effect of AA-PLGA NPs was observed in our studies. Thus, AA-PLGA NPs can act as an efficient drug delivery system against breast cancer.
    Keywords:  Apoptosis; Asiatic acid; Breast cancer; Cytotoxicity; Polymeric nanoparticles
    DOI:  https://doi.org/10.1016/j.lfs.2022.120876
  30. Nano Converg. 2022 Aug 12. 9(1): 37
    Membrane-wrapped nanoparticles for photothermal cancer therapy.
    Sara B Aboeleneen, Mackenzie A Scully, Jenna C Harris, Eric H Sterin, Emily S Day.
      Cancer is a global health problem that needs effective treatment strategies. Conventional treatments for solid-tumor cancers are unsatisfactory because they cause unintended harm to healthy tissues and are susceptible to cancer cell resistance. Nanoparticle-mediated photothermal therapy is a minimally invasive treatment for solid-tumor cancers that has immense promise as a standalone therapy or adjuvant to other treatments like chemotherapy, immunotherapy, or radiotherapy. To maximize the success of photothermal therapy, light-responsive nanoparticles can be camouflaged with cell membranes to endow them with unique biointerfacing capabilities that reduce opsonization, prolong systemic circulation, and improve tumor delivery through enhanced passive accumulation or homotypic targeting. This ensures a sufficient dose of photoresponsive nanoparticles arrives at tumor sites to enable their complete thermal ablation. This review summarizes the state-of-the-art in cell membrane camouflaged nanoparticles for photothermal cancer therapy and provides insights to the path forward for clinical translation.
    Keywords:  Biomimetic; Biomimicry; Multimodal therapy; Nanomedicine; Oncology; Phototherapy; Targeting
    DOI:  https://doi.org/10.1186/s40580-022-00328-4
  31. Drug Dev Ind Pharm. 2022 Aug 11. 1-38
    Microneedle-assisted transdermal delivery of amlodipine besylate loaded nanoparticles.
    Ahlam Zaid Alkilani, Sukaina Nimrawi, Nusaiba K Al-Nemrawi, Jehad Nasereddin.
      Transdermal drug delivery has been developed to increase drug bioavailability and improve patient compliance. The current study was carried out to formulate and evaluate a transdermal delivery system loaded with biodegradable polymeric nanoparticles for sustained delivery of amlodipine beslayate (AMB).For this purpose, AMB was incorporated into CS nanoparticles that were prepared via ionic gelation method. Three formulations containing different blends of CS and tripolyphosphate were investigated for the preparation of the nanoparticles and evaluated for particle size (PS), zeta potential (ZP), loading capacity (LC), encapsulation efficiency (EE), scanning electron microscope (SEM), and drug release kinetics. The smallest observed particle size was 321.14 nm ±7.21 nm (NP-3). Across all formulations, the highest observed EE% was 87.2% ± 0.12% (NP-2), and the highest observed LC% was 60.98 ± 0.08% (NP-2). Microneedles were formed by using 15% polyvinylalcohol (PVA) (F1), 15% PVA with 1% propylene glycol (PG) (F2), and 15% PVA with 5% PG (F3). On investigating drug release rates, it was observed that drug permeation and steady-state flux (Jss) both increased proportionally with increasing PG concentration. Nanomedicine, when combined with physical techniques, has opened new opportunities for growth and development of transdermal delivery systems in pharmaceutical industry. In conclusion, biodegradable polymeric nanoparticles-loaded in hydrogel microneedles served as a potential system for the transdermal delivery of AMB in a controlled manner.
    Keywords:  Amlodipine Besylate; Microneedle; Nanoparticles; Pediatric; Skin Delivery
    DOI:  https://doi.org/10.1080/03639045.2022.2112694
  32. Regen Biomater. 2022 ;9 rbac051
    Mitochondria-targeting polydopamine-coated nanodrugs for effective photothermal- and chemo-synergistic therapies against lung cancer.
    Ziyu Meng, Binchao Wang, Yiqiang Liu, Yejian Wan, Qianshi Liu, Huasheng Xu, Renchuan Liang, Ying Shi, Peng Tu, Hong Wu, Chuan Xu.
      Targeting mitochondria via nano platform emerged as an attractive anti-tumor pathway due to the central regulation role in cellar apoptosis and drug resistance. Here, a mitochondria-targeting nanoparticle (TOS-PDA-PEG-TPP) was designed to precisely deliver polydopamine (PDA) as the photothermal agent and alpha-tocopherol succinate (α-TOS) as the chemotherapeutic drug to the mitochondria of the tumor cells, which inhibits the tumor growth through chemo- and photothermal- synergistic therapies. TOS-PDA-PEG-TPP was constructed by coating PDA on the surface of TOS NPs self-assembled by α-TOS, followed by grafting PEG and triphenylphosphonium (TPP) on their surface to prolong the blood circulation time and target delivery of TOS and PDA to the mitochondria of tumor cells. In vitro studies showed that TOS-PDA-PEG-TPP could be efficiently internalized by tumor cells and accumulated at mitochondria, resulting in cellular apoptosis and synergistic inhibition of tumor cell proliferation. In vivo studies demonstrated that TOS-PDA-PEG-TPP could be efficiently localized at tumor sites and significantly restrain the tumor growth under NIR irradiation without apparent toxicity or deleterious effects. Conclusively, the combination strategy adopted for functional nanodrugs construction aimed at target-delivering therapeutic agents with different action mechanisms to the same intracellular organelles can be extended to other nanodrugs-dependent therapeutic systems.
    Keywords:  alpha-tocopherol succinate (α-TOS); chemo- and photothermal- synergistic therapies; lung cancer; mitochondria-targeting
    DOI:  https://doi.org/10.1093/rb/rbac051
  33. Colloids Surf B Biointerfaces. 2022 Jul 30. pii: S0927-7765(22)00406-4. [Epub ahead of print]218 112723
    Endocytosis-mediated triple-activable prodrug nanotherapeutics potentiating therapeutic efficacy and security towards solid tumors.
    Shuwen Fu, Shilin Ma, Xinxuan Peng, Han Qiao, Wenli Zang, Jing Ye, Wenfeng Zang, Mohan Li, Kexin Shi, Xuanjiayi Ye, Wei Sun, Yinglei Zhai.
      Self-assembling prodrug nanotherapeutics have emerged as a promising nanoplatform for anticancer drug delivery. The specific and efficient activation of prodrug nanotherapeutics inside tumor cells is vital for the antitumor efficacy and security. Herein, a triple-activable prodrug polymer (TAP) is synthesized by conjugating polyethylene glycol-poly-(caprolactone)-paclitaxel (PTX) polymer with two tumor-responsive bonds, disulfide and acetal. TAP could self-assemble into nanotherapeutics (TAP NTs) free of surfactant with a high drug loading (32.6%). In blood circulation, TAP NTs could remain intact to efficiently accumulate in tumor sites. Thereafter, tumor cells would internalize TAP NTs through multiple endocytosis pathways. Inside tumor cells, TAP NTs could be activated to release PTX and induce tumor cell apoptosis in triple pathways: (i) lysosomal acidity rapid activation; (ii) ROS-acidity tandem activation and (iii) GSH-acidity tandem activation. Compared with Taxol and non-activable control, TAP NTs significantly potentiate the antitumor efficacy and security of PTX against solid tumors including breast cancer and colon cancer.
    Keywords:  Chemotherapy for solid tumor; Prodrug nanotherapeutics; Prodrug polymer; Self-assembly; Tumor-stimuli activation
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112723
  34. Gen Physiol Biophys. 2022 Jul;41(4): 263-274
    Induction of apoptosis through inactivation of ROS-dependent PI3K/Akt signaling pathway by platycodin D in human bladder urothelial carcinoma cells.
    Cheol Park, Hee-Jae Cha, Hyesook Lee, Jin-Woo Jeong, MinHo Han, Kyoung Seob Song, Gi-Young Kim, Young-Chae Chang, Sun-Hee Leem, Jin Won Hyun, Heui-Soo Kim, Su Hyun Hong, Yung Hyun Choi.
      Platycodin D (PD) is a triterpenoid saponin, a major bioactive constituent of the roots of Platycodon grandiflorum, which is well known for possessing various pharmacological properties. However, the anti-cancer mechanism of PD in bladder cancer cells remains poorly understood. In the current study, we investigated the effect of PD on the growth of human bladder urothelial carcinoma cells. PD treatment significantly reduced the cell survival of bladder cancer cells associated with induction of apoptosis and DNA damage. PD inhibited the expression of inhibitor of apoptosis family members, activated caspases, and induced cleavage of poly (ADP-ribose) polymerase. PD also increased the release of cytochrome c into the cytoplasm by disrupting the mitochondrial membrane potential while upregulating the expression ratio of Bax to Bcl-2. The PD-mediated anti-proliferative effect was significantly inhibited by pre-treatment with a pancaspase inhibitor, but not by an inhibitor of necroptosis. Moreover, PD suppressed the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and the apoptosis-inducing effect of PD was further enhanced by a PI3K inhibitor. In addition, PD increased the accumulation of reactive oxygen species (ROS), whereas N-acetyl cysteine (NAC), an ROS inhibitor, significantly attenuated the growth inhibition and inactivation of the PI3K/Akt/mTOR signaling caused by PD. Furthermore, NAC significantly suppressed apoptosis, DNA damage, and decreased cell viability induced by PD treatment. Collectively, our findings indicated that PD blocked the growth of bladder urothelial carcinoma cells by inducing ROS-mediated inactivation of the PI3K/Akt/mTOR signaling.
    DOI:  https://doi.org/10.4149/gpb_2022013
  35. Front Pharmacol. 2022 ;13 935536
    Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.
    Chen Chen, Zehua Wang, Yanru Qin.
      Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the DNA, histone, and RNA level, which can alter chromatin state. For almost a century, our focus in cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic enzymes to carry out post-translational modifications of DNA and histone. Genetic mutations in metabolic enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic enzymes leading to tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking cancer metabolism, epigenetics and immunity, and seek optimal immunotherapy-based combinations.
    Keywords:  cancer metabolism; epigenetics; immunity; novel anti-cancer strategy; oncology
    DOI:  https://doi.org/10.3389/fphar.2022.935536
  36. Sci Signal. 2022 Aug 09. 15(746): eadc9816
    Heterogeneity in RAS mutations: One size does not fit all.
    Nancy E Sealover, Robert L Kortum.
      Although oncogenic driver mutations in RAS occur in 20% of cancers, heterogeneity in the biologic outputs of different RAS mutants has hampered efforts to develop effective treatments for RAS-mutated cancers. In this issue of Science Signaling, Huynh et al. show that even among KRASQ61 mutants, the specific amino acid that is substituted substantially affects mutant KRAS biologic activity and oncogenicity.
    DOI:  https://doi.org/10.1126/scisignal.adc9816
  37. Cureus. 2022 Jul;14(7): e26640
    Nature's Gold (Moringa Oleifera): Miracle Properties.
    Sonali B Rode, Amruta Dadmal, Harsh V Salankar.
      Moringa oleifera, known as a miracle tree, is a small plant cultivated all over the world due to its multiple medicinal uses.It is cultivated for its nutritious pods, edible leaves, and flowers which are very helpful as food, medicine, cosmetic oil, and forage for livestock. It is a good source of protein, oils, vitamins, fatty acids, micro-macro mineral elements, and various phenolics. Its roots, bark, gum, leaf, fruit (pods), flowers, seed, and seed oil possess various biological activities. The main flavonoids found in its leaves are myricetin, quercetin, and kaempferol. Each part of the Moringa oleifera tree is used for a variety of nutritional and medicinal purposes. The tree has anti-inflammatory, antimicrobial, antioxidant, anticancer, antihypertensive, hepatoprotective, anti-ulcer, antifertility, and diuretic properties. Its many pharmacological benefits are exploited as therapeutic remedies in the traditional medicinal system for various diseases. Moringa's hypolipidemic, antihypertensive, antioxidant, anti-cancer, anti-diabetic, and hepatoprotective properties have been attributed to quercetin, phenolic acid, tannins, and saponins. More research into this remarkable healer could lead to the creation of new drugs to treat a variety of illnesses. This article gives a quick summary of the medical potential of Moringa and its future as a component of modern medicine. According to the findings of this study, Moringa needs to be properly evaluated before it can be used as a medication in modern medicine.
    Keywords:  anti-inflammatory; anti-microbial; anti-oxidant; flavonoids; medicinal properties; moringa oleifera
    DOI:  https://doi.org/10.7759/cureus.26640
  38. Drug Dev Ind Pharm. 2022 Aug 08. 1-42
    Nisin and nisin-loaded nanoparticles: a cytotoxicity investigation.
    Tanweer Haider, Vikas Pandey, Chittaranjan Behera, Pradeep Kumar, Prem N Gupta, Vandana Soni.
       OBJECTIVE: Nisin is an antibacterial peptide with anticancer properties, but the main drawback is its rapid enzymatic degradation and limited permeation across the cell membrane. This research aims to to overcome these drawbacks by developing nisin-loaded nanoparticles with improved cytotoxic effects.
    SIGNIFICANCE: PLGA nanoparticles are one of the most effective biodegradable and biocompatible drug delivery carriers. In the present study, nisin-loaded nanoparticles showed enhanced anticancer effects.
    METHODS: NPN was prepared by a double emulsion solvent evaporation method and characterized for different parameters. The cytotoxic investigation of NPN was carried out on various cell lines, including A549, SW-620, HT-29, PC-3, MDA-MB-231, MCF-7, MiaPaca-2, and fR2 by sulforhodamine B (SRB) assay. Mechanistic investigation of cellular cytotoxicity was performed by using bright-field microscopy, DAPI staining, intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (ΔΨm), and western blotting. A comparative cytotoxicity study of nisin and NPN was performed on normal breast epithelial cells (fR-2).
    RESULTS: NPN showed spherical shape, 289.09 ± 3.63 nm particle size, and 63.37 ± 3.12% entrapment efficiency. NPN was more cytotoxic to the MDA-MB-231 cell line, showing higher nuclear fragmentation, ROS generation, and depletion of ΔΨm like apoptosis signs compared to nisin and with no cytotoxicity on normal cells.
    CONCLUSIONS: The findings suggest that nisin delivery via PLGA nanoparticles can be used to treat cancer without significant effects on healthy cells.
    Keywords:  Nisin; cytotoxicity; food preservative; lantibiotics; nanoparticles
    DOI:  https://doi.org/10.1080/03639045.2022.2111438
  39. Polymers (Basel). 2022 Jul 31. pii: 3118. [Epub ahead of print]14(15):
    Cubosomes: Design, Development, and Tumor-Targeted Drug Delivery Applications.
    Hassaan Umar, Habibah A Wahab, Amirah Mohd Gazzali, Hafsa Tahir, Waqas Ahmad.
      Because of the extraordinary advancements in biomedical nanotechnology over the last few decades, traditional drug delivery systems have been transformed into smart drug delivery systems that respond to stimuli. These well-defined nanoplatforms can boost therapeutic targeting efficacy while reducing the side effects/toxicities of payloads, which are crucial variables for enhancing patient compliance by responding to specific internal or external triggers. Cubosomes are lipid-based nano systems that are analogous to well-known vesicular systems, such as lipo- and niosomes. They could be used as part of a unique drug delivery system that includes hydro-, lipo-, and amphiphilic drug molecules. In this review, we critically analyze the relevant literature on cubosomesregarding theories of cubosomeself-assembly, composition, and manufacturing methods, with an emphasis on tumor-targeted drug delivery applications. Due to the bioadhesive and -compatible nature of cubosome dispersion, this review also focuses on a variety of drug delivery applications, including oral, ophthalmic and transdermal.
    Keywords:  active targeting; cubosomes; drug delivery; glyceryl monooleate; passive targeting
    DOI:  https://doi.org/10.3390/polym14153118
  40. J Nanobiotechnology. 2022 Aug 11. 20(1): 373
    Iron oxide@chlorophyll clustered nanoparticles eliminate bladder cancer by photodynamic immunotherapy-initiated ferroptosis and immunostimulation.
    Yu-Cheng Chin, Li-Xing Yang, Fei-Ting Hsu, Che-Wei Hsu, Te-Wei Chang, Hsi-Ying Chen, Linda Yen-Chien Chen, Zi Chun Chia, Chun-Hua Hung, Wu-Chou Su, Yi-Chun Chiu, Chih-Chia Huang, Mei-Yi Liao.
      The escape of bladder cancer from immunosurveillance causes monotherapy to exhibit poor efficacy; therefore, designing a multifunctional nanoparticle that boosts programmed cell death and immunoactivation has potential as a treatment strategy. Herein, we developed a facile one-pot coprecipitation reaction to fabricate cluster-structured nanoparticles (CNPs) assembled from Fe3O4 and iron chlorophyll (Chl/Fe) photosensitizers. This nanoassembled CNP, as a multifunctional theranostic agent, could perform red-NIR fluorescence and change the redox balance by the photoinduction of reactive oxygen species (ROS) and attenuate iron-mediated lipid peroxidation by the induction of a Fenton-like reaction. The intravesical instillation of Fe3O4@Chl/Fe CNPs modified with 4-carboxyphenylboronic acid (CPBA) may target the BC wall through glycoproteins in the BC cavity, allowing local killing of cancer cells by photodynamic therapy (PDT)-induced singlet oxygen and causing chemodynamic therapy (CDT)-mediated ferroptosis. An interesting possibility is reprogramming of the tumor microenvironment from immunosuppressive to immunostimulatory after PDT-CDT treatment, which was demonstrated by the reduction of PD-L1 (lower "off" signal to the effector immune cells), IDO-1, TGF-β, and M2-like macrophages and the induction of CD8+ T cells on BC sections. Moreover, the intravesical instillation of Fe3O4@Chl/Fe CNPs may enhance the large-area distribution on the BC wall, improving antitumor efficacy and increasing survival rates from 0 to 91.7%. Our theranostic CNPs not only demonstrated combined PDT-CDT-induced cytotoxicity, ROS production, and ferroptosis to facilitate treatment efficacy but also opened up new horizons for eliminating the immunosuppressive effect by simultaneous PDT-CDT.
    DOI:  https://doi.org/10.1186/s12951-022-01575-7
  41. Dement Geriatr Cogn Dis Extra. 2022 May-Aug;12(2):12(2): 100-106
    The Effect of the Ketogenic Diet on the Therapy of Neurodegenerative Diseases and Its Impact on Improving Cognitive Functions.
    Klaudia Grochowska, Anna Przeliorz.
      The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with controlled amounts of protein. The use of drastic caloric restriction or ultralow-carbohydrate diets increases the production of ketone bodies, which are an alternative energy substrate in situations of insufficient glucose supply. Alzheimer's disease (AD) and Parkinson's disease are the most common neurodegenerative diseases in the world. It is believed that carbohydrate metabolism disorders may affect the progression of these diseases, as confirmed by both animal and human studies. Among patients with AD, the presence of ketone bodies in the body can improve cerebral circulation. Among Parkinson's patients, the presence of ketone bodies can reduce muscle tremor and stiffness, as well as improve cognitive function. The results of the research indicate that using a low-carbohydrate diet, including a KD, may have a beneficial effect on brain function in diseases that cause neuronal damage.
    Keywords:  Alzheimer's disease; Ketogenic diet; Neurodegenerative diseases; Parkinson's disease
    DOI:  https://doi.org/10.1159/000524331
  42. Phytomedicine. 2022 Jul 10. pii: S0944-7113(22)00412-3. [Epub ahead of print]105 154333
    A systematic review on potential anticancer activities of Ficus carica L. with focus on cellular and molecular mechanisms.
    Mohammad Reza Morovati, Maryam Ghanbari-Movahed, Emily M Barton, Mohammad Hosein Farzaei, Anupam Bishayee.
       BACKGROUND: Many substances derived from nutritional or medicinal plants have been studied for their chemopreventive and antineoplastic properties. Among those studied, Ficus carica has shown to have a significant ability to inhibit tumor formation and development of cancer cells through modulating various signaling mechanisms and interaction including a large number of cell signaling molecules.
    PURPOSE: The goal of this study is to provide a critical and complete evaluation of F. carica's anticancer capacity in various malignancies, as well as related molecular targets.
    METHODS: Research was conducted electronically on scholarly scientific databases, including Science Direct, PubMed, and Scopus. Published papers were analyzed and investigated using the keywords, Ficus carica, figs, cancer, malignancies and tumor based on established selection criteria. In this systematic review, 27 individual studies were considered.
    RESULTS: Treatment with F. carica alone or in combination with other medications was linked to anticancer activity with significant evidence. Furthermore, F. carica has been shown to use multitargeted pathways to prevent cancer initiation and development by modulating numerous dysregulated signaling cascades involved in cell proliferation, cell cycle regulation, apoptosis, autophagy inflammatory processes, metastasis, invasion, and angiogenesis.
    CONCLUSION: Our findings suggest that F. carica and its phytochemicals have the potential for cancer prevention and therapy. Nonetheless, additional mechanistic studies with pure compounds derived from F. carica and well-designed clinical trials are needed to advance our knowledge to clinical application.
    Keywords:  Cancer; Ficus carica; Molecular mechanisms; Phytochemicals; Targeted therapy
    DOI:  https://doi.org/10.1016/j.phymed.2022.154333
  43. J Control Release. 2022 Aug 05. pii: S0168-3659(22)00483-7. [Epub ahead of print]
    Pulmonary delivery of size-transformable nanoparticles improves tumor accumulation and penetration for chemo-sonodynamic combination therapy.
    Siqi Ma, Zhaoqing Cong, Jiaxing Wei, Weiya Chen, Di Ge, Feifei Yang, Yonghong Liao.
      Very little is currently known about how inhaled nanomedicine for lung cancer treatment overcomes biological barriers hampering the tumor availability of drug and nanoparticles. Here, we developed a size-transformable nanocarrier (~ 119 nm) in which small-size nanoparticles (~ 28 nm) were loaded in the large nanocarrier after the addition of modified hyaluronan and could be released upon size-transformation at tumor tissue. Subsequently, the pulmonary and tumor pharmacokinetics of the two nanocarriers containing 7-ethyl-10-hydroxycamptothecin (SN38) and a covalently linked fluorescent sonosensitizer were comparatively investigated after intratracheal instillation to mice bearing orthotopic Lewis lung carcinoma tumors. The results showed that both instilled nanoparticles seemed to transport drug to tumor by direct access and transcytosis of nanoparticles, and diffusion of the released drug with the latter accounting for a great proportion of the drug tumor bioavailability. Relative to the small-size nanocarrier, the size-transformable counterpart appeared to restrict the mucociliary and absorption clearances from the lung and the clearance from the tumor interstitium to circulation, leading to increases in lung and tumor bioavailability of SN38 by 58.5% and 199%, respectively. In addition, the size-transformable nanoformulation conferred deep tumor penetration and sustained levels of both sonosensitizer and SN38 within tumors and simultaneously exerted sonodynamic- and chemo-therapies. Overall, the pulmonary delivery of size-transformable nanocarrier could co-deliver sonosensitizer and drug to deep tumor sites with enhanced tumor accumulation to realize combination therapy in lung cancer.
    Keywords:  Inhaled nanomedicine; Lung cancer; Size-transformation; Tumor penetration; Tumor pharmacokinetics
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.003
  44. Nanomaterials (Basel). 2022 Aug 04. pii: 2672. [Epub ahead of print]12(15):
    Recent Advances in Nanoparticle-Based Co-Delivery Systems for Cancer Therapy.
    Rouba D Al Bostami, Waad H Abuwatfa, Ghaleb A Husseini.
      Cancer therapies have advanced tremendously throughout the last decade, yet multiple factors still hinder the success of the different cancer therapeutics. The traditional therapeutic approach has been proven insufficient and lacking in the suppression of tumor growth. The simultaneous delivery of multiple small-molecule chemotherapeutic drugs and genes improves the effectiveness of each treatment, thus optimizing efficacy and improving synergistic effects. Nanomedicines integrating inorganic, lipid, and polymeric-based nanoparticles have been designed to regulate the spatiotemporal release of the encapsulated drugs. Multidrug-loaded nanocarriers are a potential strategy to fight cancer and the incorporation of co-delivery systems as a feasible treatment method has projected synergistic benefits and limited undesirable effects. Moreover, the development of co-delivery systems for maximum therapeutic impact necessitates better knowledge of the appropriate therapeutic agent ratio as well as the inherent heterogeneity of the cancer cells. Co-delivery systems can simplify clinical processes and increase patient quality of life, even though such systems are more difficult to prepare than single drug delivery systems. This review highlights the progress attained in the development and design of nano carrier-based co-delivery systems and discusses the limitations, challenges, and future perspectives in the design and fabrication of co-delivery systems.
    Keywords:  co-delivery; gene delivery; multi-drug resistance; nanocarriers
    DOI:  https://doi.org/10.3390/nano12152672
  45. Front Mol Biosci. 2022 ;9 816510
    Glucose Deprivation Induced by Acarbose and Oncolytic Newcastle Disease Virus Promote Metabolic Oxidative Stress and Cell Death in a Breast Cancer Model.
    Qayssar A Obaid, Ahmed Majeed Al-Shammari, Khalisa K Khudair.
      Cancer cells are distinguished by enhanced glucose uptake and an aerobic glycolysis pathway in which its products support metabolic demands for cancer cell growth and proliferation. Inhibition of aerobic glycolysis is a smart therapeutic approach to target the progression of the cancer cell. We employed acarbose (ACA), a particular alpha-glucosidase inhibitor, to induce glucose deprivation combined with oncolytic Newcastle disease virus (NDV) to enhance antitumor activity. In this work, we used a mouse model of breast cancer with mammary adenocarcinoma tumor cells (AN3) that were treated with ACA, NDV, and a combination of both. The study included antitumor efficacy, relative body weight, glucose level, hexokinase (HK-1) level by ELISA, glycolysis product (pyruvate), total ATP, oxidative stress (ROS and reduced glutathione), and apoptosis by immunohistochemistry. The results showed significant antitumor efficacy against breast cancer after treatment with combination therapy. Antitumor efficacy was accompanied by a reduction in body weight and glucose level, HK-1 downregulation, inhibition of glycolysis products (pyruvate), total ATP, induction of oxidative stress (increase ROS and decrease reduced glutathione), and apoptotic cell death. The findings propose a novel anti-breast cancer combination involving the suppression of glycolysis, glucose deprivation, oxidative stress, and apoptosis, which can be translated clinically.
    Keywords:  apoptosis; cancer; glucose deprivation; oncolytic virotherapy; oxidative stress
    DOI:  https://doi.org/10.3389/fmolb.2022.816510
  46. J Food Biochem. 2022 Aug 09. e14357
    The therapeutic role of nutraceuticals targeting the Nrf2/HO-1 signaling pathway in liver cancer.
    Khalid Saad Alharbi, Waleed Hassan Almalki, Mohammed Albratty, Abdulkarim M Meraya, Asim Najmi, Govind Vyas, Sachin Kumar Singh, Kamal Dua, Gaurav Gupta.
      Liver cancer (L.C.) is the most common cause of cancer death in the United States and the fifth most common globally. The overexpression of nuclear factor E2 related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) caused by oxidative stress has been associated with tumor growth, aggressiveness, treatment resistance, and poor prognosis. Nutraceuticals that inhibit Nrf2/HO-1 signaling may become the most effective strategy to treat liver cancer. Phytochemicals found in fruits and vegetables, also known as nutraceuticals, tend to emerge as chemopreventive agents, with the added benefit of low toxicity and high nutritional values. This paper reviews the present scientific knowledge of the Nrf2/HO-1 signaling as a possible target molecule for chemotherapeutic agents, its basic control mechanisms, and Nrf2/HO-1 inducers produced from natural products that might be employed as cancer chemopreventive drugs. The growing interest in the contribution of the Nrf2/ARE/HO-1 signaling in the development of liver cancer and the Use of nutraceuticals to treat liver cancer by targeting Nrf2/ARE/HO-1. PRACTICAL APPLICATIONS: An increase in Nrf2 expression indicates that Nrf2 is the most important player in liver cancer. Cancer patients are more resistant to chemotherapy because of this erroneous Nrf2 signaling. Furthermore, an increasing body of evidence indicates that activation of the Nrf2/HO-1 pathway results in the production of phase II detoxifying and antioxidant enzymes, which serve a defense purpose in cells. As a consequence, treating liver cancer. This master regulator may be a possibility. Nutraceuticals that reduce Nrf2/HO-1 signaling may be the most effective strategy for preventing liver cancer. The methods of action of numerous natural substances are examined in this article.
    Keywords:  HO-1; Nrf2; liver cancer; nutraceuticals; oxidative stress
    DOI:  https://doi.org/10.1111/jfbc.14357
  47. Biotechnol Bioeng. 2022 Aug 11.
    Ligand conjugated lipid-based nanocarriers for cancer theranostics.
    Rahul Kumar, Daphika S Dkhar, Rohini Kumari, Divya Supratim Mahapatra, Ananya Srivastava, Vikash Kumar Dubey, Pranjal Chandra.
      Cancer is one of the major health-related issues affecting the population worldwide and subsequently accounts for the second-largest death. Genetic and epigenetic modifications in oncogenes or tumor suppressor genes affect the regulatory systems that lead to the initiation and progression of cancer. Conventional methods, including chemotherapy/radiotherapy/appropriate combinational therapy and surgery, are being widely used for theranostics of cancer patients. Surgery is useful in treating localized tumors, but it is ineffective in treating metastatic tumors, which spread to other organs and result in a high recurrence rate and death. Also, the therapeutic application of free drugs is related to substantial issues such as poor absorption, solubility, bioavailability, high degradation rate, short shelf-life, and low therapeutic index. Therefore, these issues can be sorted out using nano lipid-based carriers (NLBCs) as promising drug delivery carriers. Still, at most, they fail to achieve site targeted drug delivery and detection. This can be achieved by selecting a specific ligand/antibody for its cognate receptor molecule expressed on the surface of cancer cell. In this review, we have mainly discussed the various types of ligands used to decorate NLBCs. A list of the ligands used to design nanocarriers to target malignant cells has been extensively undertaken. The approved ligand decorated lipid-based nanomedicines with their clinical status has been explained in tabulated form to provide a wider scope to the readers regarding ligand coupled NLBCs. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer Theranostics; Commercialization; Lipid Conjugates; Nanocarriers
    DOI:  https://doi.org/10.1002/bit.28205
  48. J Mater Chem B. 2022 Aug 09.
    Mesoporous polydopamine nanoparticles for sustained release of rapamycin and reactive oxygen species scavenging to synergistically accelerate neurogenesis after spinal cord injury.
    Haifei Shi, Lulu Jin, Jinyi Li, Kejiong Liang, Xigong Li, Ziqiang Ye, Xinyue Zhu, Joaquim Miguel Oliveira, Rui L Reis, Zhengwei Mao, Mengjie Wu.
      Spinal cord injury (SCI) is an intractable condition with complex pathological processes and poor prognosis. Reactive oxygen species (ROS) generation induced by the mammalian target of the rapamycin (mTOR) protein is one of the causes of secondary inflammation of SCI. Rapamycin (Rapa) is a pharmacological inhibitor of mTOR, which can inhibit ROS overproduction mediated by abnormal activation of the mTOR protein. Polydopamine, as a nanocarrier with excellent biological safety, has been reported to possess satisfactory ROS scavenging ability. Therefore, we designed a mesoporous polydopamine nanoparticle loaded with Rapa (mPDA@Rapa) for combination therapy, which simultaneously inhibited abnormally activated mTOR-mediated ROS production and eliminated already generated ROS. The synthesized mPDA nanoparticles could realize the effective encapsulation and sustained release of Rapa due to their mesoporous cavities and a hydrophobic benzene ring structure. In vitro experiments proved that mPDA@Rapa nanoparticles had a good ROS scavenging ability towards hydrogen peroxide and hydroxyl radicals. Furthermore, mPDA@Rapa also showed a good therapeutic effect in SCI model rats, which was evidenced by a smaller injury cavity, more coordinated hind limb movements, and a higher degree of neurogenesis and tissue regeneration. Our work provides a combined strategy to inhibit ROS overproduction and eliminate excess ROS, with potential applications not only in SCI, but also in other ROS-induced inflammations.
    DOI:  https://doi.org/10.1039/d2tb00841f
  49. Nutrients. 2022 Aug 05. pii: 3207. [Epub ahead of print]14(15):
    Why Should Pistachio Be a Regular Food in Our Diet?
    Raquel Mateos, María Desamparados Salvador, Giuseppe Fregapane, Luis Goya.
      The pistachio is regarded as a relevant source of biologically active components that, compared to other nuts, possess a healthier nutritional profile with low-fat content composed mainly of monounsaturated fatty acids, a high source of vegetable protein and dietary fibre, remarkable content of minerals, especially potassium, and an excellent source of vitamins, such as vitamins C and E. A rich composition in terms of phytochemicals, such as tocopherols, carotenoids, and, importantly, phenolic compounds, makes pistachio a powerful food to explore its involvement in the prevention of prevalent pathologies. Although pistachio has been less explored than other nuts (walnut, almonds, hazelnut, etc.), many studies provide evidence of its beneficial effects on CVD risk factors beyond the lipid-lowering effect. The present review gathers recent data regarding the most beneficial effects of pistachio on lipid and glucose homeostasis, endothelial function, oxidative stress, and inflammation that essentially convey a protective/preventive effect on the onset of pathological conditions, such as obesity, type 2 diabetes, CVD, and cancer. Likewise, the influence of pistachio consumption on gut microbiota is reviewed with promising results. However, population nut consumption does not meet current intake recommendations due to the extended belief that they are fattening products, their high cost, or teething problems, among the most critical barriers, which would be solved with more research and information.
    Keywords:  barriers; facilitator; health benefits; nutritional value; nuts; pistachio; prevalent chronic diseases
    DOI:  https://doi.org/10.3390/nu14153207
  50. ACS Appl Mater Interfaces. 2022 Aug 08.
    Oncolytic Impediment/Promotion Balance Disruption by Sonosensitizer-Free Nanoplatforms Unfreezes Autophagy-Induced Resistance to Sonocatalytic Therapy.
    Lu Lu, Taixia Wang, Chao Fang, Li Song, Cheng Qian, Zheng Lv, Yujia Fang, Xinyu Liu, Xin Yu, Xiaohong Xu, Chunxia Su, Fubo Chen, Kun Zhang.
      Autophagy as a double-edged sword features an oncolytic impediment/promotion balance, which manipulates tumor progression. From this perspective, a sonosensitizer-free targeting oncolytic nanoplatform (SFTON) consisting of chloroquine (CQ) and porphyrin-structured metal centers (PMCS) was engineered to break this balance for enhancing antitumor activity. Porphyrin structure retention in a ZIF-8-derived hydrophobic carbon skeleton retained high stability and high sonocatalytic activity, and the hydrophobic carbon skeleton capable of adsorbing air provided cavitation nuclei for further elevating sonocatalytic activity. More significantly, the encapsulated CQ as the autophagy inhibitor reprogrammed autophagy, terminated the autophagy-induced self-protection or self-detoxification, and unfroze the resistances to reactive oxygen species (ROS) therapy associated with ROS accumulation and ROS activity. Systematic experiments reveal the action principles and validate that the induced apoptosis and blockaded autophagosome escalation into the autolysosome were two activated pathways to magnify the antitumor sonocatalytic therapy. Contributed by these actions, the SFTON-unlocked oncolytic impediment/promotion balance disruption strategy acquired considerable antitumor outcomes in vivo and in vitro against liver tumor progression, especially after combining with AS1411-mediated active targeting. This impediment/promotion balance disruption enabled by the SFTON can serve as a general method to elevate ROS-based antitumor activity.
    Keywords:  autophagy reprogramming; autophagy-induced self-protection and resistance; cavitation; impediment/promotion balance; sonocatalytic therapy
    DOI:  https://doi.org/10.1021/acsami.2c09443
  51. J Nanobiotechnology. 2022 Aug 11. 20(1): 366
    Black phosphorous nanomaterials as a new paradigm for postoperative tumor treatment regimens.
    Yanhua Hou, Yang Fei, Zehong Liu, Yingqi Liu, Menghuan Li, Zhong Luo.
      Surgery is currently a mainstream treatment modality for various solid tumor indications. However, aggressive resection of tumor tissues frequently causes postoperative complications, which severely undermine the well-being of patients. Moreover, the residue tumor cells may substantially increase the risk of local and distant tumor relapse. The recent development in black phosphorus (BP)-based nanomaterials offers a promising opportunity to address these clinical challenges. BP is an emerging nanomaterial with excellent biocompatibility and versatile functionality, which has already demonstrated great potential for a variety of biomedical applications including tumor therapy and tissue engineering. In this review, the recent advances in BP-based nanobiomaterials for the post-surgery treatment of solid tumor have been summarized, while specific emphasis was placed on their capability to continuously inhibit residue tumor growth at the surgery site as well as stimulating various healing mechanisms, aiming to preventing tumor relapse while promoting the healing of surgery-induced traumatic soft/hard tissue injuries. It is anticipated that the nanoengineered BP-based materials may open new avenues to tackle those clinical challenges in surgical treatment of solid tumors.
    Keywords:  Black phosphorus; Postoperative tumor treatment; Tissue reconstruction; Wound healing
    DOI:  https://doi.org/10.1186/s12951-022-01579-3
  52. Materials (Basel). 2022 Jul 31. pii: 5290. [Epub ahead of print]15(15):
    Drug Delivery Systems with a "Tumor-Triggered" Targeting or Intracellular Drug Release Property Based on DePEGylation.
    Zhe Ren, Tao Liao, Cao Li, Ying Kuang.
      Coating nanosized anticancer drug delivery systems (DDSs) with poly(ethylene glycol) (PEG), the so-called PEGylation, has been proven an effective method to enhance hydrophilicity, aqueous dispersivity, and stability of DDSs. What is more, as PEG has the lowest level of protein absorption of any known polymer, PEGylation can reduce the clearance of DDSs by the mononuclear phagocyte system (MPS) and prolong their blood circulation time in vivo. However, the "stealthy" characteristic of PEG also diminishes the uptake of DDSs by cancer cells, which may reduce drug utilization. Therefore, dynamic protection strategies have been widely researched in the past years. Coating DDSs with PEG through dynamic covalent or noncovalent bonds that are stable in blood and normal tissues, but can be broken in the tumor microenvironment (TME), can achieve a DePEGylation-based "tumor-triggered" targeting or intracellular drug release, which can effectively improve the utilization of drugs and reduce their side effects. In this review, the stimuli and methods of "tumor-triggered" targeting or intracellular drug release, based on DePEGylation, are summarized. Additionally, the targeting and intracellular controlled release behaviors of the DDSs are briefly introduced.
    Keywords:  DePEGylationg; controlled release; dynamic protection strategy; tumor-triggered targeting
    DOI:  https://doi.org/10.3390/ma15155290
  53. Cancers (Basel). 2022 Jul 27. pii: 3661. [Epub ahead of print]14(15):
    The Differential Metabolic Signature of Breast Cancer Cellular Response to Olaparib Treatment.
    Domenica Berardi, Yasmin Hunter, Lisa van den Driest, Gillian Farrell, Nicholas J W Rattray, Zahra Rattray.
      Metabolic reprogramming and genomic instability are key hallmarks of cancer, the combined analysis of which has gained recent popularity. Given the emerging evidence indicating the role of oncometabolites in DNA damage repair and its routine use in breast cancer treatment, it is timely to fingerprint the impact of olaparib treatment in cellular metabolism. Here, we report the biomolecular response of breast cancer cell lines with DNA damage repair defects to olaparib exposure. Following evaluation of olaparib sensitivity in breast cancer cell lines, we immunoprobed DNA double strand break foci and evaluated changes in cellular metabolism at various olaparib treatment doses using untargeted mass spectrometry-based metabolomics analysis. Following identification of altered features, we performed pathway enrichment analysis to measure key metabolic changes occurring in response to olaparib treatment. We show a cell-line-dependent response to olaparib exposure, and an increased susceptibility to DNA damage foci accumulation in triple-negative breast cancer cell lines. Metabolic changes in response to olaparib treatment were cell-line and dose-dependent, where we predominantly observed metabolic reprogramming of glutamine-derived amino acids and lipids metabolism. Our work demonstrates the effectiveness of combining molecular biology and metabolomics studies for the comprehensive characterisation of cell lines with different genetic profiles. Follow-on studies are needed to map the baseline metabolism of breast cancer cells and their unique response to drug treatment. Fused with genomic and transcriptomics data, such readout can be used to identify key oncometabolites and inform the rationale for the design of novel drugs or chemotherapy combinations.
    Keywords:  DNA damage; breast cancer; metabolic reprogramming; oncometabolites; precision medicine; triple-negative
    DOI:  https://doi.org/10.3390/cancers14153661
  54. Nucleosides Nucleotides Nucleic Acids. 2022 Aug 09. 1-21
    Lower vitamin D levels and VDR variants are risk factors for breast cancer: an updated meta-analysis.
    Zhenyu Zhao, Wenyu Cai, Jing Xing, Chenhui Zhao.
      Inadequate vitamin D levels and vitamin D variants have been shown to be associated with breast cancer (BC), however the results are inconsistent. To reach a definitive conclusion the present meta-analysis was conducted. When compared to healthy controls, BC patients had reduced vitamin D levels (standard difference in means = -0.564, p = 0.003). The meta-analysis revealed that the FokI mutation was linked with an increased BC susceptibility (CC vs. TT: OR = 1.107, p = 0.001, CC vs. TC + TT: OR = 1.114, p = 0.020). There was no role of other VDR variants (BsmI, TaqI, and ApaI). FokI mutation and diminished vitamin D increase the likelihood of developing BC.
    Keywords:  Breast cancer; VDR; meta-analysis; polymorphism; susceptibility; vitamin D3
    DOI:  https://doi.org/10.1080/15257770.2022.2107217
  55. Polymers (Basel). 2022 Aug 03. pii: 3162. [Epub ahead of print]14(15):
    A Promising Review on Cyclodextrin Conjugated Paclitaxel Nanoparticles for Cancer Treatment.
    Kamini Velhal, Sagar Barage, Arpita Roy, Jaya Lakkakula, Ramesh Yamgar, Mohammed S Alqahtani, Krishna Kumar Yadav, Yongtae Ahn, Byong-Hun Jeon.
      This review presented the unique characteristics of different types of cyclodextrin polymers by non-covalent host-guest interactions to synthesize an inclusion complex. Various cancers are treated with different types of modified cyclodextrins, along with the anticancer drug paclitaxel. PTX acts as a mitotic inhibitor, but due to its low dissolution and permeability in aqueous solutions, it causes considerable challenges for drug delivery system (DDS) designs. To enhance the solubility, it is reformulated with derivatives of cyclodextrins using freeze-drying and co-solvent lyophilization methods. The present supramolecular assemblies involve cyclodextrin as a key mediator, which is encapsulated with paclitaxel and their controlled release at the targeted area is highlighted using different DDS. In addition, the application of cyclodextrins in cancer treatment, which reduces the off-target effects, is briefly demonstrated using various types of cancer cell lines. A new nano-formulation of PTX is used to improve the antitumor activity compared to normal PTX DDS in lungs and breast cancer is well defined in the present review.
    Keywords:  cyclodextrin CD; nanoparticles NPs; novel drug delivery system NDDS; paclitaxel PTX
    DOI:  https://doi.org/10.3390/polym14153162
  56. Cancers (Basel). 2022 Jul 29. pii: 3705. [Epub ahead of print]14(15):
    Drug Repurposing, a Fast-Track Approach to Develop Effective Treatments for Glioblastoma.
    Ioannis Ntafoulis, Stijn L W Koolen, Sieger Leenstra, Martine L M Lamfers.
      Glioblastoma (GBM) remains one of the most difficult tumors to treat. The mean overall survival rate of 15 months and the 5-year survival rate of 5% have not significantly changed for almost 2 decades. Despite progress in understanding the pathophysiology of the disease, no new effective treatments to combine with radiation therapy after surgical tumor debulking have become available since the introduction of temozolomide in 1999. One of the main reasons for this is the scarcity of compounds that cross the blood-brain barrier (BBB) and reach the brain tumor tissue in therapeutically effective concentrations. In this review, we focus on the role of the BBB and its importance in developing brain tumor treatments. Moreover, we discuss drug repurposing, a drug discovery approach to identify potential effective candidates with optimal pharmacokinetic profiles for central nervous system (CNS) penetration and that allows rapid implementation in clinical trials. Additionally, we provide an overview of repurposed candidate drug currently being investigated in GBM at the preclinical and clinical levels. Finally, we highlight the importance of phase 0 trials to confirm tumor drug exposure and we discuss emerging drug delivery technologies as an alternative route to maximize therapeutic efficacy of repurposed candidate drug.
    Keywords:  CNS penetration; blood–brain barrier; clinical trials; drug repurposing; drug screening platforms; efflux pumps; glioblastoma
    DOI:  https://doi.org/10.3390/cancers14153705
  57. J Biomater Sci Polym Ed. 2022 Aug 09. 1-14
    A multi-responsive targeting drug delivery system for combination photothermal/chemotherapy of tumor.
    Yuanyuan Yang, Siqi Wu, Qinlin Zhang, Zhaoxia Chen, Caixia Wang, Sijing Jiang, Yuhong Zhang.
      To achieve efficient delivery and precise release of chemotherapy drugs at tumor sites, an active targeting multi-responsive drug delivery platform was developed. Here, doxorubicin hydrochloride (DOX) was loaded onto polydopamine (PDA), which were coated by the cystamine-modified hyaluronic acid (HA-Cys), designated as DOX@PDA-HA (PDH). The combination of PDA and HA-Cys endowed the nanoplatform photothermal conversion, tumor-targeting, and pH/redox/NIR sensitive drug release capacity. Moreover, HA could be degraded by the excess hyaluronidase (HAase) in the tumor microenvironment (TME), promoting DOX release, and further enhancing the effect of chemotherapy. Experimental results demonstrated PDH good biocompatibility, high loading rate, targeted drug delivery, and efficient tumor cell killing ability. This ingenious strategy based on PDH showed huge potential in photothermal/chemotherapy combination treatment of cancer.
    Keywords:  Combination therapy; Drug delivery system; Muti-stimuli responsive; Polydopamine; Tumor-targeting
    DOI:  https://doi.org/10.1080/09205063.2022.2112310
  58. J Nanobiotechnology. 2022 Aug 06. 20(1): 362
    Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems.
    Deepak A Subramanian, Robert Langer, Giovanni Traverso.
      Oral delivery of therapeutics is the preferred route of administration due to ease of administration which is associated with greater patient medication adherence. One major barrier to oral delivery and intestinal absorption is rapid clearance of the drug and the drug delivery system from the gastrointestinal (GI) tract. To address this issue, researchers have investigated using GI mucus to help maximize the pharmacokinetics of the therapeutic; while mucus can act as a barrier to effective oral delivery, it can also be used as an anchoring mechanism to improve intestinal residence. Nano-drug delivery systems that use materials which can interact with the mucus layers in the GI tract can enable longer residence time, improving the efficacy of oral drug delivery. This review examines the properties and function of mucus in the GI tract, as well as diseases that alter mucus. Three broad classes of mucus-interacting systems are discussed: mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems. For each class of system, the basis for mucus interaction is presented, and examples of materials that inform the development of these systems are discussed and reviewed. Finally, a list of FDA-approved mucoadhesive, mucus-penetrating, and mucolytic drug delivery systems is reviewed. In summary, this review highlights the progress made in developing mucus-interacting systems, both at a research-scale and commercial-scale level, and describes the theoretical basis for each type of system.
    Keywords:  Gastrointestinal tract; Mucoadhesive; Mucus; Mucus penetration; Oral delivery
    DOI:  https://doi.org/10.1186/s12951-022-01539-x
  59. Discov Oncol. 2022 Aug 13. 13(1): 74
    Roles of exosomes as drug delivery systems in cancer immunotherapy: a mini-review.
    Zhen Fang, Yixuan Ding, Zhigang Xue, Peijuan Li, Jia Li, Fei Li.
      Exosomes can be released by a variety of cells and participate in intercellular communication in many physiological processes in the body. They can be used as carriers of cancer therapeutic drugs and have natural delivery capabilities. Some biologically active substances on exosomes, such as major histocompatibility complex (MHC), have been shown to be involved in exosome-mediated anticancer immune responses and have important regulatory effects on the immune system. Exosome-based drug delivery systems hold great promise in future cancer immunotherapy. However, there are still substantial challenges to be overcome in the clinical application of exosomes as drug carriers. This article reviews the biological characteristics of exosome drug delivery systems and their potential applications and challenges in cancer immunotherapy.
    Keywords:  Cancer; Drug delivery systems; Exosomes; Immunotherapy
    DOI:  https://doi.org/10.1007/s12672-022-00539-5
  60. Adv Food Nutr Res. 2022 ;pii: S1043-4526(22)00013-4. [Epub ahead of print]101 277-307
    Food protein-derived bioactive peptides for the management of nutrition related chronic diseases.
    Xinyi Cao, Wang Liao, Shaokang Wang.
      Dietary intervention via modifications of dietary pattern or supplementations of naturally derived bioactive compounds has been considered as an efficient approach in management of nutrition related chronic diseases. Food protein-derived bioactive peptide is representative of natural compounds which show the potential to prevent or mitigate nutrition related chronic diseases. In the past decades, substantial research has been conducted concentrating on the characterization, bioavailability, and activity assessment of bioactive peptides. Although various activities of bioactive peptides have been reported, the activity testes of most peptides were only conducted in cells and animal models. Some clinical trials of bioactive peptides were also reported but only limited to antihypertensive peptides, antidiabetic peptides and peptides modulating blood lipid profile. Hereby, clinical evidence of bioactive peptides in management of nutrition-related chronic diseases is summarized in this chapter, which aims at providing implications for the clinical studies of bioactive peptides in the future.
    Keywords:  Bioactive peptides; Cardiovascular diseases; Clinical trial; Dietary supplementation; Metabolic diseases
    DOI:  https://doi.org/10.1016/bs.afnr.2022.04.004
  61. Int J Pharm. 2022 Aug 09. pii: S0378-5173(22)00653-6. [Epub ahead of print] 122099
    A review on the latest developments of mesoporous silica nanoparticles as a promising platform for diagnosis and treatment of cancer.
    Fatemeh Ahmadi, Arezoo Sodagar-Taleghani, Pedram Ebrahimnejad, Seyyed Pouya Hadipour Moghaddam, Farzam Ebrahimnejad, Kofi Asare-Addo, Ali Nokhodchi.
      Cancer is the second cause of human mortality after cardiovascular disease around the globe. Conventional cancer therapies are chemotherapy, radiation, and surgery. In fact, due to the lack of absolute specificity and high drug concentrations, early recognition and treatment of cancer with conventional approaches have become challenging issues in the world. To mitigate against the limitations of conventional cancer chemotherapy, nanomaterials have been developed. Nanomaterials exhibit particular properties that can overcome the drawbacks of conventional therapies such as lack of specificity, high drug concentrations, and adverse drug reactions. Among nanocarriers, mesoporous silica nanoparticles (MSNs) have gained increasing attention due to their well-defined pore size and structure, high surface area, good biocompatibility and biodegradability, ease of surface modification, and stable aqueous dispersions. This review highlights the current progress with the use of MSNs for the delivery of chemotherapeutic agents for the diagnosis and treatment of cancer. Various stimuli-responsive gatekeepers, which endow the MSNs with on-demand drug delivery, surface modification strategies for targeting purposes, and multifunctional MSNs utilized in drug delivery systems (DDSs) are also addressed. Also, the capability of MSNs as flexible imaging platforms is considered. In addition, physicochemical attributes of MSNs and their effects on cancer therapy with a particular focus on recent studies is emphasized. Moreover, major challenges to the use of MSNs for cancer therapy, biosafety and cytotoxicity aspects of MSNs are discussed.
    Keywords:  Cancer therapy; Diagnostics; Drug delivery; Mesoporous silica; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122099
  62. ACS Appl Bio Mater. 2022 Aug 11.
    Defect Engineering Triggers Exceptional Sonodynamic Activity of Manganese Oxide Nanoparticles for Cancer Therapy.
    Zhixing Guo, Yanxia Yu, Liyin Shi, Ying Liao, Zifan Wang, Xiaoqing Liu, Xihong Lu, Jianwei Wang.
      Sonodynamic therapy (SDT) has received increasing interest in cancer treatment, but its clinical application is still constrained by the low activity of sonosensitizers and their unclear mechanism. Herein, a kind of oxygen-deficient manganese oxide (MnOx) nanoparticles with greatly enhanced sonodynamic activity and good biocompatibility is developed as an advanced sonosensitizer. The introduced oxygen defects can remarkably enhance the electrical conductivity of manganese oxide (MnO) nanoparticles and serve as charge trapping sites to prohibit the electron-hole pair recombination upon ultrasound (US) irradiation. Such distinct merits promote the generation of reactive oxygen species (ROS), making MnOx as a decent sonosensitizer for SDT, and thus endowing MnOx with higher ROS production under US irradiation. As a demonstration, the MnOx nanoparticles decorated by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (MnOx-DSPE-PEG), a biocompatible coverage to enhance the dispersion ability, achieve a superior tumor killing efficiency of 96%, substantially higher than the MnO-DSPE-PEG counterpart (9%). Our experimental results also reveal that MnOx-DSPE-PEG nanoparticles induce the death of tumor cells by targeting polyunsaturated fatty acids in their membrane with US-triggered ROS. Furthermore, the as-designed sonosensitizers exhibit negligible toxicity toward the treated mice.
    Keywords:  cancer therapy; defect engineering; manganese oxide; reactive oxygen species; ultrasound
    DOI:  https://doi.org/10.1021/acsabm.2c00445
  63. Front Pharmacol. 2022 ;13 900439
    The potential application of natural products in cutaneous wound healing: A review of preclinical evidence.
    E Liu, Hongjin Gao, YiJia Zhao, Yaobing Pang, Yejing Yao, Zhengru Yang, Xueer Zhang, YanJin Wang, Siming Yang, Xiao Ma, Jinhao Zeng, Jing Guo.
      Under normal circumstances, wound healing can be summarized as three processes. These include inflammation, proliferation, and remodeling. The vast majority of wounds heal rapidly; however, a large percentage of nonhealing wounds have still not been studied significantly. The factors affecting wound nonhealing are complex and diverse, and identifying an effective solution from nature becomes a key goal of research. This study aimed to highlight and review the mechanisms and targets of natural products (NPs) for treating nonhealing wounds. The results of relevant studies have shown that the effects of NPs are associated with PI3K-AKT, P38MAPK, fibroblast growth factor, MAPK, and ERK signaling pathways and involve tumor growth factor (TNF), vascular endothelial growth factor, TNF-α, interleukin-1β, and expression of other cytokines and proteins. The 25 NPs that contribute to wound healing were systematically summarized by an inductive collation of the six major classes of compounds, including saponins, polyphenols, flavonoids, anthraquinones, polysaccharides, and others, which will further direct the attention to the active components of NPs and provide research ideas for further development of new products for wound healing.
    Keywords:  inflammation; natural products; proliferation; remodeling; skin; wound healing
    DOI:  https://doi.org/10.3389/fphar.2022.900439
  64. Int J Biol Macromol. 2022 Aug 09. pii: S0141-8130(22)01721-4. [Epub ahead of print]
    Injectable and reactive oxygen species-scavenging gelatin hydrogel promotes neural repair in experimental traumatic brain injury.
    Dan Zhang, Rong Chang, Yikun Ren, Yuanmeng He, Shen Guo, Fangxia Guan, Minghao Yao.
      Oxidative stress caused by the overexpression of reactive oxygen species (ROS) plays an important role in the pathogenesis of traumatic brain injury (TBI). Accumulation of ROS can lead to cell death, neurodegeneration, and neurological deficit. Therefore, the design and application of functional materials with ROS scavenging ability is of great significance for neural repair. Herein, an injectable and antioxidant hydrogel was developed for TBI treatment based on the Schiff base reaction of gallic acid-conjugated gelatin (GGA) and oxidized dextran (Odex). The resulting GGA/Odex hydrogel could effectively scavenge DPPH and ABTS radicals, as well as protect cells from the oxidative damage in vitro. Moreover, GGA/Odex hydrogel possessed well biocompatible features. In a moderate TBI mouse model, in situ implantation of GGA6Odex hydrogel efficiently facilitated neurogenesis and promoted the motor, learning and memory abilities. Also, this composite hydrogel suppressed oxidative stress and inflammation via the activation of Nrf2/HO-1 pathway and the regulating of inflammatory factors secretion and macrophage/microglia polarization. Therefore, this injectable and ROS-scavenging GGA6Odex hydrogel is a promising biomaterial for tissue regenerative medicine, including TBI and other tissue repair relevant to raised ROS circumstance.
    Keywords:  Injectable hydrogel; Neural repair; Oxidative stress; Reactive oxygen species scavenging; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.08.027
  65. Drug Res (Stuttg). 2022 Aug 11.
    Dihydroartemesinin and Curcumin Based Self-Microemulsifying Drug Delivery System for Antimalarial Activity.
    Richa Srivastava, Zeeshan Fatima, Jagannath Sahoo, Prince Joshi, Renu Tripathi.
      Malaria is a significant global problem which still persists despite the development of various effective antimalarial drugs. It is challenging to treat this disease due to the parasite's complex life cycle and high recrudensce of antimalarial drugs. A new self-micro emulsifying drug delivery system has been developed to improve the solubility of dihydroartemisinin and curcumin. The prepared formulation contained Dihydroartemesinin, curcumin, Groundnut Oil, Cremephor RH, and Tween 80. Self-micro emulsification time, zeta potential, droplet size, polydispersity index, transmission electron microscopy, drug release, and in-vivo studies were performed for characterization. The globule size was found to be 25.59±0.40 nm and the zeta potential was-5.75±0.18 mV. The globules prepared were spherical in shape. The in-vitro dissolution performance of formulation of dihydroartemisinin and curcumin self emulsifying drug delivery system showed significantly (p<0.05, Origin Pro 8.5) higher release as compared to the pure drugs. The results of the study suggested that the prepared self emulsifying drug delivery system combination of Dihydroartemesinin and curcumin has a better potential to cure parasitemia as compared to the individual drug.
    DOI:  https://doi.org/10.1055/a-1879-2758
  66. Oxid Med Cell Longev. 2022 ;2022 8923615
    Protective Effect of Curcuma Extract in an Ex Vivo Model of Retinal Degeneration via Antioxidant Activity and Targeting the SUMOylation.
    Kambiz Hassanzadeh, Zakaria Vahabzadeh, Lucia Bucarello, Jessica Dragotto, Massimo Corbo, Rita Maccarone, Marco Feligioni.
      Retinal degeneration is the major and principal cause behind many incurable blindness diseases. Several studies indicated the neuroprotective effect of Curcuma longa in eye pathologies, specifically retinopathy. However, the molecular mechanism behind its effect has not been completely elucidated. Using an ex vivo model of retinal degeneration obtained from an ex vivo optic nerve cut (ONC), we demonstrated that Curcuma extract (Cur) exerted a neuroprotective effect. Importantly, Cur was able to modulate apoptosis and MAPK signaling pathway activation and prevent retinal ganglion cell (RGC) loss. Other well-known neuroprotective pharmacological tools, including memantine (Mem), citicoline (Cit), and ginkgolic acid (GA), were used to compare the potential mechanisms of Cur. The antioxidant activity of retinas treated with Cur following optic nerve cut was significantly higher than control, but Cur failed to change the retina glutamate content. Considering the antioxidant effect of Cur and taking advantage of our recent findings on the crosstalk between oxidative stress and post-translational protein modifiers, in particular, small ubiquitin-related modifier (SUMO), we were interested in exploring the effect of Cur on SUMOylation. We found that Cur significantly prevented the increase of protein SUMOylation, confirming our previous in vitro data indicating the cytoprotective effect of curcumin through modulating the oxidative stress and SUMO-JNK axis. Altogether, these results suggest that Curcuma protects the retina from degeneration via antioxidant activity and targets SUMOylation. Therefore, it might be considered for the combination therapy with other neuroprotective agents with different mechanisms in preclinical studies on retinal degeneration.
    DOI:  https://doi.org/10.1155/2022/8923615
  67. Proc Natl Acad Sci India Sect B Biol Sci. 2022 Jul 31. 1-8
    Effect of Different Proportions of Phenolics on Antioxidant Potential: Pointers for Bioactive Synergy/Antagonism in Foods and Nutraceuticals.
    Tripti Joshi, P R Deepa, Pankaj Kumar Sharma.
      Phenolic compounds include a broad variety of antioxidant plant substances such as flavonoids that have in common an aromatic ring with one or more hydroxyl groups. Nutraceuticals and health food supplements are designed from flavonoids as well as pure phytochemicals, often in isolation. However, studies on synergistic and antagonistic effects of such compounds are relatively few. In the current study, dual combinations prepared from five phenolic compounds (flavonoid and non-flavonoid) including rutin hydrate, quercetin dihydrate, hydroquinone, kaempferol, and resveratrol were tested for their antioxidant activities using DPPH · radical scavenging assay. The synergistic antioxidant interactions among these phenolics were evaluated by comparing their individual antioxidant effect with that obtained by a mixture of two compounds in various ratios. Quercetin dihydrate showed the highest antioxidant activity. Many combinations were found statistically synergistic in particular ratios. Rutin hydrate and resveratrol showed maximum synergy (1:1, 2:1, and 3:1 ratio). Antagonistic interactions were also identified. The results of this study could be used by industries to develop more potent nutraceutical supplements or guide the researchers for further bioactivity validation using in vivo assays.
    Keywords:  Antagonism; Antioxidant activity; DPPH assay; Flavonoids; Phenolics; Synergy
    DOI:  https://doi.org/10.1007/s40011-022-01396-6
  68. Anticancer Drugs. 2022 Aug 09.
    Purvalanol A induces apoptosis and reverses cisplatin resistance in ovarian cancer.
    Xiaoyi Zhang, Shasha Hong, Jiang Yang, Jingchun Liu, Ying Wang, Jiaxin Peng, Haoyu Wang, Li Hong.
      Cisplatin (DDP) resistance limits therapeutic efficacy in patients diagnosed with ovarian cancer. Purvalanol A (Pur) is a novel cyclin-dependent kinase (CDK) inhibitor that has been demonstrated to induce apoptosis in various cancer cells. The present study investigated the effect of the combination treatment of Pur and DDP, and the potential anticancer mechanisms in epithelial ovarian cancer (EOC) cells in vitro and in vivo. We found that Pur enhanced the anti-tumor efficacy of cisplatin in EOC cells. The combination of Pur and DDP had more significant effects on apoptosis induction in EOC cells compared with the individual-treatment groups and the control group. We further demonstrated that the combination of Pur and DDP may trigger apoptosis and autophagy in EOC cells by inducing reactive oxygen species (ROS). And the ROS/Akt/mammalian target of rapamycin signaling pathway as a potential mechanism for the initiation of autophagy induced by combination therapy. Similar results were observed in vivo. These results demonstrated that Pur sensitized the response of EOC cells to cisplatin in vitro and in vivo, reversing the resistance to cisplatin in ovarian cancer.
    DOI:  https://doi.org/10.1097/CAD.0000000000001339
  69. J Control Release. 2022 Aug 06. pii: S0168-3659(22)00485-0. [Epub ahead of print]
    Intelligent poly(l-histidine)-based nanovehicles for controlled drug delivery.
    Yu Zhang, Il Kim, Yiming Lu, Yixin Xu, Deng-Guang Yu, Wenliang Song.
      Stimuli-responsive drug delivery systems based on polymeric nanovehicles are among the most promising treatment regimens for malignant cancers. Such intelligent systems that release payloads in response to the physiological characteristics of tumor sites have several advantages over conventional drug carriers, offering, in particular, enhanced therapeutic effects and decreased toxicity. The tumor microenvironment (TME) is acidic, suggesting the potential of pH-responsive nanovehicles for enhancing treatment specificity and efficacy. The synthetic polypeptide poly(l-histidine) (PLH) is an appropriate candidate for the preparation of pH-responsive nanovehicles because the pKa of PLH (approximately 6.0) is close to the pH of the acidic TME. In addition, the pendent imidazole rings of PLH yield pH-dependent hydrophobic-to-hydrophilic phase transitions in the acidic TME, triggering the destabilization of nanovehicles and the subsequent release of encapsulated chemotherapeutic agents. Herein, we highlight the state-of-the-art design and construction of pH-responsive nanovehicles based on PLH and discuss the future challenges and perspectives of this fascinating biomaterial for targeted cancer treatment and "benchtop-to-clinic" translation.
    Keywords:  Cancer therapy; Drug delivery; Poly(l-histidine); Polypeptides; pH-responsive
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.005
  70. Iran J Basic Med Sci. 2022 Jun;25(6): 664-674
    The effects of ginger and its constituents in the prevention of metabolic syndrome: A review.
    Sanaz Salaramoli, Soghra Mehri, Fatemeh Yarmohammadi, Seyed Isaac Hashemy, Hossein Hosseinzadeh.
      Metabolic syndrome is a multifactorial disorder characterized by hyperglycemia, hyperlipidemia, obesity, and hypertension risk factors. Moreover, metabolic syndrome is the most ordinary risk factor for cardiovascular disease (CVD). Numerous chemical drugs are being synthesized to heal metabolic risk factors. Still, due to their abundant side effects, herbal medicines have a vital role in the treatment of these abnormalities. Ginger (Zingiber officinale Roscoe, Zingiberaceae) plant has been traditionally used in medicine to treat disorders, including CVD. The unique ginger properties are attributed to the presence of [6]-gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol, which through different mechanisms can be beneficial in metabolic syndrome. Ginger has a beneficial role in metabolic syndrome treatment due to its hypotensive, anti-obesity, hypoglycemic, and hypolipidemic effects. It can significantly reduce atherosclerotic lesion areas, VLDL and LDL cholesterol levels, and elevate adenosine deaminase activity in platelet and lymphocytes. Also, it promotes ATP/ADP hydrolysis. In the current article review, the critical properties of ginger and its constituents' effects on the metabolic syndrome with a special focus on different molecular and cellular mechanisms have been discussed. This article also suggests that ginger may be introduced as a therapeutic or preventive agent against metabolic syndrome after randomized clinical trials.
    Keywords:  Diabetes; Dyslipidemia; Ginger; Hypertension; Metabolic syndrome; Obesity; Zingiber
    DOI:  https://doi.org/10.22038/IJBMS.2022.59627.13231
  71. Int J Biol Macromol. 2022 Aug 09. pii: S0141-8130(22)01730-5. [Epub ahead of print]
    Self-healing pectin/cellulose hydrogel loaded with limonin as TMEM16A inhibitor for lung adenocarcinoma treatment.
    Limin Chang, Ruixue Chang, Jiafu Shen, Yong Wang, Hongzan Song, Xianjiang Kang, Youliang Zhao, Shuai Guo, Jianglei Qin.
      Lung cancer as one of the highest incident malignant tumors did not receive satisfactory chemotherapy due to lack of specific drug targets and targeted drugs. This study screened a new effective lung tumor inhibitor limonin from herbal medicine, which inhibited proliferation and promoted apoptosis of lung adenocarcinoma cells by targeting specific high expressed TMEM16A ion channel. Moreover, a novel biodegradable self-healing hydrogel was prepared from acylhydrazide functionalized carboxymethyl cellulose (CMC-AH) and oxidized pectin (pec-CHO) to reduce the side effects of the limonin to the body. The hydrogels showed fast gelation, good biocompatibility and sustained limonin release property. The limonin-loaded hydrogel significantly inhibited the growth of lung adenocarcinoma in xenografts mice because the limonin inhibited the proliferation, migration and promoted apoptosis of LA795 cells, and eliminated the acute toxicity through sustained release from the hydrogel. Combined the antitumor performance of the limonin and sustained release of pec-CHO/CMC-AH hydrogel, this limonin/hydrogel system achieved satisfactory antitumor effect and eliminated side effects in vivo. Therefore, this system has great potential application for enhanced lung adenocarcinoma therapy.
    Keywords:  Anti-tumor therapy; CMC; Limonin; Pectin; Self-healing hydrogel
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.08.037
  72. J Control Release. 2022 Aug 09. pii: S0168-3659(22)00512-0. [Epub ahead of print]
    Advancements in redox-sensitive micelles as nanotheranostics: A new horizon in cancer management.
    Anupama Sikder, Ganesh Vambhurkar, Etikala Amulya, Deepkumar Bagasariya, Paras Famta, Saurabh Shah, Dharmendra Kumar Khatri, Shashi Bala Singh, V R Sinha, Saurabh Srivastava.
      World Health Organisation (WHO) delineated cancer as one of the foremost reasons for mortality with 10 million deaths in the year 2020. Early diagnosis and effective drug delivery are of utmost importance in cancer management. The entrapment of both bio-imaging dyes and drugs will open novel avenues in the area of tumor theranostics. Elevated levels of reactive oxygen species (ROS) and glutathione (GSH) are the characteristic features of the tumor microenvironment (TME). Researchers have taken advantage of these specific TME features in recent years to develop micelle-based theranostic nanosystems. This review focuses on the advantages of redox-sensitive micelles (RSMs) and supramolecular self-assemblies for tumor theranostics. Key chemical linkers employed for the tumor-specific release of the cargo have been discussed. In vitro characterisation techniques used for the characterization of RSMs have been deliberated. Potential bottlenecks that may present themselves in the bench-to-bedside translation of this technology and the regulatory considerations have been deliberated.
    Keywords:  Characterisation; Micelles; Redox; Supramolecular assembly; Theranostics; Tumor
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.008
  73. Int J Mol Sci. 2022 Jul 28. pii: 8344. [Epub ahead of print]23(15):
    Effects of the Treatment with Flavonoids on Metabolic Syndrome Components in Humans: A Systematic Review Focusing on Mechanisms of Action.
    Henrique J C B Gouveia, Mercedes V Urquiza-Martínez, Raul Manhães-de-Castro, Bárbara J R Costa-de-Santana, José Pérez Villarreal, Rosalío Mercado-Camargo, Luz Torner, Jailane de Souza Aquino, Ana E Toscano, Omar Guzmán-Quevedo.
      Diets high in bioactive compounds, such as polyphenols, have been used to mitigate metabolic syndrome (MetS). Polyphenols are a large group of naturally occurring bioactive compounds, classified into two main classes: non-flavonoids and flavonoids. Flavonoids are distributed in foods, such as fruits, vegetables, tea, red wine, and cocoa. Studies have already demonstrated the benefits of flavonoids on the cardiovascular and nervous systems, as well as cancer cells. The present review summarizes the results of clinical studies that evaluated the effects of flavonoids on the components of the MetS and associated complications when offered as supplements over the long term. The results show that flavonoids can significantly modulate several metabolic parameters, such as lipid profile, blood pressure, and blood glucose. Only theaflavin and catechin were unable to affect metabolic parameters. Moreover, only body weight and body mass index were unaltered. Thus, the evidence presented in this systematic review offers bases in support of a flavonoid supplementation, held for at least 3 weeks, as a strategy to improve several metabolic parameters and, consequently, reduce the risk of diseases associated with MetS. This fact becomes stronger due to the rare side effects reported with flavonoids.
    Keywords:  biomarkers; blood pressure; dyslipidemias; inflammation; insulin resistance; lipid metabolism; metabolic syndrome; polyphenols
    DOI:  https://doi.org/10.3390/ijms23158344
  74. Perm J. 2022 Jun 29. 26(2): 89-97
    B Vitamins: Functions and Uses in Medicine.
    Mary Hanna, Ecler Jaqua, Van Nguyen, Jeremy Clay.
      B vitamins are a group of 8 water-soluble vitamins. The body does not store them, so they need to be replaced daily. B vitamins are found in animal proteins, dairy products, leafy green vegetables, and beans. Overall, their function can generally be divided into catabolic metabolism, leading to energy production, and anabolic metabolism, resulting in bioactive molecules. They are critical cofactors for axonal transport, synthesis of neurotransmitters, and many cellular metabolic pathways. B vitamins are cofactors for many essential enzymes involved in the biosynthesis of RNA and DNA. B vitamin deficiencies have been considered as etiological factors in the development of various neurologic disorders and a broad spectrum of pathological states. Reductions in food intake and absorption efficiency in some populations, including the geriatric population, may warrant attention to their dietary B vitamin levels. Most B vitamins are generally safe even at intake levels reached with fortified food or supplements.
    Keywords:  Vitamins; alcoholism; anemia; depression; neurologic disorder; nutrition
    DOI:  https://doi.org/10.7812/TPP/21.204
  75. J Ethnopharmacol. 2022 Aug 08. pii: S0378-8741(22)00648-1. [Epub ahead of print] 115609
    Metabolomics and integrated network pharmacology analysis reveal that ginkgolides act as potential active anticancer components by regulating one-carbon metabolism.
    Junyao Zhou, Mingmin Qian, Chenxi Li, Wenbin Zhou, Lan Yao, Yanhua Chen, Zeper Abliz.
       ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba L. is a rare tree species unique to China. Ginkgo biloba is a traditional Chinese medicinal with a long history, acting on the heart and lung meridians, and has been reported to have a significant effect on non-small cell lung cancer. However, the mechanism underlying this metabolic effect is poorly understood.
    AIM OF THE STUDY: To identify the active components of Ginkgo biloba extract that may have effects on non-small cell lung cancer and their mechanisms of metabolic regulation.
    MATERIALS AND METHODS: In this study, LC-MS/MS was used to investigate the chemical constituents of Ginkgo biloba extract. Network pharmacology was used to identify the active components potentially valuable in the treatment of non-small cell lung cancer. Antitumor activity was evaluated using CCK-8 and apoptosis assays. The mechanisms of metabolic regulation by the active components were further explored using untargeted metabolomics, targeted metabolomics, and western blot experiments.
    RESULTS: Network pharmacology and component analysis of Ginkgo biloba extract identified four ginkgolides that significantly affect non-small cell lung cancer. Their antiproliferative activity in A549 cells was evaluated using CCK-8 and apoptosis assays. The metabolomics results indicated that the ginkgolides had a significant regulatory effect on metabolic pathways related to one-carbon metabolisms, such as purine metabolism, glutathione metabolism, and the methionine cycle. Further targeted metabolomics analysis on one-carbon metabolism found that the ginkgolides may significantly affect the content of multiple metabolites in A549 cells, including purine, S-adenyl methionine, S-adenylyl homocysteine, and glutathione upregulated, and adenosine, tetrahydrofolate, and 10-Formyl-tetrahydrofolate significantly decreased. Notably, dihydrofolate reductase (DHFR) and methylenetetrahydrofolate dehydrogenases (MTHFR) were found to be altered after the treatment of ginkgolides.
    CONCLUSION: This in vitro study indicated that ginkgolides might inhibit the growth of A549 cells by targeting one-carbon metabolism. This study also demonstrated that metabolomics combined with network pharmacology is a powerful tool for identifying traditional Chinese medicines' active components and metabolic mechanisms.
    Keywords:  Cell proliferation; Ginkgolides; Metabolomics; Non-small cell lung cancer; One carbon metabolism
    DOI:  https://doi.org/10.1016/j.jep.2022.115609
  76. Curr Drug Deliv. 2022 Aug 10.
    Development and Challenges of Synthetic Retinoid Formulations in Cancer.
    Sara Assi, Hiba El Hajj, Berthe Hayar, Claudio Pisano, Walid Saad, Nadine Darwiche.
      Retinoids represent a class of chemical compounds derived from, or structurally and functionally related to vitamin A. Retinoids play crucial roles in regulating a range of crucial biological processes spanning embryonic development to adult life. These include regulation of cell proliferation, differentiation, and cell death. Due to their promising characteristics, retinoids emerged as potent anti-cancer agents, and their effects were validated in in vitro and in vivo pre-clinical models of several solid and hematological malignancies. However, their clinical translation remained limited due to their poor water solubility, photosensitivity, short half-life, and toxicity. To overcome these limitations, the development of retinoid delivery formulations was extensively studied. In this review, we will provide a comprehensive summary of some preclinical and commercial synthetic retinoids in cancer and discuss their different delivery systems.
    Keywords:  Synthetic retinoid; cancer.; delivery system; development; drug; formulation
    DOI:  https://doi.org/10.2174/1567201819666220810094708
  77. Int J Prev Med. 2022 ;13 87
    Effect of Medicinal Plants and Natural Products on Liver Enzymes in Non-alcoholic Fatty Liver Patients in Iran: A Systematic Review and Meta-Analysis.
    Moloud Fakhri, Hafez Fakheri, Mohammad Azadbakht, Mahmood Moosazadeh, Seyde Sedighe Yousefi.
       Background: Nonalcoholic fatty liver is the most common chronic liver disease. Regarding the side effects of synthetic medicines and the variety of natural products in Iran climate, the present study aimed to investigate the effect of medicinal plants and natural products on liver enzymes in patients with non-alcoholic fatty liver disease in Iran using meta-analysis.
    Methods: To extract the intended studies, internal and external databases, including SID, Magiran, IranDoc, PubMed, Scopus, Web of Science, Embase, Cochrane, and Clinical Trial Registration System of Clinical trial.gov, the ISRCTN system, as well as Clinical Trial Registration System affiliated to the World Health Organization were searched. The obtained data were analyzed in STATA.14 software. A P value less than 0.05 was considered statistically significant.
    Results: A total of 44 rstudies were reviewed with a sample size of 1298 participant; they were published in the period from 2009 to 2018, silymarin had the highest effect on the reduction of AST (SMD = -2.68), cinnamon excreted the most profound effect on ALT (SMD = -2.69). In addition, cinnamon had the highest effect on gamma-glutamyl transferase (GGT) (SMD:-3.17), and curcumin had the highest effect on alkaline phosphatase (ALP) (SMD = -1.88). In the lipid profile, the effect of medicinal herbs and natural products on lowering total cholesterol and LDL was statistically significant. In the glycemic profile, the effect of medicinal plants and natural products on the reduction of fasting blood sugar, insulin, and hemoglobin A1c levels was statistically significant.
    Conclusions: As evidenced by the obtained results, the highest effect of using natural products was observed in the reduction of GGT, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels, respectively; nonetheless, the effect of natural products on ALP reduction was not statistically significant.
    Keywords:  Biological products; Iran; herbal medicine; medicinal; non-alcoholic fatty liver disease; plants; therapeutics
    DOI:  https://doi.org/10.4103/ijpvm.IJPVM_313_20
  78. Int J Pharm. 2022 Aug 08. pii: S0378-5173(22)00618-4. [Epub ahead of print] 122064
    Folic acid-decorated PEGylated magnetite nanoparticles as efficient drug carriers to tumor cells overexpressing folic acid receptor.
    Codina Movileanu, Maria Anghelache, Mihaela Turtoi, Geanina Voicu, Ionela Andreea Neacsu, Denisa Ficai, Roxana Trusca, Ovidiu Oprea, Anton Ficai, Ecaterina Andronescu, Manuela Calin.
      The improved drug delivery systems (DDS) are needed for the targeted delivery of their therapeutic cargo (biologically active protein/peptide molecules, nucleic acids, vaccines, etc.) to diseased cells. Thus, we aimed to develop magnetite nanoparticles (Fe3O4), stabilized with polyethylene glycol (PEG) and decorated (surface-functionalized) with folic acid (FA) (Fe3O4@PEG@FA) to ensure targeted internalization in cells expressing the folic acid receptors (FR). The Fe3O4@PEG@FA nanoparticles were synthesized by co-precipitation in a one-pot methodology. Curcumin (Curc), a polyphenol with anti-tumoral activity, was loaded on the nanoparticles, and FA-targeted (Fe3O4@PEG@FA@Curc) and non-targeted (Fe3O4@PEG@Curc) systems were obtained. The internalization of Fe3O4@PEG@FA@Curc and Fe3O4@PEG@Curc nanoparticles was determined in two tumor cell lines, the FR-positive MCF-7 human breast carcinoma cell line and A549 human lung adenocarcinoma cell line, expressing a low level of FR. The results showed that MCF-7 cells internalize FA-functionalized nanoparticles to a greater extent than non-targeted ones and also than A549 cells. The competitive studies performed in the presence of FA in excess suggested that internalization is an FR-dependent process. The increased internalization of Fe3O4@PEG@FA@Curc nanoparticles in MCF-7 cells is correlated with increased cytotoxicity in this cell line compared to A549 cells. In conclusion, the FA-functionalized magnetic systems can ensure a better internalization of the nanoparticles and can be used to deliver various therapeutic agents, both in cancer treatment and also in the treatment of other inflammation-associated diseases such as rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, Crohn's disease or atherosclerosis.
    Keywords:  Cellular internalization; Folic acid decoration; Stabilized magnetite nanostructures; Targeted drug delivery; Tumor cells
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122064
  79. N Engl J Med. 2022 07 28. 387(4): 368-370
    VITAL Findings - A Decisive Verdict on Vitamin D Supplementation.
    Steven R Cummings, Clifford Rosen.
      
    DOI:  https://doi.org/10.1056/NEJMe2205993
  80. J Egypt Natl Canc Inst. 2022 Aug 08. 34(1): 33
    Drug repurposing: re-inventing therapies for cancer without re-entering the development pipeline-a review.
    Shafina Siddiqui, Ankita Jaywant Deshmukh, Priyanka Mudaliar, Apoorva Jagannath Nalawade, Deepak Iyer, Jyotirmoi Aich.
      While majority of the current treatment approaches for cancer remain expensive and are associated with several side effects, development of new treatment modalities takes a significant period of research, time, and expenditure. An alternative novel approach is drug repurposing that focuses on finding new applications for the previously clinically approved drugs. The process of drug repurposing has also been facilitated by current advances in the field of proteomics, genomics, and information computational biology. This approach not only provides cheaper, effective, and potentially safer drugs with less side effects but also increases the processing pace of drug development. In this review, we wish to highlight some recent developments in the area of drug repurposing in cancer with a specific focus on the repurposing potential of anti-psychotic, anti-inflammatory and anti-viral drugs, anti-diabetic, antibacterial, and anti-fungal drugs.
    Keywords:  Anti-bacterial; Anti-diabetic; Anti-inflammatory; Anti-psychotic; Anti-viral; Cancer; Drug repurposing; Drug resistance
    DOI:  https://doi.org/10.1186/s43046-022-00137-0
  81. Front Mol Biosci. 2022 ;9 965924
    The potential interplay between G-quadruplex and p53: their roles in regulation of ferroptosis in cancer.
    Lulu Zhang, Yi Lu, Xiaoli Ma, Yuanxin Xing, Jinbo Sun, Yanfei Jia.
      Ferroptosis is a novel form of regulated cell death trigged by various biological processes, and p53 is involved in different ferroptosis regulations and functions as a crucial regulator. Both DNA and RNA can fold into G-quadruplex in GC-rich regions and increasing shreds of evidence demonstrate that G-quadruplexes have been associated with some important cellular events. Investigation of G-quadruplexes is thus vital to revealing their biological functions. Specific G-quadruplexes are investigated to discover new effective anticancer drugs. Multiple modulations have been discovered between the secondary structure G-quadruplex and p53, probably further influencing the ferroptosis in cancer. G-quadruplex binds to ferric iron-related structures directly and may affect the p53 pathways as well as ferroptosis in cancer. In addition, G-quadruplex also interacts with p53 indirectly, including iron-sulfur cluster metabolism, telomere homeostasis, lipid peroxidation, and glycolysis. In this review, we summarized the latent interplay between G-quadruplex and p53 which focused mainly on ferroptosis in cancer to provide the potential understanding and encourage future studies.
    Keywords:  G-quadruplex; biological activities; cancer; ferroptosis; p53
    DOI:  https://doi.org/10.3389/fmolb.2022.965924
  82. Drug Deliv. 2022 Dec;29(1): 2561-2578
    Enzyme-triggered- and tumor-targeted delivery with tunable, methacrylated poly(ethylene glycols) and hyaluronic acid hybrid nanogels.
    Wioletta Liwinska, Ewelina Waleka-Bagiel, Zbigniew Stojek, Marcin Karbarz, Ewelina Zabost.
      Enzyme-responsive polymeric-based nanostructures are potential candidates for serving as key materials in targeted drug delivery carriers. However, the major risk in their prolonged application is fast disassembling of the short-lived polymeric-based structures. Another disadvantage is the limited accessibility of the enzyme to the moieties that are located inside the network. Here, we report on a modified environmentally responsive and enzymatically cleavable nanogel carrier that contains a hybrid network. A properly adjusted volume phase transition (VPT) temperature allowed independent shrinking of a) poly(ethylene glycol) methyl ether methacrylate (OEGMA) with di(ethylene glycol) and b) methyl ether methacrylate (MEO2MA) part of the network, and the exposition of hyaluronic acid methacrylate (MeHa) network based carboxylic groups for its targeted action with the cellular based receptors. This effect was substantial after raising temperature in typical hyperthermia-based treatment therapies. Additionally, novel tunable NGs gained an opportunity to store- and to efficient-enzyme-triggered release relatively low but highly therapeutic doses of doxorubicin (DOX) and mitoxantrone (MTX). The controlled enzymatic degradation of NGs could be enhanced by introducing more hyaluronidase enzyme (HAdase), that is usually overexpressed in cancer environments. MTT assay results revealed effective cytotoxic activity of the NGs against the human MCF-7 breast cancer cells, the A278 ovarian cancer cells and also cytocompatibility against the MCF-10A and HOF healthy cells. The obtained tunable, hybrid network NGs might be used as a useful platform for programmed delivery of other pharmaceuticals and diagnostics in therapeutic applications.
    Keywords:  Targeted drug delivery; controlled release; enzymatic degradation; hybrid network nanogel; methacrylated hyaluronic acid; poly(ethylene glycol)
    DOI:  https://doi.org/10.1080/10717544.2022.2105443
  83. Drug Deliv. 2022 Dec;29(1): 2621-2631
    Tumor-derived extracellular vesicles for the active targeting and effective treatment of colorectal tumors in vivo.
    Van Du Nguyen, Ho Yong Kim, You Hee Choi, Jong-Oh Park, Eunpyo Choi.
      Colorectal cancer remains one of the main causes of cancer-related deaths worldwide. Although numerous nanomedicine formulations have been developed to tackle the disease, their low selectivity still limits effective therapeutic outcomes. In this study, we isolated extracellular vesicles (EVs) from CT26 colorectal cancer cells and 4T1 murine mammary carcinoma cells, loaded them with the chemotherapeutic agent (doxorubicin, DOX). Then we evaluated the cellular uptake of the extracellular vesicles both in 2D monolayer and 3D tumor spheroid setups using confocal laser scanning microscope and flow cytometry. In vivo tumor homing of the extracellular vesicles was verified on CT26 tumor bearing BALB/c mice using in vivo imaging system. Finally, in vivo therapeutic effects were evaluated and compared using the same animal models treated with five doses of EV formulations. CT26-EV-DOX exhibited excellent biocompatibility, a high drug-loading capacity, controlled drug release behavior, and a high capability for targeting colorectal cancer cells. In particular, we verified that CT26-EV-DOX could preferentially be up taken by their parent cells and could effectively target and penetrate 3D tumor spheroids resembling colorectal tumors in vivo in comparison with their 4T1 derived EV partner. Additionally, treatment of colorectal tumor-bearing BALB/c mice with of CT26-EV-DOX significantly inhibited the growth of the tumors during the treatment course. The developed CT26-EV-DOX nanoparticles may present a novel and effective strategy for the treatment of colorectal cancer.
    Keywords:  Doxorubicin; chemotherapy; colorectal cancer; extracellular vesicle; nanoparticle drug delivery
    DOI:  https://doi.org/10.1080/10717544.2022.2105444
  84. Expert Opin Drug Deliv. 2022 Aug 09.
    Lipid-based solubilization technology via hot melt extrusion: promises and challenges.
    Ožbej Zupančič, Martin Spoerk, Amrit Paudel.
       INTRODUCTION: Self-emulsifying drug delivery systems (SEDDS) are a promising strategy to improve the oral bioavailability of poorly water-soluble drugs (PWSD). The excipients of SEDDS enable permeation through the mucus and gastro-intestinal barrier, inhibiting efflux transporters (e.g. P-glycoprotein) of drugs. Poor drug loading capacity and formulation instability are the main setbacks of traditional SEDDS. The use of polymeric precipitation inhibitors was shown to create supersaturable SEDDS with increased drug payload, and their solidification can help to overcome the instability challenge. As an alternative to several existing SEDDS solidification technologies, hot melt extrusion (HME) holds the potential for lean and continuous manufacturing of supersaturable solid-SEDDS. Despite being ubiquitously applied in solid lipid and polymeric processing, HME has not yet been widely considered for the preparation of SEDDS.
    AREAS COVERED: The review begins with the rationale why SEDDS as the preferred lipid-based delivery systems (LBDS) is suitable for the oral delivery of PWSD and discusses the common barriers to oral administration. The potential of LBDS to surmount them is discussed. SEDDS as the flagship of LBDS for PWSD is proposed with a special emphasis on solid-SEDDS. Finally, the opportunities and challenges of HME from the lipid-based excipient (LBE) processing and product performance standpoint are highlighted.
    EXPERT OPINION: HME can be a continuous, solvent-free, cost-effective, and scalable technology for manufacturing solid supersaturable SEDDS. Several critical formulations and process parameters in successfully preparing SEDDS via HME are identified.
    Keywords:  hot melt extrusion (HME); lipid-based drug delivery systems (LBDS); oral administration barriers; poor water-soluble drugs (PWSD); solid self-emulsifying drug delivery systems (S-SEDDS)
    DOI:  https://doi.org/10.1080/17425247.2022.2112173
  85. Biomater Adv. 2022 Aug 05. pii: S2772-9508(22)00354-5. [Epub ahead of print]140 213077
    Advances in aptamer-based drug delivery vehicles for cancer therapy.
    Kousar Ghasemii, Mahdieh Darroudi, Ilnaz Rahimmanesh, Matineh Ghomi, Mahnaz Hassanpour, Esmaeel Sharifi, Satar Yousefiasl, Sepideh Ahmadi, Ali Zarrabi, Assunta Borzacchiello, Mohammad Rabiee, Ana Cláudia Paiva-Santos, Navid Rabiee.
      Overall, aptamers are special classes of nucleic acid-based macromolecules that are beginning to investigate because of their capability of avidity binding to a specific target for clinical use. Taking advantage of target-specific medicine led to more effective therapeutic and limitation of side effects of drugs. Herein, we discuss several aptamers and their binding capability and capacity for selecting tumor biomarkers and usage of them as targeting ligands for the functionalization of nanomaterials. We review recent applications based on aptamers and several nanoparticles to rise efficacy and develop carrier systems such as graphene oxide, folic acid, gold, mesopores silica, and various polymers and copolymer, polyethylene glycol, cyclodextrin, chitosan. The nanocarriers have been characterized by particle size, zeta potential, aptamer conjugation, and drug encapsulation efficiency. Hydrodynamic diameter and Zeta potential can used in order to monitor aptamers' crosslinking, in-vitro drug release, intracellular delivery of nanocarriers, and cellular cytotoxicity assay. Also, they are studied for cellular uptake and internalization to types of cancer cell lines such as colorectal, breast, prostate, leukemia and etc. The results are investigated in in-vivo cytotoxicity assay and cell viability assay. Targeted cancer therapy seems a good and promising strategy to overcome the systemic toxicity of chemotherapy.
    Keywords:  Aptamer; Drug delivery; Surface modification
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213077
  86. Int J Pharm. 2022 Aug 06. pii: S0378-5173(22)00638-X. [Epub ahead of print] 122084
    A cell-mimicking platelet-based drug delivery system as a potential carrier of dimethyl fumarate for multiple sclerosis.
    Sanaz Mehdi-Alamdarlou, Fatemeh Ahmadi, Amir Azadi, Mohammad-Ali Shahbazi, Reza Heidari, Hajar Ashrafi.
      Dimethyl fumarate (DMF), is one of the lately approved therapeutic agents for the multiple sclerosis (MS) treatment. Despite the beneficial effects, DMF also suffers from low penetration into brain. In this study, we designed a precise drug delivery system of DMF to cross BBB for MS management. The novelty of this study is developing a cell based biomimetic vehicle for specific drug delivery to the inflamed area in peripheral and CNS. DMF-loaded platelet-based nanoparticle as a cell-based drug delivery system was developed and compared with chitosan nanogel and platelet membrane coated chitosan nanogel. Prepared nanoparticles were characterized for particle size, morphology, release characteristics, and drug loading parameters. In the optimum condition, all nanoparticles were prepared in desirable nano-size and showed appropriate loading parameters The neuropharmacokinetic evaluation was performed by determining the brain uptake of DMF, and brain uptake clearance for passage from BBB. Results from in vivo study demonstrated that the brain concentration of nanoparticles was higher than the free drug solution. The brain uptake clearance and AUC (0-∞) brain of DMF-loaded platelet nanoparticle were higher than platelet membrane coated chitosan nanogel and chitosan nanogel. The results demonstrated that platelet nanoparticles can be proposed as a potential biomimetic carrier for MS management.
    Keywords:  Chitosan nanogel; Dimethyl fumarate; Multiple sclerosis; Platelet membrane coated chitosan nanogel; Platelet nanoparticle; cell-mimicking
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122084
  87. J Food Biochem. 2022 Aug 09. e14358
    An update on molecular mechanisms of curcumin effect on diabetes.
    Wensong Lu, Fedora Khatibi Shahidi, Khatereh Khorsandi, Reza Hosseinzadeh, Asma Gul, Veronica Balick.
      Owing to its prevalent nature, diabetes mellitus has become one of the most serious endocrine illnesses affecting a patient's quality of life due to the manifestation of side effects such as cardiovascular diseases, retinopathy, neuropathy, and nephropathy. Curcumin ((1E, 6E) 21, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), a major compound of turmeric, has been used in conventional medicine because of its safe nature and cost-effectiveness to meliorate diabetes and its comorbidities. These effects have also been observed in rodent models of diabetes resulting in a reduction of glycemia and blood lipids. Both the preventive and therapeutic activities of this compound are due to its antioxidant and anti-inflammatory characteristics. Furthermore, preclinical outcomes and clinical investigation demonstrate that the use of curcumin neutralizes insulin resistance, obesity, and hyperglycemia. Despite the many benefits of curcumin, its two limiting factors, solubility and bioavailability, remain a challenge for researchers; therefore, several methods such as drug formulation, nano-drug delivery, and the use of curcumin analogs have been developed to deliver curcumin and increase its bioavailability. PRACTICAL APPLICATIONS: The rise of people with type 2 diabetes has become a major concern at the global healthcare level. The best diabetes treatments today are anti-diabetic drug administration, lifestyle-related interventions (such as healthy eating and daily physical activity), arterial pressure detection, and fat control. The polyphenol curcumin, found in turmeric, can promote health by acting on a variety of cellular signaling pathways. This review article discusses curcumin and its role in the treatment of diabetes.
    Keywords:  antioxidant activity; curcumin; diabetes; molecular mechanisms; oxidative stress
    DOI:  https://doi.org/10.1111/jfbc.14358
  88. J Hematol Oncol. 2022 Aug 10. 15(1): 104
    Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.
    Yuheng Yan, Lan Huang, Yiming Liu, Ming Yi, Qian Chu, Dechao Jiao, Kongming Wu.
      Characterized by the expression of the critical transcription factor forkhead box protein P3, regulatory T (Treg) cells are an essential part of the immune system, with a dual effect on the pathogenesis of autoimmune diseases and cancer. Targeting Tregs to reestablish the proinflammatory and immunogenic tumor microenvironment (TME) is an increasingly attractive strategy for cancer treatment and has been emphasized in recent years. However, attempts have been significantly hindered by the subsequent autoimmunity after Treg ablation owing to systemic loss of their suppressive capacity. Cellular metabolic reprogramming is acknowledged as a hallmark of cancer, and emerging evidence suggests that elucidating the underlying mechanisms of how intratumoral Tregs acquire metabolic fitness and superior immunosuppression in the TME may contribute to clinical benefits. In this review, we discuss the common and distinct metabolic profiles of Tregs in peripheral tissues and the TME, as well as the differences between Tregs and other conventional T cells in their metabolic preferences. By focusing on the critical roles of different metabolic programs, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, as well as their essential regulators in modulating Treg proliferation, migration, and function, we hope to provide new insights into Treg cell-targeted antitumor immunotherapies.
    Keywords:  Amino acid metabolism; Fatty acid oxidation; Fatty acid synthesis; Glycolysis; Immunotherapy; Oxidative phosphorylation; Regulatory T cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-022-01322-3
  89. Cancers (Basel). 2022 Jul 27. pii: 3649. [Epub ahead of print]14(15):
    Vitamin D, Th17 Lymphocytes, and Breast Cancer.
    Beata Filip-Psurska, Honorata Zachary, Aleksandra Strzykalska, Joanna Wietrzyk.
      Vitamin D3, which is well known to maintain calcium homeostasis, plays an important role in various cellular processes. It regulates the proliferation and differentiation of several normal cells, including immune and neoplastic cells, influences the cell cycle, and stimulates cell maturation and apoptosis through a mechanism dependent on the vitamin D receptor. The involvement of vitamin D3 in breast cancer development has been observed in numerous clinical studies. However, not all studies support the protective effect of vitamin D3 against the development of this condition. Furthermore, animal studies have revealed that calcitriol or its analogs may stimulate tumor growth or metastasis in some breast cancer models. It has been postulated that the effect of vitamin D3 on T helper (Th) 17 lymphocytes is one of the mechanisms promoting metastasis in these murine models. Herein we present a literature review on the existing data according to the interplay between vitamin D, Th17 cell and breast cancer. We also discuss the effects of this vitamin on Th17 lymphocytes in various disease entities known to date, due to the scarcity of scientific data on Th17 lymphocytes and breast cancer. The presented data indicate that the effect of vitamin D3 on breast cancer development depends on many factors, such as age, menopausal status, or obesity. According to that, more extensive clinical trials and studies are needed to assess the importance of vitamin D in breast cancer, especially when no correlations seem to be obvious.
    Keywords:  Th17 lymphocytes; breast cancer; calcitriol; dendritic cells; vitamin D
    DOI:  https://doi.org/10.3390/cancers14153649
  90. Eur J Med Chem. 2022 Aug 01. pii: S0223-5234(22)00546-3. [Epub ahead of print]241 114644
    A phthalocyanine-based photosensitizer for effectively combating triple negative breast cancer with enhanced photodynamic anticancer activity and immune response.
    Kunshan Huang, Meiqi Yan, Han Zhang, Jinping Xue, Juanjuan Chen.
      Although photodynamic therapy (PDT) has attracted great interest, the photosensitizers in clinical had weak inhibition on metastasis and invasion of cancers. Additionally the immune response induced by PDT was insufficient to eradicate cancer. Herein, indoximod, an inhibitor of indoleamine 2,3-dioxygenase (IDO), is introduced to concatenate with zinc phthalocyanines (ZnPc) for effectively overcoming above inadequacy. Due to indoximod moiety, photosensitizer 1-MT-Pc can obtain enhanced intracellular uptake and high reactive oxygen species (ROS) generation. More impressively, 1-MT-Pc can achieve remarkable photocytotoxicity towards TNBC cells and negligible damage to normal cells. Meanwhile, 1-MT-Pc effectively inhibits metastasis and invasion of TNBC cells. Importantly, 1-MT-Pc exhibit elevated inhibitory effect on 4T1 tumor by enhanced PDT and immunotherapy.
    Keywords:  IDO; Immunotherapy; Indoximod; Photodynamic therapy; Photosensitizer; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114644
  91. Nutrients. 2022 Jul 29. pii: 3136. [Epub ahead of print]14(15):
    The Circadian Regulation of Nutrient Metabolism in Diet-Induced Obesity and Metabolic Disease.
    Lauren N Woodie, Kaan T Oral, Brianna M Krusen, Mitchell A Lazar.
      Obesity and other metabolic diseases are major public health issues that are particularly prevalent in industrialized societies where circadian rhythmicity is disturbed by shift work, jet lag, and/or social obligations. In mammals, daylight entrains the hypothalamic suprachiasmatic nucleus (SCN) to a ≈24 h cycle by initiating a transcription/translation feedback loop (TTFL) of molecular clock genes. The downstream impacts of the TTFL on clock-controlled genes allow the SCN to set the rhythm for the majority of physiological, metabolic, and behavioral processes. The TTFL, however, is ubiquitous and oscillates in tissues throughout the body. Tissues outside of the SCN are entrained to other signals, such as fed/fasting state, rather than light input. This system requires a considerable amount of biological flexibility as it functions to maintain homeostasis across varying conditions contained within a 24 h day. In the face of either circadian disruption (e.g., jet lag and shift work) or an obesity-induced decrease in metabolic flexibility, this finely tuned mechanism breaks down. Indeed, both human and rodent studies have found that obesity and metabolic disease develop when endogenous circadian pacing is at odds with the external cues. In the following review, we will delve into what is known on the circadian rhythmicity of nutrient metabolism and discuss obesity as a circadian disease.
    Keywords:  circadian rhythms; metabolism; molecular clock; obesity
    DOI:  https://doi.org/10.3390/nu14153136
  92. Front Pharmacol. 2022 ;13 969827
    The use of traditional Chinese medicines in relieving exercise-induced fatigue.
    Yuzhou Liu, Congying Li, Xiaofei Shen, Yue Liu.
      Exercise-induced fatigue is a non-pathological fatigue and indicated by a reduction of muscle performance that is caused by excessive physical activity. It seriously affects the daily lives of people, in particular athletes, military personnel, and manual laborers. In recent years, increasing attention has been paid to improving the adverse effect of exercise-induced fatigue on people's daily activities. Thus, studies and applications of traditional Chinese medicines (TCMs) in relieving exercise-induced fatigue have become the focus because of their good curative effects with fewer side effects. This review aims to document and summarize the critical and comprehensive information about the biological processes of exercise-induced fatigue, and to know the types of TCMs, their active components, and possible molecular mechanisms in alleviating exercise-induced fatigue. The peripheral and central mechanisms that cause exercise-induced fatigue have been summarized. A total of 47 exercise-induced fatigue relief TCMs have been collected, mostly including the types of visceral function regulation and emotional adjustment TCMs. Polysaccharides, terpenes, flavonoids/polyphenols are demonstrated to be the major bioactive components. The underlying molecular mechanisms are mainly related to the improvement of energy metabolism, elimination of excess metabolites, inhibition of oxidative stress and inflammatory response, regulation of HPA axis and neurotransmitters. Although current results are obtained mostly from animal models, the clinic trials are still insufficient, and a very few TCMs have been reported to possess potential hepatotoxicity. These findings still offer great reference value, and the significant efficacy in relieving exercise-induced fatigue is impossible to ignore. This review is expected to give insights into the research and development of new TCMs-derived drugs and health care products in relieving exercise-induced fatigue.
    Keywords:  exercise-induced fatigue; medicinal and edible values; molecular mechanism; relieving; traditional Chinese medicines
    DOI:  https://doi.org/10.3389/fphar.2022.969827
  93. Front Chem. 2022 ;10 967312
    The application of photodynamic therapy in plastic and reconstructive surgery.
    Min Wu, Xiaoyu Huang, Lu Gao, Guoyu Zhou, Feng Xie.
      Photodynamic therapy (PDT) is a modern clinical treatment paradigm with the advantages of high selectivity, non-invasiveness, rare side-effect, no obvious drug resistance and easy combination with other therapies. These features have endowed PDT with high focus and application prospects. Studies of photodynamic therapy have been expanded in a lot of biomedical and clinical fields, especially Plastic and Reconstructive Surgery (PRS) the author major in. In this review, we emphasize the mechanism and advances in PDT related to the PRS applications including benign pigmented lesions, vascular malformations, inflammatory lesions, tumor and others. Besides, combined with clinical data analysis, the limitation of PDT and current issues that need to be addressed in the field of PRS have also been discussed. At last, a comprehensive discussion and outlooking represent future progress of PDT in PRS.
    Keywords:  clinical application; photodynamic therapy; photosensitizer; plastic and reconstructive surgery; tumor
    DOI:  https://doi.org/10.3389/fchem.2022.967312
  94. Foods. 2022 Aug 05. pii: 2337. [Epub ahead of print]11(15):
    Encapsulation of Essential Oils in Nanocarriers for Active Food Packaging.
    Shubham Sharma, Lilly Mulrey, Megan Byrne, Amit K Jaiswal, Swarna Jaiswal.
      Active packaging improves a packaging system's effectiveness by actively integrating additional components into the packaging material or the headspace around the packaging. Consumer demand and awareness have grown enough to replace chemical agents with natural active agents. Essential oils (EOs) are extensively distributed throughout nature but at low levels and sometimes with poor recovery yields, which poses an issue with their application in food. Due to the instability of EOs when added directly into a food product, they require encapsulation before being added to a packaging matrix such as liposomes, solid-lipid nanoparticles, nano-emulsions, cyclodextrins, and nanostructured lipid nano-carriers. This article is focused on the encapsulation of EOs in different types of nanocarriers. Nanocarriers can improve the efficiency of active substances by providing protection, stability, and controlled and targeted release. The advantages of the many types of nanocarriers that contain active substances that can be used to make antibacterial and antioxidant biopolymeric-based active packaging are discussed. A nanocarrier-encapsulated EO enables the controlled release of oil, stabilizing the packaging for a longer duration.
    Keywords:  active packaging; antimicrobial; antioxidant; essential oil; nanocarriers
    DOI:  https://doi.org/10.3390/foods11152337
  95. J Cachexia Sarcopenia Muscle. 2022 Aug 12.
    The beneficial therapeutic effects of plant-derived natural products for the treatment of sarcopenia.
    Mohammad Bagherniya, Atena Mahdavi, Nafiseh Shokri-Mashhadi, Maciej Banach, Stephan Von Haehling, Thomas P Johnston, Amirhossein Sahebkar.
      Sarcopenia is an age-related muscle disorder typically associated with a poor quality of life. Its definition has evolved over time, and several underlying causes of sarcopenia in the elderly have been proposed. However, the exact mechanisms involved in sarcopenia, as well as effective treatments for this condition, are not fully understood. The purpose of this article was to conduct a comprehensive review of previous evidence regarding the definition, diagnosis, risk factors, and efficacy of plant-derived natural products for sarcopenia. The methodological approach for the current narrative review was performed using PubMed, Scopus, and Web of Science databases, as well as Google Scholar (up to March 2021) in order to satisfy our objectives. The substantial beneficial effects along with the safety of some plant-derived natural products including curcumin, resveratrol, catechin, soy protein, and ginseng on sarcopenia are reported in this review. Based on clinical studies, nutraceuticals and functional foods may have beneficial effects on physical performance, including handgrip and knee-extension strength, weight-lifting capacity, time or distance travelled before feeling fatigued, mitochondrial function, muscle fatigue, mean muscle fibre area, and total number of myonuclei. In preclinical studies, supplementation with herbs and natural bioactive compounds resulted in beneficial effects including increased plantaris mass, skeletal muscle mass and strength production, increased expression of anabolic factors myogenin, Myf5 and MyoD, enhanced mitochondrial capacity, and inhibition of muscle atrophy and sarcopenia. We found that several risk factors such as nutritional status, physical inactivity, inflammation, oxidative stress, endocrine system dysfunction, insulin resistance, history of chronic disease, mental health, and genetic factors are linked or associated with sarcopenia. The substantial beneficial effects of some nutraceuticals and functional foods on sarcopenia, including curcumin, resveratrol, catechin, soy protein, and ginseng, without any significant side effects, are reported in this review. Plant-derived natural products might have a beneficial effect on various components of sarcopenia. Nevertheless, due to limited human trials, the clinical benefits of plant-derived natural products remain inconclusive. It is suggested that comprehensive longitudinal clinical studies to better understand risk factors over time, as well as identifying a treatment strategy for sarcopenia that is based on its pathophysiology, be undertaken in future investigations.
    Keywords:  Inflammation; Medicinal plants; Muscle disorder; Nutraceuticals; Sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.13057
  96. Front Oncol. 2022 ;12 940001
    Tumor-targeting cell-penetrating peptide, p28, for glioblastoma imaging and therapy.
    Sunam Mander, Samer A Naffouje, Jin Gao, Weiguo Li, Konstantin Christov, Albert Green, Ernesto R Bongarzone, Tapas K Das Gupta, Tohru Yamada.
      Despite recent advances in cancer research, glioblastoma multiforme (GBM) remains a highly aggressive brain tumor as its treatment options are limited. The current standard treatment includes surgery followed by radiotherapy and adjuvant chemotherapy. However, surgery without image guidance is often challenging to achieve maximal safe resection as it is difficult to precisely discern the lesion to be removed from surrounding brain tissue. In addition, the efficacy of adjuvant chemotherapy is limited by poor penetration of therapeutics through the blood-brain barrier (BBB) into brain tissues, and the lack of tumor targeting. In this regard, we utilized a tumor-targeting cell-penetration peptide, p28, as a therapeutic agent to improve the efficacy of a current chemotherapeutic agent for GBM, and as a carrier for a fluorescence imaging agent for a clear identification of GBM. Here, we show that a near-infrared (NIR) imaging agent, ICG-p28 (a chemical conjugate of an FDA-approved NIR dye, indocyanine green ICG, and tumor-targeting p28 peptide) can preferentially localize tumors in multiple GBM animal models. Moreover, xenograft studies show that p28, as a therapeutic agent, can enhance the cytotoxic activity of temozolomide (TMZ), one of the few effective drugs for brain tumors. Collectively, our findings highlight the important role of the tumor-targeting peptide, which has great potential for intraoperative image-guided surgery and the development of new therapeutic strategies for GBM.
    Keywords:  NIR fluorescence image; cell-penetrating peptide; glioblastoma; image-guided surgery; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2022.940001
  97. J Food Biochem. 2022 Aug 09. e14368
    Ethanolic extract of Coleus aromaticus leaves impedes the proliferation and instigates apoptotic cell death in liver cancer HepG2 cells through repressing JAK/STAT cascade.
    Rafia Shekh, Rohit Kumar Tiwari, Afza Ahmad, Irfan Ahmad, Nadiyah M Alabdallah, Mohd Saeed, Irfan Ahmad Ansari, Anuradha Mishra, Mohammad Ashfaque, Preeti Bajpai.
      Liver cancer or hepatocellular carcinoma (HCC) has become a leading cause for cancer burden across the globe, and incidences have tripled since the last two decades. Poor diagnosis of primary liver cancer and limited treatment strategies aggravate the challenges. Researchers globally have shown a steep inclination toward the exploration of plant-based compounds for their nutraceutical and anticancer potential to fit into the role of novel chemotherapeutics. Coleus aromaticus is a well-known culinary herb that earlier has been reported for several medicinal attributes. The current investigation deals with exploring the anticancer potential of ethanolic leaf extract of C. aromaticus (CoL-EtOH) against hepatocellular carcinoma HepG2 cell line. The observations made it evident that CoL-EtOH extract impeded the viability of HepG2 at 400 μg/ml (p < .01). Additionally, the extract also succeeded in escalating ROS production (p < .01) which aided dissipation of mitochondrial membrane potential and disruption of nuclear morphology. CoL-EtOH further activated caspase-8, -9, and -3 which was reaffirmed by increase in apoptosis at 400 μg/ml (p < .01). Moreover, post treatment with CaLEt-OH extract significantly reduced the expression of JAK-1 & STAT-3 genes (p < .01) along with regulated expression of Mcl1, Bcl-2, cyclinD1, p21, and p27 within HepG2 cells. This evidence portrays the promising anticancer potential of CoL-EtOH projecting it as a novel chemotherapeutic agent against HCC. PRACTICAL APPLICATIONS: The herb Coleus aromaticus belonging to Lamiaceae family and Coleus genus is known by various names in different regions of the world and several language-specific vernacular names. The herb has been used in therapeutic and medicinal applications as well as in culinary preparations. Various attributes of the nutritional strength and functional characteristics of the leaves in terms of carotenoids, minerals, phenols, dietary fiber, and antioxidant activity have been reported by several researchers. Carvacrol and thymol are majorly found in the plant, while chlorogenic acid and rosmarinic acid etc. as the phenolic components. The herb has been used in therapeutic and medicinal implications as well as in culinary preparations.
    Keywords:   Coleus aromaticus ; HepG2 cells; anticancer; apoptosis; liver cancer
    DOI:  https://doi.org/10.1111/jfbc.14368
  98. Colloids Surf B Biointerfaces. 2022 Aug 05. pii: S0927-7765(22)00441-6. [Epub ahead of print]218 112758
    Cyclodextrins as an encapsulation molecular strategy for volatile organic compounds- Pharmaceutical applications.
    Ana Cláudia Paiva-Santos, Laura Ferreira, Diana Peixoto, Fernando Silva, Maria João Soares, Mahdi Zeinali, Hajra Zafar, Filipa Mascarenhas-Melo, Faisal Raza, Priscila Gava Mazzola, Francisco Veiga.
      The use of essential oils has gained importance due to their wide range of biological properties. Essential oils comprise a complex mixture of volatile organic compounds (VOCs), so the study of VOCs as active pharmaceutical ingredients is often more precise and fruitful. VOCs are natural origin molecules that constitute a sustainable alternative to synthetic drugs due to their important therapeutic value. However, VOCs possess poor solubility in aqueous solutions, high volatility, and, consequently, low stability and bioavailability, limiting VOC handling in industry and their potential use in therapeutics, despite their promising biological properties. Thereby, cyclodextrins (CDs) have emerged as suitable carriers of VOCs, giving rise to so-called VOC/CD inclusion complexes. CDs constitute an inexpensive viable solution for encapsulating VOCs to improve their properties, namely their apparent solubility and stability toward pH, light, and temperature. This review provides a conceptual framework of several VOC/CD inclusion complexes developed. In addition, the most exploited preparation techniques and their influence on the values of encapsulation efficiency and formation constant (Kf) are highlighted. The most recent in vitro or in vivo biological experiments regarding VOC/CD inclusion complexes in the development of pharmaceutical products are also presented. Finally, the toxicological, and regulatory aspects are discussed.
    Keywords:  Cyclodextrin; Encapsulation efficiency; Essential oil; Formation constant; Inclusion complex; Volatile organic compound
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112758
  99. Nutrients. 2022 Aug 08. pii: 3245. [Epub ahead of print]14(15):
    Epigenome Modulation Induced by Ketogenic Diets.
    Paola Ungaro, Immacolata Cristina Nettore, Fabiana Franchini, Giuseppe Palatucci, Giovanna Muscogiuri, Annamaria Colao, Paolo Emidio Macchia.
      Ketogenic diets (KD) are dietary strategies low in carbohydrates, normal in protein, and high, normal, or reduced in fat with or without (Very Low-Calories Ketogenic Diet, VLCKD) a reduced caloric intake. KDs have been shown to be useful in the treatment of obesity, metabolic diseases and related disorders, neurological diseases, and various pathological conditions such as cancer, nonalcoholic liver disease, and chronic pain. Several studies have investigated the intracellular metabolic pathways that contribute to the beneficial effects of these diets. Although epigenetic changes are among the most important determinants of an organism's ability to adapt to environmental changes, data on the epigenetic changes associated with these dietary pathways are still limited. This review provides an overview of the major epigenetic changes associated with KDs.
    Keywords:  DNA methylation; Very Low-Calories Ketogenic Diet; histone modifications; ketogenic diet; miRNAs
    DOI:  https://doi.org/10.3390/nu14153245
  100. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 12. e1838
    Nanotechnology meets glioblastoma multiforme: Emerging therapeutic strategies.
    Dongdong Liu, Xingliang Dai, Lei Ye, Hua Wang, Haisheng Qian, Hongwei Cheng, Xianwen Wang.
      Glioblastoma multiforme (GBM) represents the most common and fatal form of primary invasive brain tumors as it affects a great number of patients each year and has a median overall survival of approximately 14.6 months after diagnosis. Despite intensive treatment, almost all patients with GBM experience recurrence, and their 5-year survival rate is approximately 5%. At present, the main clinical treatment strategy includes surgical resection, radiotherapy, and chemotherapy. However, tumor heterogeneity, blood-brain barrier, glioma stem cells, and DNA damage repair mechanisms hinder efficient GBM treatment. The emergence of nanometer-scale diagnostic and therapeutic approaches in cancer medicine due to the establishment of nanotechnology provides novel and promising tools that will allow us to overcome these difficulties. This review summarizes the application and recent progress in nanotechnology-based monotherapies (e.g., chemotherapy) and combination cancer treatment strategies (chemotherapy-based combined cancer therapy) for GBM and describes the synergistic enhancement between these combination therapies as well as the current standard therapy for brain cancer and its deficiencies. These combination therapies that can reduce individual drug-related toxicities and significantly enhance therapeutic efficiency have recently undergone rapid development. The mechanisms underlying these different nanotechnology-based therapies as well as the application of nanotechnology in GBM (e.g., in photodynamic therapy and chemodynamic therapy) have been systematically summarized here in an attempt to review recent developments and to identify promising directions for future research. This review provides novel and clinically significant insights and directions for the treatment of GBM, which is of great clinical importance. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.
    Keywords:  blood; brain barrier; combination therapy; glioblastoma multiforme; nanocarrier; nanotechnology
    DOI:  https://doi.org/10.1002/wnan.1838
  101. Phytomedicine. 2022 Jul 29. pii: S0944-7113(22)00438-X. [Epub ahead of print]105 154359
    Xanthorrhizol, a potential anticancer agent, from Curcuma xanthorrhiza Roxb.
    Adelina Simamora, Kris Herawan Timotius, Mukerrem Betul Yerer, Heri Setiawan, Abdul Mun'im.
       BACKGROUND: Xanthorrhizol (XTZ), a bisabolene sesquiterpenoid, is abundantly found in the plant Curcuma xanthorrhiza Roxb. Traditionally, C. xanthorrhiza is widely used for the treatment of different health conditions, including common fever, infection, lack of appetite, fatigue, liver complaints, and gastrointestinal disorders. XTZ exhibits wide-ranging pharmacological activities, including anticancer, antioxidative, anti-inflammatory, antimicrobial, and antidiabetic activities, in addition to a protective effect on multiple organs. The present review provides detailed findings on the anticancer activities of XTZ and the underlying cellular and molecular mechanisms.
    METHODS: Literature was searched systematically in main databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with keywords "tumor AND xanthorrhizol" or "cancer AND xanthorrhizol".
    RESULTS: Studies show that XTZ has preventive and therapeutic activities against different types of cancer, including breast, cervical, colon, liver, lung, oral and esophageal, and skin cancers. XTZ regulates multiple signaling pathways that block carcinogenesis and proliferation. In vitro and in vivo studies showed that XTZ targets different kinases, inflammatory cytokines, apoptosis proteins, and transcription factors, leading to the suppression of angiogenesis, metastasis, and the activation of apoptosis and cell cycle arrest.
    CONCLUSION: The potential anticancer benefits of XTZ recommend further in vivo studies against different types of cancer. Further, XTZ needs to be confirmed for its toxicity, bioavailability, protective, antifatigue, and energy booster activities. Future studies for the therapeutic development of XTZ may be directed to cancer-related fatigue.
    Keywords:  Anticancer; Antioxidant; Bisabolene; Inflammation; Xanthorrhizol
    DOI:  https://doi.org/10.1016/j.phymed.2022.154359
  102. World J Gastrointest Oncol. 2022 Jun 15. 14(6): 1115-1123
    Can dietary flavonoids be useful in the personalized treatment of colorectal cancer?
    Cristina Pereira-Wilson.
      Activating mutations in the oncogenes KRAS, BRAF and PI3K define molecular colorectal cancer (CRC) subtypes because they play key roles in promoting CRC development and in determining the efficacy of chemotherapeutic agents such as 5-fluorouracil and anti-epidermal growth factor receptor monoclonal antibodies. Survival of patients with cancers displaying these molecular profiles is low. Given the limited efficacy of therapeutic strategies for CRC presenting mutational activations in mitogen-activated protein kinase and/or PI3K pathways, developing combination therapies with natural flavonoids or other phytochemicals with demonstrated effects on these pathways (and little or no toxic effects) may constitute a valuable path forward. Much has been published on the anticancer effects of dietary phytochemicals. However, even an exhaustive characterization of potential beneficial effects produced by in vitro studies cannot be extrapolated to effects in humans. So far, the available data constitute a good starting point. Published results show quercetin and curcumin as possibly the best candidates to be further explored in the context of adjuvant CRC therapy either as part of dietary prescriptions or as purified compounds in combination regimens with the drugs currently used in CRC treatment. Clinical trial data is still largely missing and is urgently needed to verify relevant effects and for the development of more personalized treatment approaches.
    Keywords:  BRAF; Colorectal cancer; Curcumin; KRAS; Personalized treatment; Quercetin
    DOI:  https://doi.org/10.4251/wjgo.v14.i6.1115
  103. Biochem Pharmacol. 2022 Aug 06. pii: S0006-2952(22)00292-1. [Epub ahead of print]203 115198
    AMPKα2/HNF4A/BORIS/GLUT4 pathway promotes hepatocellular carcinoma cell invasion and metastasis in low glucose microenviroment.
    Yuan Huang, Longjun Xian, Zhongjian Liu, Ling Wei, Lu Qin, Yimei Xiong, Lei Hu, Siqi Zhou, Qiang Fu, Bo Li, Yang Qin.
      Increasing evidence has revealed that the invasion and metastasis of HCC are intimately related to the low-glucose microenvironment, but the intrinsic regulatory mechanism remains unclear. It has been well documented that AMPK regulates the transcriptional expression of GLUT4 and its catalytic subunit AMPKα2 can negatively regulate the downstream target molecule HNF4A. Meanwhile, BORIS (Brother of the Regulator of Imprinted Sites) is able to modulate the Warburg effect by regulating the splicing of pyruvate kinase M2 (PKM2), a critical enzyme in glycolysis. Through bioinformatic analysis and a series of overexpression, knockdown, and complementation experiments, we demonstrated that HNF4A can directly act on BORIS and negatively regulate its expression, thereby inhibiting hepatoma cell motility and tumor metastasis, whereas BORIS can directly act on GLUT4 and positively regulate its expression to enhance hepatoma cell motility and tumor metastasis. We also found that HNF4A agonist (Benfluorex) and GLUT4 inhibitor (antiviral drug Ritonavir) can suppress HCC cell proliferation and glucose uptake. Taken together, these results all suggest that activation of the AMPKα2/HNF4A/BORIS/GLUT4 signaling pathway in a low-glucose microenvironment can significantly promote the invasion and metastasis of HCC cells, while HNF4A and GLUT4 may have important potential applications as prognostic or drug target molecules.
    Keywords:  BORIS; Benfluorex and Ritonavir; GLUT4; HCC; Invasion; Low glucose microenviroment
    DOI:  https://doi.org/10.1016/j.bcp.2022.115198
  104. Molecules. 2022 Aug 08. pii: 5042. [Epub ahead of print]27(15):
    Targeting Glutaminase by Natural Compounds: Structure-Based Virtual Screening and Molecular Dynamics Simulation Approach to Suppress Cancer Progression.
    Shams Tabrez, Torki A Zughaibi, Mehboob Hoque, Mohd Suhail, Mohammad Imran Khan, Azhar U Khan.
      Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.
    Keywords:  cancer; glutaminase; glutamine; natural compounds
    DOI:  https://doi.org/10.3390/molecules27155042
  105. Int J Pharm. 2022 Aug 03. pii: S0378-5173(22)00634-2. [Epub ahead of print] 122080
    Vilazodone-phospholipid mixed micelles for enhancing oral bioavailability and reducing pharmacokinetic variability between fed and fasted states.
    Hala S El Said, Aikaterini Lalatsa, Abdulaziz M Al-Mahallawi, Eman Saddar El Leithy, Dalia M Ghorab.
      Despite the effectiveness and high tolerability of vilazodone (VLZ) as an antidepressant, its use is still limited due to its poor solubility and food dependent absorption. This study aims to load VLZ-phospholipid complex into self-assembled micelles forming VLZ-PL mixed micelles (VLZ-PL-MM), that can enhance VLZ solubility, improve its bioavailability and reduce the pharmacokinetic variability between the fed and fasting conditions. The effect of the surfactant type and concentration was assessed using four different non-ionic surfactants (Brij 58, Tween 80, Labrasol and Pluronic F127) in four different weight ratios between the drug-complex and surfactant (1:0.5, 1:1, 1:2 and 1:3 w/w). Two VLZ-PL-MM formulae prepared using Brij 58 and Labrasol in 1:3 w/w ratio were selected as optimised ones since they have the highest encapsulation efficiency (100.83 and 93.87%, respectively), a particle size below 250 nm (206.73 and 221.33 nm, respectively) and negative zeta potential values (-29.63, -17.20 mV, respectively). Lyophilisation of these formulations using 3% sucrose was successful with no statistical changes in particle size and zeta potential upon rehydration. Both formulations elicited faster and higher in-vitro drug release profiles compared to the pure drug and the marketed tablet. In addition, both selected formulae improved ex-vivo permeation across rabbit intestinal membrane compared to the pure drug and the marketed tablet, with marked superiority of the one prepared using Brij 58. The results of the in vivo study in male albino rabbits revealed similar AUC0-24 values after the oral administration of the best achieved VLZ-PL-MM system under fed and fasting conditions (769.89 and 741.55 ng.h mL-1, respectively). On the other hand, the marketed product showed significantly lower values of the AUC0-24 relative to the VLZ-PL-MM system and there was a marked enhancement of absorption of drug from the marketed product in presence of food (244.24 and 174.96 ng.h mL-1 under fed and fasting conditions, respectively. In addition, VLZ concentrations in the brain after 24 hours obtained from the selected VLZ-PL-MM were significantly higher than those obtained from marketed tablet under fed and fasting conditions. Thus, the phospholipid mixed micelle formulation enhances the oral bioavailability of the poorly soluble drug and reduces the pharmacokinetic variability between fasting and fed conditions.
    Keywords:  Drug-phospholipid complex; Oral bioavailability; Self-assembled micelles; Solubility; Vilazodone
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122080
  106. ACS Omega. 2022 Aug 02. 7(30): 25974-25990
    Natural Antioxidant Compounds as Potential Pharmaceutical Tools against Neurodegenerative Diseases.
    Attilio Marino, Matteo Battaglini, Nadia Moles, Gianni Ciofani.
      Natural antioxidants are a very large diversified family of molecules classified by activity (enzymatic or nonenzymatic), chemical-physical properties (e.g., hydrophilic or lipophilic), and chemical structure (e.g., vitamins, polyphenols, etc.). Research on natural antioxidants in various fields, such as pharmaceutics, nutraceutics, and cosmetics, is among the biggest challenges for industry and science. From a biomedical point of view, the scavenging activity of reactive oxygen species (ROS) makes them a potential tool for the treatment of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, dementia, and amyotrophic lateral sclerosis (ALS). In addition to the purified phytochemical compounds, a variety of natural extracts characterized by a complex mixture of antioxidants and anti-inflammatory molecules have been successfully exploited to rescue preclinical models of these diseases. Extracts derived from Ginkgo biloba, grape, oregano, curcumin, tea, and ginseng show multitherapeutic effects by synergically acting on different biochemical pathways. Furthermore, the reduced toxicity associated with many of these compounds limits the occurrence of side effects. The support of nanotechnology for improving brain delivery, controlling release, and preventing rapid degradation and excretion of these compounds is of fundamental importance. This review reports on the most promising results obtained on in vitro systems, in vivo models, and in clinical trials, by exploiting natural-derived antioxidant compounds and extracts, in their free form or encapsulated in nanocarriers.
    DOI:  https://doi.org/10.1021/acsomega.2c03291
  107. Cancer Treat Res Commun. 2022 Jul 29. pii: S2468-2942(22)00107-1. [Epub ahead of print]32 100616
    Vitamin D and colorectal cancer - A practical review of the literature.
    Renata D'Alpino Peixoto, Leandro Jonata de Carvalho Oliveira, Thaís de Melo Passarini, Aline Chaves Andrade, Paulo Henrique Diniz, Gabriel Prolla, Larissa Costa Amorim, Mariana Gil, Flora Lino, Bernardo Garicochea, Alexandre Jácome, Kimmie Ng.
      Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the United States and the second cause worldwide. Its incidence rates have been decreasing in the overall population in the US in the past few decades, but with increasing rates in the population younger than 50 years old. Environmental factors are supposed to be involved in the development of the disease, with strong evidence favoring an influence of the diet and lifestyle. A diet high in red meat and calories, and low in fiber, fruits and vegetables increases the risk of CRC, as well as physical inactivity. The influence of low calcium intake and low levels of vitamin D on the risk of the disease and on the clinical outcomes of CRC patients has also been investigated. Hypovitaminosis D has been highly prevalent worldwide and associated with several chronic diseases, including malignancies. Vitamin D is a steroid hormone with the main function of regulating bone metabolism, but with many other physiological functions, such as anti-inflammatory, immunomodulatory, and antiangiogenic effects, potentially acting as a carcinogenesis inhibitor. In this review, we aim to describe the relation of vitamin D with malignant diseases, mainly CRC, as well as to highlight the results of the studies which addressed the potential role of vitamin D in the development and progression of the disease. In addition, we will present the results of the pivotal randomized clinical trials that evaluated the impact of vitamin D supplementation on the clinical outcomes of patients with CRC.
    Keywords:  Calcitriol; Cholecalciferol; Colon neoplasms; Recurrence; Survival; Vitamin D deficiency
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100616
  108. J Control Release. 2022 Aug 04. pii: S0168-3659(22)00481-3. [Epub ahead of print]
    Stimuli-responsive liposomal nanoformulations in cancer therapy: Pre-clinical & clinical approaches.
    Milad Ashrafizadeh, Masoud Delfi, Ali Zarrabi, Ashkan Bigham, Esmaeel Sharifi, Navid Rabiee, Ana Cláudia Paiva-Santos, Alan Prem Kumar, Shing Cheng Tan, Kiavash Hushmandi, Jun Ren, Ehsan Nazarzadeh Zare, Pooyan Makvandi.
      The site-specific delivery of antitumor agents is of importance for providing effective cancer suppression. Poor bioavailability of anticancer compounds and the presence of biological barriers prevent their accumulation in tumor sites. These obstacles can be overcome using liposomal nanostructures. The challenges in cancer chemotherapy and stimuli-responsive nanocarriers are first described in the current review. Then, stimuli-responsive liposomes including pH-, redox-, enzyme-, light-, thermo- and magneto-sensitive nanoparticles are discussed and their potential for delivery of anticancer drugs is emphasized. The pH- or redox-sensitive liposomes are based on internal stimulus and release drug in response to a mildly acidic pH and GSH, respectively. The pH-sensitive liposomes can mediate endosomal escape via proton sponge. The multifunctional liposomes responsive to both redox and pH have more capacity in drug release at tumor site compared to pH- or redox-sensitive alone. The magnetic field and NIR irradiation can be exploited for external stimulation of liposomes. The light-responsive liposomes release drugs when they are exposed to irradiation; thermosensitive-liposomes release drugs at a temperature of >40 °C when there is hyperthermia; magneto-responsive liposomes release drugs in presence of magnetic field. These smart nanoliposomes also mediate co-delivery of drugs and genes in synergistic cancer therapy. Due to lack of long-term toxicity of liposomes, they can be utilized in near future for treatment of cancer patients.
    Keywords:  Advanced nanostructures; Cancer therapy; Drug resistance; Liposomes; Targeted delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.001
  109. Folia Neuropathol. 2022 ;pii: 47507. [Epub ahead of print]60(2): 153-164
    Resveratrol attenuates autophagy and inflammation after traumatic brain injury by activation of PI3K/Akt/mTOR pathway in rats.
    Yan Feng, Yaru Ju, Zhongjie Yan, Mingjun Ji, Jingchen Li, Qiang Wu, Ming Yang, Guozhu Sun.
       AIM OF THE STUDY: Accumulating studies have demonstrated that neuronal autophagy and inflammation are crucial for hippocampus development in rats subjected to traumatic brain injury (TBI). Therefore, we have investigated whether resveratrol is protective against brain damage through the attenuation of neuronal autophagy and inflammation, and explored underlying mechanisms.
    MATERIAL AND METHODS: Rats were injected with resveratrol (50 mg/kg, i.p.), following controlled cortical impact (CCI) injury. Brain water content, behavioral studies, and mNSS score were measured to assess the effects of resveratrol treatment. Autophagy-related proteins and inflammatory cytokines in the hippocampus were detected by Western blotting at 12, 24, and 48 hours after TBI. In addition, spatial distribution of LC3 was evaluated with immunofluorescence analysis 24 hours after injury. Finally, factors related to PI3K/Akt/mTOR signaling pathway were assessed at the same time in the hippocampus.
    RESULTS: Our results depicted that resveratrol could reduce the cerebral edema caused by TBI and improve the recovery of functional deficits in rats. Resveratrol was also able to remarkably reduce the expression of LC3 II and Beclin-1, while increased the expression levels of P62 in the hippocampus. Moreover, we found that interleukin b (IL-1b) and tumor necrosis factor a (TNF-a) were significantly decreased in resveratrol-treated rats. Indeed, we observed an activation of the PI3K/Akt/mTOR pathway after TBI, which may be related to the neuro-protective effect of resveratrol.
    CONCLUSIONS: Data presented herein support that resveratrol is a potential treatment against TBI through the inhibition of neuronal autophagy and inflammation by activation of PI3K/Akt/mTOR pathway.
    Keywords:   PI3K/Akt/mTOR; autophagy; inflammation; traumatic brain injury; resveratrol
    DOI:  https://doi.org/10.5114/fn.2022.118184
  110. Photodiagnosis Photodyn Ther. 2022 Aug 06. pii: S1572-1000(22)00342-8. [Epub ahead of print] 103056
    The effect of hypoxia on photodynamic therapy with 5-aminolevulinic acid in malignant gliomas.
    Tomohiro Ihata, Naosuke Nonoguchi, Takahiro Fujishiro, Naoki Omura, Shinji Kawabata, Yoshinaga Kajimoto, Masahiko Wanibuchi.
       BACKGROUND: Glioblastoma (GBM) is a high-grade, poor prognosis tumor that is resistant to standard treatment. The presence of a small number of glioma stem cells (GSCs) surviving in the harsh microenvironment is responsible for their refractoriness. This study aimed to investigate the effect of a hypoxic environment on the sensitivity of GSCs to photodynamic therapy with 5-aminolevulinic acid (ALA-PDT).
    MATERIALS AND METHODS: Six human GSC lines, Mesenchymal types HGG13, HGG30, HGG1123, and Proneural types HGG146, HGG157, HGG528, were divided into two groups: normoxia (O2 21%)-cultured cells (Normoxia-GSCs), and hypoxia (O2 5%)-cultured cells (Hypoxia-GSCs). To compare the effects of different oxygen partial pressures on photoporphyrin Ⅸ (PpⅨ) biosynthetic activity, PpⅨ biosynthetic enzyme and transporter expression levels were examined by qRT-PCR; the intracellular PpⅨ concentration was determined using flow cytometry. Additionally, the sensitivity of these two groups of cells to ALA-PDT was evaluated in vitro.
    RESULTS: Hypoxia-GSCs showed higher mRNA levels of FECH (ferrochelatase), which is required for iron synthesis to convert PpⅨ to heme, compared with Normoxia-GSCs. Flow cytometry revealed that the accumulation of PpⅨ in Hypoxia-GSCs reduced upon incubation with ALA. However, Hypoxia-GSCs showed less reduction in sensitivity to ALA-PDT than Normoxia-GSCs.
    CONCLUSION: Hypoxia-GSCs had lower intracellular PpⅨ accumulation than Normoxia-GSCs due to increased gene expression of FECH, and that their sensitivity to ALA-PDT was reduced less, despite accumulating lower concentrations of PpⅨ. ALA-PDT is a potentially effective therapy for hypoxia-tolerant GSCs that exist in hypoxia at 5% oxygen concentration.
    Keywords:  Aminolevulinic acid; Glioma stem cell; Hypoxia; Malignant glioma; Photodynamic therapy; Protoporphyrin-Ⅸ
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103056
  111. Bioengineered. 2022 Jun;13(6): 14681-14718
    Advances in delivery methods of Arthrospira platensis (spirulina) for enhanced therapeutic outcomes.
    Omar Ashraf ElFar, Nashiru Billa, Hooi Ren Lim, Kit Wayne Chew, Wai Yan Cheah, Heli Siti Halimatul Munawaroh, Deepanraj Balakrishnan, Pau Loke Show.
      Arthrospira platensis (A. platensis) aqueous extract has massive amounts of natural products that can be used as future drugs, such as C-phycocyanin, allophycocyanin, etc. This extract was chosen because of its high adaptability, which reflects its resolute genetic composition. The proactive roles of cyanobacteria, particularly in the medical field, have been discussed in this review, including the history, previous food and drug administration (FDA) reports, health benefits and the various dose-dependent therapeutic functions that A. platensis possesses, including its role in fighting against lethal diseases such as cancer, SARS-CoV-2/COVID-19, etc. However, the remedy will not present its maximal effect without the proper delivery to the targeted place for deposition. The goal of this research is to maximize the bioavailability and delivery efficiency of A. platensis constituents through selected sites for effective therapeutic outcomes. The solutions reviewed are mainly on parenteral and tablet formulations. Moreover, suggested enteric polymers were discussed with minor composition variations applied for better storage in high humid countries alongside minor variations in the polymer design were suggested to enhance the premature release hindrance of basic drugs in low pH environments. In addition, it will open doors for research in delivering active pharmaceutical ingredients (APIs) in femtoscale with the use of various existing and new formulations.Abbrevations: SDGs; Sustainable Development Goals, IL-4; Interleukin-4, HDL; High-Density Lipoprotein, LDL; Low-Density Lipoprotein, VLDL; Very Low-Density Lipoprotein, C-PC; C-Phycocyanin, APC; Allophycocyanin, PE; Phycoerythrin, COX-2; Cyclooxygenase-2, RCTs; Randomized Control Trials, TNF-α; Tumour Necrosis Factor-alpha, γ-LFA; Gamma-Linolenic Fatty Acid, PGs; Polyglycans, PUFAs: Polyunsaturated Fatty Acids, NK-cell; Natural Killer Cell, FDA; Food and Drug Administration, GRAS; Generally Recognized as Safe, SD; Standard Deviation, API; Active Pharmaceutical Ingredient, DW; Dry Weight, IM; Intramuscular, IV; Intravenous, ID; Intradermal, SC; Subcutaneous, AERs; Adverse Event Reports, DSI-EC; Dietary Supplement Information Executive Committee, cGMP; Current Good Manufacturing Process, A. platensis; Arthrospira platensis, A. maxima; Arthrospira maxima, Spirulina sp.; Spirulina species, Arthrospira; Spirulina, Tecuitlatl; Spirulina, CRC; Colorectal Cancer, HDI; Human Development Index, Tf; Transferrin, TfR; Transferrin Receptor, FR; Flow Rate, CPP; Cell Penetrating Peptide, SUV; Small Unilamenar Vesicle, LUV; Large Unilamenar Vesicle, GUV; Giant Unilamenar Vesicle, MLV; Multilamenar Vesicle, COVID-19; Coronavirus-19, PEGylated; Stealth, PEG; Polyethylene Glycol, OSCEs; Objective Structured Clinical Examinations, GI; Gastrointestinal Tract, CAP; Cellulose Acetate Phthalate, HPMCP, Hydroxypropyl Methyl-Cellulose Phthalate, SR; Sustained Release, DR; Delay Release, Poly(MA-EA); Polymethyl Acrylic Co-Ethyl Acrylate, f-DR L-30 D-55; Femto-Delay Release Methyl Acrylic Acid Co-Ethyl Acrylate Polymer, MW; Molecular Weight, Tg; Glass Transition Temperature, SN2; Nucleophilic Substitution 2, EPR; Enhance Permeability and Retention, VEGF; Vascular Endothelial Growth Factor, RGD; Arginine-Glycine-Aspartic Acid, VCAM-1; Vascular Cell Adhesion Molecule-1, P; Coefficient of Permeability, PES; Polyether Sulfone, pHe; Extracellular pH, ζ-potential; Zeta potential, NTA; Nanoparticle Tracking Analysis, PB; Phosphate Buffer, DLS; Dynamic Light Scattering, AFM; Atomic Force Microscope, Log P; Partition Coefficient, MR; Molar Refractivity, tPSA; Topological Polar Surface Area, C log P; Calculated Partition Coefficient, CMR; Calculated Molar Refractivity, Log S; Solubility Coefficient, pka; Acid Dissociation Constant, DDAB; Dimethyl Dioctadecyl Ammonium Bromide, DOPE; Dioleoylphosphatidylethanolamine, GDP; Good Distribution Practice, RES; Reticuloendothelial System, PKU; Phenylketonuria, MS; Multiple Sclerosis, SLE; Systemic Lupus Erythematous, NASA; National Aeronautics and Space Administration, DOX; Doxorubicin, ADRs; Adverse Drug Reactions, SVM; Support Vector Machine, MDA; Malondialdehyde, TBARS; Thiobarbituric Acid Reactive Substances, CRP; C-Reactive Protein, CK; Creatine Kinase, LDH; Lactated Dehydrogenase, T2D; Type 2 Diabetes, PCB; Phycocyanobilin, PBP; Phycobiliproteins, PEB; Phycoerythrobilin, DPP-4; Dipeptidyl Peptidase-4, MTT; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide, IL-2; Interleukin-2, IL-6; Interleukin-6, PRISMA; Preferred Reporting Items for Systematic Reviews and Meta-Analyses, STATA; Statistics, HepG2; Hepatoblastoma, HCT116; Colon Cancer Carcinoma, Kasumi-1; Acute Leukaemia, K562; Chronic Leukaemia, Se-PC; Selenium-Phycocyanin, MCF-7; Breast Cancer Adenocarcinoma, A375; Human Melanoma, RAS; Renin-Angiotensin System, IQP; Ile-Gln-Pro, VEP; Val-Glu-Pro, Mpro; Main Protease, PLpro; Papin-Like Protease, BMI; Body Mass Index, IC50; Inhibitory Concentration by 50%, LD50; Lethal Dose by 50%, PC12 Adh; Rat Pheochromocytoma Cells, RNS; Reactive Nitrogen Species, Hb1Ac; hemoglobin A1c.
    Keywords:  Arthrospira maxima; Arthrospira platensis; controlled release; delay release; drug delivery; femtoscale; formulation development; liposomes; polymer optimization
    DOI:  https://doi.org/10.1080/21655979.2022.2100863
  112. Photodiagnosis Photodyn Ther. 2022 Aug 03. pii: S1572-1000(22)00339-8. [Epub ahead of print] 103053
    Enhancement of the c ytotoxic effect of dihydroartemisinin in high-riskhuman papillomavirus-infected cells by aminolevulinic acid via the Bax/Bcl-2-caspase pathway.
    Qilei Che, Qi Wang, Hongyan Lu, Changxing Li, Kang Zeng.
       BACKGROUND: Traditional treatments for human papillomavirus-related cutaneous diseases include 5-aminolevulinic acid photodynamic therapy, cryotherapy, microwave ablation, and surgical resection. These treatment methods involvevarious adverse reactions; therefore, it remains necessary to explore new treatment methods. Dihydroartemisinin shows cytotoxic effects against several malignancies by producing reactive oxygen species, and heme environments reportedly enhance its activity. However, the underlying mechanismsare still unclear. Therefore, we investigated the mechanism of dihydroartemisininin inhuman papillomavirus-infected cells.
    METHODS: HeLa cells were treated with dihydroartemisinin, 5-aminolevulinic acid, and succinylacetone. The cell viability, apoptosis, mitochondrial membrane potential, and reactive oxygen species levels were investigated, and via western blotting analysis and polymerase chain reaction, dihydroartemisinin activity-related pathways were also determined.
    RESULTS: Dihydroartemisinin inhibited HeLa cell proliferation and promoted cell apoptosis via the Bax/Bcl-2-Caspase pathway in a concentration-dependent manner. The specific cytotoxicity toward HeLa cells was enhanced by the addition of 5-aminolevulinic acid, a clinically used heme-synthesis precursor, owing to an increase in heme levels. Conversely, following the addition of succinylacetone, a heme synthesis blocker, heme levels decreased. Furthermore, dihydroartemisinin significantly increased reactive oxygen species levels as intracellular heme synthesis increased. Moreover, photodynamic therapy following dihydroartemisinin and 5-aminolevulinic acid treatment further enhanced the cytotoxic effect of dihydroartemisinin on high-risk human papillomavirus-infected cells.
    CONCLUSIONS: Dihydroartemisinin exerts acytotoxic effect on high-risk human papillomavirus-infected cells by modulating heme levels via the Bax/Bcl-2-Caspase pathway, and the dihydroartemisinin, 5-aminolevulinic acid, photodynamic therapy combination treatment significantly enhanced its cytotoxic effect on human papillomavirus-infected cells.
    Keywords:  5-aminolevulinic acid; Dihydroartemisinin; HO-1; cytotoxicity; human papillomavirus-infected cells
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103053
  113. Polymers (Basel). 2022 Aug 08. pii: 3217. [Epub ahead of print]14(15):
    Natural Polysaccharide-Based Nanodrug Delivery Systems for Treatment of Diabetes.
    Aijun Qiu, Yunyun Wang, Genlin Zhang, Hebin Wang.
      In recent years, natural polysaccharides have been considered as the ideal candidates for novel drug delivery systems because of their good biocompatibility, biodegradation, low immunogenicity, renewable source and easy modification. These natural polymers are widely used in the designing of nanocarriers, which possess wide applications in therapeutics, diagnostics, delivery and protection of bioactive compounds or drugs. A great deal of studies could be focused on developing polysaccharide nanoparticles and promoting their application in various fields, especially in biomedicine. In this review, a variety of polysaccharide-based nanocarriers were introduced, including nanoliposomes, nanoparticles, nanomicelles, nanoemulsions and nanohydrogels, focusing on the latest research progress of these nanocarriers in the treatment of diabetes and the possible strategies for further study of polysaccharide nanocarriers.
    Keywords:  diabetes; drug delivery system; nanocarriers; natural polysaccharides
    DOI:  https://doi.org/10.3390/polym14153217
  114. Photodiagnosis Photodyn Ther. 2022 Aug 03. pii: S1572-1000(22)00335-0. [Epub ahead of print] 103049
    In-Vitro Use of Verteporfin for Photodynamic Therapy in Glioblastoma.
    Sebastian Jeising, Gerd Geerling, Rainer Guthoff, Daniel Hänggi, Michael Sabel, Marion Rapp, Ann-Christin Nickel.
       BACKGROUND: Stummer et al. established fluorescence-guided surgery (FGS) for glioblastoma (GBM) using 5-aminolevulinic acid (5-ALA). Its metabolite, protoporphyrin IX (PPIX), is also a photosensitizer and can be used for photodynamic therapy (PDT) using a laser beam of 635 nm. The porphyrin derivate verteporfin (VP) was discovered to have properties to penetrate the brain, pharmacologically target glioma cells, and is approved for PDT of choroidal neovascularization in wet age-related macular degeneration at 689 nm.
    OBJECTIVE: To elucidate whether GBM cell lines are susceptible to PDT with second-generation photosensitizer VP.
    METHODS: Human glioma cell lines LN229, HSR-GBM1, and a low-passage patient-derived GBM cell line P1 were treated with variable concentrations of VP for 24 h, followed by PDT at 689 nm using a diode laser light. Cell viability was measured using the MTT assay and VP uptake was measured using a desktop cytometer.
    RESULTS: Significantly higher cell death following PDT with VP compared to VP treatment alone or no treatment was detected in all cell models (LN229, HSR-GBM1, P1). Flowcytometric measurements revealed a concentration-dependent cellular uptake of VP after 24 h incubation up to 99% at 10 µM (HSR-GBM1).
    CONCLUSION: This study demonstrates that PDT with VP causes cell death in GBM cells at marginal concentrations. Additionally, red spectrum fluorescence was detected at therapeutic concentrations in all cell lines, validating the cellular uptake of VP in GBM cells. VP, therefore, is not only a potential drug for targeting GBM pharmacologically but can be used as an optical imaging dye in surgery and photosensitizer to make GBM susceptible to PDT.
    Keywords:  Benzoporphyrin derivative; Glioblastoma; Photodynamic therapy; Verteporfin; Visudyne
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103049
  115. Int J Mol Sci. 2022 Aug 04. pii: 8681. [Epub ahead of print]23(15):
    Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells.
    Katsumasa Tsurushima, Masanobu Tsubaki, Tomoya Takeda, Takuya Matsuda, Akihiro Kimura, Honoka Takefuji, Akane Okada, Chiaki Sakamoto, Toshihiko Ishizaka, Shozo Nishida.
      Triple-negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes. Recently, the activation of NF-κB, which is involved in the growth and survival of malignant tumors, has been demonstrated in TNBC, suggesting that NF-κB may serve as a new therapeutic target. In the present study, we examined whether dimethyl fumarate (DMF), an NF-κB inhibitor, induces apoptosis in TNBC cells and enhances the apoptosis-inducing effect of paclitaxel and adriamycin. Cell survival was analyzed by the trypan blue assay and apoptosis assay. Protein detection was examined by immunoblotting. The activation of NF-κB p65 was correlated with poor prognosis in patients with TNBC. DMF induced apoptosis in MDA-MB-231 and BT-549 cells at concentrations that were non-cytotoxic to the normal mammary cell line MCF-10A. Furthermore, DMF inhibited NF-κB nuclear translocation and Survivin, XIAP, Bcl-xL, and Bcl-2 expression in MDA-MB-231 and BT-549 cells. Moreover, DMF enhanced the apoptosis-inducing effect of paclitaxel and adriamycin in MDA-MB-231 cells. These findings suggest that DMF may be an effective therapeutic agent for the treatment of TNBC, in which NF-κB is constitutively active. DMF may also be useful as an adjuvant therapy to conventional anticancer drugs.
    Keywords:  NF-κB; adriamycin; dimethyl fumarate; paclitaxel; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/ijms23158681
  116. ACS Omega. 2022 Aug 02. 7(30): 25948-25957
    Recent Advances in Garcinia cambogia Nutraceuticals in Relation to Its Hydroxy Citric Acid Level. A Comprehensive Review of Its Bioactive Production, Formulation, and Analysis with Future Perspectives.
    Mostafa H Baky, Heba Fahmy, Mohamed A Farag.
      Garcinia cambogia (Gaertn.) Desr. (known as Malabar tamarind) is a popular traditional herbal medicine and is one of the well-known folk medicines reported for the treatment of obesity and incorporated in several nutraceuticals worldwide. These effects are mediated by a myriad of bioactive compounds with most effects attributed to its hydroxy citric acid (HCA) content. This review aims to present a holistic overview on novel trends in the production of G. cambogia bioactive components and how extraction optimization is important to ensure best product quality with its reported nanoformulations with particular emphasis on HCA content. Further, an overview of the different analytical approaches used for quality control assessment of G. cambogia plant and its nutraceuticals is presented highlighting both advantages and limitations. Moreover, analytical approaches for detecting G. cambogia metabolites in biological fluids with emphasis on HCA level to determine its pharmacokinetics and proof of efficacy are presented for the first time.
    DOI:  https://doi.org/10.1021/acsomega.2c02838
  117. J Pharm Sci. 2022 Aug 07. pii: S0022-3549(22)00340-9. [Epub ahead of print]
    Synthesis of ciprofloxacin-capped gold nanoparticles conjugates with enhanced sonodynamic antimicrobial activity in vitro.
    Mengyuan Wang, Xin Wang, Bin Liu, Chenyu Lang, Wei Wang, Yu Liu, Xiao Wang.
      The purpose of this article is to discuss whether gold nanoparticles (GNPs) play an auxo-action on ciprofloxacin (CIP)-mediated sonodynamic antimicrobial chemotherapy (SACT) in vitro. The measuring criterion of SACT, bactericidal efficiency, was measured by plate colony-counting methods. According to research findings, the duration of ultrasound (US) exposure, solution temperature and CIP:GNPs concentration were all critical influencing factors of SACT. Furthermore, scanning electron microscopy revealed that the group of CIP:GNPs combined with US showed the most severe damaged effect on Escherichia coli and Staphylococcus aureus, resulting in the loss of their typical microbial morphology and the disclosure of contents. Therefore, the above experimental results confirmed initially that GNPs could enhance the bacteriostasis of CIP-mediated SACT. And the intracellular reactive oxygen species (ROS) detection assays proved that this acceleration might be connected to the ROS generated through the ultrasonic mechanics. In conclusion, GNPs would be regarded as a promising auxiliary material for SACT, since they are both used to be the medication carriers and sonosensitizer accelerants.
    Keywords:  Ciprofloxacin; Conjugates; Gold nanoparticles; Sonodynamic antimicrobial activity
    DOI:  https://doi.org/10.1016/j.xphs.2022.08.004
  118. J Nutr Biochem. 2022 Aug 04. pii: S0955-2863(22)00184-X. [Epub ahead of print] 109116
    1α,25-dihydroxyvitamin D reduction of MCF10A-ras cell viability in extracellular matrix detached conditions is dependent on regulation of pyruvate carboxylase.
    Madeline P Sheeley, Violet A Kiesel, Chaylen Andolino, Nadia A Lanman, Shawn S Donkin, Stephen D Hursting, Michael K Wendt, Dorothy Teegarden.
      An emerging hallmark of cancer is cellular metabolic reprogramming to adapt to varying cellular environments. Throughout the process of metastasis cancer cells gain anchorage independence which confers survival characteristics when detached from the extracellular matrix (ECM). Previous work demonstrates that the bioactive metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)2D), suppresses cancer progression, potentially by suppressing the ability of cells to metabolically adapt to varying cellular environments such as ECM detachment. The purpose of the present study was to determine the mechanistic bases of the effects of 1,25(OH)2D on cell survival in ECM-detached conditions. Pretreatment of MCF10A-ras breast cancer cells for three days with 1,25(OH)2D reduced the viability of cells in subsequent detached conditions by 11%. Enrichment of 13C5-glutamine was reduced in glutamate (21%), malate (30%), and aspartate (23%) in detached compared to attached MCF10A-ras cells. Pretreatment with 1,25(OH)2D further reduced glutamine flux into downstream metabolites glutamate (5%), malate (6%), and aspartate (10%) compared to detached vehicle treated cells. Compared to attached cells, detachment increased pyruvate carboxylase (PC) mRNA abundance and protein expression by 95% and 190%, respectively. Consistent with these results, 13C6-glucose derived M+3 labelling was shown to preferentially replenish malate and aspartate, but not citrate pools, demonstrating increased PC activity in detached cells. In contrast, 1,25(OH)2D pretreatment of detached cells reduced PC mRNA abundance and protein expression by 63% and 56%, respectively, and reduced PC activity as determined by decreased 13C6-glucose derived M+3 labeling in citrate (8%) and aspartate (50%) pools, relative to vehicle-treated detached cells. While depletion of PC with doxycycline-inducible shRNA reduced detached cell viability, PC knockdown in combination with 1,25(OH)2D treatment did not additionally affect the viability of detached cells. Further, PC overexpression improved detached cell viability, and inhibited the effect of 1,25(OH)2D on detached cell survival, suggesting that 1,25(OH)2D mediates its effects in detachment through regulation of PC expression. These results suggest that inhibition of PC by 1,25(OH)2D suppresses cancer cell anchorage independence.
    Keywords:  1 25-dihydroxyvitamin D; breast cancer; energy metabolism; glucose metabolism; glutamine metabolism; pyruvate carboxylase
    DOI:  https://doi.org/10.1016/j.jnutbio.2022.109116
  119. Curr Neuropharmacol. 2022 Aug 10.
    Expanding Arsenal against Neurodegenerative Diseases using Quercetin based Nanoformulations: Breakthroughs and Bottlenecks.
    Sukriti Vishwas, Rajesh Kumar, Rubiya Khursheed, Arya Kadukkattil Ramanunny, Rajan Kumar, Ankit Awasthi, Leander Corrie, Omji Porwal, Mohammed F Arshad, Mohammed Kanan Alshammari, Abdulrahman A Alghitran, Ashwaq N Qumayri, Saif M Alkhaldi, Abdulaziz Khalaf Alshammari, Dinesh Kumar Chellappan, Gaurav Gupta, Trudi Collet, Jon Adams, Kamal Dua, Monica Gulati, Sachin Kumar Singh.
      Quercetin (Qu), a dietary flavonoid, is obtained from many fruits and vegetables such as coriander, broccoli, capers, asparagus, onion, figs, radish leaves, cranberry, walnuts, and citrus fruits. It has proven its role as a nutraceutical owing to numerous pharmacological effects against various diseases in preclinical studies. Despite these facts, Qu and its nanoparticles are less explored in clinical research as a nutraceutical. The present review covers various neuroprotective actions of Qu against various neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis. A literature search was conducted to systematically review the various mechanistic pathways through which Qu elicits its neuroprotective actions and the challenges associated with raw Qu that compromise therapeutic efficacy. The nanoformulations developed to enhance Qu's therapeutic efficacy are also covered. Various ongoing/completed clinical trials related to Qu in treating various diseases, including NDs, are also tabulated. Despite these many successes, the exploration of research on Qu-loaded nanoformulations is limited mostly to preclinical studies, probably due to poor drug loading and stability of the formulation, time-consuming steps involved in the formulation, and their poor scale-up capacity. Hence, future efforts are required in this area to reach Qu nanoformulations to the clinical level.
    Keywords:  Alzheimer’s disease; Antioxidant; Neurodegenerative disease; Neuroinflammation; Novel drug delivery systems; Quercetin
    DOI:  https://doi.org/10.2174/1570159X20666220810105421
  120. Anal Chem. 2022 Aug 12.
    Amplified Drug Delivery System with a Pair of Master Keys Triggering Precise Drug Release for Chemo-Photothermal Therapy.
    Sujuan Ye, Longfei Ma, Jihua Zhang, Ronghua Li, Huanong Cheng.
      A versatile drug delivery system (DDS) enabling highly effective and targeting oncotherapy has always been of great significance in medical research. In the development of a stimuli-responsive DDS, compared with a single-factor stimulation DDS, a multifactor activation DDS has higher therapeutic specificity between diseased and normal tissue, but there are challenges in drug-release efficiency and united targeting cancer therapy. Herein, a novel dual-microRNA (dual-miRNA)-mediated 1:N-amplified DDS is fabricated. The gold nanocage (AuNC) was synthesized and used as a carrier. A DNA bridge motif as a nanolock (DNA bridge nanolock) was designed and modified on the surface of AuNCs, which could seal the holes of AuNCs. Using the dual-miRNAs as a pair of master keys, through DNA strand migration and DNAzyme self-assembly, a cell endogenous substance Mg2+-dependent DNAzyme cyclic shear reaction could perform the function of the master keys to open multiple locks for the enhanced release of doxorubicin from the AuNCs. In addition, under near-infrared irradiation, via absorption of light and heat release, the AuNC is activated to perform the function of photothermal therapy. Thereby, the system achieves precise chemo-photothermal therapy. Using the in vitro and in vivo anti-tumor analysis, the DDS could be proved to present a novel design of enhanced and targeted drug-release system for highly effective cancer therapy.
    DOI:  https://doi.org/10.1021/acs.analchem.2c01663
  121. Crit Rev Oncol Hematol. 2022 Aug 05. pii: S1040-8428(22)00203-7. [Epub ahead of print]178 103779
    Effect of exercise on tumor markers - Is exercise anti-tumorigenic in humans?: A scoping review of preliminary clinical investigations.
    Dong-Woo Kang, Oscar Barnes, Matthew G Vander Heiden, Christina M Dieli-Conwright.
      It has been increasingly conceptualized that exercise may be able to suppress cancer progression itself based on the preclinical evidence suggesting various mechanisms. The challenges exist in investigating the effects of exercise on tumor progression in human settings. Circulating or tissue-driven tumor markers can be a useful and cost-effective tool in monitoring the progression of some cancers. This scoping review summarized the current evidence on the use of tumor markers in clinical exercise oncology trials. A total of 14 studies were identified, and tumor markers included prostate-specific antigen for prostate cancer, carcinoembryonic antigen and circulating tumor cells for colorectal cancer, and Ki-67 for breast cancer. Treatment settings and exercise prescriptions were highly heterogeneous, while most studies did not find significant exercise-mediated effects on tumor markers. Nevertheless, we provide an insight into the utility and considerations in using tumor markers in clinical exercise oncology research.
    Keywords:  Cancer progression; Clinical trials; Exercise; Translational trials; Tumor markers
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103779
  122. BMC Cancer. 2022 Aug 09. 22(1): 870
    Sodium selenite inhibits proliferation and metastasis through ROS-mediated NF-κB signaling in renal cell carcinoma.
    Xiao Liu, Meng Jiang, Chenggang Pang, Jianning Wang, Lijuan Hu.
       BACKGROUND: Sodium selenite (SSE) has been reported to exert anti-tumor effects in several cancer cells. However, the underlying mechanisms in renal cancer are yet to be elucidated. The effects of SSE on the proliferation, metastasis, and apoptosis of renal cancer cells, as well as its mechanism, were investigated in this study.
    METHODS: ACHN and 786-O renal cancer cells were treated with different concentrations of SSE, MTT, and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using scratch-wound-healing and transwell-migration assays. The effect of SSE on apoptosis was assessed by AnnexinV-FITC/PI double staining. Besides, Western blotting was employed to detect the protein-expression level and elucidate the underlying pathways. We also made subcutaneous xenografts in athymic mice to verify the effect of SSE on tumor growth in vivo.
    RESULTS: Our results demonstrated that treatment with SSE resulted in significant inhibition of cell proliferation and migration. Flow cytometry and Western blot confirmed that SSE induced apoptosis via the endogenous apoptotic pathway. We also confirmed that SSE treatment causes an increase in intracellular reactive oxygen species (ROS) levels, resulting in the inhibition of nuclear transcription factor-κB (NF-κB) signaling. Modulation of the ROS level by the chemical inhibitor N-acetyl-cysteine reversed the effect of SSE on cells. Similarly, subcutaneous xenografts in athymic mice models showed that SSE inhibits tumor growth in vivo.
    CONCLUSION: These results indicate that SSE inhibits proliferation and migration and induces apoptosis via ROS mediated inhibition of NF-κB signaling in renal cancer cells.
    Keywords:  Migration; NF-κB; Proliferation; Renal Cancer; Sodium selenite
    DOI:  https://doi.org/10.1186/s12885-022-09965-8
  123. J Dairy Sci. 2022 Aug 05. pii: S0022-0302(22)00444-1. [Epub ahead of print]
    Effect of epigallocatechin gallate on the fermentative and physicochemical properties of fermented milk.
    Xiaoqian Chen, Zifu Zhao, Chenyi Zhang, Chao Shang, Lu Gao, Chun Li, Guofang Zhang, Libo Liu.
      Yogurt, a traditional fermented dairy product, is made with a starter that contains Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus. The aim of this study was to investigate the effects of different concentrations of epigallocatechin gallate (EGCG; 0, 0.5, 1.0, 3.0, and 5.0 mg/mL) on the growth, metabolism, and acid production of lactic acid bacteria, as well as the texture, stability, and antioxidant activity of fermented milk (yogurt). The results showed that a low concentration of EGCG had no significant effect on the acid production capacity of the starter or on the water-holding capacity of the yogurt but did increase its viscosity. A high concentration (5.0 mg/mL) of EGCG delayed the acid production rate of the starter and decreased the water-holding capacity, but significantly increased the antioxidant activity of yogurt. The addition of EGCG significantly increased the hardness of yogurt. Therefore, EGCG can improve the texture of fermented milk and enhance its antioxidant activity and stability, thus improving the overall quality of yogurt.
    Keywords:  antioxidant activity; epigallocatechin gallate (EGCG); fermented milk; lactic acid bacteria; texture
    DOI:  https://doi.org/10.3168/jds.2021-21709
  124. Plants (Basel). 2022 Jul 30. pii: 1993. [Epub ahead of print]11(15):
    Calluna vulgaris as a Valuable Source of Bioactive Compounds: Exploring Its Phytochemical Profile, Biological Activities and Apitherapeutic Potential.
    Alexandra-Antonia Cucu, Gabriela-Maria Baci, Alexandru-Bogdan Cucu, Ştefan Dezsi, Cristian Lujerdean, Iuliana Cristina Hegeduş, Otilia Bobiş, Adela Ramona Moise, Daniel Severus Dezmirean.
      Calluna vulgaris, belonging to the Ericaceae family, is an invasive plant that has widely spread from Europe all across Asia, North America, Australia and New Zealand. Being able to survive in rigid soil and environmental conditions, it is nowadays considered to be of high nature-conservation value. Known for its nutritional and medicinal properties, C. vulgaris stands out for its varied physiochemical composition, spotlighting a wide range of biological activity. Among the most important bioactive compounds identified in C. vulgaris, the phenolic components found in different parts of this herbaceous plant are the main source of its diverse pro-health properties (antioxidant, anti-inflammatory, antimicrobial, chemoprotective, etc.). Nonetheless, this plant exhibits an excellent nectariferous potential for social insects such as honeybees; therefore, comparing the bioactive compounds observed in the plant and in the final product of the beehive, namely honey, will help us understand and find new insights into the health benefits provided by the consumption of C. vulgaris-related products. Thus, the main interest of this work is to review the nutritional profile, chemical composition and biological activities of the C. vulgaris plant and its related honey in order to encourage the future exploration and use of this health-promoting plant in novel foods, pharmacological products and apitherapy.
    Keywords:  Calluna vulgaris; antioxidant potential; apitherapy; bioactive compounds; biological activities; health benefits; heather honey; invasive plant; therapeutic value
    DOI:  https://doi.org/10.3390/plants11151993
  125. Phytochemistry. 2022 Aug 08. pii: S0031-9422(22)00257-6. [Epub ahead of print] 113341
    What is the role of phenolic compounds of yerba mate (Ilex paraguariensis) in gut microbiota?
    Daiane Santos, Elionio Galvão Frota, Bruna Krieger Vargas, Cintia Cassia Tonieto Gris, Lára Franco Dos Santos, Telma Elita Bertolin.
      Diet actively influences gut microbiota and body homeostasis. The predominance of beneficial species results in symbiosis, while dysbiosis is characterized by an imbalance between microbial communities. Food plays a key role in this dynamic and in promoting the health of individuals. Ilex paraguariensis, also known as yerba mate, is a traditional plant from Latin America that has a complex matrix of bioactive substances, including methylxanthines, triterpenes, saponins, and phenolics. The consumption of yerba mate is associated with antioxidant, cardioprotective, anti-inflammatory, and anti-obesity effects. However, to the best of our knowledge, there have been no studies on yerba mate as a modulating agent of intestinal microbiota. Phenolics are the major compounds in yerba mate and have been reported to act in modulating the microbiome. In this review, we explore the activity of yerba mate as a possible stimulant of gut microbiota and present its main phenolics and their biological effects. We also propose different mechanisms of action of these phenolics and possible doses for their effectiveness.
    Keywords:  Aquifoliaceae; Bioactive compounds; Gut microbial composition; Ilex paraguariensis; Metabolic effects; Microbiota modulation; Phytochemicals
    DOI:  https://doi.org/10.1016/j.phytochem.2022.113341
  126. Ultrason Sonochem. 2022 Aug 01. pii: S1350-4177(22)00204-8. [Epub ahead of print]89 106109
    Impact of ultrasonication applications on color profile of foods.
    Naciye Kutlu, R Pandiselvam, Aybike Kamiloglu, Irem Saka, N U Sruthi, Anjineyulu Kothakota, Claudia Terezia Socol, Cristina Maria Maerescu.
      Food color is a feature that provides preliminary information about their preference or consumption. There are dominant pigments that determine the color of each food; the most important pigments are anthocyanins (red-purple color), chlorophylls (green color), carotenoids (yellow-orange color), and betalains (red color). These pigments can be easily affected by temperature, light, oxygen, or pH, thereby altering their properties. Therefore, while processing, it is necessary to prevent the deterioration of these pigments to the maximum possible extent. Ultrasonication, which is one of the emerging non-thermal methods, has multidimensional applications in the food industry. The present review collates information on various aspects of ultrasonication technology, its mechanism of action, influencing factors, and the competence of different ultrasonication applications (drying, irradiation, extraction, pasteurization, cooking, tempering, etc.) in preserving the color of food. It was concluded that ultrasonication treatments provide low-temperature processing at a short time, which positively influences the color properties. However, selecting optimum ultrasonic processing conditions (frequency, power, time, etc.) is crucial for each food to obtain the best color. The key challenges and limitations of the technique and possible future applications are also covered in the paper, serving as a touchstone for further research in this area.
    Keywords:  Anthocyanins; Betalains; Carotenoids; Chlorophylls; Color; Food; Ultrasonication
    DOI:  https://doi.org/10.1016/j.ultsonch.2022.106109
  127. Sci Rep. 2022 Aug 12. 12(1): 13746
    Oral sorafenib-loaded microemulsion for breast cancer: evidences from the in-vitro evaluations and pharmacokinetic studies.
    Nishtha Chaurawal, Charu Misra, Harshita Abul Barkat, Reena Jatyan, Deepak Chitkara, Md Abul Barkat, Teenu Sharma, Bhupinder Singh, Kaisar Raza.
      Sorafenib tosylate (SFB) is a multikinase inhibitor that inhibits tumour growth and proliferation for the management of breast cancer but is also associated with issues like toxicity and drug resistance. Also, being a biopharmaceutical class II (BCS II) drug, its oral bioavailability is the other challenge. Henceforth, this report intended to encapsulate SFB into a biocompatible carrier with biodegradable components, i.e., phospholipid. The microemulsion of the SFB was prepared and characterized for the surface charge, morphology, micromeritics and drug release studies. The cell viability assay was performed on 4T1 cell lines and inferred that the IC50 value of sorafenib-loaded microemulsion (SFB-loaded ME) was enhanced compared to the naïve SFB at the concentrations of about 0.75 µM. More drug was available for the pharmacological response, as the protein binding was notably decreased, and the drug from the developed carriers was released in a controlled manner. Furthermore, the pharmacokinetic studies established that the developed nanocarrier was suitable for the oral administration of a drug by substantially enhancing the bioavailability of the drug to that of the free SFB. The results bring forth the preliminary evidence for the future scope of SFB as a successful therapeutic entity in its nano-form for effective and safer cancer chemotherapy via the oral route.
    DOI:  https://doi.org/10.1038/s41598-022-17333-6
  128. Int J Pharm. 2022 Aug 04. pii: S0378-5173(22)00635-4. [Epub ahead of print] 122081
    An injectable thermosensitive hydrogel for dual delivery of diclofenac and Avastin® to effectively suppress inflammatory corneal neovascularization.
    Hui Shi, Yutuo Zhu, Chunyan Xing, Shan Li, Zhishu Bao, Lei Lei, Dan Lin, Yuqin Wang, Hao Chen, Xu Xu.
      Corneal neovascularization (CNV) is a sequela of anterior segment inflammation, which could lead to vision impairment and even blindness. In the present study, the dual delivery of anti-inflammatory agent (i.e., diclofenac; DIC) and anti-VEGF antibody (i.e., Avastin®; Ava) by the thermosensitive hydrogel (Poly(DL-lactide)-poly(ethylene glycol)-poly(DL-lactide); PDLLA-PEG-PDLLA) is expected to effectively inhibit CNV via their synergistic effects. The optimal DIC micelles were formulated and then mixed with Ava and PDLLA-PEG-PDLLA aqueous solution to generate various DIC@Ava-loaded hydrogels. The co-encapsulation of DIC micelles and Ava did not influence the gelling behavior of the system, and the resulting DIC@Ava-loaded hydrogel provided sustained drug release of both DIC and Ava without compromising their pharmacological activity over 19 days. As indicated by in vitro cytotoxicity and in vivo ocular biocompatibility test, the proposed PDLLA-PEG-PDLLA hydrogel caused minimal cytotoxicity against all tested cell lines at a polymeric concentration ranging from 0.05 mg/mL to 0.8 mg/mL and demonstrated good ocular biocompatibility after a single subconjunctival injection. Using the rabbit CNV model, we documented the superior anti-angiogenic effects of the DIC@Ava-loaded hydrogel over Ava alone medication (treatment with Ava solution and Ava-loaded hydrogel) due to synergistic effects of anti-VEGF and anti-inflammatory action. Overall, the proposed DIC@Ava-loaded hydrogel might be a powerful strategy to reduce CNV.
    Keywords:  Anti-VEGF; Anti-inflammatory; Corneal neovascularization; Hydrogel; Synergistic effects
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122081
  129. J Immunol Res. 2022 ;2022 4472509
    Anticancer Effect of Puerarin on Ovarian Cancer Progression Contributes to the Tumor Suppressor Gene Expression and Gut Microbiota Modulation.
    Yongju Ye, Yang Gao, Yuan Fang, Lixia Xu, Fule He.
      Ovarian cancer (OC) causes more deaths than any other cancer of the female reproductive system due to its late presentation and malignant nature. Although significant progress has been made in the diagnosis and treatment of OC over the last decade, chemotherapeutic drug resistance and cancer recurrence remain serious challenges in OC management. In the field of cancer therapy, traditional Chinese herbal medicines and their active compounds have been widely reported to have favorable therapeutic effects on cancer. Recent studies have also revealed the protective effect of puerarin in cancer, but the exact role and underlying mechanism of puerarin in OC remain unclear. Here, we established in vivo and in vitro OC models to evaluate the anticancer effect of puerarin. It was found that puerarin significantly inhibited OC cell viability and proliferation and induced cell apoptosis. In OC model mice, puerarin treatment suppressed tumor formation and modulated the gut microbiome. In addition, the expression of tumor suppressor genes was activated by puerarin in vitro and in vivo. These findings add to the existing knowledge on the usefulness of herbal active ingredients for the prevention and treatment of OC and provide a new perspective regarding the therapeutic potential of puerarin in cancer.
    DOI:  https://doi.org/10.1155/2022/4472509
  130. Cancer Cell Int. 2022 Aug 06. 22(1): 245
    Nanobodies; new molecular instruments with special specifications for targeting, diagnosis and treatment of triple-negative breast cancer.
    Hamid Bakherad, Fahimeh Ghasemi, Maryam Hosseindokht, Hamed Zare.
      Breast cancer is the most common type of cancer in women and the second leading cause of cancer death in female. Triple-negative breast cancer has a more aggressive proliferation and a poorer clinical diagnosis than other breast cancers. The most common treatments for TNBC are chemotherapy, surgical removal, and radiation therapy, which impose many side effects and costs on patients. Nanobodies have superior advantages, which makes them attractive for use in therapeutic agents and diagnostic kits. There are numerous techniques suggested by investigators for early detection of breast cancer. Nevertheless, there are fewer molecular diagnostic methods in the case of TNBC due to the lack of expression of famous breast cancer antigens in TNBC. Although conventional antibodies have a high ability to detect tumor cell markers, their large size, instability, and costly production cause a lot of problems. Since the HER-2 do not express in TNBC diagnosis, the production of nanobodies for the diagnosis and treatment of cancer cells should be performed against other antigens expressed in TNBC. In this review, nanobodies which developed against triple negative breast cancer, were classified based on type of antigen.
    Keywords:  Diagnosis; Nanobody; TNBC; Treatment; VHH
    DOI:  https://doi.org/10.1186/s12935-022-02665-0
  131. Biochimie. 2022 Aug 08. pii: S0300-9084(22)00197-3. [Epub ahead of print]
    Plant lectin: A promising future anti-tumor drug.
    Emadeldin Hassan E Konozy, Makarim El-Fadil M Osman.
      Since the early discovery of plant lectins at the end of the 19th century, and the finding that they could agglutinate erythrocytes and precipitate glycans from their solutions, many applications and biological roles have been described for these proteins. Later, the observed erythrocytes clumping features were attributed to the lectin-cell surface glycoconjugates recognition. Neoplastic transformation leads to various cellular alterations which impact the growth of the cell and its persistence, among which is the mutation in the outer surface glycosylation signatures. Quite a few lectins have been found to act as excellent biomarkers for cancer diagnosis while some were presented with antiproliferative activity that initiated by lectin bindning to the respective glycocalyx receptors. These properties are blocked by the hapten sugar that is competing for the lectin affinity binding site. In vitro investigations of lectin-cancer cell's glycocalyx interactions lead to a series of immunological reactions that result in autophagy or apoptosis of the transformed cells. Mistletoe lectin, an agglutinin purified from the European Viscum album is the first plant lectin employed in the treatment of cancer to enter into the clinical trial phases. The entrapment of lectin in nanoparticles besides other techniques to promote bioavailability and stability have also been recently studied. This review summarizes our up-to-date understanding of the future applications of plant lectins in cancer prognosis and diagnosis. With the provision of many examples of lectins that exhibit anti-neoplastic properties.
    Keywords:  Antiproliferation; Clinical trials; Diagnosis; Glycocalx; Mistletoe; Plant agglutinin
    DOI:  https://doi.org/10.1016/j.biochi.2022.08.002
  132. Int J Pharm. 2022 Aug 09. pii: S0378-5173(22)00656-1. [Epub ahead of print] 122102
    Selective delivery of pentamidine toward cancer cells by self-assembled nanoparticles.
    I Andreana, E Gazzano, E Gianquinto, G Piatti, V Bincoletto, D Kryza, G Lollo, F Spyrakis, C Riganti, S Arpicco, B Stella.
      Pentamidine (PTM) is an aromatic diamidine approved for the treatment of parasitic infections that has been recently proposed for possible repositioning as an anticancer drug. To this aim, efforts have been made to improve its therapeutic efficacy and reduce associated adverse effects through both covalent derivatization and association with nanocarriers. To efficiently encapsulate PTM into biocompatible nanoparticles and to enhance its selectivity toward cancer cells, a squalene (SQ) derivative (1,1',2-tris-norsqualenoic acid, SQ-COOH) was selected to prepare PTM-loaded nanocarriers. Indeed, SQ and its derivatives self-assemble into nanoparticles in aqueous media. Furthermore, SQ-bioconjugates strongly interact with low-density lipoproteins (LDL), thus favoring preferential accumulation in cells overexpressing the LDL receptor (LDLR). We report here the preparation of nanocarriers by ion-pairing between the negatively charged SQ-COOH and the positively charged PTM free base (PTM-B), which allowed the covalent grafting of SQ to PTM to be avoided. The nanoparticles were characterized (mean size <200 nm and zeta potential <-20 mV for SQ-COOH/PTM-B 3:1 molar ratio) and molecular modelling studies of the SQ-COOH/PTM-B interaction confirmed the nanocarrier stability. Finally, the ability to indirectly target LDLR-overexpressing cancer cells was evaluated by in vitro cell viability assays and confirmed by LDLR silencing, serum privation and simvastatin treatment.
    Keywords:  Cancer cells; Low-density lipoprotein receptor; Molecular modelling; Nanoparticles; Pentamidine; Squalene
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122102
  133. Front Pharmacol. 2022 ;13 921070
    Potential targets and treatments affect oxidative stress in gliomas: An overview of molecular mechanisms.
    Shiyu Liu, Lihua Dong, Weiyan Shi, Zhuangzhuang Zheng, Zijing Liu, Lingbin Meng, Ying Xin, Xin Jiang.
      Oxidative stress refers to the imbalance between oxidation and antioxidant activity in the body. Oxygen is reduced by electrons as part of normal metabolism leading to the formation of various reactive oxygen species (ROS). ROS are the main cause of oxidative stress and can be assessed through direct detection. Oxidative stress is a double-edged phenomenon in that it has protective mechanisms that help to destroy bacteria and pathogens, however, increased ROS accumulation can lead to host cell apoptosis and damage. Glioma is one of the most common malignant tumors of the central nervous system and is characterized by changes in the redox state. Therapeutic regimens still encounter multiple obstacles and challenges. Glioma occurrence is related to increased free radical levels and decreased antioxidant defense responses. Oxidative stress is particularly important in the pathogenesis of gliomas, indicating that antioxidant therapy may be a means of treating tumors. This review evaluates oxidative stress and its effects on gliomas, describes the potential targets and therapeutic drugs in detail, and clarifies the effects of radiotherapy and chemotherapy on oxidative stress. These data may provide a reference for the development of precise therapeutic regimes of gliomas based on oxidative stress.
    Keywords:  Reactive Oxygen Species (ROS); gliomas; oxidative stress; target gene; therapeutic strategy
    DOI:  https://doi.org/10.3389/fphar.2022.921070
  134. ACS Appl Mater Interfaces. 2022 Aug 12.
    Antibacterial Properties and Mechanisms of Action of Sonoenzymatically Synthesized Lignin-Based Nanoparticles.
    Angela Gala Morena, Arnau Bassegoda, Michal Natan, Gila Jacobi, Ehud Banin, Tzanko Tzanov.
      In recent years, lignin has drawn increasing attention for different applications due to its intrinsic antibacterial and antioxidant properties, coupled with biodegradability and biocompatibility. However, chemical modification or combination with metals is usually required to increase its antimicrobial functionality and produce biobased added-value materials for applications wherein bacterial growth should be avoided, such as biomedical and food industries. In this work, a sonoenzymatic approach for the simultaneous functionalization and nanotransformation of lignin to prepare metal-free antibacterial phenolated lignin nanoparticles (PheLigNPs) is developed. The grafting of tannic acid, a natural phenolic compound, onto lignin was achieved by an environmentally friendly approach using laccase oxidation upon the application of high-intensity ultrasound to rearrange lignin into NPs. PheLigNPs presented higher antibacterial activity than nonfunctionalized LigNPs and phenolated lignin in the bulk form, indicating the contribution of both the phenolic content and the nanosize to the antibacterial activity. Studies on the antibacterial mode of action showed that bacteria in contact with the functionalized NPs presented decreased metabolic activity and high levels of reactive oxygen species (ROS). Moreover, PheLigNPs demonstrated affinity to the bacterial surface and the ability to cause membrane destabilization. Antimicrobial resistance studies showed that the NPs did not induce resistance in pathogenic bacteria, unlike traditional antibiotics.
    Keywords:  antibacterial; antimicrobial resistance; enzymatic grafting; laccase; lignin; nanoparticle; sonochemistry
    DOI:  https://doi.org/10.1021/acsami.2c05443
  135. Cells. 2022 Aug 03. pii: 2388. [Epub ahead of print]11(15):
    Adipocyte-Derived Extracellular Vesicles Promote Prostate Cancer Cell Aggressiveness by Enabling Multiple Phenotypic and Metabolic Changes.
    Fabrizio Fontana, Martina Anselmi, Emanuela Carollo, Patrizia Sartori, Patrizia Procacci, David Carter, Patrizia Limonta.
       BACKGROUND: In recent decades, obesity has widely emerged as an important risk factor for prostate cancer (PCa). Adipose tissue and PCa cells have been shown to orchestrate a complex interaction network to support tumor growth and evolution; nonetheless, the study of this communication has only been focused on soluble factors, although increasing evidence highlights the key role of extracellular vesicles (EVs) in the modulation of tumor progression.
    METHODS AND RESULTS: In the present study, we found that EVs derived from 3T3-L1 adipocytes could affect PC3 and DU145 PCa cell traits, inducing increased proliferation, migration and invasion. Furthermore, conditioning of both PCa cell lines with adipocyte-released EVs resulted in lower sensitivity to docetaxel, with reduced phosphatidylserine externalization and decreased caspase 3 and PARP cleavage. In particular, these alterations were paralleled by an Akt/HIF-1α axis-related Warburg effect, characterized by enhanced glucose consumption, lactate release and ATP production.
    CONCLUSIONS: Collectively, these findings demonstrate that EV-mediated crosstalk exists between adipocytes and PCa, driving tumor aggressiveness.
    Keywords:  Warburg effect; adipocytes; chemoresistance; extracellular vesicles; metastasis; obesity; prostate cancer
    DOI:  https://doi.org/10.3390/cells11152388
  136. Front Endocrinol (Lausanne). 2022 ;13 927329
    Molecular mechanisms underlying the role of hypoxia-inducible factor-1 α in metabolic reprogramming in renal fibrosis.
    Xuejiao Wei, Yue Hou, Mengtuan Long, Lili Jiang, Yujun Du.
      Renal fibrosis is the result of renal tissue damage and repair response disorders. If fibrosis is not effectively blocked, it causes loss of renal function, leading to chronic renal failure. Metabolic reprogramming, which promotes cell proliferation by regulating cellular energy metabolism, is considered a unique tumor cell marker. The transition from oxidative phosphorylation to aerobic glycolysis is a major feature of renal fibrosis. Hypoxia-inducible factor-1 α (HIF-1α), a vital transcription factor, senses oxygen status, induces adaptive changes in cell metabolism, and plays an important role in renal fibrosis and glucose metabolism. This review focuses on the regulation of proteins related to aerobic glycolysis by HIF-1α and attempts to elucidate the possible regulatory mechanism underlying the effects of HIF-1α on glucose metabolism during renal fibrosis, aiming to provide new ideas for targeted metabolic pathway intervention in renal fibrosis.
    Keywords:  aerobic glycolysis; hypoxia-inducible factor-1α; metabolic reprogramming; oxidative phosphorylation; renal fibrosis
    DOI:  https://doi.org/10.3389/fendo.2022.927329
  137. Exp Ther Med. 2022 Sep;24(3): 596
    Curcumin activates autophagy and attenuates high glucose-induced apoptosis in HUVECs through the ROS/NF-κB signaling pathway.
    Qi-Hui Jin, Xu-Jun Hu, Hai-Yan Zhao.
      Curcumin (CUR) is well known for its anti-inflammatory and antioxidant effects. However, the endothelial protective effect of CUR in diabetes and the underlying signaling pathway remains unclear. The goal of the current study was to provide evidence regarding the protective mechanism of CUR against the high glucose (HG)-induced damage to human umbilical vein endothelial cells (HUVECs). HG-induced HUVECs injury model was used to evaluate the protective effect and the underlying mechanism of CUR against endothelial injury. The cell viability was determined by the MTT method. The cell reactive oxygen species (ROS) were determined by using flow cytometry. The protein expression levels of Bcl-2, Bax, LC3-II/I, Beclin-1, p62, cleaved caspase-3, IκBα and NF-κB were measured by the western blotting. Results showed that CUR significantly decreased the cell apoptosis, the ROS generation and the inflammatory cytokine NF-κB activity in the HG-induced HUVECs versus the control, P<0.05. In addition, CUR significantly increased the expressions of LC3-II/I, Beclin-1, IκBα and Bax/Bcl-2 in the HG-induced HUVECs versus the control, P<0.05. Furthermore, the addition of autophagy inhibitor 3-MA impaired the autophagy, exacerbated the apoptotic death and increased the ROS and NF-κB levels in HUVECs under the high glucose condition, P<0.05. In brief, autophagy served a protective role in the HG-induced apoptosis in HUVECs and CUR alleviated apoptosis by promoting autophagy and inhibiting the ROS/NF-κB signaling pathway.
    Keywords:  NF-κB; apoptosis; autophagy; curcumin; high glucose; reactive oxygen species
    DOI:  https://doi.org/10.3892/etm.2022.11533
  138. Polymers (Basel). 2022 Aug 01. pii: 3135. [Epub ahead of print]14(15):
    Bilayer Hydrogels for Wound Dressing and Tissue Engineering.
    Olga Luneva, Roman Olekhnovich, Mayya Uspenskaya.
      A large number of different skin diseases such as hits, acute, and chronic wounds dictate the search for alternative and effective treatment options. The wound healing process requires a complex approach, the key step of which is the choice of a dressing with controlled properties. Hydrogel-based scaffolds can serve as a unique class of wound dressings. Presented on the commercial market, hydrogel wound dressings are not found among proposals for specific cases and have a number of disadvantages-toxicity, allergenicity, and mechanical instability. Bilayer dressings are attracting great attention, which can be combined with multifunctional properties, high criteria for an ideal wound dressing (antimicrobial properties, adhesion and hemostasis, anti-inflammatory and antioxidant effects), drug delivery, self-healing, stimulus manifestation, and conductivity, depending on the preparation and purpose. In addition, advances in stem cell biology and biomaterials have enabled the design of hydrogel materials for skin tissue engineering. To improve the heterogeneity of the cell environment, it is possible to use two-layer functional gradient hydrogels. This review summarizes the methods and application advantages of bilayer dressings in wound treatment and skin tissue regeneration. Bilayered hydrogels based on natural as well as synthetic polymers are presented. The results of the in vitro and in vivo experiments and drug release are also discussed.
    Keywords:  bilayer hydrogel; drug release; in vivo experiments; skin sensors; wound dressing; wound healing
    DOI:  https://doi.org/10.3390/polym14153135
  139. J Photochem Photobiol B. 2022 Jul 31. pii: S1011-1344(22)00151-8. [Epub ahead of print]234 112537
    Inhibition of hypoxia-inducible factor 1 by acriflavine renders glioblastoma sensitive for photodynamic therapy.
    Shuai Ma, Fang Wang, Jiawei Dong, Nan Wang, Shengzhong Tao, Jianyang Du, Shaoshan Hu.
       BACKGROUND: photodynamics therapy (PDT) induces tumor cell death through oxidative stress and is closely associated with the expression of hypoxia inducible factor-1a (HIF1a), which activates multiple downstream survival signaling pathways. Therefore, the purpose of this study was to investigate the expression levels of HIF1a proteins in PDT-treated GBM cells and to determine whether inhibition of HIF1a reduces survival signals to enhance the efficacy of PDT.
    RESULTS: PDT combined with Acriflavine (ACF, PA) decreased the expression of HIF1a and regulated the downstream expression of GLUT-1, GLUT-3, HK2 and other gluconeogenic pathway proteins. PA group significantly suppressed tumor growth to improve the efficacy of PDT.
    METHODS: We first performed the correlation of HIF1a, GLUT-1, GLUT-3, and HK2, and quantified the expression of HIF1a on tumor grades and IDH mutation classification by TCGA and CGGA databases. Then, we used immunohistochemistry method to detect four gene expression levels in human GBM tissues. Besides, we examined the effects of different treatments on the proliferation, migration and invasion ability of GBM cell lines by CCK8, wound healing and transwell assays. ACF, a HIF1a/HIF1β dimerization inhibitor, was used to evaluate its adjuvant effect on the efficacy of PDT.
    CONCLUSION: HIF1a is activated in GBM cell lines and contributes to the survival of tumor cells after PDT in vitro and in vivo. PA group inhibited HIF1a expression and improved PDT efficacy in the treatment of recalcitrant GBM.
    Keywords:  Acriflavine; GLUT-1; GLUT-3; HIF1a; HK2; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112537
  140. Plants (Basel). 2022 Aug 06. pii: 2060. [Epub ahead of print]11(15):
    Antioxidant Capacity, Vitamin C and Polyphenol Profile Evaluation of a Capsicum chinense By-Product Extract Obtained by Ultrasound Using Eutectic Solvent.
    Kevin Alejandro Avilés-Betanzos, Julio Enrique Oney-Montalvo, Juan Valerio Cauich-Rodríguez, Marisela González-Ávila, Matteo Scampicchio, Ksenia Morozova, Manuel Octavio Ramírez-Sucre, Ingrid Mayanin Rodríguez-Buenfil.
      Habanero pepper leaves and stems (by-products) have been traditionally considered waste; however, bioactive compounds such as polyphenols, vitamin C and carotenoids have been identified that can be used for formulation of nutraceuticals or functional foods. Furthermore, the extraction of these bioactive compounds by using environmentally friendly methods and solvents is desirable. Thus, the aim of this study was to assess the antioxidant capacity, total polyphenol content (TPC), the phenolic profile and vitamin C content in extracts obtained from by-products (stems and leaves) of two varieties (Mayapan and Jaguar) of habanero pepper by ultrasound-assisted extraction (UAE) using natural deep eutectic solvents (NADES). The results showed that NADES leads to extracts with significantly higher TPC, higher concentrations of individual polyphenols (gallic acid, protocatechuic acid, chlorogenic acid, cinnamic acid, coumaric acid), vitamin C and, finally, higher antioxidant capacity (9.55 ± 0.02 eq mg Trolox/g DM) than UAE extraction performed with methanol as the solvent. The association of individual polyphenols with NADES was confirmed by principal component analysis (PCA). Overall, NADES is an innovative and promising "green" extraction technique that can be applied successfully for the extraction of phenolic compounds from habanero pepper by-products.
    Keywords:  Capsicum chinense; NADES; antioxidant capacity; by-product; natural deep eutectic solvent; polyphenols
    DOI:  https://doi.org/10.3390/plants11152060
  141. Saudi J Biol Sci. 2022 Sep;29(9): 103393
    Shilajit potentiates the effect of chemotherapeutic drugs and mitigates metastasis induced liver and kidney damages in osteosarcoma rats.
    Ebtihaj J Jambi, Fawzia Abdulaziz Alshubaily.
      Osteosarcoma is a primary malignant cancer of the bone identified by the direct formation of osteoid tissue or immature bone by cancer cells. The liver and kidneys represent two major secondary organs to which osteosarcoma metastasizes. In this study, we assessed Shilajit, a phytomineral diffusion traditionally used in Ayurvedic medicine, for its possible protective effects against metastasis induced liver and kidney damages in an osteosarcoma rat model. Osteosarcoma rats displayed typical dysregulation of serum levels of hepatic and renal functional markers (p < 0.05) including aspartate aminotransferase (AST)* and alanine aminotransferase (ALT), alkaline phosphatase (ALP), total proteins, albumin, bilirubin, creatinine, urea, and uric acid. Changes in functional markers were also positively correlated with marked histopathological alterations in liver and kidney tissues. Whereas Shilajit's treatment of osteosarcoma rates in combination with CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy drug cocktail significantly (p < 0.05) reversed the studied functional markers to their near-normal levels. Co-treatment of shilajit and drug cocktails also markedly alleviated histopathological changes in liver and kidney tissues. Correlation co-efficient analysis of hepatic and renal functional markers revealed a significant inter-association among these markers. Collectively, present data indicate that shilajit may potentiate the effects of chemotherapy drugs and mitigate the metastasis-induced liver and kidney damage in osteosarcoma. Thus, the findings of this study substantiate the beneficial health effects of shilajit and promote its regular consumption.
    Keywords:  ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMF, cyclophosphamide, methotrexate and 5, fluorouracil; HDS, high dose shilajit; Histology; Kidney; LDS, low dose shilajit; Liver; Metastasis; OS, osteosarcoma; Osteosarcoma; Shilajit
    DOI:  https://doi.org/10.1016/j.sjbs.2022.103393
  142. Expert Opin Drug Deliv. 2022 Aug 10.
    Combinations of chemo-, immuno-, and gene therapies using nanocarriers as a multifunctional drug platform.
    Caroline Hopkins, Kaila Javius-Jones, Yixin Wang, Quanyin Hu, Seungpyo Hong.
       INTRODUCTION: Cancer immunotherapies have created a new generation of therapeutics to employ the immune system to attack cancer cells. However, these therapies are typically based on biologics that are non-specific and often exhibit poor tumor penetration and dose-limiting toxicities. Nanocarriers allow the opportunity to overcome these barriers as they have the capabilities to direct immunomodulating drugs to tumor sites via passive and active targeting, decreasing potential adverse effects from non-specific targeting. In addition, nanocarriers can be multifunctionalized to deliver multiple cancer therapeutics in a single drug platform, offering synergistic potential from co-delivery approaches.
    AREAS COVERED: This review focuses on the delivery of cancer therapeutics using emerging nanocarriers to achieve synergistic results via co-delivery of immune-modulating components (i.e. chemotherapeutics, monoclonal antibodies, and genes).
    EXPERT OPINION: Nanocarrier-mediated delivery of combinatorial immunotherapy creates the opportunity to fine-tune drug release while achieving superior tumor targeting and tumor cell death, compared to free drug counterparts. As these nanoplatforms are constantly improved upon, combinatorial immunotherapy will afford the greatest benefit to treat an array of tumor types while inhibiting cancer evasion pathways.
    Keywords:  Cancer; chemoimmunotherapy; delivery; gene; immunotherapy; nanocarrier; nanomedicine; nanoparticle
    DOI:  https://doi.org/10.1080/17425247.2022.2112569
  143. Front Immunol. 2022 ;13 891822
    Efficacy and Safety of Curcumin and Curcuma longa Extract in the Treatment of Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trial.
    Liuting Zeng, Tiejun Yang, Kailin Yang, Ganpeng Yu, Jun Li, Wang Xiang, Hua Chen.
       Background: Modern pharmacological research found that the chemical components of Curcuma longa L. are mainly curcumin and turmeric volatile oil. Several recent randomized controlled trials (RCT) have shown that curcumin improves symptoms and inflammation in patients with arthritis.
    Methods: Pubmed, Cochran Library, CNKI, and other databases were searched to collect the randomized controlled trials (RCTs). Then, the risk of bias of RCTs were assessed and data of RCTs were extracted. Finally, RevMan 5.3 was utilized for meta-analysis.
    Results: Twenty-nine (29) RCTs involving 2396 participants and 5 types of arthritis were included. The arthritis included Ankylosing Spondylitis (AS), Rheumatoid Arthritis (RA), Osteoarthritis (OA), Juvenile idiopathic arthritis (JIA) and gout/hyperuricemia. Curcumin and Curcuma longa Extract were administered in doses ranging from 120 mg to 1500 mg for a duration of 4-36 weeks. In general, Curcumin and Curcuma longa Extract showed safety in all studies and improved the severity of inflammation and pain levels in these arthritis patients. However, more RCTs are needed in the future to elucidate the effect of Curcumin and Curcuma longa Extract supplementation in patients with arthritis, including RA, OA, AS and JIA.
    Conclusion: Curcumin and Curcuma longa Extract may improve symptoms and inflammation levels in people with arthritis. However, due to the low quality and small quantity of RCTs, the conclusions need to be interpreted carefully.
    Keywords:  Curcuma longa extract; ankylosing spondylitis; curcumin; juvenile idiopathic arthritis; meta-analysis; osteoarthritis; rheumatoid arthritis; systematic review
    DOI:  https://doi.org/10.3389/fimmu.2022.891822
  144. ACS Appl Mater Interfaces. 2022 Aug 11.
    Size-Controllable DNA Origami-Stacked Gold Nanoparticles for Deep Tumor-Penetrating Therapy.
    Dening Gu, Yanqi Qiao, Hongli Fu, Hongjie Zhao, Xinmin Yue, Shuo Wang, Yongmei Yin, Rimo Xi, Xiaoling Fu, Xiujie Zhao, Meng Meng.
      With the rapid development of nanotechnology, researchers have designed a variety of intelligent nanodelivery systems to enhance tumor targeting of anticancer drugs. However, increased tumor accumulation does not indicate deeper penetration in the tumor tissue, without which the tumor cells in the core area cannot be sufficiently killed. Herein, we develop a size-controllable nanoparticle system for deep-penetrating cancer therapy, which will be programmably disassembled with the decrease of the pH from the normal tissue to the tumor microenvironment and to the intracellular area. The integrated nanoparticle is composed of a gold nanoparticle (GNP, ∼30 nm) and a tetrahedral DNA nanostructure (TDN, ∼25 nm) loaded with doxorubicin (DOX). Initially, the nanoparticles maintain a larger size (∼100 nm) to accumulate in the tumor through the enhanced permeability and retention effect. At a pH of about 6.5 at the tumor microenvironment, with the linkage of DNA sequences converting into a triplex structure, the TDNs detach from the GNP and penetrate deeply into the tumor interstitium and then are internalized into the cells. Finally, in acidic lysosomes with pH 5.0, the TDNs release DOX by forming an i-motif structure. This nanosmart delivery system thus shows effective deep penetration into the tumor core with good antitumor efficacy and satisfactory biocompatibility and provides new insights into the development of intelligent nanosystems for anti-cancer treatment.
    Keywords:  deep penetration; gold nanoparticles; pH response; size-controllable; tetrahedral DNA nanostructure (TDN)
    DOI:  https://doi.org/10.1021/acsami.2c05750
  145. Int J Nanomedicine. 2022 ;17 3313-3324
    Mechanism of Enhanced Oral Absorption of a Nano-Drug Delivery System Loaded with Trimethyl Chitosan Derivatives.
    Ying Zhao, Shiyuan Lin, Ruiyue Fang, Yaling Shi, Wei Wu, Wei Zhang, Hui Chen.
       Introduction: In the previous study, nanoparticles coated with trimethyl chitosan (TMC) derivatives (PPTT-NPs) could promote the oral bioavailability of panax notoginseng saponins (PNS). Herein, we chose PPTT-NPs as a model drug to study the property and mechanism of intestinal absorption in vitro and in vivo.
    Methods: The stability of PPTT-NPs was evaluated using simulated gastric fluid and simulated intestinal fluid. The uptake and transport of PPTT-NPs were investigated in Caco-2 and Caco-2&HT29 co-culture cells. The biosafety, intestinal permeability, adhesion, and absorption mechanism of PPTT-NPs were investigated using SD rats in vivo. The live imaging and biodistribution of PPTT-NPs were observed by IVIS. Furthermore, the effects on CYP3A4 of PPTT-NPs were investigated using testosterone as the probe substrate.
    Results: The results of the stability assay showed that PPTT-NPs had a strong tolerance to the pH and digestive enzymes in the gastrointestinal environment. In vitro cell experiments showed that the uptake of drugs exhibited a time-dependent. When the ratio of TMC-VB12 and TMC-Cys was 1:3, the uptake capacity of PPTT-NPs was the highest. PPTT-NPs could enhance the paracellular transport of drugs by reversibly opening a tight junction. Animal experiments demonstrated that PPTT-NPs have good biological safety. PPTT-NPs had good adhesion and permeability to small intestinal mucosa. Meanwhile, PPTT-NPs needed energy and various protein to participate in the uptake of drugs. The live imaging of NPs illustrated that PPTT-NPs could prolong the residence time in the intestine. Moreover, TMC-VB12 and TMC-Cys could reduce the metabolism of drugs by inhibiting CYP3A4 to a certain extent.
    Conclusion: The results show that TMC-VB12 and TMC-Cys are effective in the transport of PPTT-NPs. PPTT-NPs can increase the intestinal adhesion of drugs and exert high permeation by intestinal enterocytes which demonstrate significant and efficient potential for oral delivery of the BCS III drugs.
    Keywords:  Caco-2&HT29 co-culture cells; Panax notoginseng saponins; TMC derivatives; nanoparticles; oral absorption
    DOI:  https://doi.org/10.2147/IJN.S358832
  146. Mol Biol Rep. 2022 Aug 08.
    Modulatory effect of berberine on plasma lipoprotein (or lipid) profile: a review.
    Navid Nourizadeh, Leila Vazifeh Mostaan, Ehsan Saburi, Seyed Isaac Hashemy.
      Berberine is a bioactive isoquinoline alkaloid compound extracted from various medicinal plants, such as Barberry. Berberine shows various pharmacological properties that are mainly attributed to its anti-inflammatory and antioxidant effects. A growing body of evidence has shown that berberine influences cholesterol metabolism, and consequently, may ameliorate dyslipidemias and atherosclerosis. Plasma high-density lipoprotein cholesterol (HDL-C) is known to have an independent negative association with incident cardiovascular disease (CVD). However, several outcomes trials and genetic studies have failed to meet expecting the beneficial effects of elevating plasma HDL-C concentrations. Hence, investigations are currently focused on enhancing the functionality of HDL particles, independent of their plasma concentrations. HDL particles show various qualities because of a heterogeneous composition. Consistent with complex metabolism and composition, various biological functions are found for HDL, such as anti-inflammatory, antioxidant, anti-apoptotic, and anti-thrombotic activities. Protective effects of berberine may impact the functionality of HDL; therefore, the present literature review was intended to determine whether berberine can amplify HDL function. It was concluded that berberine may regulate markers of HDL activity, such as apo-AI, cholesterol efflux, LCAT, PON1, and S1P activities and levels. Consequently, berberine may recuperate conditions with dysfunctional HDL and, therefore, have the potential to emerge as a therapeutic agent. However, further human trials of berberine are warranted to evaluate its impact on HDL function and cholesterol metabolism.
    Keywords:  Berberine; Cholesterol efflux; Dyslipidemia; High-density lipoprotein
    DOI:  https://doi.org/10.1007/s11033-022-07623-7
  147. Transl Lung Cancer Res. 2022 Jul;11(7): 1405-1419
    BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming.
    Kai Xie, Jian Feng, Dingwei Fan, Shi Wang, Jing Luo, Zhijian Ren, Chao Zheng, Yifei Diao, Ramon Andrade De Mello, Simona Tavolari, Giovanni Brandi, Anja C Roden, Binhui Ren, Yi Shen, Lin Xu.
       Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD).
    Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2.
    Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming.
    Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.
    Keywords:  BARX2; HK2; Transcription factor; glucose metabolism; lung adenocarcinoma (LUAD)
    DOI:  https://doi.org/10.21037/tlcr-22-465
  148. Anticancer Drugs. 2022 Aug 10.
    Defibrotide suppresses brain metastasis by activating the adenosine A2A receptors.
    Ce Dong, Lin Zhu, Xiongfei Yue, Zheng Sun, Cong Wang, Zhanying Ye, Baogen Pan.
      Brain metastasis is a devastating clinical condition globally as one of the most common central nervous system malignancies. The current study aimed to assess the effect of defibrotide, an Food and Drug Administration-approved drug, against brain metastasis and the underlying molecular mechanisms. Two tumor cell lines with high brain metastasis potential, PC-9 and 231-BR, were subjected to defibrotide treatment of increasing dosage. The metastasis capacity of the tumor cells was evaluated by cell invasion and migration assays. Western blotting was employed to determine the levels of tight junction proteins in the blood-brain barrier (BBB) including Occludin, Zo-1, and Claudin-5, as well as metastasis-related proteins including CXCR4, MMP-2, and MMP-9. The in-vitro observations were further verified in nude mice, by monitoring the growth of xenograft tumors, mouse survival and brain metastasis foci following defibrotide treatment. Defibrotide inhibited proliferation, migration, invasion, and promotes lactate dehydrogenase release of brain metastatic tumor cells, elevated the levels of BBB tight junction proteins and metastasis-related proteins. Such beneficial role of defibrotide was mediated by its inhibitory action on the SDF-1/CXCR4 signaling axis both in vitro and in vivo, as CXCR4 agonist SDF1α negated the anti-tumoral effect of defibrotide on mouse xenograft tumor growth, mouse survival and brain metastasis. Defibrotide inhibits brain metastasis through activating the adenosine A2A receptors, which in turn inhibits the SDF-1/CXCR4 signaling axis. Our study hereby proposes defibrotide as a new and promising candidate drug against brain metastasis of multiple organ origins.
    DOI:  https://doi.org/10.1097/CAD.0000000000001372
  149. Polymers (Basel). 2022 Aug 05. pii: 3205. [Epub ahead of print]14(15):
    In Vitro Evaluation of Kaempferol-Loaded Hydrogel as pH-Sensitive Drug Delivery Systems.
    Qin Zhang, Xinying Yang, Yifang Wu, Chang Liu, Hongmei Xia, Xiaoman Cheng, Yongfeng Cheng, Ying Xia, Yu Wang.
      The purpose of this study was to prepare and evaluate kaempferol-loaded carbopol polymer (acrylic acid) hydrogel, investigate its antioxidant activity in vitro, and compare the effects on drug release under different pH conditions. Drug release studies were conducted in three different pH media (pH 3.4, 5.4, and 7.4). The kaempferol-loaded hydrogel was prepared by using carbopol 934 as the hydrogel matrix. The morphology and viscosity of the preparation were tested to understand the fluidity of the hydrogel. The antioxidant activity of the preparation was studied by scavenging hydrogen peroxide and 2,2-diphenyl-1-picrilhidrazil (DPPH) radicals in vitro and inhibiting the production of malondialdehyde in mouse tissues. The results showed that kaempferol and its preparations had high antioxidant activity. In vitro release studies showed that the drug release at pH 3.4, 5.4, and 7.4 was 27.32 ± 3.49%, 70.89 ± 8.91%, and 87.9 ± 10.13%, respectively. Kaempferol-loaded carbopol hydrogel displayed greater swelling and drug release at higher pH values (pH 7.4).
    Keywords:  antioxidation; carbopol 934; different pH; drug release; kaempferol
    DOI:  https://doi.org/10.3390/polym14153205
  150. Mol Pharm. 2022 Aug 08.
    Linoleic Acid-Glucosamine Hybrid for Endogenous Iron-Activated Ferroptosis Therapy in High-Grade Serous Ovarian Cancer.
    Ying Chen, Xiaoming Liao, Pei Jing, Liangkui Hu, Zengqiu Yang, Yongchao Yao, Chunyan Liao, Shiyong Zhang.
      As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA-GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA-GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA-GlcN. The in vitro study demonstrated that LA-GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA-GlcN at the dose of 50 mg kg-1 achieved a comparable tumor inhibition as doxorubicin hydrochloride (4 mg kg-1) while the overall survival of mice was extended largely due to the low toxicity, and when the dose was increased to 100 mg kg-1, the therapeutic outcomes could be improved further. This dietary hybrid which targets the excess endogenous iron to activate ferroptosis represents a promising drug for HGSOC treatment.
    Keywords:  ferroptosis; glucosamine; high-grade serous ovarian cancer (HGSOC); hybrid; linoleic acid
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00333
  151. J Ethnopharmacol. 2022 Aug 04. pii: S0378-8741(22)00633-X. [Epub ahead of print] 115594
    Licorice: Resources, applications in ancient and modern times.
    Yiming Ding, Eric Brand, Wenquan Wang, Zhongzhen Zhao.
       ETHNOPHARMACOLOGICAL RELEVANCE: Licorice has been widely used as a medicinal herb since ancient times. Licorice is also spelled as "liquorice" and it is known as "Glycyrrhizae Radix et Rhizoma" (Chinese: gan cao) in the Chinese Pharmacopoeia. Licorice root has a wide range of pharmacological effects, including adrenocortical hormone-like effects, as well as multiple pharmacological effects on the digestive system, immune system, and cardiovascular system.
    AIM OF THE REVIEW: This review aims to comprehensively investigate the history of licorice and its medicinal and industrial applications in China and other nations, including research and application prospects related to the aerial parts of licorice.
    METHOD: An extensive review of the literature was carried out, including ancient and modern texts, doctoral and masters' theses, monographs on medicinal plants, pharmacopoeias and electronic databases, including Web of Science, Springer, CNKI, and Google Scholar.
    RESULTS: The ancient and modern applications of licorice were systematically investigated. In ancient times, practitioners in China discovered the medicinal potential of licorice and used it widely. In modern times, licorice is widely used in food, medicines and supplements, tobacco, chemical applications, environmental applications, animal husbandry and other industries. The potential of the aerial portion of the plant is also gradually being researched, developed, and utilized.
    CONCLUSION: Licorice is one of the oldest and most widely used herbal medicines in the world. This article reviews its medicinal potential and application in various fields, and briefly introduces current research into its aerial parts. This review aims to highlight the importance of licorice and provide direction for its future development.
    DOI:  https://doi.org/10.1016/j.jep.2022.115594
  152. Front Pharmacol. 2022 ;13 929854
    Recent Advance in Tumor Microenvironment-Based Stimuli-Responsive Nanoscale Drug Delivery and Imaging Platform.
    Fengzhi Cui, Jianhua Liu, Siwen Pang, Bo Li.
      The tumor microenvironment (TME) plays an important role in the development, progression, and metastasis of cancer, and the extremely crucial feature is hypoxic and acidic. Cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), mesenchymal cells, blood vessels, and interstitial fluid are widely recognized as fundamentally crucial hallmarks for TME. As nanotechnology briskly boomed, the nanoscale drug delivery and imaging platform (NDDIP) emerged and has attracted intensive attention. Based on main characteristics of TME, NDDIP can be classified into pH-sensitive delivery and imaging platforms, enzyme-sensitive delivery and imaging platforms, thermo-sensitive delivery and imaging platforms, redox-sensitive delivery and imaging platforms, and light-sensitive delivery and imaging platforms. Furthermore, imageology is one of the significant procedures for disease detection, image-guided drug delivery, and efficacy assessment, including magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), and fluorescence imaging. Therefore, the stimuli-responsive NDDIP will be a versatile and practicable tumor disease diagnostic procedure and efficacy evaluation tool. In this review article, we mainly introduce the characteristics of TME and summarize the progress of multitudinous NDDIP as well as their applications.
    Keywords:  TME; cancer therapy; imaging platform; nanomaterials; stimuli-responsive nanoscale drug delivery
    DOI:  https://doi.org/10.3389/fphar.2022.929854
  153. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 10. e1841
    Nano-embedded medical devices and delivery systems in interventional radiology.
    Erin Marie D San Valentin, Allan John R Barcena, Carleigh Klusman, Benjamin Martin, Marites P Melancon.
      Nanomaterials research has significantly accelerated the development of the field of vascular and interventional radiology. The incorporation of nanoparticles with unique and functional properties into medical devices and delivery systems has paved the way for the creation of novel diagnostic and therapeutic procedures for various clinical disorders. In this review, we discuss the advancements in the field of interventional radiology and the role of nanotechnology in maximizing the benefits and mitigating the disadvantages of interventional radiology theranostic procedures. Several nanomaterials have been studied to improve the efficacy of interventional radiology interventions, reduce the complications associated with medical devices, improve the accuracy and efficiency of drug delivery systems, and develop innovative imaging modalities. Here, we summarize the recent progress in the development of medical devices and delivery systems that link nanotechnology in vascular and interventional radiology. This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease.
    Keywords:  interventional radiology; nano-drug delivery; nanodevice; nanotechnology; vascular radiology
    DOI:  https://doi.org/10.1002/wnan.1841
  154. J Nanobiotechnology. 2022 Aug 11. 20(1): 372
    Injectable pH-responsive hydrogel for combinatorial chemoimmunotherapy tailored to the tumor microenvironment.
    Jun Gu, Gang Zhao, Jiangkun Yu, Pei Xu, Jiabin Yan, Zhengshuai Jin, Sheng Chen, Yong Wang, Leshuai W Zhang, Yangyun Wang.
      Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects.
    Keywords:  Chemoimmunotherapy; Injectable hydrogel; Silk-chitosan composite; Tumor microenvironment; pH-responsive
    DOI:  https://doi.org/10.1186/s12951-022-01561-z
  155. Evid Based Complement Alternat Med. 2022 ;2022 6229444
    Study on the Action Mechanism of the Yifei Jianpi Tongfu Formula in Treatment of Colorectal Cancer Lung Metastasis Based on Network Analysis, Molecular Docking, and Experimental Validation.
    Wanli Zhu, Rundong Zhang, Chenchao Ma, Yangyang Hu, Xuan Shi, Xiyu Wang, Xing Wu, Kaixing Ai.
       Objective: The lung is the second most common site of colorectal cancer (CRC) metastasis. This study aims to investigate the therapeutic effects and potential action mechanisms of Yifei Jianpi Tongfu formula (YJTF) in CRC lung metastasis in a comprehensive and systematic way by network analysis, molecular docking, and experimental verification.
    Methods: The main ingredients in YJTF were screened from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID), and the disease-related targets from the Online Mendelian Inheritance in Man (OMIM) and GeneCards and the compound-related targets from SwissTargetPrediction were collected. Then, Metascape was used for pathway annotation and enrichment analysis, and meanwhile, a protein-protein interaction (PPI) network was constructed. Molecular docking was carried out to investigate interactions between the active compounds and the potential targets. The in vivo effect of YJTF on CRC lung metastasis was observed in a tail vein injection mouse model.
    Results: A total of 243 active compounds and 81 disease-related targets of YJTF were selected for analysis. The results of multiple network analysis showed that the core targets of YJTF were enriched onto various cancer-related pathways, especially focal adhesion and adherens junction. The results of molecular docking demonstrated that all core compounds (quercetin, kaempferol, luteolin, apigenin, and isorhamnetin) were capable of binding with AKT1, EGFR, SRC, ESR1, and PTGS2. Experimental validation in vivo demonstrated that YJTF combined with oxaliplatin could significantly reduce the number of lung metastases and improve the quality of life in mice. Further research suggested that YJTF inhibited CRC lung metastasis probably by modulating epithelial-to-mesenchymal transition (EMT).
    Conclusions: According to the analysis, YJTF can be considered as an effective adjuvant therapy for CRC lung metastasis.
    DOI:  https://doi.org/10.1155/2022/6229444
  156. Front Oncol. 2022 ;12 939089
    Emerging roles of platelets in cancer biology and their potential as therapeutic targets.
    Lei Wang, Xueying Wang, Erliang Guo, Xionghui Mao, Susheng Miao.
      The main role of platelets is to control bleeding and repair vascular damage via thrombosis. They have also been implicated to promote tumor metastasis through platelet-tumor cell interactions. Platelet-tumor cell interactions promote tumor cell survival and dissemination in blood circulation. Tumor cells are known to induce platelet activation and alter platelet RNA profiles. Liquid biopsies based on tumor-educated platelet biomarkers can detect tumors and correlate with prognosis, personalized therapy, treatment monitoring, and recurrence prediction. Platelet-based strategies for cancer prevention and tumor-targeted therapy include developing drugs that target platelet receptors, interfere with the release of platelet particles, inhibit platelet-specific enzymes, and utilize platelet-derived "nano-platelets" as a targeted drug delivery platform for tumor therapy. This review elaborates on platelet-tumor cell interactions and the molecular mechanisms and discusses future research directions for platelet-based liquid biopsy techniques and platelet-targeted anti-tumor strategies.
    Keywords:  NETosis; immune escape; liquid biopsy; platelet activation; platelet aggregation activity; tumor metastasis; tumor treatment
    DOI:  https://doi.org/10.3389/fonc.2022.939089
  157. Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00647-5. [Epub ahead of print]
    Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.
    Consuelo Torrini, Trang Thi Thu Nguyen, Chang Shu, Angeliki Mela, Nelson Humala, Aayushi Mahajan, Erin Heather Seeley, Guoan Zhang, Mike-Andrew Westhoff, Georg Karpel-Massler, Jeffrey N Bruce, Peter Canoll, Markus D Siegelin.
      Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.
    Keywords:  ATAC-seq; ChIP-seq; glioblastoma; lactate; metabolic flux analysis; tumor metabolism
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.030
  158. Int J Pharm. 2022 Aug 09. pii: S0378-5173(22)00655-X. [Epub ahead of print] 122101
    Nanotechnology based drug delivery systems: Does shape really matter?
    Saurabh Shah, Paras Famta, Deepkumar Bagasariya, Kondasingh Charankumar, Etikala Amulya, Dharmendra Kumar Khatri, Rajeev Singh Raghuvanshi, Shashi Bala Singh, Saurabh Srivastava.
      As of today, the era of nanomedicine has brought numerous breakthroughs and overcome challenges in the treatment of various disorders. Various factors like size, charge and surface hydrophilicity have garnered significant attention by nanotechnologists. However, more exploration in the field of nanoparticle shape and geometry, one of the basic physical phenomenon is required. Tuning nanoparticle shape and geometry could potentially overcome pitfalls in therapeutics and biomedical fields. Thus, in this article, we unveil the importance of tuning nanoparticle shape selection across the delivery platforms. This article provides an in-depth understanding of nanoparticle shape modulation and advise the researchers on the ideal morphology selection tailored for each implication. We deliberated the importance of nanoparticle shape selection for specific implications with respect to organ targeting, cellular internalization, pharmacokinetics and bio-distribution, protein corona formation as well as RES evasion and tumor targeting. An additional section on the significance of shape transformation, a recently introduced novel avenue with applications in drug delivery was discussed. Furthermore, regulatory concerns towards nanoparticle shape which need to be addressed for harnessing their clinical translation will be explained.
    Keywords:  Biofilm; Blood-brain barrier; Nanoparticle geometry; Pharmacokinetics; Protein corona
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122101
  159. Adv Pharm Bull. 2022 May;12(3): 524-530
    Melanoma Cancer Therapy Using PEGylated Nanoparticles and Semiconductor Laser.
    Abdorreza Asrar, Zahra Sobhani, Mohammad Ali Behnam.
      Purpose: Photothermal therapy (PTT) is a procedure that converts laser beam energy to heat so can disturb tumor cells. Carbon nanotubes (CNTs) have unique properties in absorption optical energy and could change optical power into heat in PTT procedures. Additionally, titanium dioxide (TiO2) nanoparticles (NPs) have a unique feature in absorbing and scattering light. Therefore, these mentioned NPs could play a synergistic role in the PTT method. Methods: CNTs and TiO2 NPs were injected into the melanoma tumor sites of cancerous mice. Then sites were excited using the laser beam (λ = 808 nm, P = 2 W, and I = 4 W/cm2). Injected NPs caused hyperthermia in solid tumors. Tumor size assay, statistical analysis, and histopathological study of the treated cases were performed to assess the role of mentioned NPs in PTT of murine melanoma cancer. Results: The results showed that CNTs performed better than TiO2 NPs in destroying murine melanoma cancer cells in animals. Conclusion: The present study compared the photothermal activity of excited CNTs and TiO2 NPs in cancer therapy at the near-infrared spectrum of light. Tumors were destroyed selectively because of their weakened heat resistance versus normal tissue. PTT of malignant melanoma through CNTs caused remarkable necrosis into the tumor tissues versus TiO2 NPs.
    Keywords:  Cancer therapy; Carbon nanotube; Hyperthermia; Melanoma; Photothermal therapy; TiO2 NPs
    DOI:  https://doi.org/10.34172/apb.2022.055
  160. Mol Pharm. 2022 Aug 08.
    Kidney-Targeted Drug Delivery System Based on Metformin-Grafted Chitosan for Renal Fibrosis Therapy.
    Haihan Sun, Kun Shi, Bangjie Zuo, Xin Zhang, Yue Liu, Dong Sun, Fengzhen Wang.
      Our previous study demonstrated that metformin plays an anti-fibrotic role in addition to its hypoglycemic effect. Worryingly, it often requires more than 5 times the hypoglycemic dose to achieve a satisfactory anti-fibrotic effect, which greatly increases the risk of systemic acidosis caused by metformin overdose. Low-molecular-weight chitosan (LMWC) has natural kidney-targeting properties and good biocompatibility and degradability. Thus, we synthesized a novel carrier metformin-grafted chitosan (CS-MET) based on an imine reaction between oxidized chitosan and metformin. Then, GFP was recruited to form GFP-loaded CS-MET nanoparticles (CS-MET/GFP NPs) with controllable particle size. We hypothesized that CS-MET/GFP NPs would enrich in the kidney and be absorbed by HK-2 cells via megalin-mediated endocytosis by intravenous injection, which may avoid systemic acidosis caused by metformin overdose. Subsequently, the nanoparticle ruptures and releases metformin to exert its anti-apoptotic, anti-inflammatory, and anti-fibrotic effects. Our results showed that CS-MET/GFP NPs have great transfection efficiency and could enter HK-2 cells mainly through megalin-mediated endocytosis. Compared to the free metformin, CS-MET/GFP NPs showed similar anti-apoptotic ability but better therapeutic effects on cellular inflammation and fibrosis in vitro. On the other hand, CS-MET/GFP NPs showed great kidney-targeting ability and superior anti-apoptotic, anti-inflammatory, and anti-fibrotic effects in vivo.
    Keywords:  chitosan; kidney-targeting; metformin; renal fibrosis
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00827
  161. J Oncol Pharm Pract. 2022 Aug 08. 10781552221118848
    KRAS-targeted therapy in the treatment of non-small cell lung cancer.
    Jina Yun, Reid Nakagawa, Kenneth Tham.
       OBJECTIVE: KRAS mutations are one of the most common driver mutations in non-small cell lung cancer. Though previously believed to be an undruggable target, recent advances in therapeutics have seen new targeted agents against KRAS mutations. The objective of this article is to review currently available and upcoming KRAS-targeted treatments.
    DATA SOURCES: Currently available trials examining KRAS-targeted therapy in non-small cell lung cancer were examined by searching for the keyword "KRAS inhibitors." The pivotal trials for sotorasib and adagrasib were reviewed for this article.
    DATA SUMMARY: Mutated KRAS can be challenging to target for a variety of reasons. In 2021, the US Food and Drug Administration approved sotorasib for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutation as determined by a Food and Drug Administration-approved test, who have received at least one prior systemic therapy. A multicenter, single-group, open-label, phase 2 trial was able to demonstrate that sotorasib was able to demonstrate objective response, progression-free survival, and overall survival in this patient population. A phase 3 trial comparing sotorasib to docetaxel in the subsequent-line treatment of KRAS G12C non-small cell lung cancer is currently ongoing. There are other KRAS-targeted agents currently under study, including adagrasib, with growing interest in targeting KRAS downstream pathways.
    CONCLUSION: Further trials need to be conducted in order to identify other targeted agents for KRAS and the appropriate place in therapy among currently approved treatments for non-small cell lung cancer.
    Keywords:  KRAS; adagrasib; non-small cell lung cancer; sotorasib; targeted therapy
    DOI:  https://doi.org/10.1177/10781552221118848
  162. Food Sci Nutr. 2022 Aug;10(8): 2582-2589
    Fabrication of nanoemulsion delivery system with high bioaccessibility of carotenoids from Lycium barbarum by spontaneous emulsification.
    Chunlan Zhang, Bin Li.
      The interest in incorporating carotenoids into foods and beverages is growing due to their potential health benefits. However, the poor water solubility and low bioavailability of carotenoids are still challenges in food application. This work aimed to study the influence of system composition and preparation conditions on the physical properties of carotenoids-loaded nanoemulsions prepared by spontaneous emulsification. Furthermore, the bioaccessibility of carotenoids in the nanoemulsions was evaluated. The nanoemulsions with the smallest droplet size were produced when the ratio of Span 80:Tween 80 was 1.5:8.5. The droplet size increased slightly with the increase of organic phase content (24%-40%). The droplet size decreased gradually with the increase of stirring speed (200-1000 rpm (revolutions per minute)). The ratio of mixed surfactants and surfactant-to-oil ratio (SOR) had an appreciable impact on the droplet size. Carotenoids-loaded nanoemulsions with small mean droplet size (d < 50 nm) could be prepared with the optimized conditions. The initial digestion rate decreased as the SOR increased. The bioaccessibility could reach up to about 80% at SOR=2-5 in vitro digestion. These results have important implications for the design of effective delivery systems to encapsulate carotenoids and other lipophilic bioactive components in food applications.
    Keywords:  bioaccessibility; carotenoids; nanoemulsions; spontaneous emulsification
    DOI:  https://doi.org/10.1002/fsn3.2863
  163. Polymers (Basel). 2022 Jul 31. pii: 3126. [Epub ahead of print]14(15):
    Functional Thermoresponsive Hydrogel Molecule to Material Design for Biomedical Applications.
    Sagar Pardeshi, Fouad Damiri, Mehrukh Zehravi, Rohit Joshi, Harshad Kapare, Mahendra Kumar Prajapati, Neha Munot, Mohammed Berrada, Prabhanjan S Giram, Satish Rojekar, Faraat Ali, Md Habibur Rahman, Hasi Rani Barai.
      Temperature-induced, rapid changes in the viscosity and reproducible 3-D structure formation makes thermos-sensitive hydrogels an ideal delivery system to act as a cell scaffold or a drug reservoir. Moreover, the hydrogels' minimum invasiveness, high biocompatibility, and facile elimination from the body have gathered a lot of attention from researchers. This review article attempts to present a complete picture of the exhaustive arena, including the synthesis, mechanism, and biomedical applications of thermosensitive hydrogels. A special section on intellectual property and marketed products tries to shed some light on the commercial potential of thermosensitive hydrogels.
    Keywords:  biosensing; drug delivery; hydrogel; release kinetics; thermoresponsive
    DOI:  https://doi.org/10.3390/polym14153126
  164. Cancers (Basel). 2022 Jul 30. pii: 3717. [Epub ahead of print]14(15):
    Association between Vitamin D Supplementation and Cancer Mortality: A Systematic Review and Meta-Analysis.
    Renjie Zhang, Yu Zhang, Zheran Liu, Yiyan Pei, Ping Xu, Weelic Chong, Yang Hai, Ling He, Yan He, Jiayi Yu, Jingjing Wang, Fang Fang, Xingchen Peng.
       BACKGROUND: Vitamin D deficiency is related to increased cancer risk and deaths. However, whether vitamin D supplementation reduces cancer mortality remains unclear, and several randomized controlled trials yield inconsistent results.
    METHODS: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched from their inception until 28 June 2022, for randomized controlled trials investigating vitamin D supplementation. Pooled relative risks (RRs) and their 95% confidence intervals (CIs) were estimated. Trials with vitamin D supplementation combined with calcium supplementation versus placebo alone and recruiting participants with cancer at baseline were excluded in the present study.
    RESULTS: This study included 12 trials with a total of 72,669 participants. Vitamin D supplementation did not reduce overall cancer mortality (RR 0.96, 95% CI 0.80-1.16). However, vitamin D supplementation was associated with a reduction in lung cancer mortality (RR 0.63, 95% CI 0.45-0.90).
    CONCLUSIONS: Vitamin D supplementation could not reduce cancer mortality in this highly purified meta-analysis. Further RCTs that evaluate the association between vitamin D supplementation and total cancer mortality are still needed.
    Keywords:  Vitamin D supplementation; cancer incidence; cancer mortality; meta-analysis
    DOI:  https://doi.org/10.3390/cancers14153717
  165. Int J Surg. 2022 Aug 08. pii: S1743-9191(22)00595-7. [Epub ahead of print] 106818
    Nanoparticles in clinical trials of COVID-19: An update.
    Abdur Rauf, Tareq Abu-Izneid, Anees Ahmed Khalil, Nabia Hafeez, Ahmed Olatunde, Mominur Rahman, Prabhakar Semwal, Yahya Saleh Al-Awthan, Omar Salem Bahattab, Ishaq N Khan, Muhammad Arslan Khan, Rohit Sharma.
      Once the World Health Organization (WHO) declared the COVID-19 (Coronavirus Infectious Disease-19) outbreak to be pandemic, massive efforts have been launched by researchers around the globe to combat this emerging infectious disease. Strategies that must be investigated such as expanding testing capabilities, developing effective medicines, as well as developing safe and effective vaccines for COVID-19 disease that produce long-lasting immunity to human system. Now-a-days, bio-sensing, medication delivery, imaging, and antimicrobial treatment are just a few of the medical applications for nanoparticles (NPs). Since the early 1990s, nanoparticle drug delivery methods have been employed in clinical trials. Since then, the discipline of nanomedicine has evolved in tandem with expanding technological demands to better medicinal delivery. Newer generations of NPs have emerged in recent decades that are capable of performing additional delivery tasks, allowing for therapy via novel therapeutic modalities. Many of these next generation NPs and associated products have entered clinical trials and have been approved for diverse indications in the present clinical environment. For systemic applications, NPs or nanomedicine-based drug delivery systems have substantial benefits over their non-formulated and free drug counterparts. Nanoparticle systems, for example, are capable of delivering medicines and treating parts of the body that are inaccessible to existing delivery systems. As a result, NPs medication delivery is one of the most studied preclinical and clinical systems. NPs-based vaccines delivering SARS-CoV-2 antigens will play an increasingly important role in prolonging or improving COVID-19 vaccination outcomes. This review provides insights about employing NPs-based drug delivery systems for the treatment of COVID-19 to increase the bioavailability of current drugs, reducing their toxicity, and to increase their efficiency. This article also exhibits their capability and efficacy, and highlighting the future aspects and challenges on nanoparticle products in clinical trials of COVID-19.
    Keywords:  COVID-19; Drug delivery; Immunotherapy; Nanoparticles; Pandemic; Vaccines
    DOI:  https://doi.org/10.1016/j.ijsu.2022.106818
  166. Regen Biomater. 2022 ;9 rbac050
    Anti-melanoma effect and action mechanism of a novel chitosan-based composite hydrogel containing hydroxyapatite nanoparticles.
    Kejia Xu, Yifu Wang, Yao Xie, Xiaoyan Zhang, Wei Chen, Zhongtao Li, Tingting Wang, Xiao Yang, Bo Guo, Lin Wang, Xiangdong Zhu, Xingdong Zhang.
      Hydroxyapatite nanoparticles (HANPs) have been increasingly regarded and reported due to their potential anti-tumor ability. Previously, we found that the rod-like HANPs had good application potential for cutaneous melanoma (CMM). To satisfy the actual requirements in repairing post-operative skin defects and inhibiting CMM recurrence after tumorectomy, we constructed a novel chitosan/alginate (CS/Alg) hydrogel containing the aforementioned HANPs. The in vitro cell experiments confirmed that activated mitochondrial-dependent apoptosis was tightly related to the anti-tumor ability of HANPs. Specifically, we further discovered several target proteins might be involved in abnormal activating Wnt, proteoglycans in cancer, oxidative phosphorylation and p53 signaling pathways. The in vivo animal experiments demonstrated that the HANPs-loaded CS/Alg hydrogel (CS/Alg/HANPs) had a similar effect on inhibiting tumor growth as HANPs, and CS/Alg hydrogel as well as phosphate buffered saline (PBS) group (control) not showed any effect, proving the key role of HANPs. The immunohistochemical staining demonstrated a tumor inhibition via the mitochondria-mediated apoptosis pathway, consistent with the in vitro evaluation. Moreover, CS/Alg/HANPs exhibited no additional biosafety risk to the functions of major organs. Overall, this CS/Alg/HANPs hydrogel has substantial application potential for treating CMM.
    Keywords:  biosafety; composite hydrogel; hydroxyapatite nanoparticles; melanoma; tumor inhibition
    DOI:  https://doi.org/10.1093/rb/rbac050
  167. Adv Pharm Bull. 2022 May;12(3): 437-448
    Polymeric Hydrogel Scaffolds: Skin Tissue Engineering and Regeneration.
    Varuna Naga Venkata Arjun Uppuluri, Shanmugarajan Thukani Sathanantham, Sai Krishna Bhimavarapu, Lokesh Elumalai.
      Tissue engineering is a novel regenerative approach in the medicinal field that promises the regeneration of damaged tissues. Moreover, tissue engineering involves synthetic and natural biomaterials that facilitate tissue or organ growth outside the body. Not surprisingly, the demand for polymer-based therapeutical approaches in skin tissue defects has increased at an effective rate, despite the pressing clinical need. Among the 3D scaffolds for tissue engineering and regeneration approaches, hydrogel scaffolds have shown significant importance for their use as 3D cross-linked scaffolds in skin tissue regeneration due to their ideal moisture retention property and porosity biocompatibility, biodegradable, and biomimetic characteristics. In this review, we demonstrated the choice of ideal biomaterials to fabricate the novel hydrogel scaffolds for skin tissue engineering. After a short introduction to the bioactive and drug-loaded polymeric hydrogels, the discussion turns to fabrication and characterisation techniques of the polymeric hydrogel scaffolds. In conclusion, we discuss the excellent wound healing potential of stem cell-loaded hydrogels and Nano-based approaches to designing hydrogel scaffolds for skin tissue engineering.
    Keywords:  Hydrogel; Skin; Tissue engineering; Wound healing
    DOI:  https://doi.org/10.34172/apb.2022.069
  168. Int J Pharm. 2022 Aug 08. pii: S0378-5173(22)00647-0. [Epub ahead of print] 122093
    Advances on nanoformulation approaches for delivering plant-derived antioxidants: A case of quercetin.
    Sachin Rathod, Shristi Arya, Shirisha Kanike, Shailesh A Shah, Pratap Bahadur, Sanjay Tiwari.
      Oxidative stress has been implicated in tumorigenic, cardiovascular, neuro-, and age-related degenerative changes. Antioxidants minimize the oxidative damage through neutralization of reactive oxygen species (ROS) and other causative agents. Ever since the emergence of COVID-19, plant-derived antioxidants have received enormous attention, particularly in the Indian subcontinent. Quercetin (QCT), a bio-flavonoid, exists in the glycosylated form in fruits, berries and vegetables. The antioxidant potential of QCT analogs relates to the number of free hydroxyl groups in their structure. Despite presence of these groups, QCT exhibits substantial hydrophobicity. Formulation scientists have tested nanotechnology-based approaches for its improved solubilization and delivery to the intended site of action. By the virtue of its hydrophobicity, QCT gets encapsulated in nanocarriers carrying hydrophobic domains. Apart from passive accumulation, active uptake of such formulations into the target cells can be facilitated through well-studied functionalization strategies. In this review, we have discussed the approaches of improving solubilization and bioavailability of QCT with the use of nanoformulations.
    Keywords:  Antioxidants; Colloidal formulations; Flavonoids; Oxidative stress; Reactive oxygen species; Self-assembly
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122093
  169. Ethiop J Health Sci. 2022 Jul;32(4): 833-840
    The Effects of Chitosan-PEG Nanoparticles Based on Channa striata Protein Hydrolyzate on Decreasing Diabetes Mellitus in Diabetic Rats.
    Lintang Dian Saraswati, Bagoes Widjanarko, Vivi Endar Herawati, Apriliani Ismi Fauziah.
       Background: Channa striata has several good nutrients, including 70% protein, 20% albumin, complete amino acids, zinc, selenium, and iron. However, no study has investigated the chitosan-PEG nanoparticles based on Channa striata protein hydrolyzate. This study's purpose was to determine the role of 10% Channa striata protein hydrolyzate, chitosan-PEG 4000 nanoparticles, and chitosan-PEG 6000 nanoparticles in reducing diabetes mellitus in diabetic rats.
    Method: A randomized pretest-posttest control group design was used, with male Sprague-Dawley rats being divided into five groups: STZ, acarbose, hydrolyzate, chitosan-PEG 4000 nanoparticles, and chitosan-PEG 6000 nanoparticles. Diabetes was induced by a single injection of streptozotocin at 1 ml in each formulation. Blood glucose levels were analyzed using a glucometer 7, 14, and 21 days after treatment. The CHOD-PAP method was used to analyze the lipid profile. Pancreas and liver histology analyses were carried out using a microscope.
    Results: The formulation of 10% Channa striata protein hydrolyzate and PEG 6000 was the most effective in lowering blood glucose concentrations, and the response was close to the acarbose result. The glucose concentration decreased after daily oral administration of chitosan-PEG nanoparticles for 21 days. The plasma cholesterol, triglycerides, LDL, and HDL concentrations were lower in treated than in untreated diabetic rats.
    Conclusion: This study concluded that the formulation of 10% Channa striata protein hydrolyzate and chitosan-PEG 6000 nanoparticles was more effective than acarbose.
    Keywords:  Channa striata; Chitosan nanoparticles; Diabetes mellitus; blood glucose; lipid profile
    DOI:  https://doi.org/10.4314/ejhs.v32i4.21
  170. Adv Pharm Bull. 2022 May;12(3): 490-508
    Nanotechnology Approaches for Enhanced CNS Drug Delivery in the Management of Schizophrenia.
    Rajalakshmi Rajendran, Krishnakumar Neelakandha Menon, Sreeja Chandrasekharan Nair.
      Schizophrenia is a neuropsychiatric disorder mainly affecting the central nervous system (CNS), presented with auditory and visual hallucinations, delusion and withdrawal from society. Abnormal dopamine levels mainly characterise the disease; various theories of neurotransmitters explain the pathophysiology of the disease. The current therapeutic approach deals with the systemic administration of drugs other than the enteral route, altering the neurotransmitter levels within the brain and providing symptomatic relief. Fluid biomarkers help in the early detection of the disease, which would improve the therapeutic efficacy. However, the major challenge faced in CNS drug delivery is the blood-brain barrier (BBB). Nanotherapeutic approaches may overcome these limitations, which will improve safety, efficacy, and targeted drug delivery. This review article addresses the main challenges faced in CNS drug delivery and the significance of current therapeutic strategies and nanotherapeutic approaches for a better understanding and enhanced drug delivery to the brain, which improve the quality of life of schizophrenia patients.
    Keywords:  Biomarkers; Blood-brain barrier; Drug delivery systems; Nanotechnology; Schizophrenia
    DOI:  https://doi.org/10.34172/apb.2022.052
  171. Molecules. 2022 Jul 29. pii: 4871. [Epub ahead of print]27(15):
    Natural Dietary Compounds in the Treatment of Arsenic Toxicity.
    Geir Bjørklund, Md Shiblur Rahaman, Mariia Shanaida, Roman Lysiuk, Petro Oliynyk, Larysa Lenchyk, Salvatore Chirumbolo, Christos T Chasapis, Massimiliano Peana.
      Chronic exposure to arsenic (As) compounds leads to its accumulation in the body, with skin lesions and cancer being the most typical outcomes. Treating As-induced diseases continues to be challenging as there is no specific, safe, and efficacious therapeutic management. Therapeutic and preventive measures available to combat As toxicity refer to chelation therapy, antioxidant therapy, and the intake of natural dietary compounds. Although chelation therapy is the most commonly used method for detoxifying As, it has several side effects resulting in various toxicities such as hepatotoxicity, neurotoxicity, and other adverse consequences. Drugs of plant origin and natural dietary compounds show efficient and progressive relief from As-mediated toxicity without any particular side effects. These natural compounds have also been found to aid the elimination of As from the body and, therefore, can be more effective than conventional therapeutic agents in ameliorating As toxicity. This review provides an overview of the recently updated knowledge on treating As poisoning through natural dietary compounds. This updated information may serve as a basis for defining novel prophylactic and therapeutic formulations.
    Keywords:  arsenic; medicinal plants; natural compounds; toxicity; trace elements; vitamins
    DOI:  https://doi.org/10.3390/molecules27154871
  172. Pharm Nanotechnol. 2022 Aug 06.
    Targeted Nanotherapies For The Posterior Segment Of The Eye: An Integrative Review On Recent Advancements And Challenges.
    Niva Rani Gogoi, Daphisha Marbaniang, Paulami Pal, Subhabrata Ray, Bhaskar Mazumder.
      The eye is a one-of-a-kind sensory organ with intricate anatomy and physiology. It is protected by a variety of barriers, ranging from static barriers to dynamic barriers. Although these barriers are very effective at protecting the eye from exogenous substances and external stress, they are highly compromised by various vision-impairing diseases of both the anterior and the posterior segment of the eye. Due to ocular elimination systems and intricate obstacles that selectively limit drug entry into the eye, effective drug delivery to the posterior segment of the eye (PSE) continues to be a challenge in ophthalmology. Since more than half of the most debilitating eye illnesses are thought to originate in the posterior segment (PS), understanding the physiology and clearance mechanism of the eye could help design improved formulations that could be noninvasive and intended for targeted posterior segment therapeutics. Moreover, the major drawback associated with the conventional drug delivery system to PSE is minimal therapeutic drug concentration in the desired ocular tissue and life-threatening ophthalmic complications. One possible approach that can be implemented to overcome these ocular barriers for efficient ocular therapy, noninvasive and targeted drug action to the posterior tissues is by designing nanomedicines. This review summarizes the recent non-invasive and patient compliant advances in designing nanomedicines targeting PSE. The various routes and pathways of drug administration to the ocular tissue are also summarized.
    Keywords:  Diabetic retinopathy; Nanotherapies; Non-invasive drug delivery; Ocular barrier; Ocular pharmacology; Posterior segment of the eye; Retinal drug delivery
    DOI:  https://doi.org/10.2174/2211738510666220806102612
  173. Chem Biol Interact. 2022 Aug 04. pii: S0009-2797(22)00253-8. [Epub ahead of print]365 110048
    Targeting mucus barrier in respiratory diseases by chemically modified advanced delivery systems.
    Parteek Prasher, Mousmee Sharma, Sachin Kumar Singh, Monica Gulati, Niraj Kumar Jha, Piyush Kumar Gupta, Gaurav Gupta, Dinesh Kumar Chellappan, Flavia Zacconi, Terezinha de Jesus Andreoli Pinto, Yinghan Chan, Gang Liu, Keshav Raj Paudel, Philip M Hansbro, Brian Gregory George Oliver, Kamal Dua.
      Mucus gel constitutes of heavily cross-linked mucin fibers forming a viscoelastic, dense porous network that coats all the exposed epithelia not covered with the skin. The layer provides protection to the underlying gastrointestinal, respiratory, and female reproductive tracts, in addition to the organs such as the surface of eye by trapping the pathogens, irritants, environmental fine particles, and potentially hazardous foreign matter. However, this property of mucus gel poses a substantial challenge for realizing the localized and sustained drug delivery across the mucosal surfaces. The mucus permeating particles that spare the protective properties of mucus gel improve the therapeutic potency of the drugs aimed at the management of diseases, including sexually transmitted infections, lung cancer, irritable bowel disease, degenerative eye diseases and infections, and cystic fibrosis. As such, the mucoadhesive materials conjugated with drug molecules display a prolonged retention time in the mucosal gel that imparts a sustained release of the deliberated drug molecules across the mucosa. The contemporarily developed mucus penetrating materials for drug delivery applications comprise of a finer size, appreciable hydrophilicity, and a neutral surface to escape the entrapment within the cross-inked mucus fibers. Pertaining to the mucus secretion as a first line of defence in respiratory tract in response to the invading physical, chemical, and biological pathogens, the development of mucus penetrating materials hold promise as a stalwart approach for revolutionizing the respiratory drug delivery paradigm. The present review provides an epigrammatic collation of the mucus penetrating/mucoadhesive materials for achieving a controlled/sustained release of the cargo pharmaceutics and drug molecules across the respiratory mucus barrier.
    Keywords:  Chronic respiratory diseases; Mucoadhesive; Mucus penetration; Nanoparticles
    DOI:  https://doi.org/10.1016/j.cbi.2022.110048
  174. Antioxid Redox Signal. 2022 Aug 09.
    Ferroptosis as ultimate target of cancer therapy.
    Yashiro Motooka, Shinya Toyokuni.
      Ferroptosis is a new form of regulated non-apoptotic cell death, which is characterized by iron-dependent lipid peroxidation, leading eventually to plasma membrane rupture. Its core mechanisms have been elucidated consisting of a driving force as catalytic Fe(II)-dependent Fenton reaction and an incorporation of polyunsaturated fatty acids to membrane phospholipids via peroxisome-dependent and -independent pathways, whereas suppressing factors are the prevention of lipid peroxidation by glutathione peroxidase 4 to protect lipid peroxidation and direct membrane repair via coenzyme Q10 and ESCRT-III pathways. The significance of ferroptosis in cancer therapeutics has now been unveiled. Specific ferroptosis inducers are expected as a promising strategy for cancer treatment, especially in cancers with epithelial mesenchymal transition and possibly in cancers with activated Hippo signaling pathways, both of which cause resistance to traditional chemotherapy but tend to show ferroptosis susceptibility. Developments of ferroptosis inducers are in progress by nanotechnology-based drugs or by innovative engineering devices. Especially, low-temperature (non-thermal) plasma is a novel technology at the preclinical stage. The exposure can induce ferroptosis selectively in cancer cells which are generally rich in catalytic Fe(II). Here we summarize and discuss the recently uncovered responsible molecular mechanisms in association with iron metabolism, ferroptosis and cancer therapeutics. Finally, we also highlight the current classification of ferroptosis inducers.
    DOI:  https://doi.org/10.1089/ars.2022.0048
  175. Am J Chin Med. 2022 Aug 11. 1-18
    Chinese Medicine in the Treatment of Ulcerative Colitis: The Mechanisms of Signaling Pathway Regulations.
    Shihao Zheng, Tianyu Xue, Bin Wang, Haolin Guo, Qiquan Liu.
      Ulcerative colitis (UC) is a common clinical inflammatory bowel disease characterized by repeated attacks, difficult treatment, and great harm to the physical and mental health of the patients. The occurrence and development of UC were closely related to the physiological and pathological processes, such as intestinal inflammatory reaction, oxidizing reaction, and immune response. Treatment of ulcerative colitis using Western medicine is often associated with a number of limitations and adverse events. There is a long history of using traditional Chinese medicine in dealing with this medical condition. Commonly used traditional Chinese medicines for the treatment of UC include Caulis Sargentodoxae, Flos Lonicerae, Fructus Cnidii, etc. Additionally, classic prescriptions such as Gegen Qinlian Formulae and Zuojin Pills can also be used to treat UC. To enrich the traditional Chinese medicine theory, the cognitive theory and perspective of network pharmacology and bioinformatics research of cell signal transduction mechanism of UC are emerging rapidly. Modern pharmacological studies focus on underlying mechanisms for the management of UC with Chinese medicine monomers, single Chinese medicines, and traditional Chinese medicine formulations, alleviating the symptoms of UC, controlling the development of intestinal inflammation, and restoring intestinal function through the regulation of key molecular signaling pathways, including PI3K/Akt, NF-[Formula: see text]B, JAK/STAT, MAPK and Notch. By summarizing current research progressions, this review provides key references for the in-depth exploration of the mechanisms focused on signaling pathways for the clinical management of UC using traditional Chinese medicine.
    Keywords:  Curcumin; Emodin; Herbal Medicine; Lonicerin; Luteolin; Osthole; Signaling Pathway; TCM Formulation; Traditional Chinese Medicine; Ulcerative Colitis
    DOI:  https://doi.org/10.1142/S0192415X22500756
  176. Int Breastfeed J. 2022 Aug 08. 17(1): 56
    The association of maternal dietary quality and the antioxidant-proxidant balance of human milk.
    Samira Karbasi, Afsane Bahrami, Zahra Asadi, Fatemeh Shahbeiki, Mohsen Naseri, Asghar Zarban, Gordon A Ferns.
       BACKGROUND: Human milk composition varies over time within an individual mother as well as between lactating mothers due to several factors including maternal health, diet, and nutritional status. Therefore, improving nutrition status during gestation and breastfeeding is crucial for improving the health of both mothers and infants. Diet can enhance the oxidant-antioxidant balance of human milk. This study aimed to investigate the association between human milk oxidant-antioxidant balance with dietary patterns of lactating mothers identified by using principal component analysis.
    METHOD: This cross-sectional study included 350 breastfeeding women between the ages of 20 to 35 years. The dietary intakes of the women in the study were estimated using a validated food frequency questionnaire, which included 65 food items. The oxidant-antioxidant balance of milk samples was assessed using the ferric reducing antioxidant power (FRAP), 2, 2'-diphenyl-1-picrylhydrazyl (DPPH), thiobarbituric acid reactive substances (TBARs), and Ellman's assay. The milk concentration of total protein, calcium, and triglyceride was also measured using commercial kits.
    RESULT: Two predominant dietary patterns were recognized that we defined as a healthy and unhealthy pattern. There were higher levels of DPPH and thiol in the milk from mothers in the third tertile (highest adherence) of a healthy dietary pattern compared to the first tertile (lowest adherence; p < 0.05). Milk calcium and thiol were significantly lower in the third tertile of mothers with an unhealthy dietary pattern versus the first tertile (P < 0.05). In multivariate multinomial logistic regression analyses adjusted for mother's age, body mass index (BMI), energy intake, and infant's sex, adherence to a healthy dietary pattern was associated with higher levels of milk DPPH (OR = 1.32, 95% confidence interval (CI): 1.01, 1.80) and milk thiol (OR = 1.21, 95% CI: 1.10, 1.50). On the other adherence to the unhealthy dietary pattern was correlated with low levels of milk thiol (OR = 1.29; 95%CI: 1.09, 1.59) and milk calcium (OR = 1.28; 95%CI: 1.11, 1.55).
    CONCLUSION: Our findings demonstrated that adherence to a healthy dietary pattern, identified by higher consumption of green vegetables, other vegetables, and fruits is associated with a higher milk oxidant-antioxidant status in breastfeeding mothers.
    Keywords:  Breastfeeding mothers; Dietary pattern; Human milk; Infant; Oxidant-antioxidant balance
    DOI:  https://doi.org/10.1186/s13006-022-00498-1
  177. Front Bioeng Biotechnol. 2022 ;10 960501
    Biodegradable Silk Fibroin Nanocarriers to Modulate Hypoxia Tumor Microenvironment Favoring Enhanced Chemotherapy.
    Li Bin, Yuxiao Yang, Feiyu Wang, Rong Wang, Hongxin Fei, Siliang Duan, Linling Huang, Na Liao, Shimei Zhao, Xinbo Ma.
      Biopolymer silk fibroin (SF) is a great candidate for drug carriers characterized by its tunable biodegradability, and excellent biocompatibility properties. Recently, we have constructed SF-based nano-enabled drug delivery carriers, in which doxorubicin (Dox) and atovaquone (Ato) were encapsulated with Arg-Gly-Asp-SF-Polylactic Acid (RSA) to form micellar-like nanoparticles (RSA-Dox-Ato NPs). The RGD peptide was decorated on micellar-like nanoparticles, promoting tumor accumulation of the drug. Meanwhile, Ato, as a mitochondrial complex III inhibitor inhibiting mitochondrial respiration, would reverse the hypoxia microenvironment and enhance chemotherapy in the tumor. In vitro, the biopolymer alone showed extremely low cytotoxicity to 4T1 cell lines, while the RSA-Dox-Ato demonstrated a higher inhibition rate than other groups. Most significantly, the ROS levels in cells were obviously improved after being treated with RSA-Dox-Ato, indicating that the hypoxic microenvironment was alleviated. Eventually, SF-based targeted drug carrier provides biocompatibility to reverse hypoxia microenvironment in vivo for enhancing chemotherapy, strikingly suppressing tumor development, and thereby suggesting a promising candidate for drug delivery system.
    Keywords:  atovaquone; biocompatibility; breast cancer; chemotherapy; hypoxia
    DOI:  https://doi.org/10.3389/fbioe.2022.960501
  178. Polim Med. 2022 Aug 12.
    Spray drying and nano spray drying as manufacturing methods of drug-loaded polymeric particles.
    Dominik Strojewski, Anna Krupa.
      In this review, benefits and drawbacks of the process of spray drying and nano spray drying with regard to the manufacturing of polymeric particles for pharmaceutical applications are discussed. Spray drying has been used for many years in the food, chemical and pharmaceutical industries for converting liquids into solids, in order to form products of uniform appearance. The construction of spray dryer enables to atomize the liquid into small droplets, which ensures a large surface area for heat and mass transfer, and significantly shortens the processing. Each droplet dries to an individual solid microparticle of characteristic features that can be tailored by optimizing formulation variables and critical process parameters. Since spray drying technology is easy to scale up and can be used for drying almost any drug in a solution or suspension, there are numerous examples of products in clinical use, in which this process has been successfully applied to improve drug stability, enhance bioavailability or control its release rate. In recent years, nano spray drying technology has been proposed as a method for lab-scale manufacturing of nanoparticles. Such an approach is of particular interest at early stages of drug development, when a small amount of new chemical entities is available. Here, the nebulization technique is used for feed atomization, while laminar gas flow in the drying chamber ensures gentle drying conditions. Moreover, electrostatic collectors have gradually replaced cyclone separators, ensuring high effectiveness in producing solid nanoparticles, even if a small volume of the sample is processed.
    Keywords:  microparticles; nano spray drying; nanoparticles; polymeric particles; spray drying
    DOI:  https://doi.org/10.17219/pim/152230
  179. Photodiagnosis Photodyn Ther. 2022 Aug 04. pii: S1572-1000(22)00338-6. [Epub ahead of print] 103052
    Mesoporous Silica Nanoparticles Incorporated with Ir(III) complexes: From Photophysics to Photodynamic Therapy.
    Bianca M Estevão, Raquel R C Vilela, Isabella P Geremias, Kassio P S Zanoni, Andrea S S de Camargo, Valtencir Zucolotto.
      Organically modified mesoporous silica nanoparticles (MSNs) containing Ir complexes (Ir1, Ir2 and Ir3) were successfully synthesized. Ir-entrapped MCM41-COOH have shown relevant photophysical characteristics including high efficiency in the photoproduction and delivery of singlet oxygen (1O2), which is particularly promising for photodynamic therapy (PDT) applications. In vitro tests have evidenced that complex@MCM41-COOH are able to reduce cell proliferation after 10 min of blue-light irradiation in Hep-G2 liver cancer cells.
    Keywords:  Ir(III) complexes; Mesoporous silica nanoparticles; PDT; liver cancer; photophysics
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103052
  180. Phytochemistry. 2022 Aug 08. pii: S0031-9422(22)00261-8. [Epub ahead of print] 113345
    Phytochemical and biological diversity of triterpenoid saponins from family Sapotaceae: A comprehensive review.
    Mostafa H Baky, Mostafa B Elsaid, Mohamed A Farag.
      Sapotaceae is a flowering plants family reported for its richness in triterpenoid saponins. Sapotaceae comprises a large number of fruit-producing plants of nutritional and medicinal value. Different species of family Sapotaceae received a considerable interest owing to their rich triterpenoid saponins content of a myriad pharmacological effects and health benefits. Several databases were searched for collecting papers for this review in the scope of phytochemistry, bioactivity and record of triterpenoid saponins from family Sapotacese such as PubMed, Google Scholar, Web of Science, Scopus and Reaxys from 1990 till now. Triterpenoid saponins reported from Sapotaceae plants are mostly of protobassic acid, 16-α-hydroxyprotobassic acid, bayogenin, and oleanolic acid derivatives with both monodesmosidic and/or bidesmosidic attached sugar side chains. Besides, the most frequently attached sugar units are glucose, glucoronic acid, apiose, xylose, rhamnose, and arabinose. The reported health effects of Sapotaceae plants in folk medicine in relation to their bioactive saponins were also reviewed with special attention to anti-inflammatory, antiulcer activity, antimicrobial activity, cytotoxic, anti-hypercholesterolemic, antioxidant, and immunomodulatory activities. This review aims to present a holistic compile on the phytochemical and biological diversity of triterpenoid saponins reported from family Sapotaceae with future perspectives.
    Keywords:  16-α-hydroxyprotobassic acid; Ethnopharmacological properties; Oleanolic acid; Protobassic acid; Sapotaceae; Triterpenoid saponins
    DOI:  https://doi.org/10.1016/j.phytochem.2022.113345
  181. Cancers (Basel). 2022 Jul 28. pii: 3683. [Epub ahead of print]14(15):
    Application of Elastin-like Polypeptide in Tumor Therapy.
    Xianggang Shi, Dongfeng Chen, Guodong Liu, Hailing Zhang, Xiaoyan Wang, Zhi Wu, Yan Wu, Feng Yu, Qinggang Xu.
      Elastin-like polypeptides (ELPs) are stimulus-responsive artificially designed proteins synthesized from the core amino acid sequence of human tropoelastin. ELPs have good biocompatibility and biodegradability and do not systemically induce adverse immune responses, making them a suitable module for drug delivery. Design strategies can equip ELPs with the ability to respond to changes in temperature and pH or the capacity to self-assemble into nanoparticles. These unique tunable biophysicochemical properties make ELPs among the most widely studied biopolymers employed in protein purification, drug delivery, tissue engineering and even in tumor therapy. As a module for drug delivery and as a carrier to target tumor cells, the combination of ELPs with therapeutic drugs, antibodies and photo-oxidation molecules has been shown to result in improved pharmacokinetic properties (prolonged half-life, drug targeting, cell penetration and controlled release) while restricting the cytotoxicity of the drug to a confined infected site. In this review, we summarize the latest developments in the application methods of ELP employed in tumor therapy, with a focus on its conjugation with peptide drugs, antibodies and photosensitizers.
    Keywords:  elastin-like peptides; peptide drugs; photosensitizer; temperature response; tumor therapy
    DOI:  https://doi.org/10.3390/cancers14153683
  182. Polymers (Basel). 2022 Jul 30. pii: 3110. [Epub ahead of print]14(15):
    Advancements and Applications in the Composites of Silk Fibroin and Graphene-Based Materials.
    Zhimin Xu, Yujie Ma, Huanyan Dai, Shuang Tan, Bing Han.
      Silk fibroin and three kinds of graphene-based materials (graphene, graphene oxide, and reduced graphene oxide) have been widely investigated in biomedical fields. Recently, the hybrid composites of silk fibroin and graphene-based materials have attracted much attention owing to their combined advantages, i.e., presenting outstanding biocompatibility, mechanical properties, and excellent electrical conductivity. However, maintaining bio-toxicity and biodegradability at a proper level remains a challenge for other applications. This report describes the first attempt to summarize the hybrid composites' preparation methods, properties, and applications to the best of our knowledge. We strongly believe that this review will open new doors for coming researchers.
    Keywords:  Cocoon; biocompatibility; graphene; hybrid composites; polymers; silk fibroin
    DOI:  https://doi.org/10.3390/polym14153110
  183. Molecules. 2022 Aug 01. pii: 4914. [Epub ahead of print]27(15):
    Propolis Contra Pharmacological Interventions in Bees.
    Joanna Wojtacka.
      In addition to wax, propolis is a mixture of resins, terpenes, and etheric and aromatic oils. This composition supports its very strong biochemical activity that affects bee health. Bee colonies are externally exposed to the activity of other different pharmacologically active substances and toxic agents used in beekeeping procedures, veterinary interventions, and the environment. Even if free form common diseases, they may suffer from parasites or toxins. In any such case the abundance and variety of honeyflow, besides proper therapy, is crucial for the maintenance of bee health. Propolis itself cannot be considered as food but can be considered as micro-nutrients for bees. This is due to the fact that some of its compounds may penetrate different bee products, and this way be consumed by bees and their larvae, while stored in the hive. This perspective shows propolis as natural agent reducing the toxicity of pyrethroid acaricides, stimulating production of detoxification enzymes, enhancing the action of antibiotics, and increasing expression of genes that encode proteins responsible for detoxication. The aim of this review is to summarize current data on the possible impact on veterinary public health of the introduction into propolis of residues of pharmacological agents approved in the EU for use in the treatment of bee colonies and their environment.
    Keywords:  MRL; VMP; acaricides; honey bee; pesticides; propolis; residues; varroacides; veterinary medicinal products; veterinary public health
    DOI:  https://doi.org/10.3390/molecules27154914
  184. Am J Transl Res. 2022 ;14(7): 4591-4605
    Arsenic exposure increases susceptibility to Ptpn11-induced malignancy in mouse embryonic fibroblasts through mitochondrial hypermetabolism.
    Fan Yang, Zhenya Tan, Yuanjuan Dai, Xingxing Wang, Zhen Huang, Chen Kan, Siying Wang.
       OBJECTIVE: To explore the synergistic effect and metabolic mechanism of chronic arsenic exposure and PTPN11 gain-of-function mutation on tumorigenesis.
    METHODS: Arsenic-transformed Ptpn11+/+ (WT-As) and Ptpn11D61G/+ -mutant (D61G-As) mouse embryonic fibroblasts (MEFs) were established by chronic treatment of low-dose arsenic. We used cell counting, plate colony and soft agar colony formation, and a nude mouse xenograft model to detect malignant transformation and tumorigenesis in vitro and in vivo. To detect mitochondrial oxidative phosphorylation (OXPHOS), we used Seahorse real-time cell metabolic analysis as well as adenosine triphosphate (ATP) and ROS production assays. Lastly, we examined mTOR signaling pathway changes by western blotting.
    RESULTS: Low-dose arsenic exposure promoted WT MEFs proliferation and exacerbated malignancy driven by Ptpn11D61G/+ mutation. Additionally, Ptpn11D61G/+ -mutant MEFs exhibited increased mitochondrial metabolism and low-dose arsenic amplified this malignant metabolic activity. Mechanistically, the mTOR signaling pathway was activated in Ptpn11D61G/+ -mutant MEFs and was further phosphorylated in arsenic-treated MEFs expressing Ptpn11D61G/+ . Critically, tumorigenesis induced by the synergistic effect of low-dose arsenic and Ptpn11D61G/+ mutation was prevented by mTOR pathway inhibition via rapamycin.
    CONCLUSION: This study found that metabolic reprogramming, particularly mitochondrial hyperactivation, is a core mechanism underlying tumorigenesis induced by the synergistic effect of Ptpn11D61G/+ mutation and arsenic exposure. Furthermore, these findings suggested mTOR is a therapeutic target for Ptpn11-associated cancers.
    Keywords:  Arsenic; PTPN11; mTOR; mitochondrial hypermetabolism
  185. Anal Chim Acta. 2022 Aug 15. pii: S0003-2670(22)00739-5. [Epub ahead of print]1221 340168
    An enzyme-particle hybrid ink for one step screen-printing and long-term metabolism monitoring.
    Chengcheng Wang, Xinran Zhang, Yuqiao Liu, Junmin Li, Ling Zhu, Yan Lu, Xishan Guo, Dajing Chen.
      Targeting the long-term monitoring of biological carbohydrate metabolism, we developed a one-step screen-printing method to fabricate electrochemical sensors using an enzyme microparticle hybrid ink. Most enzymes have low stability in high temperatures and organic solvents, making conventional enzyme modification a bottom-up procedure to be performed after electrode fabrication, resulting in inactivation and detachment in long-term work. Enzyme-loaded microparticles prepared by manganese carbonate co-precipitation had higher stability than free enzymes, which could to be mixed directly with carbon paste for direct screen-printing. Due to the co-printing immobilization and the local hydration environment in enzyme particles, the prepared electrodes exhibited higher long-term operational stability than the conventional multi-step cross-linking method. In the sensing applications, we prepared microparticles loaded with single enzyme (glucose oxidase) and dual enzymes (β-galactosidase and glucose oxidase) for glucose and lactose monitoring, respectively. Both electrodes can accurately measure the consumption of the corresponding carbohydrates throughout the cell or bacterial culture period thus providing a sensing platform for bio-metabolic monitoring and drug screening.
    Keywords:  Co-print; Electrochemical; Enzyme microparticles; Metabolism
    DOI:  https://doi.org/10.1016/j.aca.2022.340168
  186. Nat Commun. 2022 Aug 08. 13(1): 4640
    Author Correction: 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.
      
    DOI:  https://doi.org/10.1038/s41467-022-32459-x
  187. Life Sci. 2022 Aug 07. pii: S0024-3205(22)00570-7. [Epub ahead of print] 120870
    Modulation of autophagy by melatonin via sirtuins in stroke: From mechanisms to therapies.
    Fereshteh Azedi, Shima Tavakol, Arsh Haj Mohamad Ebrahim Ketabforoush, Ghasem Khazaei, Atefeh Bakhtazad, Kazem Mousavizadeh, Mohammad Taghi Joghataei.
      Sirtuins perform an important effect on the neural cell fate following stroke. Several mechanisms that have been correlated with stroke are oxidative stress, apoptosis, necrosis and autophagy. Autophagy is usually regarded as unitary of the neural cell survival mechanisms. Recently, the importance of the sirtuins effect on autophagy by antioxidant agents for stroke treatment mentioned in various studies. One of these agents is melatonin. Melatonin can modulate autophagy by changing on sirtuin pathways. Melatonin and its metabolites adjust various sirtuins pathways related to apoptosis, proliferation, metastases, autophagy and inflammation in case of stroke. In this review, we will discuss about the modulation of autophagy by melatonin via sirtuins in stroke.
    Keywords:  Autophagy; Cerebrovascular disease; Melatonin; Sirtuins; Stroke
    DOI:  https://doi.org/10.1016/j.lfs.2022.120870
  188. Chem Soc Rev. 2022 Aug 08.
    How can we use the endocytosis pathways to design nanoparticle drug-delivery vehicles to target cancer cells over healthy cells?
    Vu Thanh Cong, Jacinta L Houng, Maria Kavallaris, Xin Chen, Richard D Tilley, J Justin Gooding.
      Targeted drug delivery in cancer typically focuses on maximising the endocytosis of drugs into the diseased cells. However, there has been less focus on exploiting the differences in the endocytosis pathways of cancer cells versus non-cancer cells. An understanding of the endocytosis pathways in both cancer and non-cancer cells allows for the design of nanoparticles to deliver drugs to cancer cells whilst restricting healthy cells from taking up anticancer drugs, thus efficiently killing the cancer cells. Herein we compare the differences in the endocytosis pathways of cancer and healthy cells. Second, we highlight the importance of the physicochemical properties of nanoparticles (size, shape, stiffness, and surface chemistry) on cellular uptake and how they can be adjusted to selectively target the dominated endocytosis pathway of cancer cells over healthy cells and to deliver anticancer drug to the target cells. The review generates new thought in the design of cancer-selective nanoparticles based on the endocytosis pathways.
    DOI:  https://doi.org/10.1039/d1cs00707f
  189. Evid Based Complement Alternat Med. 2022 ;2022 5912396
    Therapeutic Effects and Metabolic Spectrum of Traditional Chinese Medicine Hengqing II Prescription on Alzheimer's Disease.
    Shengxi Meng, Shaopeng Li, Huize Chen, Chujun Deng, Zeyu Meng, Yimo Wang.
      Alzheimer's disease (AD) seriously damages elders' social and daily abilities around the world. Traditional Chinese medicine (TCM), a rich drug resource bank, could help research AD. In order to explore the role of TCM in AD treatment, 86 AD patients were recruited from the hospital, then treated with Hengqing II prescription and donepezil hydrochloride. The cognitive and serum lipid levels were investigated before and after treatment. The patient's urine was collected after three months of treatment. Metabolites in the urine samples were extracted with methanol and detected on the UHPLC-MS platform. Results proved that Hengqing II can improve cognitive levels and reduce the levels of Hcy, D-D, FIB, Apo B, TC, and LDL-C compared with donepezil hydrochloride (P < 0.05). The results of multivariate statistical analysis revealed that the metabolism of HQII was significantly different compared with Control groups. A total of 66 differential metabolites were found in this comparison (50 were down-regulated and 16 were up-regulated). Four amino acid pathways and one linoleic acid pathway were found through these metabolites. After receiver operating characteristic analysis, it was suggested that palmitic acid, palmitoleic acid, linoleic acid, oleic acid, SAH, and methionine can be used as biomarkers for treating AD, while the effects of daidzein, genistein, and naringenin on the treatment of AD need to be further studied.
    DOI:  https://doi.org/10.1155/2022/5912396
  190. Molecules. 2022 Jul 30. pii: 4891. [Epub ahead of print]27(15):
    A Preliminary Assessment of the Nutraceutical Potential of Acai Berry (Euterpe sp.) as a Potential Natural Treatment for Alzheimer's Disease.
    Maryam N ALNasser, Ian R Mellor, Wayne G Carter.
      Alzheimer's disease (AD) is characterised by progressive neuronal atrophy and the loss of neuronal function as a consequence of multiple pathomechanisms. Current AD treatments primarily operate at a symptomatic level to treat a cholinergic deficiency and can cause side effects. Hence, there is an unmet need for healthier lifestyles to reduce the likelihood of AD as well as improved treatments with fewer adverse reactions. Diets rich in phytochemicals may reduce neurodegenerative risk and limit disease progression. The native South American palm acai berry (Euterpe oleraceae) is a potential source of dietary phytochemicals beneficial to health. This study aimed to screen the nutraceutical potential of the acai berry, in the form of aqueous and ethanolic extracts, for the ability to inhibit acetyl- and butyryl-cholinesterase (ChE) enzymes and scavenge free radicals via 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) or 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) assays. In addition, this study aimed to quantify the acai berry's antioxidant potential via hydrogen peroxide or hydroxyl scavenging, nitric oxide scavenging, lipid peroxidation inhibition, and the ability to reduce ferric ions. Total polyphenol and flavonoid contents were also determined. Acai aqueous extract displayed a concentration-dependent inhibition of acetyl- and butyryl-cholinesterase enzymes. Both acai extracts displayed useful concentration-dependent free radical scavenging and antioxidant abilities, with the acai ethanolic extract being the most potent antioxidant and displaying the highest phenolic and flavonoid contents. In summary, extracts of the acai berry contain nutraceutical components with anti-cholinesterase and antioxidant capabilities and may therefore provide a beneficial dietary component that limits the pathological deficits evidenced in AD.
    Keywords:  Alzheimer’s disease; Euterpe oleraceae; acai berry; antioxidant; cholinesterase inhibitors; nutraceuticals
    DOI:  https://doi.org/10.3390/molecules27154891
  191. Cancer Lett. 2022 Aug 05. pii: S0304-3835(22)00341-X. [Epub ahead of print] 215857
    Annexin A5 as a targeting agent for cancer treatment.
    Alexis Woodward, Gabriela Nf Faria, Roger G Harrison.
      Identifying a universal biomarker for cancer treatment remains a major challenge in cancer therapy. Extracellular exposure of phosphatidylserine (PS) is tightly regulated and is an "eat me" signal for phagocytosis in healthy cells. Although cancer cells and vasculature express high levels of externalized PS, they do not undergo apoptosis, making them a promising biomarker for cancer treatment. Annexin A5 (ANXA5) is the native binding partner of PS and can actively target and deliver chemotherapies to the tumor microenvironment (TME) via PS expression. ANXA5 acts as a bridge between the innate and adaptive immune systems and contributes to an immunostimulatory profile in the TME. ANXA5-enzyme prodrug therapies allow for systemic delivery of prodrugs and targeted killing at the tumor site. ANXA5-carbon nanotube conjugates have been used to physically ablate tumors via photothermal therapy. This review aims to explore the expression of PS in cancer cells and how ANXA5 has been used as a chemotherapeutic and targeting agent for cancer.
    Keywords:  Annexin A5; Carbon nanotubes; Fusion proteins; Immune modulation; Phosphatidylserine
    DOI:  https://doi.org/10.1016/j.canlet.2022.215857
  192. Cell Prolif. 2022 Aug 12. e13321
    Pump proton inhibitors display anti-tumour potential in glioma.
    Bihan Li, Liping Rao.
       OBJECTIVES: Glioma is one of the most aggressive brain tumours with poor overall survival despite advanced technology in surgical resection, chemotherapy and radiation. Progression and recurrence are the hinge causes of low survival. Our aim is to explain the concrete mechanism in the proliferation and progression of tumours based on tumour microenvironment (TME). The main purpose is to illustrate the mechanism of proton pump inhibitors (PPIs) in affecting acidity, hypoxia, oxidative stress, inflammatory response and autophagy based on the TME to induce apoptosis and enhance the sensitivity of chemoradiotherapy.
    FINDINGS: TME is the main medium for tumour growth and progression. Acidity, hypoxia, inflammatory response, autophagy, angiogenesis and so on are the main causes of tumour progress. PPIs, as a common clinical drug to inhibit gastric acid secretion, have the advantages of fast onset, long action time and small adverse reactions. Nowadays, several kinds of literature highlight the potential of PPIs in inhibiting tumour progression. However, long-term use of PPIs alone also has obvious side effects. Therefore, till now, how to apply PPIs to promote the effect of radio-chemotherapy and find the concrete dose and concentration of combined use are novel challenges.
    CONCLUSIONS: PPIs display the potential in enhancing the sensitivity of chemoradiotherapy to defend against glioma based on TME. In the clinic, it is also necessary to explore specific concentrations and dosages in synthetic applications.
    DOI:  https://doi.org/10.1111/cpr.13321
  193. J Nanobiotechnology. 2022 Aug 11. 20(1): 371
    Mechanisms of chemotherapeutic resistance and the application of targeted nanoparticles for enhanced chemotherapy in colorectal cancer.
    Yu Guo, Min Wang, Yongbo Zou, Longhai Jin, Zeyun Zhao, Qi Liu, Shuang Wang, Jiannan Li.
      Colorectal cancer is considered one of the major malignancies that threaten the lives and health of people around the world. Patients with CRC are prone to post-operative local recurrence or metastasis, and some patients are advanced at the time of diagnosis and have no chance for complete surgical resection. These factors make chemotherapy an indispensable and important tool in treating CRC. However, the complex composition of the tumor microenvironment and the interaction of cellular and interstitial components constitute a tumor tissue with high cell density, dense extracellular matrix, and high osmotic pressure, inevitably preventing chemotherapeutic drugs from entering and acting on tumor cells. As a result, a novel drug carrier system with targeted nanoparticles has been applied to tumor therapy. It can change the physicochemical properties of drugs, facilitate the crossing of drug molecules through physiological and pathological tissue barriers, and increase the local concentration of nanomedicines at lesion sites. In addition to improving drug efficacy, targeted nanoparticles also reduce side effects, enabling safer and more effective disease diagnosis and treatment and improving bioavailability. In this review, we discuss the mechanisms by which infiltrating cells and other stromal components of the tumor microenvironment comprise barriers to chemotherapy in colorectal cancer. The research and application of targeted nanoparticles in CRC treatment are also classified.
    Keywords:  Chemotherapeutic resistance; Colorectal cancer; Targeted nanoparticles
    DOI:  https://doi.org/10.1186/s12951-022-01586-4
  194. Small. 2022 Aug 13. e2202694
    Reactive Oxygen Species Responsive Cleavable Hierarchical Metallic Supra-Nanostructure.
    Hyunjun Choi, Bongseo Choi, Jun-Hyeok Han, Ha Eun Shin, Wooram Park, Dong-Hyun Kim.
      A reactive oxygen species (ROS) responsive cleavable hierarchical metallic supra-nanostructure (HMSN) is reported. HMSN structured with thin branches composed of primary gold (Au) nanocrystals and silver (Ag) nano-linkers is synthesized by a one-pot aqueous synthesis with a selected ratio of Au/Ag/cholate. ROS responsive degradability of HMSN is tested in the presence of endogenous and exogeneous ROS. Significant ROS-responsive structural deformation of HMSN is observed in the ROS exposure with hydrogen peroxide (H2 O2 ) solution. The ROS responsiveness of HMSN is significantly comparable with negligible structural changes of conventional spherical gold nanoparticles. The demonstrated ROS responsive degradation of HMSN is further confirmed in various in vitro ROS conditions of each cellular endogenous ROS and exogeneous ROS generated by photodynamic therapy (PDT) or X-ray radiation. Then, in vivo ROS responsive degradability of HMSN is further evaluated with intratumoral injection of HMSN and exogeneous ROS generation via PDT in a mouse tumor model. Additional in vivo biodistribution and toxicity of intravenously administrated HMSN at 30-day post-injection are investigated for potential in vivo applications. The observed ROS responsive degradability of HMSN will provide a promising option for a type of ROS responsive-multifunctional nanocarriers in cancer treatment and various biomedical applications.
    Keywords:  cancer therapy; degradable metal nanoparticles; degradable nanostructures; gold nanoparticles; reactive oxygen species
    DOI:  https://doi.org/10.1002/smll.202202694
  195. Saudi J Biol Sci. 2022 Sep;29(9): 103396
    The anti-inflammatory properties of the methanolic extract of Cucumis melo Linn. against prostate enlargement in Wistar rats.
    R S Rajasree, Sibi P Ittiyavirah, Punnoth Poonkuzhi Naseef, Mohamed Saheer Kuruniyan, Muhammed Elayadeth-Meethal, S Sankar.
      In different parts of the world, Cucumis melo Linn. (C melo) is used for its medicinal properties. The present study examined the effects of a methanolic extract of C melo Linn. (F1 hybrid, MECM) on benign prostatic hyperplasia in adult male Wistar rats and evaluated its anti-inflammatory activity in vivo. MECM treatment reduced prostate weight mildly. Histopathological studies showed that the extract produced a strong protective effect against the development of BPH by testosterone. The MECM also showed protection from testosterone-induced benign prostatic hyperplasia (BPH). MECM was tested against carrageenan-induced inflammation in rats' paws to determine its anti-inflammatory activity. It was shown that MECM had a pronounced effect on the inflammatory response in the late phase, i.e., one hour after carrageenan injection. Prostaglandins and nitric oxide are primarily responsible for this phase indicating that MECM can modify the production and release of prostaglandin and nitric oxide. A novel formulation containing C melo may be able to treat the conditions mentioned above.
    Keywords:  Bioactive compounds; Drug discovery; Inflammation; Inflammation-associate diseases: Benign prostatic hyperplasia (BPH); Medicinal plants; Phytochemicals
    DOI:  https://doi.org/10.1016/j.sjbs.2022.103396
  196. Front Oncol. 2022 ;12 903033
    Metabolic Reprogramming Helps to Define Different Metastatic Tropisms in Colorectal Cancer.
    Ana Montero-Calle, Marta Gómez de Cedrón, Adriana Quijada-Freire, Guillermo Solís-Fernández, Victoria López-Alonso, Isabel Espinosa-Salinas, Alberto Peláez-García, María Jesús Fernández-Aceñero, Ana Ramírez de Molina, Rodrigo Barderas.
      Approximately 25% of colorectal cancer (CRC) patients experience systemic metastases, with the most frequent target organs being the liver and lung. Metabolic reprogramming has been recognized as one of the hallmarks of cancer. Here, metabolic and functional differences between two CRC cells with different metastatic organotropisms (metastatic KM12SM CRC cells to the liver and KM12L4a to the lung when injected in the spleen and in the tail vein of mice) were analysed in comparison to their parental non-metastatic isogenic KM12C cells, for a subsequent investigation of identified metabolic targets in CRC patients. Meta-analysis from proteomic and transcriptomic data deposited in databases, qPCR, WB, in vitro cell-based assays, and in vivo experiments were used to survey for metabolic alterations contributing to their different organotropism and for the subsequent analysis of identified metabolic markers in CRC patients. Although no changes in cell proliferation were observed between metastatic cells, KM12SM cells were highly dependent on oxidative phosphorylation at mitochondria, whereas KM12L4a cells were characterized by being more energetically efficient with lower basal respiration levels and a better redox management. Lipid metabolism-related targets were found altered in both cell lines, including LDLR, CD36, FABP4, SCD, AGPAT1, and FASN, which were also associated with the prognosis of CRC patients. Moreover, CD36 association with lung metastatic tropism of CRC cells was validated in vivo. Altogether, our results suggest that LDLR, CD36, FABP4, SCD, FASN, LPL, and APOA1 metabolic targets are associated with CRC metastatic tropism to the liver or lung. These features exemplify specific metabolic adaptations for invasive cancer cells which stem at the primary tumour.
    Keywords:  CRC (colorectal cancer); fatty acids (FA); metabolic reprograming; obesity; organotropism; tropism of metastasis
    DOI:  https://doi.org/10.3389/fonc.2022.903033
  197. Foods. 2022 Aug 05. pii: 2335. [Epub ahead of print]11(15):
    Evaluation of Microwave-Assisted Extraction as a Potential Green Technology for the Isolation of Bioactive Compounds from Saffron (Crocus sativus L.) Floral By-Products.
    Débora Cerdá-Bernad, João P Baixinho, Naiara Fernández, María José Frutos.
      The saffron flower stigmas are used for the saffron spice production while the remaining saffron floral by-products, that are a valuable source of natural bioactive compounds, remain underutilized. The aim of this study was to evaluate the microwave-assisted extraction (MAE) through response surface methodology to obtain high value-added compounds from saffron tepals as ingredients with potential application in the food, pharmaceutical and/or cosmetic industries. A central composite design was applied to optimize process variables: temperature, time and ethanol solvent concentration. Extracts were characterized in terms of total phenolic and total flavonoid content, and antioxidant capacity (ORAC and HOSC assays), being the maximum values obtained: 126.20 ± 2.99 mg GAE/g dry matter; 8.05 ± 0.11 mg CE/g dry matter; 6219 ± 246 μmol TEAC/dry matter; 3131 ± 205 μmol TEAC/dry matter, respectively. Results indicated that the optimal extraction conditions were the combination of low temperature (25 °C)-high extraction time (5 min) using ethanol as solvent (100%). MAE revealed to be an efficient technique to isolate bioactive compounds from saffron floral by-products with a low energy footprint.
    Keywords:  Crocus sativus L.; antioxidant activity; bio-residues; food by-products; green chemistry; high value-added ingredients; microwave-assisted extraction; polyphenols; sustainability; valorization
    DOI:  https://doi.org/10.3390/foods11152335
  198. Crit Rev Food Sci Nutr. 2022 Aug 12. 1-31
    Health functions and related molecular mechanisms of ellagitannin-derived urolithins.
    Gopalsamy Rajiv Gandhi, Poovathumkal James Antony, Stanislaus Antony Ceasar, Alan Bruno Silva Vasconcelos, Monalisa Martins Montalvão, Mariana Nobre Farias de Franca, Ayane de Sá Resende, Chelankara Suresh Sharanya, Yi Liu, Govindasamy Hariharan, Ren-You Gan.
      Ellagitannins are vital bioactive polyphenols that are widely distributed in a variety of plant-based foods. The main metabolites of ellagitannins are urolithins, and current research suggests that urolithins provide a variety of health benefits. This review focused on the role of the gut bacteria in the conversion of ellagitannins to urolithins. Based on the results of in vitro and in vivo studies, the health benefits of urolithins, including antioxidant, anti-inflammatory, anti-cancer, anti-obesity, anti-diabetic, anti-aging, cardiovascular protective, neuroprotective, kidney protective, and muscle mass protective effects, were thoroughly outlined, with a focus on their associated molecular mechanisms. Finally, we briefly commented on urolithins' safety. Overall, urolithins' diverse health benefits indicate the potential utilization of ellagitannins and urolithins in the creation of functional foods and nutraceuticals to treat and prevent some chronic diseases.
    Keywords:  Urolithins; cancer; ellagitannins; gut metabolites; inflammation
    DOI:  https://doi.org/10.1080/10408398.2022.2106179
  199. Nutrients. 2022 Aug 03. pii: 3183. [Epub ahead of print]14(15):
    Carotenoids in Palliative Care-Is There Any Benefit from Carotenoid Supplementation in the Adjuvant Treatment of Cancer-Related Symptoms?
    Anna Zasowska-Nowak, Piotr Jan Nowak, Aleksandra Cialkowska-Rysz.
      Carotenoids are organic, liposoluble pigments found in nature, which are responsible for the characteristic colors of ripe tomatoes, carrots, peppers, and crustaceans, among others. Palliative care provided to patients with an incurable disease is aimed at improving the patient's quality of life through appropriate treatment of symptoms accompanying the disease. Palliative care patients with burdensome symptoms related to advanced-stage cancers are especially interested in the use of natural dietary supplements and herbal remedies to reduce symptoms' intensity and ameliorate the quality of life. Carotenoids seem to be a group of natural compounds with particularly promising properties in relieving symptoms, mainly due to their strong antioxidant, anti-inflammatory, and neuroprotective properties. Moreover, carotenoids have been used in folk medicine to treat various diseases and alleviate the accompanying symptoms. In this narrative review, the authors decided to determine whether there is any scientific evidence supporting the rationale for carotenoid supplementation in advanced-stage cancer patients, with particular emphasis on the adjuvant treatment of cancer-related symptoms, such as neuropathic pain and cancer-related cachexia.
    Keywords:  cancer cachexia; cancer-related fatigue; carotenoids; neuropathic pain; palliative care
    DOI:  https://doi.org/10.3390/nu14153183
  200. Molecules. 2022 Jul 27. pii: 4814. [Epub ahead of print]27(15):
    Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects.
    Benjamín Robles-Bañuelos, Lorena María Durán-Riveroll, Edgar Rangel-López, Hugo Isidro Pérez-López, Leticia González-Maya.
      The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules' origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.
    Keywords:  angiogenesis inhibitor; antiproliferative activity; apoptosis; bioactive metabolites; cytoskeleton disruptor; histone deacetylase inhibitor
    DOI:  https://doi.org/10.3390/molecules27154814
  201. Cancer Cell Int. 2022 Aug 08. 22(1): 246
    Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview.
    Eunus S Ali, Shamima Akter, Sarker Ramproshad, Banani Mondal, Thoufiqul Alam Riaz, Muhammad Torequl Islam, Ishaq N Khan, Anca Oana Docea, Daniela Calina, Javad Sharifi-Rad, William C Cho.
      MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.
    Keywords:  Cancer; Chemoprevention; Chemoresistance; MAPK (ERK); Molecular mechanisms; Natural bioactive compounds; Ras oncogenes; Ras signaling
    DOI:  https://doi.org/10.1186/s12935-022-02666-z
  202. Cancers (Basel). 2022 Jul 30. pii: 3722. [Epub ahead of print]14(15):
    Emerging Roles of the Nervous System in Gastrointestinal Cancer Development.
    Chunhua Wan, Xiaoqin Yan, Baoying Hu, Xinhua Zhang.
      Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy.
    Keywords:  chronic stress; gastrointestinal cancer; nervous system; neurogenesis; neurotransmitter; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14153722
  203. Trop Anim Health Prod. 2022 Aug 08. 54(5): 248
    Blend of secondary metabolites from mesquite to improve nutrient digestibility, microbial protein, efficient use of nitrogen, ruminal parameters, and blood metabolites in sheep.
    Steyce Neves Barbosa, José Ricardo Coelho da Silva, Thaysa Rodrigues Torres, Robson Magno Liberal Véras, Adriana Lima de Carvalho, Abraão Jeferson de Souza, Elias Leocádio Dos Santos Neto, Gilberto de Carvalho Sobral, Elaine Rosa Fagundes Feitoza, Italo Marcos Vasconcelos Morais, Evaristo Jorge Oliveira de Souza.
      Although chemical additives are able to improve the efficiency of ruminal fermentation, they can leave residues in the meat. However, a blend of secondary metabolites can improve ruminal fermentation without harming the population welfare. Five levels (0.0, 1.5, 3.0, 4.5, and 6.0 g/day) of a blend of secondary metabolites from mesquite extract in sheep feed to promote increases in the nutritional value, ruminal parameters, nitrogen (N) use efficiency, microbial protein (MP) synthesis, and blood metabolites. Ten intact male Santa Inês sheep with average body weight of 55 ± 9.81 kg were used in a 5 × 5 Latin square design, replicated twice. There was a quadratic response of the digestibility of dry matter (DM), organic matter (OM), crude protein (CP), and total digestible nutrients (TDN). Microbial protein concentrations, MP synthesis efficiency, propionic acid levels, and acetic/propionic acid ratio also showed a quadratic response. The blend promoted a quadratic effect on plasma glucose and lactate levels. On the other hand, it decreased the concentrations of ammoniacal nitrogen, plasma urea, and plasma cholesterol. It is recommended to supply a blend of secondary metabolites at 3.43 g/day.
    Keywords:  Alkaloids; Bioactive compounds; Condensed tannins; Natural drugs
    DOI:  https://doi.org/10.1007/s11250-022-03267-8
  204. Int J Biol Macromol. 2022 Aug 04. pii: S0141-8130(22)01684-1. [Epub ahead of print]
    Chitosan/PLGA shell nanoparticles as Tylotoin delivery platform for advanced wound healing.
    Yirong Wang, Li Guo, Jiao Liu, Xiaofei Huang, XinXin Wang, Xiaolong Guo, Xinguo You, Wenhui Li, Lili Li, Tongyi Sun, Yuanyuan Gao.
      Wound treatment remains one of the most prevalent healthcare issues. Tylotoin is a skin repair peptide identified from salamander (Tylototriton verrucosus) and exhibits skin wound healing properties. Noticeably, the easy degradation and frequent administration limit its application in wound healing. Chitosan (CS) -PLGA-Tylotoin nanoparticles (CPT NPs) were prepared to circumvent this limitation and deliver Tylotoin for the promotion of the healing of skin wounds. Results showed that optimized CPT NPs particle size, zeta potential, encapsulation efficiency and drug loading were 297.80 ± 5.37 nm, 20.37 ± 0.83 mV, 81.00 % and 1.74 %, respectively. In vitro, CPT NPs exhibited good antibacterial properties and biocompatibility and persistently promoted the cell migration of HaCaT cells and HUVECs due to the long-term sustained release of Tylotoin within 14 days (64.81 %). In vivo, the scarless healing of skin wound promotion was evaluated in mouse back full-thickness wound models. We demonstrated that mouse back full-thickness wounds topically treated with CPT NPs once every two weeks exhibited better scarless healing than those treated with Tylotoin once daily. We envision that CPT NPs, as a Tylotoin delivery platform might, may be potentially utilized to in skin wounds healing in clinics in the future.
    Keywords:  Chitosan; PLGA; Sustained-release; Tylotoin; Wound healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.244
  205. Biomed Res Int. 2022 ;2022 1231446
    Big Data Analysis of Manufacturing and Preclinical Studies of Nanodrug-Targeted Delivery Systems: A Literature Review.
    Qiang Cao, Xiaochen Li, Qi Zhang, Kexuan Zhou, Ying Yu, Zixu He, Zhibiao Xiang, Yi Qiang, Wei Qi.
       Objective: Nanodelivery is a modern technology involving improved delivery methods and drug formulations. The current development and initial applications of nanocarriers are pointing to new directions in the current development of nanomedicine. Researchers are increasingly applying nanodelivery to the delivery of therapeutic or diagnostic agents. This article discusses the preparation and application of nanocomplexes and nanoparticles, as well as their potential future value in clinical research. Through a review and analysis, it is hoped that this will serve as a guide for the future development of various nanodelivery technologies and help researchers learn more about these technologies.
    Materials and Methods: A literature search was conducted using the keywords "Nano drug delivery" or "Nanomedical materials" or "Nano". A literature search was conducted in three major databases, PubMed, Web of Science, and Google Scholar, using the keywords such as "Nano drug delivery", "Nanomedical materials", or "Nanobubble drug delivery". The initial search was screened by title and abstract. In the full-text review, the titles or abstracts were reviewed according to the selection criteria based on the inclusion criteria. The risk of bias and study quality was assessed according to the Cochrane guidelines, and possible biases such as selection bias and good selection bias were included in the review.
    Results: A total of 297 studies were included in this study, of which 219 were excluded based on the screening criteria, resulting in the inclusion of 78 studies, the majority of which were original studies and clinical trials, and a small number of which provided design and route of administration analysis of nanomaterial particles and effect fluorograms and were studied in more depth. This paper summarises and reviews the views and directions of the included articles. The main directions include cyclodextrin-based or grafted cyclodextrin nanomaterials, nanobubbles, and stimuli-sensitive and temperature-sensitive nanodelivery systems.
    Conclusion: The use of innovative, targeted drug delivery systems is effective in cancer drug delivery by summarising the previous studies. However, nanodelivery systems' risks and therapeutic effects need to be evaluated before clinical application. Future research in the field of targeted drug delivery nanosystems should focus on the development of nanocarriers with high in vivo delivery capacity, good synergy with therapeutic agents, and milder short-term and long-term toxicological effects and conduct comprehensive preclinical trials on nanodrug delivery systems with high potential for clinical application as soon as possible, to find nanodrug delivery systems suitable for clinical use and put them into the clinical application as soon as possible.
    DOI:  https://doi.org/10.1155/2022/1231446
  206. Front Cell Dev Biol. 2022 ;10 859236
    Computational Metabolomics Reveals the Potential Mechanism of Matrine Mediated Metabolic Network Against Hepatocellular Carcinoma.
    Kexin Wang, Xiangmin Ye, Chuanhui Yin, Qing Ren, Yupeng Chen, Xuemei Qin, Chuanzhi Duan, Aiping Lu, Li Gao, Daogang Guan.
      Hepatocellular carcinoma (HCC) is a complex issue in cancer treatment in the world at present. Matrine is the main active ingredient isolated from Sophora flavescens air and possesses excellent antitumor effects in HCC. However, the specific underlying mechanisms, especially the possible relationships between the anti-HCC effect of matrine and the related metabolic network of HCC, are not yet clear and need further clarification. In this study, an integrative metabolomic-based bioinformatics algorithm was designed to explore the underlying mechanism of matrine on HCC by regulating the metabolic network. Cell clone formation, invasion, and adhesion assay were utilized in HCC cells to evaluate the anti-HCC effect of matrine. A cell metabolomics approach based on LC-MS was used to obtain the differential metabolites and metabolic pathways regulated by matrine. The maximum activity contribution score model was developed and applied to calculate high contribution target genes of matrine, which could regulate a metabolic network based on the coexpression matrix of matrine-regulated metabolic genes and targets. Matrine significantly repressed the clone formation and invasion, enhanced cell-cell adhesion, and hampered cell matrix adhesion in SMMC-7721 cells. Metabolomics results suggested that matrine markedly regulated the abnormal metabolic network of HCC by regulating the level of choline, creatine, valine, spermidine, 4-oxoproline, D-(+)-maltose, L-(-)-methionine, L-phenylalanine, L-pyroglutamic acid, and pyridoxine, which are involved in D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, etc. Our proposed metabolomic-based bioinformatics algorithm showed that the regulating metabolic networks of matrine exhibit anti-HCC effects through acting on MMP7, ABCC1, PTGS1, etc. At last, MMP7 and its related target β-catenin were validated. Together, the metabolomic-based bioinformatics algorithm reveals the effects of the regulating metabolic networks of matrine in treating HCC relying on the unique characteristics of the multitargets and multipathways of traditional Chinese medicine.
    Keywords:  Hepatocellular carcinoma; MACS model; computational metabolomics; matrine; mechanism; metabolic network
    DOI:  https://doi.org/10.3389/fcell.2022.859236
  207. Angew Chem Int Ed Engl. 2022 Aug 08.
    A Carbon-Carbon Bond Cleavage-Based Prodrug Activation Strategy Applied to β-Lapachone for Cancer-Specific Targeting.
    Qijie Gong, Xiang Li, Tian Li, Xingsen Wu, Jiabao Hu, Fulai Yang, Xiaojin Zhang.
      Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (C-C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of β-lapachone (β-lap), an ortho -quinone natural product without traditional modifiable groups for the construction of C-N/C-O bond cleavage-based prodrugs. The designed β-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing β-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1-rich cancer cells over normal cells both in vitro and in vivo . This significantly amplified the therapeutic window of β-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.
    Keywords:  C-C cleavage; ROS; antitumor; prodrugs; β-lapachone
    DOI:  https://doi.org/10.1002/anie.202210001
  208. Int J Biol Macromol. 2022 Aug 08. pii: S0141-8130(22)01717-2. [Epub ahead of print]
    Zwitterionic meso-silica/polypeptide hybrid nanoparticles for efficient azithromycin delivery and photodynamic therapy for synergistic treatment of drug-resistant bacterial infection.
    Ya-Li Xiang, Shuang-Hui Huang, Qiu-Hui Hu, Qiu-Yue Wang, Mei-Qi Zhao, Yu-Chen Jiang, Xiao Chen, Juan Lin, Qing-Han Zhou.
      The treatment of drug-resistant bacterial infections attributed to the overuse of antibiotics still remains a serious challenge globally. Herein, zwitterionic charge switchable meso-silica/polypeptide hybrid nanoparticles (MSPNs) were prepared for the synergistic chemo-photodynamic therapy in the treatment of drug-resistant bacterial infections. Subsequently, azithromycin (AZT) and methylene blue (MB) were loaded in the MSPNs to form the combined chemo-photodynamic therapeutic nanoparticles (MSPNs-AZT/MB) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Remarkably, the as-prepared MSPNs-AZT/MB exhibited a negative surface charge of -5.2 mV at physiological pH while switching into positive surface charge of 24.7 mv in an acidic environment, leading to enhanced binding with bacterial surface. The lipase-triggered AZT release up to 77.9 % was achieved, and the loaded MB demonstrated efficient singlet oxygen (1O2) generation for photodynamic therapy. The in vitro experimental results displayed an excellent antibacterial effect against MRSA in both planktonic and biofilm phenotypes. Additionally, the as-prepared MSPNs-AZT/MB exhibited synergistic and enhanced antibacterial infection effect up to 94 % comparing to monotherapy in a mice model. Considering the above advantages, the as-prepared combined chemo-photodynamic therapeutic nanoparticles showed promising biocompatibility and clinical potential for the efficient therapy of drug-resistant bacteria.
    Keywords:  Antibacteria; Chemo-photodynamic combined therapy; Nanocomposites
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.08.022
  209. Mol Med Rep. 2022 Oct;pii: 300. [Epub ahead of print]26(4):
    Biological and neurological activities of astaxanthin (Review).
    Pan Si, Chenkai Zhu.
      Astaxanthin is a lipid‑soluble carotenoid produced by various microorganisms and marine animals, including bacteria, yeast, fungi, microalgae, shrimps and lobsters. Astaxanthin has antioxidant, anti‑inflammatory and anti‑apoptotic properties. These characteristics suggest that astaxanthin has health benefits and protects against various diseases. Owing to its ability to cross the blood‑brain barrier, astaxanthin has received attention for its protective effects against neurological disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia/reperfusion, subarachnoid hemorrhage, traumatic brain injury, spinal cord injury, cognitive impairment and neuropathic pain. Previous studies on the neurological effects of astaxanthin are mostly based on animal models and cellular experiments. Thus, the biological effects of astaxanthin on humans and its underlying mechanisms are still not fully understood. The present review summarizes the neuroprotective effects of astaxanthin, explores its mechanisms of action and draws attention to its potential clinical implications as a therapeutic agent.
    Keywords:  Alzheimer's disease; Parkinson disease; amyotrophic lateral sclerosis; astaxanthin; cerebral ischemia/reperfusion; subarachnoid hemorrhage
    DOI:  https://doi.org/10.3892/mmr.2022.12816
  210. Immun Ageing. 2022 Aug 11. 19(1): 36
    Neurohormetic phytochemicals in the pathogenesis of neurodegenerative diseases.
    Adeleh Sahebnasagh, Samira Eghbali, Fatemeh Saghafi, Antoni Sureda, Razieh Avan.
      The world population is progressively ageing, assuming an enormous social and health challenge. As the world ages, neurodegenerative diseases are on the rise. Regarding the progressive nature of these diseases, none of the neurodegenerative diseases are curable at date, and the existing treatments can only help relieve the symptoms or slow the progression. Recently, hormesis has increased attention in the treatment of age-related neurodegenerative diseases. The concept of hormesis refers to a biphasic dose-response phenomenon, where low levels of the drug or stress exert protective of beneficial effects and high doses deleterious or toxic effects. Neurohormesis, as the adaptive aspect of hormetic dose responses in neurons, has been shown to slow the onset of neurodegenerative diseases and reduce the damages caused by aging, stroke, and traumatic brain injury. Hormesis was also observed to modulate anxiety, stress, pain, and the severity of seizure. Thus, neurohormesis can be considered as a potentially innovative approach in the treatment of neurodegenerative and other neurologic disorders. Herbal medicinal products and supplements are often considered health resources with many applications. The hormesis phenomenon in medicinal plants is valuable and several studies have shown that hormetic mechanisms of bioactive compounds can prevent or ameliorate the neurodegenerative pathogenesis in animal models of Alzheimer's and Parkinson's diseases. Moreover, the hormesis activity of phytochemicals has been evaluated in other neurological disorders such as Autism and Huntington's disease. In this review, the neurohormetic dose-response concept and the possible underlying neuroprotection mechanisms are discussed. Different neurohormetic phytochemicals used for the better management of neurodegenerative diseases, the rationale for using them, and the key findings of their studies are also reviewed.
    Keywords:  Hormesis; Neurodegenerative disorders; Neurological disorders; Phytochemicals
    DOI:  https://doi.org/10.1186/s12979-022-00292-x
  211. Nutrients. 2022 Jul 29. pii: 3120. [Epub ahead of print]14(15):
    A Comparison of the Impact of Restrictive Diets on the Gastrointestinal Tract of Mice.
    András Gregor, Laura Huber, Sandra Auernigg-Haselmaier, Felix Sternberg, Magdalena Billerhart, Andreas Dunkel, Veronika Somoza, Manfred Ogris, Barbara Kofler, Valter D Longo, Jürgen König, Kalina Duszka.
      The rate of gut inflammatory diseases is growing in modern society. Previously, we showed that caloric restriction (CR) shapes gut microbiota composition and diminishes the expression of inflammatory factors along the gastrointestinal (GI) tract. The current project aimed to assess whether prominent dietary restrictive approaches, including intermittent fasting (IF), fasting-mimicking diet (FMD), and ketogenic diet (KD) have a similar effect as CR. We sought to verify which of the restrictive dietary approaches is the most potent and if the molecular pathways responsible for the impact of the diets overlap. We characterized the impact of the diets in the context of several dietary restriction-related parameters, including immune status in the GI tract; microbiota and its metabolites; bile acids (BAs); gut morphology; as well as autophagy-, mitochondria-, and energy restriction-related parameters. The effects of the various diets are very similar, particularly between CR, IF, and FMD. The occurrence of a 50 kDa truncated form of occludin, the composition of the microbiota, and BAs distinguished KD from the other diets. Based on the results, we were able to provide a comprehensive picture of the impact of restrictive diets on the gut, indicating that restrictive protocols aimed at improving gut health may be interchangeable.
    Keywords:  caloric restriction; fasting; gastrointestinal tract
    DOI:  https://doi.org/10.3390/nu14153120
  212. Biomaterials. 2022 Aug 05. pii: S0142-9612(22)00344-1. [Epub ahead of print] 121704
    Multifunctional nanolocks with GSH as the key for synergistic ferroptosis and anti-chemotherapeutic resistance.
    Jiawei Zhu, Xiaorui Wang, Yan Su, Jinjun Shao, Xuejiao Song, Wenjun Wang, Liping Zhong, Lu Gan, Yongxiang Zhao, Xiaochen Dong.
      The emergence of chemotherapeutic resistance, which is closely related to the oxidative stress defense induced by the imbalance of reactive oxygen species (ROS), is one of the important reasons for the failure of anti-tumor therapy. Herein, a GSH-triggered ferroptosis/apoptosis integrated tumor therapy strategy was successfully implemented to prohibit the mitoxantrone (MTO) resistance. Owing to the overexpressed GSH in the tumor microenvironment, the tumor active targeting MTO-Cu(Ⅱ)-cRGD nanolocks could be dissociated to release Cu(Ⅰ) and MTO, which could persistently catalyze hydrogen peroxide into hydroxyl radicals (•OH) via Fenton-like reaction and generate photothermal effect, respectively. The depletion of GSH inactivated GPX4 for the accumulation of lipid peroxides (LPO) and inducing ferroptosis. With the destruction of oxidative stress defenses, the formation of chemotherapeutic resistance could be effectively prohibited. The nanolocks could eliminate the solid tumors through ferroptosis-sensitized chemotherapy under the guidance of photoacoustic imaging. The study proposed the mechanism of reversing chemotherapeutic resistance by ferroptosis, providing a feasible strategy for the treatment of drug-resistant tumors.
    Keywords:  Chemotherapeutic resistance; Ferroptosis; GSH-Triggered; Photoacoustic imaging; Structural transformation
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121704
  213. Front Oncol. 2022 ;12 914032
    A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma.
    Sarfraz Ahmed, Mohammad Mobashir, Lamya Ahmed Al-Keridis, Nawaf Alshammari, Mohd Adnan, Mohammad Abid, Md Imtaiyaz Hassan.
      MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with various biological functions, including neuronal migration, cell polarity, microtubule dynamics, apoptosis, and cell cycle regulation, specifically in the G1/S checkpoint, cell signaling, and differentiation. It plays a critical role in different types of cancers. Hepatocellular carcinoma (HCC) is the one of the most common forms of liver cancer caused due to mutations, epigenetic aberrations, and altered gene expression patterns. Here, we have applied an integrated network biology approach to see the potential links of MARK4 in HCC, and subsequently identified potential herbal drugs. This work focuses on the naturally-derived compounds from medicinal plants and their properties, making them targets for potential anti-hepatocellular treatments. We further analyzed the HCC mutated genes from the TCGA database by using cBioPortal and mapped out the MARK4 targets among the mutated list. MARK4 and Mimosin, Quercetin, and Resveratrol could potentially interact with critical cancer-associated proteins. A set of the hepatocellular carcinoma altered genes is directly the part of infection, inflammation, immune systems, and cancer pathways. Finally, we conclude that among all these drugs, Gingerol and Fisetin appear to be the highly promising drugs against MARK4-based targets, followed by Quercetin, Resveratrol, and Apigenin.
    Keywords:  HCC; MARK4; biological networks; clinical relevance; herbal drugs; potential genes; signaling pathways
    DOI:  https://doi.org/10.3389/fonc.2022.914032
  214. Autophagy. 2022 Aug 08. 1-2
    Lipid droplets promote efficient mitophagy.
    Maeve Long, Thomas G McWilliams.
      Mitophagy neutralizes defective mitochondria via lysosomal elimination. Increased levels of mitophagy hallmark metabolic transitions and are induced by iron depletion, yet its metabolic basis has not been studied in-depth. How mitophagy integrates with different homeostatic mechanisms to support metabolic integrity is incompletely understood. We examined metabolic adaptations in cells treated with deferiprone (DFP), a therapeutic iron chelator known to induce PINK1-PRKN-independent mitophagy. We found that iron depletion profoundly rewired the cellular metabolome, remodeling lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurs upstream of mitochondrial turnover, with many LDs bordering mitochondria upon iron chelation. Surprisingly, DGAT1 inhibition restricts mitophagy in vitro by lysosomal dysfunction. Genetic depletion of mdy/DGAT1 in vivo impairs neuronal mitophagy and locomotor function in Drosophila, demonstrating the physiological relevance of our findings.
    Keywords:  DGAT1; iron; lipid droplet; metabolism; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2089956
  215. World J Clin Oncol. 2022 Jun 24. 13(6): 505-519
    Nicotinic receptors modulate antitumor therapy response in triple negative breast cancer cells.
    Alejandro Español, Yamila Sanchez, Agustina Salem, Jaqueline Obregon, Maria Elena Sales.
       BACKGROUND: Triple negative breast cancer is more aggressive than other breast cancer subtypes and constitutes a public health problem worldwide since it has high morbidity and mortality due to the lack of defined therapeutic targets. Resistance to chemotherapy complicates the course of patients' treatment. Several authors have highlighted the participation of nicotinic acetylcholine receptors (nAChR) in the modulation of conventional chemotherapy treatment in cancers of the airways. However, in breast cancer, less is known about the effect of nAChR activation by nicotine on chemotherapy treatment in smoking patients.
    AIM: To investigate the effect of nicotine on paclitaxel treatment and the signaling pathways involved in human breast MDA-MB-231 tumor cells.
    METHODS: Cells were treated with paclitaxel alone or in combination with nicotine, administered for one or three 48-h cycles. The effect of the addition of nicotine (at a concentration similar to that found in passive smokers' blood) on the treatment with paclitaxel (at a therapeutic concentration) was determined using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The signaling mediators involved in this effect were determined using selective inhibitors. We also investigated nAChR expression, and ATP "binding cassette" G2 drug transporter (ABCG2) expression and its modulation by the different treatments with Western blot. The effect of the treatments on apoptosis induction was determined by flow cytometry using annexin-V and 7AAD markers.
    RESULTS: Our results confirmed that treatment with paclitaxel reduced MDA-MB-231 cell viability in a concentration-dependent manner and that the presence of nicotine reversed the cytotoxic effect induced by paclitaxel by involving the expression of functional α7 and α9 nAChRs in these cells. The action of nicotine on paclitaxel treatment was linked to modulation of the protein kinase C, mitogen-activated protein kinase, extracellular signal-regulated kinase, and NF-κB signaling pathways, and to an up-regulation of ABCG2 protein expression. We also detected that nicotine significantly reduced the increase in cell apoptosis induced by paclitaxel treatment. Moreover, the presence of nicotine reduced the efficacy of paclitaxel treatment administered in three cycles to MDA-MB-231 tumor cells.
    CONCLUSION: Our findings point to nAChRs as responsible for the decrease in the chemotherapeutic effect of paclitaxel in triple negative tumors. Thus, nAChRs should be considered as targets in smoking patients.
    Keywords:  Breast cancer; Drug therapy; Drug transporter; Nicotinic acetylcholine receptors; Paclitaxel; Signal transduction
    DOI:  https://doi.org/10.5306/wjco.v13.i6.505
  216. Int J Mol Sci. 2022 Aug 05. pii: 8733. [Epub ahead of print]23(15):
    Lithium Enhances Hippocampal Glucose Metabolism in an In Vitro Mice Model of Alzheimer's Disease.
    Camila Gherardelli, Pedro Cisternas, Nibaldo C Inestrosa.
      Impaired cerebral glucose metabolism is an early event that contributes to the pathogenesis of Alzheimer's disease (AD). Importantly, restoring glucose availability by pharmacological agents or genetic manipulation has been shown to protect against Aβ toxicity, ameliorate AD pathology, and increase lifespan. Lithium, a therapeutic agent widely used as a treatment for mood disorders, has been shown to attenuate AD pathology and promote glucose metabolism in skeletal muscle. However, despite its widespread use in neuropsychiatric disorders, lithium's effects on the brain have been poorly characterized. Here we evaluated the effect of lithium on glucose metabolism in hippocampal neurons from wild-type (WT) and APPSwe/PS1ΔE9 (APP/PS1) mice. Our results showed that lithium significantly stimulates glucose uptake and replenishes ATP levels by preferential oxidation of glucose through glycolysis in neurons from WT mice. This increase was also accompanied by a strong increase in glucose transporter 3 (Glut3), the major carrier responsible for glucose uptake in neurons. Similarly, using hippocampal slices from APP-PS1 mice, we demonstrate that lithium increases glucose uptake, glycolytic rate, and the ATP:ADP ratio in a process that also involves the activation of AMPK. Together, our findings indicate that lithium stimulates glucose metabolism and can act as a potential therapeutic agent in AD.
    Keywords:  Alzheimer’s disease; glucose; lithium; metabolism
    DOI:  https://doi.org/10.3390/ijms23158733
  217. Phytomedicine. 2022 Jul 21. pii: S0944-7113(22)00433-0. [Epub ahead of print]105 154354
    A literature review of the studies concerning selected plant-derived adaptogens and their general function in body with a focus on animal studies.
    Niusha Esmaealzadeh, Amin Iranpanah, Jerome Sarris, Roja Rahimi.
       BACKGROUND: Adaptogens are generally referred to the substances, mostly found in plants, which non-specifically increase resilience and chances of survival by activation of signaling pathways in affected cells.
    PURPOSE: This literature review was conducted to summarize the investigation, until March 2021, on selected adaptogenic plants and plant-derived substances.
    STUDY DESIGN: Electronic databases were searched (up to March 2021) for in vitro and animal studies, as well as clinical trials. Moreover, all modes of action connected with the adaptogenic effects of plants and phytochemicals were collected.
    METHODS: The search of relevant studies was performed within electronic databases including Scopus, Science Direct, PubMed, and Cochrane library. The most important keywords were adaptogen, plant, phytochemical, and plant-derived.
    RESULTS: The most investigated medicinal herbs for their adaptogenic activity are Eleutherococcus senticosus, Panax ginseng, Withania somnifera, Schisandra chinensis, and Rhodiola spp., salidroside, ginsenosides, andrographolide, methyl jasmonate, cucurbitacin R, dichotosin, and dichotosininare are phytochemicals that have shown a considerable adaptogenic activity. Phytochemicals that have been demonstrated adaptogenic properties mainly belong to flavonoids, terpenoids, and phenylpropanoid glycosides.
    CONCLUSION: It is concluded that the main modes of action of the selected adaptogenic plants are stress modulatory, antioxidant, anti-fatigue, and physical endurance enhancement. Other properties were nootropic, immunomodulatory, cardiovascular, and radioprotective activities.
    Keywords:  Adaptogen; Cognition; Fatigue; Herb; Phytochemical; Stress
    DOI:  https://doi.org/10.1016/j.phymed.2022.154354
  218. Int J Pharm. 2022 Aug 03. pii: S0378-5173(22)00626-3. [Epub ahead of print] 122072
    Tumoral Oxygenation and Biodistribution of Lonidamine Oxygen Microbubbles Following Localized Ultrasound-Triggered Delivery.
    Quezia Lacerda, Ankit Rochani, Brian Oeffinger, Ji-Bin Liu, Corinne E Wessner, Aylin Tahmasebi, Hebah Falatah, Philip Lee, Dennis B Leeper, Flemming Forsberg, Joseph Curry, Scott W Keith, Patrick O'Kane, Gagan Kaushal, Margaret A Wheatley, John R Eisenbrey.
      Prior work has shown that microbubble-assisted delivery of oxygen improves tumor oxygenation and radiosensitivity, albeit over a limited duration. Lonidamine (LND) has been investigated because of its ability to stimulate glycolysis, lactate production, inhibit mitochondrial respiration, and inhibit oxygen consumption rates in tumors but suffers from poor bioavailability. The goal of this work was to characterize LND-loaded oxygen microbubbles and assess their ability to oxygenate a human head and neck squamous cell carcinoma (HNSCC) tumor model, while also assessing LND biodistribution. In tumors treated with surfactant-shelled microbubbles with oxygen core (SE61O2) and ultrasound, pO2 levels increased to a peak 19.5±9.7 mmHg, 50 seconds after injection and returning to baseline after 120 seconds. In comparison, in tumors treated with SE61O2/LND and ultrasound, pO2 levels showed a peak increase of 29.0±8.3 mmHg, which was achieved 70 seconds after injection returning to baseline after 300 seconds (p<0.001). The co-delivery of O2andLNDvia SE61 also showed an improvement of LND biodistribution in both plasma and tumor tissues (p<0.001). In summary, ultrasound-sensitive microbubbles loaded with O2 and LND provided prolonged oxygenation relative to oxygenated microbubbles alone, as well as provided an ability to locally deliver LND, making them more appropriate for clinical translation.
    Keywords:  Lonidamine; contrast-enhanced ultrasound; drug delivery; head and neck cancer; hypoxia; microbubbles; oxygen delivery
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122072
  219. Nutrients. 2022 Aug 04. pii: 3194. [Epub ahead of print]14(15):
    Extracts Rich in Nutrients as Novel Food Ingredients to Be Used in Food Supplements: A Proposal Classification.
    Ricardo López-Rodríguez, Laura Domínguez, Virginia Fernández-Ruiz, Montaña Cámara.
      Consumers' commitment to healthy lifestyles and a varied diet has experienced rapid growth in recent decades, causing an increase in the demand of better food quality and variety. The food industry has opted for innovation and the search for new sources of food, and these trends led to the need to develop a European regulatory framework. Novel foods are under Regulation (EU) 2015/2283 (formerly Regulation (EC) No 258/97), and this concept includes all food not used in an important measure for human consumption in the EU before 15 May 1997, and which is included in any of the food categories established. Currently, there are 26 extracts authorized as novel foods or ingredients, being one of the most numerous groups. These extracts are concentrated sources of nutrients, and 23 of them can be used in food supplements. Given their heterogeneous composition and the perceptive risk assessments performed, sometimes, the authorizations are limited to certain population groups. The present work is a comprehensive review of the extracts rich in nutrients authorized as novel ingredients to be used in food supplements within the EU. A classification is proposed according to their source of origin, resulting in four main groups: extracts of plant, animal, algae, and fungal origins. A description of each extract as well as the evaluation of the potential use restriction and health benefits are also addressed.
    Keywords:  extracts; food supplements; novel foods; novel ingredients; risk assessment
    DOI:  https://doi.org/10.3390/nu14153194
  220. Front Psychiatry. 2022 ;13 929139
    Editorial: Natural products as sources of innovative approaches in psychiatry.
    Elaine Elisabetsky, Chun-Tao Che.
      
    Keywords:  drug development; innovative antidepressants; medicinal plants revisited; mental disorders; natural products
    DOI:  https://doi.org/10.3389/fpsyt.2022.929139
  221. Proc Nutr Soc. 2022 May;81(2): 190-198
    Plant-based diets and long-term health: findings from the EPIC-Oxford study.
    Timothy J Key, Keren Papier, Tammy Y N Tong.
      The concept of plant-based diets has become popular due to the purported benefits for both human health and environmental impact. Although 'plant-based' is sometimes used to indicate omnivorous diets with a relatively small component of animal foods, here we take it to mean either vegetarian (plant-based plus dairy products and/or eggs) or vegan (100% plant-based). Important characteristics of plant-based diets which would be expected to be beneficial for long-term health are low intakes of saturated fat and high intakes of dietary fibre, whereas potentially deleterious characteristics are the risk of low intakes of some micronutrients such as vitamin B12, vitamin D, calcium and iodine, particularly in vegans. Vegetarians and vegans typically have lower BMI, serum LDL cholesterol and blood pressure than comparable regular meat-eaters, as well as lower bone mineral density. Vegetarians in the EPIC-Oxford study have a relatively low risk of IHD, diabetes, diverticular disease, kidney stones, cataracts and possibly some cancers, but a relatively high risk of stroke (principally haemorrhagic stroke) and bone fractures, in comparison with meat-eaters. Vegans in EPIC-Oxford have a lower risk of diabetes, diverticular disease and cataracts and a higher risk of fractures, but there are insufficient data for other conditions to draw conclusions. Overall, the health of people following plant-based diets appears to be generally good, with advantages but also some risks, and the extent to which the risks may be mitigated by optimal food choices, fortification and supplementation is not yet known.
    Keywords:  Cancer; Cardiovascular; Plant-based; Vegan; Vegetarian
    DOI:  https://doi.org/10.1017/S0029665121003748
  222. PLoS One. 2022 ;17(8): e0266905
    Nitrite lowers the oxygen cost of ATP supply in cultured skeletal muscle cells by stimulating the rate of glycolytic ATP synthesis.
    Anthony G Wynne, Charles Affourtit.
      Dietary nitrate lowers the oxygen cost of human exercise. This effect has been suggested to result from stimulation of coupling efficiency of skeletal muscle oxidative phosphorylation by reduced nitrate derivatives. In this paper, we report the acute effects of sodium nitrite on the bioenergetic behaviour of cultured rat (L6) myocytes. At odds with improved efficiency of mitochondrial ATP synthesis, extracellular flux analysis reveals that a ½-hour exposure to NaNO2 (0.1-5 μM) does not affect mitochondrial coupling efficiency in static myoblasts or in spontaneously contracting myotubes. Unexpectedly, NaNO2 stimulates the rate of glycolytic ATP production in both myoblasts and myotubes. Increased ATP supply through glycolysis does not emerge at the expense of oxidative phosphorylation, which means that NaNO2 acutely increases the rate of overall myocellular ATP synthesis, significantly so in myoblasts and tending towards significance in contractile myotubes. Notably, NaNO2 exposure shifts myocytes to a more glycolytic bioenergetic phenotype. Mitochondrial oxygen consumption does not decrease after NaNO2 exposure, and non-mitochondrial respiration tends to drop. When total ATP synthesis rates are expressed in relation to total cellular oxygen consumption rates, it thus transpires that NaNO2 lowers the oxygen cost of ATP supply in cultured L6 myocytes.
    DOI:  https://doi.org/10.1371/journal.pone.0266905
  223. Eur J Pharmacol. 2022 Aug 05. pii: S0014-2999(22)00444-7. [Epub ahead of print]931 175183
    c-kit inhibitor masitinib induces reactive oxygen species-dependent apoptosis in c-kit-negative HepG2 cells.
    Yuta Semba, Shintaro Yamamoto, Shunsuke Takahashi, Takahisa Shinomiya, Yukitoshi Nagahara.
      Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-L-cysteine or a c-Jun N-terminal kinase/stress-activated protein kinase (JNKs) inhibitor. Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies.
    Keywords:  Masitinib; Mitochondrial apoptosis; Reactive oxygen species (ROS); Receptor tyrosine kinase; c-Jun N-Terminal kinases (JNKs)
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175183
  224. Nutrients. 2022 Aug 08. pii: 3238. [Epub ahead of print]14(15):
    Beneficial Effects of Flaxseed and/or Mulberry Extracts Supplementation in Ovariectomized Wistar Rats.
    Jéssica Petrine Castro Pereira, Erika Aparecida Oliveira, Fernanda Aparecida Castro Pereira, Josilene Nascimento Seixas, Camila Souza de Oliveira Guimaraes, Bruno Del Bianco Borges.
      Low endogenous estrogen action causes several injuries. Medicinal plants, such as flaxseed and mulberry, contain substances that have been shown to be effective to the organism. The aim was to verify the effects of flaxseed and/or mulberry extracts on ovariectomized Wistar rats. The animals received supplements of extracts and estrogen or saline by gavage for 60 days and were weighed weekly. Vaginal wash, blood, pituitary, uterus, liver, and kidneys were collected. Phenolic compounds and the antioxidant activity of the extracts, lipid profile, uric acid, liver enzymes, and pituitary weight were measured. Histomorphometric for uterine wall and histopathological analyses for liver and kidney were performed. Flaxseed and mulberry extracts showed great antioxidant activity and large amounts of phenolic compounds. The treatment with extracts had less weight gain, increased pituitary weight, the predominance of vaginal epithelial cells, and reduced TC, LDL-c and lipase activity, similar to estrogen animals. Estrogen or flaxseed + mulberry animals reduced VLDL-c and TAG. HDL-c, uric acid, and liver enzymes did not differ. Estrogen or extracts demonstrated trophic action on the endometrial thickness and have not shown hepatotoxicity or nephrotoxicity. We suggested the beneficial effects of flaxseed and mulberry extract as an alternative to reduce and/or prevent the negative effects caused by low estrogenic action.
    Keywords:  antioxidants; body weight; compound phenolics; estrogen; metabolism; phytoestrogens
    DOI:  https://doi.org/10.3390/nu14153238
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