bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–07–17
178 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Programmable Therapeutic Nanoscale Covalent Organic Framework for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy.
  2. Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review.
  3. Polymer-based drug delivery systems for anticancer drugs: A systematic review.
  4. Targeting mitochondrial metabolism for precision medicine in cancer.
  5. Plant-derived bioactive compounds in colon cancer treatment: An updated review.
  6. A nanoparticle-based tour de force for enhancing immunogenic cell death elicited by photodynamic therapy.
  7. Historical perspective of tumor glycolysis: A century with Otto Warburg.
  8. Tumor metabolic reprogramming in lung cancer progression.
  9. Oxaliplatin-loaded nanoemulsion containing Teucrium polium L. essential oil induces apoptosis in Colon cancer cell lines through ROS-mediated pathway.
  10. Bufalin exacerbates Photodynamic Therapy of Colorectal Cancer by targeting SRC-3/HIF-1α pathway.
  11. Natural products derived from medicinal plants and microbes might act as a game-changer in breast cancer: a comprehensive review of preclinical and clinical studies.
  12. Application of Nano Drug Delivery System (NDDS) in Cancer Therapy: A Review.
  13. How to improve photodynamic therapy-induced antitumor immunity for cancer treatment?
  14. A chemical biology toolbox to overcome the hypoxic tumor microenvironment for photodynamic therapy: a review.
  15. Arginase: Mechanisms and Clinical Application in Hematologic Malignancy.
  16. Opportunities and challenges for co-delivery nanomedicines based on combination of phytochemicals with chemotherapeutic drugs in cancer treatment.
  17. Brain extracellular matrix attenuates photodynamic cytotoxicity of glioma cells.
  18. 5-Demethylnobiletin: Insights into its pharmacological activity, mechanisms, pharmacokinetics and toxicity.
  19. Advanced methylene blue - nanoemulsions for in vitro photodynamic therapy on oral and cervical human carcinoma.
  20. Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms.
  21. Engineering dual catalytic nanomedicine for autophagy-augmented and ferroptosis-involved cancer nanotherapy.
  22. The potential role of prebiotics, probiotics, and synbiotics in adjuvant cancer therapy especially colorectal cancer.
  23. Satureja khuzistanica Essential Oil-Loaded Solid Lipid Nanoparticles Modified With Chitosan-Folate: Evaluation of Encapsulation Efficiency, Cytotoxic and Pro-apoptotic Properties.
  24. Physical Exercise and Tumor Energy Metabolism.
  25. GOx-Functionalized Platelet Membranes-Camouflaging Nanoreactors for Enhanced Multimodal Tumor Treatment.
  26. Mitochondrial oxidative phosphorylation became functional under aglycemic hypoxia conditions in A549 cells.
  27. Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes.
  28. Tumor pH-Responsive Nanocarriers With Light-Activatable Drug Release for Chemo-Photodynamic Therapy of Breast Cancer.
  29. The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling.
  30. Dual-sensitive drug-loaded hydrogel system for local inhibition of post-surgical glioma recurrence.
  31. Evaluation of the wound healing effect of neomycin-silver nano-composite gel in rats.
  32. Laser-assisted photodynamic therapy in proliferative verrucous oral leukoplakia.
  33. Indispensable role of microbes in anticancer drugs and discovery trends.
  34. Better Bioactivity, Cerebral Metabolism and Pharmacokinetics of Natural Medicine and Its Advanced Version.
  35. Promising potent in vitro activity of curcumin and quercetin nano-niosomes against Trichomonas vaginalis.
  36. Medicinal Plants for the Treatment of Gastrointestinal Cancers From the Metabolomics Perspective.
  37. Upconversion Nanomaterials and Delivery Systems for Smart Photonic Medicines and Healthcare Devices.
  38. Ferrocene-based multifunctional nanoparticles for combined chemo/chemodynamic/photothermal therapy.
  39. Flexible nano-liposomes-based transdermal hydrogel for targeted delivery of dexamethasone for rheumatoid arthritis therapy.
  40. The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target-a narrative review.
  41. Microenvironment-tailored micelles restrain carcinoma-astrocyte crosstalk for brain metastasis.
  42. Proton export upregulates aerobic glycolysis.
  43. Acoustic triggered nanobomb for US imaging guided sonodynamic therapy and activating antitumor immunity.
  44. Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest.
  45. Natural product-based radiopharmaceuticals: Focus on curcumin and its analogs, flavonoids, and marine peptides.
  46. Strategies for enhancing the oral bioavailability of cannabinoids.
  47. Delivery of enzalutamide via nanoparticles for effectively inhibiting prostate cancer progression.
  48. Complexity of Tumor Microenvironment: Therapeutic Role of Curcumin and Its Metabolites.
  49. Genistein: Therapeutic and Preventive Effects, Mechanisms, and Clinical Application in Digestive Tract Tumor.
  50. Pharmacological Effects of Caffeic Acid and Its Derivatives in Cancer: New Targeted Compounds for the Mitochondria.
  51. Traditonal Uses, Pharmacological, and Phytochemical Studies of Euphorbia: a Review.
  52. Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy.
  53. Fabrication of novel ruthenium loaded silk fibroin nanomaterials for fingolimod release improved antitumor efficacy in hepatocellular carcinoma.
  54. The Phytochemical Potential for Brain Disease Therapy and the Possible Nanodelivery Solutions for Brain Access.
  55. Medicinal herbs in treating chemotherapy-induced nausea and vomiting: A review.
  56. Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches.
  57. A comprehensive review of flaxseed (Linum usitatissimum L.): health-affecting compounds, mechanism of toxicity, detoxification, anticancer and potential risk.
  58. Nanomagnet-facilitated pharmaco-compatibility for cancer diagnostics: Underlying risks and the emergence of ultrasmall nanomagnets.
  59. High dietary methionine intake may contribute to the risk of nonalcoholic fatty liver disease by inhibiting hepatic H2S production.
  60. PEGylated drug delivery systems in the pharmaceutical field: past, present and future perspective.
  61. Thermosensitive liposomes: A promising step towards locsalised chemotherapy.
  62. Development of branched polyphenolic poly(beta amino esters) to facilitate post-synthesis processing.
  63. Recent Progress in Development of Dressings Used for Diabetic Wounds with Special Emphasis on Scaffolds.
  64. Piperine-loaded electrospun nanofibers, an implantable anticancer controlled delivery system for postsurgical breast cancer treatment.
  65. An active tumor-targeting organic photochemotherapy agent with naproxen for enhanced cancer therapy.
  66. Docetaxel in combination with metformin enhances antitumour efficacy in metastatic breast carcinoma models: a promising cancer targeting based on PEGylated liposomes.
  67. Synergistic Effect of Conventional Medicinal Herbs against Different Pharmacological Activity.
  68. The Effect of Hypoxia-Induced Exosomes on Anti-Tumor Immunity and Its Implication for Immunotherapy.
  69. Curcumin-loaded multifunctional chitosan gold nanoparticles: An enhanced PDT/PTT dual-modal phototherapeutic and pH-responsive antimicrobial agent.
  70. Low-dose exposure to phytosynthesized gold nanoparticles combined with glutamine deprivation enhances cell death in the cancer cell line HeLa via oxidative stress-mediated mitochondrial dysfunction and G0/G1 cell cycle arrest.
  71. 3-Bromopyruvic acid regulates glucose metabolism by targeting the c-Myc/TXNIP axis and induces mitochondria-mediated apoptosis in TNBC cells.
  72. The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging.
  73. Alpha Tocopherol Loaded Polymeric Nanoparticles: Preparation, Characterizations, and In Vitro Assessments Against Oxidative Stress in Spinal Cord Injury Treatment.
  74. Molecular bases for the use of functional foods in the management of healthy aging: Berries, curcumin, virgin olive oil and honey; three realities and a promise.
  75. Reactive Oxygen Species-Responsive and Self-Illuminating Nanoparticles for Inflammation and Tumor Imaging.
  76. Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor.
  77. Biocompatible Supramolecular Mesoporous Silica Nanoparticles as the Next-Generation Drug Delivery System.
  78. Nanomaterial Technology and Soft Tissue Sarcomas.
  79. Role of curcumin in the treatment of acute kidney injury: research challenges and opportunities.
  80. Herbal nanocosmeceuticals: A review on cosmeceutical innovations.
  81. Recent Advances and Perspectives on the Health Benefits of Urolithin B, A Bioactive Natural Product Derived From Ellagitannins.
  82. KRAS mutation in intrahepatic cholangiocarcinoma: linkage with metastasis-free survival and reduced E-cadherin expression.
  83. Untapping the protective role of carotenoids against respiratory diseases.
  84. Inhibition of Mitochondrial Biosynthesis using a "Right-Side-Out" Membrane Camouflaged Micelle to Facilitate the Therapeutic Effects of Shikonin on Triple-Negative Breast Cancer.
  85. Organic extract of Geodia cydonium induces cell cycle block in human mesothelioma cells.
  86. Enhancing the bioaccessibility of vitamin D using mixed micelles - An in vitro study.
  87. The Role and Therapeutic Perspectives of Sirtuin 3 in Cancer Metabolism Reprogramming, Metastasis, and Chemoresistance.
  88. Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer.
  89. Co-delivery of Interleukin-12 and Doxorubicin Loaded Nano-delivery System for Enhanced Immunotherapy with Polarization toward M1-type Macrophages.
  90. Proteomic alterations in Paracoccidioides brasiliensis caused by exposure to curcumin.
  91. Estrone-Conjugated PEGylated Liposome Co-Loaded Paclitaxel and Carboplatin Improve Anti-Tumor Efficacy in Ovarian Cancer and Reduce Acute Toxicity of Chemo-Drugs.
  92. Effect of chitosan and curcumin nanoparticles against skeletal muscle fibrosis at early regenerative stage of glycerol-injured rat muscles.
  93. Research on the progress of Traditional Chinese medicine components and preparations on histone deacetylase inhibitors - Like effects in the course of disease treatment.
  94. Nanoformulations of curcumin and quercetin with silver nanoparticles for inactivation of bacteria.
  95. Therapeutic potential of autophagy activators and inhibitors in lung and breast cancer- a review.
  96. Eugenol: A New Option in Combination Therapy with Sorafenib for the Treatment of Undifferentiated Thyroid Cancer.
  97. Differentiating Cannabis Products: Drugs, Food, and Supplements.
  98. A comprehensive review on bioavailability, safety and antidepressant potential of natural bioactive components from tea.
  99. Review article: Dietary management of coeliac disease.
  100. Vitamin C supramolecular hydrogel for enhanced cancer immunotherapy.
  101. Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity.
  102. Design, Characterization and In Vivo Performance of Solid Lipid Nanoparticles (SLNs)-Loaded Mucoadhesive Buccal Tablets for Efficient Delivery of Lornoxicam in Experimental Inflammation.
  103. Generation of Hybrid Extracellular Vesicles by Fusion with Functionalized Liposomes.
  104. Review Effects of time-restricted feeding with different feeding windows on metabolic health: A systematic review of human studies.
  105. Vitamin A aldehyde-taurine adducts function in photoreceptor cells.
  106. 'Warburg effect' controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives.
  107. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells.
  108. Effect of curcumin supplementation on exercise-induced muscle damage: a narrative review.
  109. Targeted intelligent mesoporous polydopamine nanosystems for multimodal synergistic tumor treatment.
  110. Investigating Polyphenol Nanoformulations for Therapeutic Targets against Diabetes Mellitus.
  111. Reactive Oxygen Species Scavenging Functional Hydrogel Delivers Procyanidins for the Treatment of Traumatic Brain Injury in Mice.
  112. Targeted Delivery of Doxorubicin as a Potential Chemotherapeutic Agent.
  113. Exploration and validation of Taraxacum mongolicum anti-cancer effect.
  114. Gene Expression of Antioxidant Metabolic Enzymes in Grape Extracts.
  115. Metallated phthalocyanines and their hydrophilic derivatives for multi-targeted oncological photodynamic therapy.
  116. Bioactive potential of beetroot (Beta vulgaris).
  117. Nanocomposites based on lanthanide-doped upconversion nanoparticles: diverse designs and applications.
  118. Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR.
  119. Improving the oral delivery of benznidazole nanoparticles by optimizing the formulation parameters through a design of experiment and optimization strategy.
  120. Immunostimulation in experimental gas plasma therapy for breast cancer.
  121. Underutilized green leafy vegetables: frontier in fortified food development and nutrition.
  122. In vitro and in vivo activity of thermosensitive liposomes loaded with doxorubicin and cisplatin.
  123. Comparative characteristics of small cell lung cancer and Ewing's sarcoma: a narrative review.
  124. Sea urchins: an update on their pharmacological properties.
  125. Manganese-Based Prussian Blue Nanocatalysts Suppress Non-Small Cell Lung Cancer Growth and Metastasis via Photothermal and Chemodynamic Therapy.
  126. Patient-Derived Sarcoma Organoids Offer a Novel Platform for Personalized Precision Medicine.
  127. Chicoric Acid: Natural Occurrence, Chemical Synthesis, Biosynthesis, and Their Bioactive Effects.
  128. Antioxidant, anti-inflammatory activity of Thymus vulgaris-mediated selenium nanoparticles: An in vitro study.
  129. Dietary flavonoids prevent diabetes through epigenetic regulation: advance and challenge.
  130. A Cosmeceutical Topical Water-in-Oil Nanoemulsion of Natural Bioactives: Design of Experiment, in vitro Characterization, and in vivo Skin Performance Against UVB Irradiation-Induced Skin Damages.
  131. Bile acid-based advanced drug delivery systems, bilosomes and micelles as novel carriers for therapeutics.
  132. Isovalerylspiramycin I suppresses non-small cell lung carcinoma growth through ROS-mediated inhibition of PI3K/AKT signaling pathway.
  133. The landscape of metabolic brain alterations in Alzheimer's disease.
  134. Physicochemical degradation of phycocyanin and means to improve its stability: A short review.
  135. Nutraceuticals: Pharmacologically Active Potent Dietary Supplements.
  136. Dietary Drivers and Challenges of Australian Breast Cancer Survivors: A Qualitative Study.
  137. Identification and pharmacological modification of resistance mechanisms to protoporphyrin-mediated photodynamic therapy in human cutaneous squamous cell carcinoma cell lines.
  138. Hydroxyethyl starch and its derivatives as nanocarriers for delivery of diagnostic and therapeutic agents towards cancers.
  139. Chitosan IR806 dye-based polyelectrolyte complex nanoparticles with mitoxantrone combination for effective chemo-photothermal therapy of metastatic triple-negative breast cancer.
  140. Low-carbohydrate diet score is associated with improved blood pressure and cardio-metabolic risk factors among obese adults.
  141. A novel active mitochondrion-selective fluorescent probe for the NIR fluorescence imaging and targeted photodynamic therapy of gastric cancer.
  142. Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment.
  143. The mechanisms of action of Tumor Treating Fields.
  144. Immunosuppressive Effects and Potent Anti-tumor Efficacy of mTOR Inhibitor Everolimus in Breast Tumor-bearing Mice.
  145. Complex Physiology and Clinical Implications of Time-restricted Eating.
  146. FAP-Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts.
  147. Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives.
  148. Hesperetin ameliorates glioblastoma by inhibiting proliferation, inducing apoptosis, and suppressing metastasis.
  149. The Edible Plant Crithmum maritimum Shows Nutraceutical Properties by Targeting Energy Metabolism in Hepatic Cancer.
  150. Promising disruptors of p53-MDM2 dimerization from some medicinal plant phytochemicals: a molecular modeling study.
  151. Dietary strategies with anti-aging potential: Dietary patterns and supplements.
  152. Management of bone diseases: looking at scaffold-based strategies for drug delivery.
  153. Decorated bacteria and the application in drug delivery.
  154. Synchronous breast cancer and non-Hodgkin lymphoma: A case report.
  155. Dietary factors that affect the risk of pre-eclampsia.
  156. Protective effect of surfactant modified phytosterol oleogels on loaded curcumin.
  157. Efficacy of front-of-pack nutrition labels in improving health status.
  158. Anticancer effect and apoptosis induction by azaflavanone derivative in human prostate cancer cells.
  159. Gankyrin modulated non-small cell lung cancer progression via glycolysis metabolism in a YAP1-dependent manner.
  160. Saponins and their derivatives: potential candidates to alleviate anthracycline-induced cardiotoxicity and multidrug resistance.
  161. The response of the canine mammary simple carcinoma and carcinosarcoma cells to 5-aminolaevulinic acid-based photodynamic therapy: An in vitro study.
  162. Iron oxide nanoparticles with photothermal performance and enhanced nanozyme activity for bacteria-infected wound therapy.
  163. Anti-prostate cancer protection and therapy in the framework of predictive, preventive and personalised medicine - comprehensive effects of phytochemicals in primary, secondary and tertiary care.
  164. Macromolecular conjugated cyanine fluorophore nanoparticles for tumor-responsive photo nanotheranostics.
  165. Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells.
  166. The Association Between Fasting Blood Sugar and Index of Nutritional Quality in Adult Women.
  167. Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.
  168. TRAIL & EGFR affibody dual-display on a protein nanoparticle synergistically suppresses tumor growth.
  169. Targeting purinergic pathway to enhance radiotherapy-induced immunogenic cancer cell death.
  170. Experimental study on anti angiogenesis of recombinant mouse angiostatin gene in mice with gallbladder carcinoma.
  171. A poloxamer/hyaluronic acid/chitosan-based thermosensitive hydrogel that releases dihydromyricetin to promote wound healing.
  172. Effect of Dihydroquercetin on Energy Metabolism in LPS-Induced Inflammatory Mice.
  173. Skin-Targeted Delivery of Extracellular Vesicle-Encapsulated Curcumin Using Dissolvable Microneedle Arrays.
  174. Targeting the Mitochondria with Pseudo-Stealthy Nanotaxanes to Impair Mitochondrial Biogenesis for Effective Cancer Treatment.
  175. Drug Repurposing by Tumor Tissue Editing.
  176. Phytosterol: nutritional significance, health benefits, and its uses in poultry and livestock nutrition.
  177. The Interaction Between Dietary Fructose and Gut Microbiota in Hyperuricemia and Gout.
  178. Nanoscale Hf-hematoporphyrin frameworks for synergetic sonodynamic/radiation therapy of deep-seated tumors.
  1. Acta Biomater. 2022 Jul 07. pii: S1742-7061(22)00397-X. [Epub ahead of print]
    Programmable Therapeutic Nanoscale Covalent Organic Framework for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy.
    Haozhe He, Lihua Du, Hongman Xue, Jun Wu, Xintao Shuai.
      Clinical photodynamic therapy (PDT) only has a limited cancer therapeutic effect and typically leads to a more hypoxic milieu owing to the hypoxic conditions of the solid tumor microenvironment that limit the singlet oxygen (1O2), generation. To address this issue, the PDT, in combination with hypoxia-activated prodrugs, has recently been investigated as a possible clinical treatment modality for cancer therapy. By cross-linking the photosensitizer tetra(4-hydroxyphenyl)porphine (THPP) and a 1O2-cleavable thioketal (TK) linker, a multifunctional nanoscale covalent organic framework (COF) platform with a high porphyrin loading capacity was synthesized, which significantly improve the reactive oxygen species (ROS) generation efficiency and contributes to PDT. As-synthesized THPPTK-PEG nanoparticles (NPs) possess a high THPP photosensitizer content and mesoporous structure for further loading of the hypoxia-responsive prodrug banoxantrone (AQ4N) into the COF with a high-loading content. The nano-carriers surfaces are coated with a thick PEG coating to promote their dispersibility in physiological surroundings and therapeutic performance. When exposed to 660 nm radiation, such a nanoplatform can efficiently create cytotoxic 1O2 for PDT. Similarly, oxygen intake may exacerbate the hypoxic environment of the tumor, inducing the activation of AQ4N to achieve hypoxia-activated cascade chemotherapy and increased treatment efficacy. This study provides a new nanoplatform for photodynamic-chemical synergistic therapy and offers critical new insights for designing and developing a multifunctional supramolecular drug delivery system. STATEMENT OF SIGNIFICANCE: : Here, we designed a laser-activated hypoxia-responsive nanoscale COF nanoplatform for hypoxia-activated cascade chemotherapy and PDT. When exposed to laser light, thus this nanoplatform can efficiently create cytotoxic 1O2 for PDT while consuming oxygen at the tumor location. However, increased oxygen consumption can exacerbate the tumor's hypoxic environment, causing AQ4N to become active, allowing for programmed hypoxia-triggered cascade chemotherapy and improved therapeutic efficacy. In addition, this innovative nanoscale COF nanoplatform allows for laser-controlled drug delivery in specific areas, which dramatically improves tumor inhibition. This research suggests a method for attaining ultrasensitive drug release and effective cascade therapy for cancer treatments.
    Keywords:  AQ4N; PDT; controlled drug release; hypoxia-activated cascade chemotherapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.07.003
  2. Drug Deliv. 2022 Dec;29(1): 2130-2161
    Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review.
    Bingqian Li, Huili Shao, Lei Gao, Huan Li, Huagang Sheng, Liqiao Zhu.
      Chemotherapy drugs have been used for a long time in the treatment of cancer, but serious side effects are caused by the inability of the drug to be solely delivered to the tumor when treating cancer with chemotherapy. Natural products have attracted more and more attention due to the antitumor effect in multiple ways, abundant resources and less side effects. Therefore, the combination of natural active ingredients and chemotherapy drugs may be an effective antitumor strategy, which can inhibit the growth of tumor and multidrug resistance, reduce side effects of chemotherapy drugs. Nano-drug co-delivery system (NDCDS) can play an important role in the combination of natural active ingredients and chemotherapy drugs. This review provides a comprehensive summary of the research status and application prospect of nano-delivery strategies for the combination of natural active ingredients and chemotherapy drugs, aiming to provide a basis for the development of anti-tumor drugs.
    Keywords:  Nano-drug co-delivery system; chemotherapy drugs; combination therapy; nanocarrier; natural active ingredients
    DOI:  https://doi.org/10.1080/10717544.2022.2094498
  3. Cancer Treat Res Commun. 2022 Jul 06. pii: S2468-2942(22)00095-8. [Epub ahead of print]32 100605
    Polymer-based drug delivery systems for anticancer drugs: A systematic review.
    Nader Salari, Farahnaz Faraji, Fatemeh Mansouri Torghabeh, Fatemeh Faraji, Kamran Mansouri, Farzaneh Abam, Shamarina Shohaimi, Hakimeh Akbari, Masoud Mohammadi.
      Recent advances in nanotechnology sciences lead to the development of new treatment approaches for various diseases such as cancer. Nanotechnology advances can potentially minimize the side effects of drugs through the employment of effective and controlled drug delivery systems (DDSs). Polymers are optimal tools providing drug delivery mechanisms through the unique features of pharmacokinetics, circulation time, biocompatibility, and biodegradability. This systematic review aimed to evaluate polymer-based DDSs for anticancer drugs and their various therapeutic applications in cancer treatment. This study was conducted with no time limitation by November 2021. Related articles were collected through a deep search in English and Persian databases of SID, MagIran, Scopus, Web Of Science (WoS), PubMed, Science Direct, and Google Scholar. Keywords included drug delivery system, anticancer agent, polymeric nanostructure-based drug delivery, polymer-based drug delivery, and polymeric system. As the results showed, polymeric nanoparticles (PNPs) have influential roles in cancer treatment than conventional chemotherapy procedures. PNPs can reduce cytotoxicity following chemotherapy drug administration, improve the solubility characteristics of these therapeutic agents and inhibit the rate of tumor growth.
    Keywords:  Anticancer agent; Polymer-based drug delivery; Systematic review
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100605
  4. Cell Death Differ. 2022 Jul;29(7): 1304-1317
    Targeting mitochondrial metabolism for precision medicine in cancer.
    Lourdes Sainero-Alcolado, Judit Liaño-Pons, María Victoria Ruiz-Pérez, Marie Arsenian-Henriksson.
      During decades, the research field of cancer metabolism was based on the Warburg effect, described almost one century ago. Lately, the key role of mitochondria in cancer development has been demonstrated. Many mitochondrial pathways including oxidative phosphorylation, fatty acid, glutamine, and one carbon metabolism are altered in tumors, due to mutations in oncogenes and tumor suppressor genes, as well as in metabolic enzymes. This results in metabolic reprogramming that sustains rapid cell proliferation and can lead to an increase in reactive oxygen species used by cancer cells to maintain pro-tumorigenic signaling pathways while avoiding cellular death. The knowledge acquired on the importance of mitochondrial cancer metabolism is now being translated into clinical practice. Detailed genomic, transcriptomic, and metabolomic analysis of tumors are necessary to develop more precise treatments. The successful use of drugs targeting metabolic mitochondrial enzymes has highlighted the potential for their use in precision medicine and many therapeutic candidates are in clinical trials. However, development of efficient personalized drugs has proved challenging and the combination with other strategies such as chemocytotoxic drugs, immunotherapy, and ketogenic or calorie restriction diets is likely necessary to boost their potential. In this review, we summarize the main mitochondrial features, metabolic pathways, and their alterations in different cancer types. We also present an overview of current inhibitors, highlight enzymes that are attractive targets, and discuss challenges with translation of these approaches into clinical practice. The role of mitochondria in cancer is indisputable and presents several attractive targets for both tailored and personalized cancer therapy.
    DOI:  https://doi.org/10.1038/s41418-022-01022-y
  5. Biomed Pharmacother. 2022 Jul 09. pii: S0753-3322(22)00773-9. [Epub ahead of print]153 113384
    Plant-derived bioactive compounds in colon cancer treatment: An updated review.
    Akanksha Esmeeta, Subhamay Adhikary, V Dharshnaa, P Swarnamughi, Z Ummul Maqsummiya, Antara Banerjee, Surajit Pathak, Asim K Duttaroy.
      Colon cancer is the third most predominant cancer caused by genetic, environmental and nutritional factors. Plant-based compounds are very well known to regress colon cancer in many ways, like delaying tumor growth, managing chemotherapy and radiation therapy side-effects, and working at the molecular levels. Medicinal plants contain many bioactive phytochemicals such as flavonoids, polyphenol compounds, caffeic acid, catechins, saponins, polysaccharides, triterpenoids, alkaloids, glycosides, phenols, quercetin, luteolin, kaempferol and luteolin glycosides, carnosic acid, oleanolic acid, rosmarinic acid, emodin, and eugenol and anthricin. These bioactive compounds can reduce tumor cell proliferation via several mechanisms, such as blocking cell cycle checkpoints and promoting apoptosis through activating initiator and executioner caspase. Traditional medicines have been used globally to treat cancers because of their anti-cancer effects, antioxidant properties, anti-inflammatory properties, anti-mutagenic effects, and anti-angiogenic effects. In addition, these medicines effectively suppress early and intermediate stages of carcinogenesis when administered in their active and pure form. However, traditional medicine is not very popular due to some critical challenges. These include poor solubility and absorption of these compounds, intellectual property-related issues, involvement of drug synergism, absence of drug-likeness, and unsure protocols for their extraction from the plant source. Using bioactive compounds in colon cancer has equal advantages and limitations. This review highlights the benefits and challenges of using bioactive compounds derived from plants for colon cancer. We have also discussed using these compounds to target cancer stem cell self-renewal, its effects on cancer cell metabolism, safety parameters, easy modulation, and their bioavailability.
    Keywords:  Anti-cancer mechanism; Carcinogenesis; Chemoprevention; Colon cancer; Plant-derived compounds
    DOI:  https://doi.org/10.1016/j.biopha.2022.113384
  6. Oncoimmunology. 2022 ;11(1): 2098658
    A nanoparticle-based tour de force for enhancing immunogenic cell death elicited by photodynamic therapy.
    Oliver Kepp, Guido Kroemer.
      Immunogenic cell death (ICD) involves the release of ATP, which can be destroyed by ectonucleotidases, converting it into immunosuppressive adenosine. Hence, inhibition of such ectonucleotidases is a strategy for enhancing ICD-elicited anticancer immunity. In a recent paper in Science Translational Medicine, Mao et al. report the construction of reactive oxygen-labile nanoparticles that bear two functionalities, namely (i) the capacity to sensitize cancer cells to near-infrared light (NIL) irradiation, hence inducing ICD in the context of photodynamic therapy, and (ii) the peculiarity to respond to NIL by releasing a pharmacological inhibitor of ectonucleotidases, hence enhancing intratumoral concentrations of ATP. In preclinical models, these nanoparticles are highly efficient in inducing anticancer immune responses.
    DOI:  https://doi.org/10.1080/2162402X.2022.2098658
  7. Semin Cancer Biol. 2022 Jul 06. pii: S1044-579X(22)00162-6. [Epub ahead of print]
    Historical perspective of tumor glycolysis: A century with Otto Warburg.
    Giulia Bononi, Samuele Masoni, Valeria Di Bussolo, Tiziano Tuccinardi, Carlotta Granchi, Filippo Minutolo.
      Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg. Since then, this peculiar metabolic switch in tumors has been addressed by extensive studies covering several areas of research. In this historical perspective, we aim at illustrating the evolution of these studies over time and their implication in various fields of science.
    Keywords:  Aerobic glycolysis; Historical perspective; Reverse Warburg effect; Tumor metabolism; Warburg effect
    DOI:  https://doi.org/10.1016/j.semcancer.2022.07.003
  8. Oncol Lett. 2022 Aug;24(2): 287
    Tumor metabolic reprogramming in lung cancer progression.
    Xin Li, Minghui Liu, Hongyu Liu, Jun Chen.
      Metabolic reprogramming is an important characteristic of tumor cells. Tumor cells reprogram their metabolic pathways to meet the material, energy and redox force needs for rapid proliferation. Metabolic reprogramming changes the level or type of specific metabolites inside and outside cells, and promotes tumor growth by affecting gene expression, cell state and the tumor microenvironment. Glucose metabolism, glutamine metabolism and lipid metabolism are significant metabolic pathways in tumors. Targeting metabolic reprogramming can significantly inhibit tumor growth and induce apoptosis. Metabolic reprogramming also plays an important role in maintaining the growth advantage of tumor cells and enhancing the chemotherapy tolerance of lung cancer. This review summarizes abnormal changes in the metabolism of glucose, fat and amino acids in lung cancer, and the underlying molecular mechanism, with the aim of providing novel ideas for the prevention, early diagnosis and treatment of lung cancer.
    Keywords:  lung cancer; metabolic reprogramming
    DOI:  https://doi.org/10.3892/ol.2022.13407
  9. Drug Deliv. 2022 Dec;29(1): 2190-2205
    Oxaliplatin-loaded nanoemulsion containing Teucrium polium L. essential oil induces apoptosis in Colon cancer cell lines through ROS-mediated pathway.
    Waad A Al-Otaibi, Sahar M AlMotwaa.
      Oxaliplatin (Oxa)-associated adverse side effects have considerably limited the clinical use of the drug in colon cancer therapy. Mutant p53 has diverse mutational profiles in colon cancer, and it influences the potencies of various chemotherapeutic drugs, including Oxa. Thus, it would be highly beneficial to identify an alternative therapeutic strategy that not only reduces the toxicity of Oxa, but also exerts a synergistic effect against colon cancers, regardless of their p53 profiles. The present study was aimed at preparing and optimizing Teucrium polium L. essential oil nanoemulsion (TPO-NANO) and investigating its effect on the sensitivity of colon cancer cells with differences in p53 status (HCT116 wild-type and HT-29 mutant-type) to Oxa. The viability of treated cells was determined and the combination index (CI) was calculated. Morphological changes were determined under inverted microscopy, while percentage apoptosis was assayed using flow cytometry. Intracellular ROS and the protein levels of p53 and Bax were measured. The colony-forming potential of treated cells was determined using colony assay. The size of TPO-NANO was markedly increased from 12.90 ± 0.04 nm to 14.47 ± 0.53 nm after loading Oxa (p ≤ 0.05). The combination (Oxa + TPO-NANO) produced a synergetic effect in HCT116 and HT-29, with CI of 0.94 and 0.88, respectively. Microscopic examination and flow cytometric analysis revealed that cells treated with Oxa + TPO-NANO had a higher percentage of apoptosis than cells exposed to monotherapy. Cumulatively, Oxa exerted an apoptotic effect on wild or mutant p53 colon cancer cells when combined with TPO-NANO, through a mechanism involving ROS-mediated mitochondrial apoptosis.
    Keywords:   Teucrium polium L. essential oil; Combination therapy; Oxaliplatin; ROS-mediated mitochondrial apoptosis; Reactive oxygen species; flow cytometry; nano-delivery system; nanoemulsion
    DOI:  https://doi.org/10.1080/10717544.2022.2096711
  10. Int J Pharm. 2022 Jul 12. pii: S0378-5173(22)00573-7. [Epub ahead of print] 122018
    Bufalin exacerbates Photodynamic Therapy of Colorectal Cancer by targeting SRC-3/HIF-1α pathway.
    Zeting Yuan, Chaolian Liu, Yuji Sun, Yue Li, Honglei Wu, Shuli Ma, Jing Shang, Yueping Zhan, Peihao Yin, Feng Gao.
      Photodynamic therapy (PDT) induces tumour cell death by producing reactive oxygen species (ROS), and hypoxia is one of the main factors that limits its efficiency. In our previous study, bufalin (BU) enhanced photosensitizer mTHPC-mediated PDT therapy in colorectal cancer (CRC) cells, but its mechanism was not elucidated. To explore a strategy for improving the efficacy of PDT, we designed iRGD-modified nanoparticles to co-capsuled mTHPC and BU for simultaneous delivery to the tumour site and explored the underlying mechanism of the synergistic anti-CRC effect. In our study, mTHPC&BU@VES-CSO/TPGS-RGD nanoparticles (T-B@NP) had a particle size of 148.3 ± 2.5 nm and a zeta potential of 22.8 ± 2.0 mV. Specifically, these nanoparticles passively accumulated in tumour cells, and under laser irradiation, mTHPC induced cell apoptosis and death. In addition, the sustained release of BU inhibited HIF-1α and reduced VEGF-mediated angiogenesis by targeting the SRC-3/HIF-1α pathway, which induced a strong PDT effect against CRC. In vivo studies demonstrated that codelivery of the nanoparticles under laser irradiation exhibited a superior antitumour effect (84.2%) and significantly prolonged survival time of mice, with the mechanisms of alleviating hypoxia and inhibiting angiogenesis. In summary, mTHPC and BU codelivery via nanoparticles efficiently enhances the therapeutic effects of PDT by inhibiting the SRC-3/HIF-1α pathway in CRC. This work provides an effective strategy to combat hypoxia-induced tumour resistance and overcome the barriers of PDT treatment.
    Keywords:  Bufalin; Colorectal cancer; HIF-1α; Nanoparticles; Photodynamic therapy; SRC-3
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122018
  11. Crit Rev Food Sci Nutr. 2022 Jul 15. 1-45
    Natural products derived from medicinal plants and microbes might act as a game-changer in breast cancer: a comprehensive review of preclinical and clinical studies.
    Rajeev K Singla, Xiaoyan Wang, Rohit Gundamaraju, Shikha Joon, Christos Tsagkaris, Sahar Behzad, Johra Khan, Rupesh Gautam, Rajat Goyal, Jaruporn Rakmai, Ankit Kumar Dubey, Jesus Simal-Gandara, Bairong Shen.
      Breast cancer (BC) is the most prevalent neoplasm among women. Genetic and environmental factors lead to BC development and on this basis, several preventive - screening and therapeutic interventions have been developed. Hormones, both in the form of endogenous hormonal signaling or hormonal contraceptives, play an important role in BC pathogenesis and progression. On top of these, breast microbiota includes both species with an immunomodulatory activity enhancing the host's response against cancer cells and species producing proinflammatory cytokines associated with BC development. Identification of novel multitargeted therapeutic agents with poly-pharmacological potential is a dire need to combat advanced and metastatic BC. A growing body of research has emphasized the potential of natural compounds derived from medicinal plants and microbial species as complementary BC treatment regimens, including dietary supplements and probiotics. In particular, extracts from plants such as Artemisia monosperma Delile, Origanum dayi Post, Urtica membranacea Poir. ex Savigny, Krameria lappacea (Dombey) Burdet & B.B. Simpson and metabolites extracted from microbes such as Deinococcus radiodurans and Streptomycetes strains as well as probiotics like Bacillus coagulans and Lactobacillus brevis MK05 have exhibited antitumor effects in the form of antiproliferative and cytotoxic activity, increase in tumors' chemosensitivity, antioxidant activity and modulation of BC - associated molecular pathways. Further, bioactive compounds like 3,3'-diindolylmethane, epigallocatechin gallate, genistein, rutin, resveratrol, lycopene, sulforaphane, silibinin, rosmarinic acid, and shikonin are of special interest for the researchers and clinicians because these natural agents have multimodal action and act via multiple ways in managing the BC and most of these agents are regularly available in our food and fruit diets. Evidence from clinical trials suggests that such products had major potential in enhancing the effectiveness of conventional antitumor agents and decreasing their side effects. We here provide a comprehensive review of the therapeutic effects and mechanistic underpinnings of medicinal plants and microbial metabolites in BC management. The future perspectives on the translation of these findings to the personalized treatment of BC are provided and discussed.
    Keywords:  anticancer agents; breast cancer; cytotoxic; hormone-sensitive cancer; medicinal plants; metabolites; natural compounds; tumor heterogeneity
    DOI:  https://doi.org/10.1080/10408398.2022.2097196
  12. Recent Pat Anticancer Drug Discov. 2022 Jul 13.
    Application of Nano Drug Delivery System (NDDS) in Cancer Therapy: A Review.
    Junyu Liu, Shuqin Li, Jia Wang, Nannan Li, Jingna Zhou, Haixia Chen.
       BACKGROUND: Cancer is the biggest killer that threatens human health. Poor bioavailability and strong drug resistance of cancer drugs are common defects. In recent years, drug delivery therapy based on nanotechnology has become a focused research area, and nano drug delivery system has been widely studied in cancer treatment.
    OBJECTIVE: Based on the articles and patents published on the application of nano drug delivery systems in cancer treatment in the past five years, this paper summarizes the types of nano drug delivery systems and their advantages and limitations in cancer treatment, in order to provide reference for future anticancer research of nano drug delivery systems.
    METHODS: This perspective summarizes the types of nano drug delivery systems and their advantages and limitations in cancer treatment in recent five years, and proposes the development direction of nano drug delivery systems in the future.
    RESULTS: Based on the review of articles and patents, we found that the nano drug delivery system is mainly divided into encapsulated nano drug delivery system and covalently bound nano-prodrug delivery system. Its advantages in cancer treatment are mainly reflected in enhancing drug stability, improving bioavailability, reducing toxicity and better application in cancer diagnosis. However, nano drug delivery system is a new field of science, some have high toxicity and low bioavailability, the off-target phenomenon often occurs, and most studies are just focused in the early stage, its mechanism of action, clinical efficacy and patient tolerance, toxicity of treatment remains to be further investigated.
    CONCLUSION: This perspective systematically summarizes the types of nano drug delivery systems and their advantages and limitations in cancer treatment based on the published articles and patents obtained in the last five years. Future research on nano drug delivery system should consider its potential risks, and design stable and efficient nano drug delivery system to treat cancer by changing nanomaterials or functionalizing nanomaterials.
    Keywords:  Cancer Therapy; Nano Drug Delivery System
    DOI:  https://doi.org/10.2174/1574892817666220713150521
  13. Theranostics. 2022 ;12(10): 4629-4655
    How to improve photodynamic therapy-induced antitumor immunity for cancer treatment?
    Min Zhang, Yifan Zhao, He Ma, Yusong Sun, Jie Cao.
      Photodynamic therapy (PDT) is a promising method of tumor ablation and function-preserving oncological intervention, which is minimally invasive, repeatable, and has excellent function and cosmetic effect, with no cumulative toxicity. More importantly, PDT can induce immunogenic cell death and local inflammation, thus stimulating the body's immune response. However, the weak immunity induced by PDT alone is insufficient to trigger a systemic immune response towards cancer cells. To overcome this obstacle, multiple strategies have been investigated, including tumor microenvironment remodeling, tumor vaccines, subcellular-targeted PDT, and synergistic therapies. This review summarizes the latest progress in the development of strategies to improve the PDT-induced immune effect for enhanced cancer treatment.
    Keywords:  Antitumor immunity; Photodynamic therapy; Synergistic therapies; Tumor microenvironment; Tumor vaccine
    DOI:  https://doi.org/10.7150/thno.72465
  14. Biomater Sci. 2022 Jul 13.
    A chemical biology toolbox to overcome the hypoxic tumor microenvironment for photodynamic therapy: a review.
    Xuwei Zheng, Wen Sun, Minzi Ju, Jichun Wu, He Huang, Baoxing Shen.
      Cancer is a disease that seriously threatens human health. Over the past few decades, researchers have continued to find ways to cure cancer. Currently, the most commonly used clinical techniques are surgery, chemotherapy, radiotherapy and so on. Among them, photodynamic therapy (PDT) has received extensive attention due to its better therapeutic effect and lower side effects. However, the inherent microenvironmental hypoxia of tumor tissue leads to unsatisfactory therapeutic effects. Therefore, researchers have conducted in-depth research on the hypoxia problem in PDT therapy. This review classified photodynamic therapy according to the response mechanism and summarized the strategies developed to overcome tumor hypoxia in recent years. Among them, research strategies can be divided into five types: type I PDT photosensitizers, introducing exogenous oxygen, O2 carriers using nanomaterials, generating endogenous oxygen by catalytic reactions, and combination with prodrugs that inhibit the consumption of endogenous oxygen. Finally, we also list some studies using combination therapy, such as microbes, photothermal therapy, etc. It can be guaranteed that the review can provide theoretical guidance for the development of anti-hypoxic PDT tools.
    DOI:  https://doi.org/10.1039/d2bm00776b
  15. Front Oncol. 2022 ;12 905893
    Arginase: Mechanisms and Clinical Application in Hematologic Malignancy.
    Zefan Du, Tianwen Li, Junbin Huang, Yun Chen, Chun Chen.
      Compared to normal tissues and cells, the metabolic patterns of tumor illnesses are more complex, and there are hallmarks of metabolic reprogramming in energy metabolism, lipid metabolism, and amino acid metabolism. When tumor cells are in a state of fast growth, they are susceptible to food shortage, resulting in growth suppression. Using this metabolic sensitivity of tumor cells to construct amino acid consumption therapy does not harm the function of normal cells, which is the focus of metabolic therapy research at the moment. As a non-essential amino acid, arginine is involved in numerous crucial biological processes, including the signaling system, cell proliferation, and material metabolism. Rapidly dividing tumor cells are more likely to be deficient in arginine; hence, utilizing arginase to consume arginine can suppress tumor growth. Due to the absence of arginine succinate synthase, arginine succinate lyase, and ornithine carbamoyl transferase in some blood tumors, arginases may be employed to treat blood tumors. By investigating the mechanism of arginase treatment and the mechanism of drug resistance in greater depth, arginase treatment becomes more successful in hematological cancers and a new anti-cancer agent in clinical practice.
    Keywords:  arginase; clinical application; hematologic malignancy; mechanisms; therapy
    DOI:  https://doi.org/10.3389/fonc.2022.905893
  16. Adv Drug Deliv Rev. 2022 Jul 09. pii: S0169-409X(22)00335-0. [Epub ahead of print] 114445
    Opportunities and challenges for co-delivery nanomedicines based on combination of phytochemicals with chemotherapeutic drugs in cancer treatment.
    Quan Gao, Jiao Feng, Wencheng Liu, Chengyong Wen, Yihan Wu, Qian Liao, Liang Zou, Xinbing Sui, Tian Xie, Jinming Zhang, Yichen Hu.
      The therapeutic limitations such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects are frequently caused by the long duration monotherapy based on chemotherapeutic drugs. multiple combinational anticancer strategies such as nucleic acids combined with chemotherapeutic agents, chemotherapeutic combinations, chemotherapy and tumor immunotherapy combinations have been embraced, holding great promise to counter these limitations, while still taking including some potential risks. Nowadays, an increasing number of research has manifested the anticancer effects of phytochemicals mediated by modulating cancer cellular events directly as well as the tumor microenvironment. Specifically, these natural compounds exhibited suppression of cancer cell proliferation, apoptosis, migration and invasion of cancer cells, P-glycoprotein inhibition, decreasing vascularization and activation of tumor immunosuppression. Due to the low toxicity and multiple modulation pathways of these phytochemicals, the combination of chemotherapeutic agents with natural compounds acts as a novel approach to cancer therapy to increase the efficiency of cancer treatments as well as reduce the adverse consequences. In order to achieve the maximized combination advantages of small-molecule chemotherapeutic drugs and natural compounds, a variety of functional nano-scaled drug delivery systems, such as liposomes, host-guest supramolecules, supramolecules, dendrimers, micelles and inorganic systems have been developed for dual/multiple drug co-delivery. These co-delivery nanomedicines can improve pharmacokinetic behavior, tumor accumulation capacity, and achieve tumor site-targeting delivery. In that way, the improved antitumor effects through multiple-target therapy and reduced side effects by decreasing dose can be implemented. Here, we present the synergistic anticancer outcomes and the related mechanisms of the combination of phytochemicals with small-molecule anticancer drugs. We also focus on illustrating the design concept, and action mechanisms of nanosystems with co-delivery of drugs to synergistically improve anticancer efficacy. In addition, the challenges and prospects of how these insights can be translated into clinical benefits are discussed.
    Keywords:  Co-delivery; Drug combination; Drug resistance; Nanosystem; phytochemicals
    DOI:  https://doi.org/10.1016/j.addr.2022.114445
  17. Photodiagnosis Photodyn Ther. 2022 Jul 08. pii: S1572-1000(22)00294-0. [Epub ahead of print] 103008
    Brain extracellular matrix attenuates photodynamic cytotoxicity of glioma cells.
    Cong Shen, Guoying Huang, Dan Hu, Hongjian Zhao.
      Glioma is the most common tumor in the central nervous system, which is often accompanied by poor prognosis. Brain extracellular matrix (ECM) plays an important role in regulating the growth and migration of glioma. Photodynamic therapy (PDT) has been an effective method for the treatment of solid tumors by oxidative modifications in recent years, and ECM may have an impact on the cytotoxicity of photodynamic therapy. In this work, we prepared decellularized brain ECM by chemical method to investigate the influence of the photodynamic effect of glioma C6 cells. Compared with decellularized liver ECM, brain ECM reduces PDT cytotoxicity. By observing the content of reactive oxygen species produced by near-infrared light active indocyanine green in cells, it was found that ECM did not affect the production of reactive oxygen species. Therefore, it is speculated that brain ECM may enhance the oxidative stress adaptability of glioma cells through potential signal regulation, or protect photodynamic targeting biomolecules (such as proteins and other cellular components) from oxidation in PDT mediated by indocyanine green and 808 nm laser in glioma cells.
    Keywords:  Extracellular matrix; Photodynamic therapy; glioma
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103008
  18. Phytomedicine. 2022 Jun 18. pii: S0944-7113(22)00364-6. [Epub ahead of print]104 154285
    5-Demethylnobiletin: Insights into its pharmacological activity, mechanisms, pharmacokinetics and toxicity.
    Haiyan Ding, Qiang You, Dan Li, Youping Liu.
       BACKGROUND: 5-Demethylnobiletin (5DN) is a polymethoxyflavone (PMF) primarily found in citrus fruits. It has various health-promoting properties and hence has attracted significant attention from scholars worldwide.
    PURPOSE: This review is the first to systematically summarize the recent research progress of 5DN, including its pharmacological activity, mechanism of action, pharmacokinetics, and toxicological effects. In addition, the pharmacological mechanism of action of 5DN has been discussed from a molecular biological perspective, and data from in vivo and in vitro animal studies have been compiled to provide a more thorough understanding of 5DN as a potential lead drug.
    METHODS: Data were extracted from SciFinder, PubMed, ScienceDirect and China National Knowledge Infrastructure (CNKI) from database inception to January 2022.
    RESULTS: 5DN has broad pharmacological activities. It exerts anti-inflammatory effects, promotes apoptosis and autophagy, and induces melanogenesis mainly by regulating the JAK2/STAT3, caspase-dependent apoptosis, ROS-AKT/mTOR, MAPK and PKA-CREB signaling pathways. 5DN can be used for treating diseases such as cancer, inflammation-related diseases, rheumatoid arthritis, and neurodegenerative diseases. To date, there have been only a few toxicological studies on 5DN, and both in vitro and in vivo on 5DN have not revealed significant toxic side effects. Pharmacokinetic studies have revealed that the metabolites of 5DN are mainly 5,3'-didemethylnobiletin (M1); 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), in either, glucuronide-conjugated or monomeric form. The pharmacokinetic products of 5DN, especially M1, possess better activity than 5DN for the treatment of cancer.
    CONCLUSION: The anticancer effects of 5DN and its metabolites warrant further investigation as potential drug candidates, especially through in vivo studies. In addition, the therapeutic effects of 5DN in neurodegenerative diseases should be examined in more experimental models, and the absorption and metabolism of 5DN should be further investigated in vivo.
    Keywords:  5-demethylnobiletin; Anti-inflammatory; Anticancer; Mechanistic studies; Neuroprotection activity; Pharmacological activities
    DOI:  https://doi.org/10.1016/j.phymed.2022.154285
  19. Lasers Med Sci. 2022 Jul 12.
    Advanced methylene blue - nanoemulsions for in vitro photodynamic therapy on oral and cervical human carcinoma.
    Stéphanie R do Amaral, Camila F Amantino, Sarah R De Annunzio, Ariela V de Paula, Carla R Fontana, Fernando L Primo.
      Photodynamic therapy (PDT) is a therapeutic modality with high contributions in the treatment of cancer. This approach is based on photophysical principles, which presents as a less invasive strategy than conventional therapies. Combined with nanotechnology, the therapy becomes more efficient because nanoparticles (NPs) have advantageous characteristics such as biocompatibility, controlled, and targeted release, promoting solubility and decreasing the toxicity and side effects involved. In this work were developed nanoemulsions containing the methylene blue photosensitizer (MB) (MB/NE) and in the empty form (unloaded/NE). Subsequently, the mentioned nanomaterials were characterized by the measurement of dynamic light scattering (DLS). The MB/NE and unloaded/NE showed appropriate physical and chemical characteristics, with particle size ≤ 200 nm, polydispersity index close to 0.3, and zeta potential exhibiting negative charge, showing stable values during the analysis. The incorporation of the MB did not cause changes in the photophysical profile of the photosensitizer. The quantification performed showed an incorporation rate of 81.9%. Viability studies showed an absence of cytotoxicity for MB/NE in the concentrations of 10-75 µmol·L-1, free MB at the concentration of 75 µmol·L-1, and unloaded NE 47.5% (v/v), presenting viability close to 90%, respectively. PDT in vitro protocols applied to OSCC and HeLa cells showed a decrease in cell viability through only one irradiation, evidencing the photodynamic activity of the formulation when applied to cancer cells. The results obtained were superior to those found in the literature where they use free MB, showing that the association between nanotechnology and PDT optimizes the proposed protocol. From the results obtained, it is possible to indicate that the NE have high stability, with satisfactory physical-chemical parameters, in addition to not presenting cytotoxicity in the tested concentrations, showing their in vitro biocompatibility, in addition to presenting satisfactory effects when combined MB/NE with PDT, showing the potential of MB/NE as a very promising nanostructured photosensitizer for the treatment of some types of cancer.
    Keywords:  Laser applications; Methylene blue; Nanomedicine; Nanotechnology; Photodynamic therapy; Polymeric nanoemulsions
    DOI:  https://doi.org/10.1007/s10103-022-03603-2
  20. Adv Drug Deliv Rev. 2022 Jul 11. pii: S0169-409X(22)00339-8. [Epub ahead of print] 114449
    Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms.
    Yixuan Zi, Kaiyun Yang, Jianhua He, Zimei Wu, Jianping Liu, Wenli Zhang.
      The Enhanced Permeability and Retention (EPR) effect has been recognized as the central paradigm in tumor-targeted delivery in the last decades. In the wake of this concept, nanotechnologies have reached phenomenal levels in research. However, clinical tumors display a poor manifestation of EPR effect. Factors including tumor heterogeneity, complicating tumor microenvironment, and discrepancies between laboratory models and human tumors largely contribute to poor efficiency in tumor-targeted delivery and therapeutic failure in clinical translation. In this article, approaches for evaluation of EPR effect in human tumor were overviewed as guidance to employ EPR effect for cancer treatment. Strategies to augment EPR-mediated tumoral delivery are discussed in different dimensions including enhancement of vascular permeability, depletion of tumor extracellular matrix and optimization of nanoparticle design. Besides, the recent development in alternative tumor-targeted delivery mechanisms are highlighted including transendothelial pathway, endogenous cell carriers and non-immunogenic bacteria-mediated delivery. In addition, the emerging preclinical models better reflect human tumors are introduced. Finally, more rational applications of EPR effect in other disease and field are proposed. This article elaborates on fundamental reasons for the gaps between theoretical expectation and clinical outcomes, attempting to provide some perspective directions for future development of cancer nanomedicines in this still evolving landscape.
    Keywords:  EPR effect; Nanomedicine; clinical translation; independent of EPR effect; preclinical models; transendothelial pathway
    DOI:  https://doi.org/10.1016/j.addr.2022.114449
  21. Biomaterials. 2022 Jul 05. pii: S0142-9612(22)00308-8. [Epub ahead of print]287 121668
    Engineering dual catalytic nanomedicine for autophagy-augmented and ferroptosis-involved cancer nanotherapy.
    Zhifang Li, Chunmei Wang, Chen Dai, Ruizhi Hu, Li Ding, Wei Feng, Hui Huang, Yin Wang, Jianwen Bai, Yu Chen.
      Chemodynamic therapy represents a distinct anti-tumor strategy by activating intratumoral chemical catalytic reactions to produce highly toxic reactive oxygen species (ROS) from non-/limited-toxic nanocatalysts. However, the low efficacy of ROS generation still remains a major challenge for further clinical translation. Herein, a liposomal nanosystem which simultaneously encapsulated copper peroxide nanodots (CPNs) and artemisinin (ART) was constructed for autophagy-enhanced and ferroptosis-involved cancer cell death owing to Cu-based dual catalytic strategy. To be specific, the CPN components, served as a H2O2 self-supplying platform, release H2O2 and Cu2+ under acidic tumor environment and endogenously generate .OH via Fenton-like reaction (catalytic reaction I). In addition, Cu2+ species catalyze ART components to produce ROS radicals (catalytic reaction II), further augmenting the intracellular oxidative damage and lipid peroxide accumulation, leading to cancer cell death. Specifically, ART also acted as a potent autophagy inducer increasing the level of intracellular iron pool through degradation of ferritin, which could promote cancer cell ferroptosis, producing the best antineoplastic effect. After accumulation into the tumor sites, ultrasound irradiation was applied to trigger the release of CPNs and ART from liposomal nanosystems, and amplify the efficacy of catalytic reaction for maximum therapeutic effect. Both in vitro and in vivo therapeutic outcomes suggest the outstanding autophagy-augmented ferroptosis-involved cancer-therapeutic efficacy, which was further corroborated by transcriptome sequencing. In this work, Cu was firstly proven to trigger ART to produce ROS species, but also provide a TME-responsive nanoplatform for potentially suppressing tumor growth by autophagy-augmented ferroptosis-involved cancer nanotherapy.
    Keywords:  Artemisinin; Autophagy; Chemodynamic therapy; CuO(2); Ferroptosis
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121668
  22. J Food Biochem. 2022 Jul 11. e14302
    The potential role of prebiotics, probiotics, and synbiotics in adjuvant cancer therapy especially colorectal cancer.
    Zahoor Alam, Xiaoya Shang, Khansa Effat, Freeha Kanwal, Xiaoqin He, Yanye Li, Chunlan Xu, Weining Niu, Abdul Rouf War, Yong Zhang.
      Cancer is a global health issue that is rising swiftly with younger people and an increased number of patients. The role of human microbiota in the pathophysiology of tumors has been paid more and more attention. Microecologics including prebiotics, probiotics, and synbiotics are among the best validated/proven resources for the application of microbiological prophylaxis and therapy. There is strong evidence that microecologics have anti-cancer activity and their potential association with cancer is significant. In this review, we will focus on the role of prebiotics, probiotics, and synbiotics in tumor suppression in maintaining the colon barrier, metabolism, immune regulation, inhibition of host tumor cell proliferation, and epidemiological-based recommendations. Besides, other signs illuminate the role of microecological agents to adjunct the cancer treatment and counter the toxic side effects of cancer drugs. In addition, we will explore their role in chemotherapy, where these probiotics can be used as an adjunct to chemotherapy, counteracting the toxic side effects of chemotherapy drugs to minimize or optimize the therapeutic effect. In the treatment of cancer, we can see the role of prebiotics, probiotics, synbiotics, and their application in cancer patients, and the effectiveness effect can be considered as a clinical benefit. PRACTICAL APPLICATIONS: A large number of studies have shown that microecologics including prebiotics, probiotics, and synbiotics play an important role in regulating intestinal microecology and contribute to the prevention and treatment of cancer, indicating that prebiotics, probiotics, and synbiotics have the potential to be used as microecological modulators in the adjuvant therapy of cancer. However, it is not clear what is the anti-tumor mechanism of these microecologics and how they antagonize the side effects of cancer chemotherapy and protect normal cells. This paper reviews the role of prebiotics, probiotics, and synbiotics in tumor suppression in maintaining the colon barrier, metabolism, immune regulation, and prevention of rapid growth of host cells, as well as their potential role in cancer chemotherapy. This review helps to better understand the relationship between prebiotics, probiotics, and synbiotics with immune regulation, intestinal microecology, metabolic regulation, and cell proliferation and provides strong evidence for their potential application as microecologics in cancer adjuvant therapy.
    Keywords:  cancer treatment; chemotherapy; gut microflora; prebiotics; probiotics; synbiotics
    DOI:  https://doi.org/10.1111/jfbc.14302
  23. Front Chem. 2022 ;10 904973
    Satureja khuzistanica Essential Oil-Loaded Solid Lipid Nanoparticles Modified With Chitosan-Folate: Evaluation of Encapsulation Efficiency, Cytotoxic and Pro-apoptotic Properties.
    Seyedeh Farnoosh Tabatabaeain, Ehsan Karimi, Mehrdad Hashemi.
      The study aimed to synthesize Satureja khuzistanica essential oil-loaded SLN nanoparticles and to modify the surface of nanoparticles with folate-bound chitosan (SEO-SCF-NPs), and finally to investigate the effects of its toxicity and pro-apoptosis. For this purpose, the SEO-SLN nanoparticles were prepared using stearic acid, lecithin, tween 80, and water by high-pressure homogenization method. After characterization by FTIR, SEM, DLS, and ZETA potential methods, its toxicity effect against normal (HFF) and cancer (MCF-7) cells were evaluated by MTT assay. The occurrence of apoptosis in MCF-7 cells was assessed by flow cytometry and molecular analysis. The obtained results revealed the formation of round nanoparticles with a size of 279.40 nm, single dispersed (PDI: 0.3) and stable (ζ-potential: +31.69 mV). SEO-SCF-NPs indicated the effect of selective toxicity against MCF-7 cells (IC50: 88 μg/ml). Molecular analysis showed that SEO-SCF-NPs could inhibit cancer cells by activating the internal pathway of apoptosis as well as cell cycle disruption. Our finding suggests that SEO-SCF-NPs is a suitable candidate for preclinical cancer studies.
    Keywords:  Satureja khuzistanica essential oil; anticancer potential; chitosan; folate; solid lipid nanoparticles
    DOI:  https://doi.org/10.3389/fchem.2022.904973
  24. Cancer Treat Res Commun. 2022 Jun 30. pii: S2468-2942(22)00090-9. [Epub ahead of print] 100600
    Physical Exercise and Tumor Energy Metabolism.
    Anderson Vulczak, Luciane Carla Alberici.
      Evidence supports the antitumoral effects of physical activity, either in experimental animal models or humans. However, the biological mechanisms by which physical exercise modulates tumoral development are still unclear. An important feature of the tumor cells is the altered energy metabolism, often associated with definitions of tumor aggressiveness. Nevertheless, exercise can cause global metabolic changes in the body, as well as modulate tumor metabolism. Here we specifically discuss the metabolic changes found in tumors and how exercise can contribute to anti-tumoral effects by modulating the mitochondrial function, and tricarboxylic acid cycle-related metabolites of cancer cells. The effect of physical exercise on tumor metabolism is a new possibility for comprehension of cancer biology and developing therapies focused on tumor energy metabolism.
    Keywords:  Anti-tumoral; Cancer; Mitochondria; OXPHOS; TCA cycle
    DOI:  https://doi.org/10.1016/j.ctarc.2022.100600
  25. Int J Nanomedicine. 2022 ;17 2979-2993
    GOx-Functionalized Platelet Membranes-Camouflaging Nanoreactors for Enhanced Multimodal Tumor Treatment.
    Ying Du, Shujun Wang, Jianfeng Luan, Meilin Zhang, Baoan Chen, Yanfei Shen.
       Background: Glucose oxidase (GOx)-based starvation therapy is a new cancer treatment strategy. However, the characteristics such as limited curative effect and hypoxic tumor environment hinder its further application seriously.
    Methods: Herein, doxorubicin (DOX) loaded in hollow mesoporous copper sulfide (HMCuS) nanoparticles assembled with manganese dioxide (HMMD) as nanoshell was prepared. We developed a targeted enhanced cancer treatment method to camouflage HMMD by GOx-functionalized platelet (PLT) membranes (HMMD@PG).
    Results: GOx can be specially transported to the tumor site with PLT membrane for effective starvation treatment. Glucose and oxygen (O2) in the tumor were converted to H2O2 under the catalysis of GOx. HMMD can catalyze H2O2 to produce O2 and consume glutathione (GSH) in time, which regulates the tumor microenvironment (TME) and improves the adverse conditions of anti-tumor. In addition, DOX encapsulated in HMCuS-MnO2 release was accelerated from the nanoparticles after the "gatekeeper" MnO2 is consumed. The study of anti-tumor mechanism shows that the remarkable tumor suppressive ability of HMMD@PG comes from the three peaks synergy of starvation treatment, photothermal treatment (PTT), and chemotherapy. This nanoplatform disguised by PLT membrane has significant tumor inhibition ability, good biocompatibility and almost has no side effects in main organs.
    Conclusion: This work broadens the application mode of GOx and shows the new development of a multi-mode collaborative processing system of nanoplatforms based on cell membrane camouflage.
    Keywords:  PLT membrane; glucose oxidase; nanoparticles; tumor microenvironment; tumor treatment
    DOI:  https://doi.org/10.2147/IJN.S358138
  26. Mol Biol Rep. 2022 Jul 14.
    Mitochondrial oxidative phosphorylation became functional under aglycemic hypoxia conditions in A549 cells.
    Yüksel Öğünç Keçeci, Zerrin İncesu.
       BACKGROUND: Normal cells produce energy (ATP) through mitochondrial oxidative phosphorylation in the presence of oxygen. However, many of the cancer cells produce energy with accelerated glycolysis and perform lactic acid production even under normoxic conditions called "The Warburg Effect". In this study, human lung carcinoma cells (A549) were incubated in either a normoxic or hypoxic environment containing 5 mM glucose (Glc 5), 25 mM glucose (Glc 25), or 10 mM galactose (OXPHOS/aglycemic), and then the bioenergetic pathway was anaylsed.
    METHODS AND RESULTS: HIF-1α stabilization of A549 cells with different metabolic conditions in normoxia and hypoxia (1% O2) was determined using the western blot method. After that, L-lactic acid analysis, p-PDH/PDH expression ratio, ATP analysis, and citrate synthase activity experiments were also performed. It was determined that HIF-1α stabilization reached the maximum level at the 4 h. It has been found that glycolytic cells produce approximately five times more lactate than OXPHOS cells under both normoxia and hypoxia conditions and also have a higher p-PDH/PDH ratio. It has been determined that citrate synthase activity in hypoxia of all metabolic conditions is lower than normoxia. It has been determined that Glc 5 and Glc 25 cells have more ATP production under normoxia than Glc 5 and Glc 25 cells in hypoxia. OXPHOS cells have showed more ATP production in hypoxia.
    CONCLUSION: It has been determined that oxidative phosphorylation became functional in a hypoxic aglycemic environment despite the metabolic programming regulated by HIF-1α. This data is important in determining targets for therapeutic intervention.
    Keywords:  A549 cells; Glucose metabolism; Oxidative phosphorylation; Tumor hypoxia; Warburg effect
    DOI:  https://doi.org/10.1007/s11033-022-07400-6
  27. J Agric Food Chem. 2022 Jul 11.
    Preclinical Studies of Natural Products Targeting the Gut Microbiota: Beneficial Effects on Diabetes.
    Xiaofang Jiang, Boyu Sun, Zheng Zhou.
      Diabetes mellitus (DM) is a serious metabolic disease characterized by persistent hyperglycemia, with a continuously increasing morbidity and mortality. Although traditional treatments including insulin and oral hypoglycemic drugs maintain blood glucose levels within the normal range to a certain extent, there is an urgent need to develop new drugs that can effectively improve glucose metabolism and diabetes-related complications. Notably, accumulated evidence implicates that the gut microbiota is unbalanced in DM individuals and is involved in the physiological and pathological processes of this metabolic disease. In this review, we introduce the molecular mechanisms by which the gut microbiota contributes to the development of DM. Furthermore, we summarize the preclinical studies of bioactive natural products that exert antidiabetic effects by modulating the gut microbiota, aiming to expand the novel therapeutic strategies for DM prevention and management.
    Keywords:  diabetes mellitus; glucose metabolism; gut microbiota; insulin resistance; natural products
    DOI:  https://doi.org/10.1021/acs.jafc.2c02960
  28. Front Chem. 2022 ;10 905645
    Tumor pH-Responsive Nanocarriers With Light-Activatable Drug Release for Chemo-Photodynamic Therapy of Breast Cancer.
    Zhang Zhang, An Gao, Chunyang Sun.
      Developing bioresponsive nanocarriers with particular tumor cell targeting and on-demand payload release has remained a great challenge for combined chemo-photodynamic therapy (chemo-PDT). In this study, an intelligent nanocarrier (DATAT-NPCe6) responded to hierarchical endogenous tumor pH, and an exogenous red light was developed through a simple mixed micelle approach. The outside TAT ligand was masked to prevent an unexpected interaction in blood circulation. Following the accumulation of DATAT-NPCe6 in tumor tissues, tumor acidity at pH ∼6.5 recovered its targeting ability via triggering DA moiety degradation. Furthermore, the cascaded chemo-PDT was accomplished through light-stimulated nanocarrier disassembly and doxorubicin (DOX) release. Taking advantage of stability and controllability, this work provides a facile approach to designing bioresponsive nanocarriers and represents a proof-of-concept combinatorial chemo-PDT treatment.
    Keywords:  TAT presenting; chemo-photodynamic combination therapy; nanocarrier; on-demand drug release; tumor acidity responsive
    DOI:  https://doi.org/10.3389/fchem.2022.905645
  29. Antioxid Redox Signal. 2022 Jul 12.
    The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling.
    Kenneth R Olson, Paul J Derry, Thomas A Kent, Karl D Straub.
       SIGNIFICANCE: Nutraceuticals are ingested for health benefits in addition to their general nutritional value. These dietary supplements have become increasingly popular since the late twentieth century and they are a rapidly expanding global industry approaching a half-trillion US dollars annually. Many nutraceuticals are promulgated as potent antioxidants.
    RECENT ADVANCES: Experimental support for the efficacy of nutraceuticals has lagged behind anecdotal exuberance. However, accumulating epidemiological evidence, and recent, well-controlled clinical trials, are beginning to support earlier animal and in vitro studies. Although still somewhat limited, encouraging results have been suggested in essentially all organ systems and against a wide range of pathophysiological conditions.
    CRITICAL ISSUES: Health benefits of the 'antioxidant' nutraceuticals are largely attributed to their ability to scavenge oxidants. This has been criticized based on several factors including limited bioavailability, short tissue retention time, and the preponderance of endogenous antioxidants. Recent attention has turned to nutraceutical activation of downstream antioxidant systems, especially the Keap 1/Nrf2 axis. The question now becomes, how do nutraceuticals activate this axis?
    FUTURE DIRECTIONS: Reactive sulfur species (RSS), including hydrogen sulfide (H2S) and its metabolites are potent activators of the Keap 1/Nrf2 axis and avid scavengers of reactive oxygen species (ROS). Evidence is beginning to accumulate that a variety of nutraceuticals increase cellular RSS by directly providing RSS in the diet, or through a number of catalytic mechanisms that increase endogenous RSS production. We propose that nutraceutical-specific targeting of RSS metabolism will lead to the design and development of even more efficacious antioxidant therapeutic strategies.
    DOI:  https://doi.org/10.1089/ars.2022.0077
  30. J Control Release. 2022 Jul 11. pii: S0168-3659(22)00421-7. [Epub ahead of print]
    Dual-sensitive drug-loaded hydrogel system for local inhibition of post-surgical glioma recurrence.
    Sunhui Chen, Qiujun Qiu, Dongdong Wang, Dejun She, Bo Yin, Guolong Gu, Meihong Chai, Dong Nyoung Heo, Huining He, Jianxin Wang.
      Local treatment after resection to inhibit glioma recurrence is thought to able to meet the real medical needs. However, the only clinically approved local glioma treatment-wafer containing bis(2-chloroethyl) nitrosourea (BCNU) showed very limited effects. Herein, in order to inhibit tumor recurrence with prolonged and synergistic therapeutic effect of drugs after tumor resection, an in situ dual-sensitive hydrogel drug delivery system loaded with two synergistic chemo-drugs BCNU and temozolomide (TMZ) was developed. The thermosensitive hydrogel was loaded with reactive oxygen species (ROS)-sensitive poly (lactic-co-glycolic) acid nanoparticles (NPs) encapsulating both BCNU and TMZ and also free BCNU and TMZ. The in vitro synergistic effect of BCNU and TMZ and in vivo presence of ROS at the residual tumor site were confirmed. The prepared ROS-sensitive NPs and thermosensitive hydrogel, as well as the long-term release behavior of drugs and NPs, were fully characterized both in vitro and in vivo. After >90% glioblastoma resection, the dual-sensitive hydrogel drug delivery system was injected into the resection cavity. The median survival time of the experimental group reached 65 days which was twice as long as the Resection only group, implying that this in situ drug delivery system effectively inhibited tumor recurrence. Overall, this study provides new ideas and strategies for the inhibition of postoperative glioma recurrence.
    Keywords:  Glioma recurrence; Magnetic resonance imaging; Reactive oxygen species-sensitive nanoparticles; Synergistic effect; Thermo-sensitive hydrogel
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.011
  31. Int J Immunopathol Pharmacol. 2022 Jan-Dec;36:36 3946320221113486
    Evaluation of the wound healing effect of neomycin-silver nano-composite gel in rats.
    Ahmed Hossni El Banna, Fady Sayed Youssef, Hisham Youssef Elzorba, Ahmed M Soliman, Gehad Genidy Mohamed, Sameh Hamed Ismail, Mohamed Refaat Mousa, Hossny Awad Elbanna, Afaf Sayed Osman.
      Objectives: Both nano silver and neomycin have wound healing properties. Silver nanoparticles have been used as main compounds for therapeutic drug delivery systems against various ailments. The present study aimed to prepare a neomycin silver nano-composite gel easily, rapidly, and cheaply method to improve wound healing. Methods: Forty-five Wistar rats (150-200 g) divided into nine groups: wound untreated, wound fusidic acid treated, wound neomycin treated, three groups with wound and neomycin silver nano-composite gel at 1:1, 1:2, and 1:3 concentrations, respectively, and three groups wound treated silver nano gel at the previous concentrations, respectively. Percentages of wound healing and histopathological examination of the wound area were assessed in all groups. Results: Atomic force microscopy (AFM) and transmission electron microscopy (TEM) images demonstrated the spherical shape of neomycin silver nano-composite gel without aggregation but homogenous dispersion in a gel matrix. Dynamic light scattering (DLS) showed a 4 nm size of nano silver, which agrees with AFM image data analysis but not with TEM image due to the good coating of the gel matrix to silver nanoparticles. Dynamic light scattering Zeta potential was -21 mV, illustrating the high bioactivity of the neomycin silver nano-composite. The groups receiving neomycin silver nano-composite gel showed a significantly higher and dose dependent wound healing compared to other treatment groups. Conclusion: The present work confirmed the potential wound healing activity of neomycin silver nano-composite gel compared to either alone.
    Keywords:  neomycin; neomycin silver nano-composite gel; silver nanoparticles; wound healing
    DOI:  https://doi.org/10.1177/03946320221113486
  32. Photodiagnosis Photodyn Ther. 2022 Jul 06. pii: S1572-1000(22)00288-5. [Epub ahead of print] 103002
    Laser-assisted photodynamic therapy in proliferative verrucous oral leukoplakia.
    Yujie Yan, Zhenglei Li, Xin Tian, Xin Zeng, Qianming Chen, Jiongke Wang.
      Proliferative verrucous leukoplakia (PVL) is a rapidly progressing, easily relapsed, and cancer-prone oral potential malignant disease (OPMD), for which treatment options are currently limited. Non-invasive photodynamic therapy (PDT) uses specific wavelengths of light to excite photosensitizers and generate reactive oxygen species to induce cytotoxic effects, and it is selective for malignant tissues. However, the lesions of PVL often show hyperkeratosis, which limits the penetration of photosensitizers into the tissue and affects the effectiveness of PDT. Laser, a safe and efficient treatment, has shown great advantages in aiding photosensitizer delivery, due to its ability to accelerate the penetration of 5-aminolevulinic acid (5-ALA) and improve the accumulation of protoporphyrin IX (PPIX) in tissues. In the case report, we achieved complete remission and no recurrence at least 8 months in a patient with PVL through laser-assisted PDT, which obtained satisfactory clinical effect and well protected the appearance and function of oral cavity.
    Keywords:  Diode laser; Oral leukoplakia; Photodynamic therapy; Photosensitizer delivery; Proliferative verrucous leukoplakia
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103002
  33. Appl Microbiol Biotechnol. 2022 Jul 11.
    Indispensable role of microbes in anticancer drugs and discovery trends.
    Ridam Kapoor, Anamika Saini, Deepika Sharma.
      Recent years have seen an increased focus on the advancement of naturally derived products for the treatment of cancer. Since the beginning of recorded history, nature has provided a variety of medicinal agents, and an overwhelming number of drugs that we have today are derived from natural sources. Such natural agents are prominently used to treat several diseases such as diabetes, malaria, Alzheimer's, pulmonary disorders, etc. with cancer being the highlight of this review. Due to the rapid development of resistance to chemotherapeutic drugs, the hunt for effective novel drugs is still a paramount concern in cancer treatment. Moreover, many chemotherapy drugs typically have high toxicity and adverse side effects, which necessitates the need to develop anti-tumor drugs that can be employed to treat deadly tumors with fewer negative effects on health and better efficacy. Isolation of several chemotherapeutic drugs has been conducted from a wide range of natural sources which include plants, microbes, fungi, and marine microorganisms. Considering the trends of previous decades, microbial diversity has grown to play a significant role in the formulation of pharmaceuticals and drugs, especially antibiotics and anti-cancer medications. Microbe-derived antitumor antibiotics such as anthracycline, epothilones, bleomycin, actinomycin, and staurosporine are amongst the widely used cancer chemotherapeutic agents. This review deals majorly with microbe-derived anticancer drugs taking into account their derivatives, mechanism of action, isolation procedures, limitations, and tumors targeted by them. This article also reports the phase of clinical study these drugs are undergoing. Moreover, it intends to portray the indispensable part that these microbes have been playing since time immemorial in the odyssey of chemotherapeutic agents. KEY POINTS: • Microbial diversity contributes heavily towards the formulation of anticancer drugs. • Polypeptides, carbohydrates, and alkaloids are prevalent microbe-based drug classes. • Microbe-derived anticancer agents target various sarcomas, carcinomas, and lymphomas.
    Keywords:  Chemotherapeutic agents; Clinical trials; Extraction methods; Microbe-derived drugs; Targeted tumors
    DOI:  https://doi.org/10.1007/s00253-022-12046-2
  34. Front Pharmacol. 2022 ;13 937075
    Better Bioactivity, Cerebral Metabolism and Pharmacokinetics of Natural Medicine and Its Advanced Version.
    Jiaxi Xie, Cailing Zhong, Tingting Wang, Dan He, Luyang Lu, Jie Yang, Ziyi Yuan, Jingqing Zhang.
      Currently, many people are afflicted by cerebral diseases that cause dysfunction in the brain and perturb normal daily life of people. Cerebral diseases are greatly affected by cerebral metabolism, including the anabolism and catabolism of neurotransmitters, hormones, neurotrophic molecules and other brain-specific chemicals. Natural medicines (NMs) have the advantages of low cost and low toxicity. NMs are potential treatments for cerebral diseases due to their ability to regulate cerebral metabolism. However, most NMs have low bioavailability due to their low solubility/permeability. The study is to summarize the better bioactivity, cerebral metabolism and pharmacokinetics of NMs and its advanced version. This study sums up research articles on the NMs to treat brain diseases. NMs affect cerebral metabolism and the related mechanisms are revealed. Nanotechnologies are applied to deliver NMs. Appropriate delivery systems (exosomes, nanoparticles, liposomes, lipid polymer hybrid nanoparticles, nanoemulsions, protein conjugation and nanosuspensions, etc.) provide better pharmacological and pharmacokinetic characteristics of NMs. The structure-based metabolic reactions and enzyme-modulated catalytic reactions related to advanced versions of NMs alter the pharmacological activities of NMs.
    Keywords:  cerebral metabolism; delivery systems; natural medicines; pharmacodynamics; pharmacokinetics
    DOI:  https://doi.org/10.3389/fphar.2022.937075
  35. Ann Parasitol. 2022 ;68(2): 263-273
    Promising potent in vitro activity of curcumin and quercetin nano-niosomes against Trichomonas vaginalis.
    Hajar Ziaei Hezarjaribi, Fatemeh Mollarostami, Pedram Ebrahimnejad, Bahman Rahimi Esboei, Mahdi Fakhar, Zaynab Sadeghi-Ghadi.
      Trichomonosis, caused by infection with a motile protozoan parasite called Trichomonas vaginalis, is the most common non-viral sexually transmitted disease worldwide. Since the 1960s, metronidazole has been used as a drug of choice. Considering increased resistance to anti-trichomonial drugs, alternative treatments are urgently needed. In this study, the standard strain of T. vaginalis was cultured in TYM medium. Curcumin and quercetin loaded with hyaluronic acid niosomes were prepared by the thin film hydration method. The mean vesicle size, polydispersity index, and zeta potential of each prepared formulation were characterized, and its anti-Trichomonas activity was assessed by concentrations of 0.01, 0.1, 1, 10 and 100 mg/ml. The cytotoxicity effects of the mentioned drugs were determined using a MTT assay on L929 fibroblast cell viability. The particle sizes of curcumin, quercetin, and curcumin-quercetin entrapped modified nano-niosomes were characterised as 243 ± 5.28, 223 ± 7.21 and 266 ± 4.81 nm. The results showed that quercetin and curcumin at a concentration of 100 mg/ml after 24 h had anti-T. vaginalis activity. However, curcumin at a concentration of 100 at time 3h with 97% growth inhibition had better performance than positive control (metronidazole). According to the results of the MTT assay, all drugs, even at the highest concentration (400 mg/ml), had no toxic effect on the fibroblast cell line. According to potent in vitro activity of curcumin and quercetin nanoniosomes against T. vaginalis in comparison with metronidazole, it can be concluded these compounds could be promising therapeutic candidates for trichomonosis in future.
    DOI:  https://doi.org/10.17420/ap6802.432
  36. Front Pharmacol. 2022 ;13 909755
    Medicinal Plants for the Treatment of Gastrointestinal Cancers From the Metabolomics Perspective.
    Wei Guo, Peng Cao, Xuanbin Wang, Min Hu, Yibin Feng.
      Gastrointestinal cancer (GIC), primarily including colorectal cancer, gastric cancer, liver cancer, pancreatic cancer, and esophageal cancer, is one of the most common causes of cancer-related deaths with increasing prevalence and poor prognosis. Medicinal plants have been shown to be a great resource for the treatment of GIC. Due to their complex manifestations of multi-component and multi-target, the underlying mechanisms how they function against GIC remain to be completely deciphered. Cell metabolism is of primary importance in the initialization and development of GIC, which is reported to be a potential target. As an essential supplement to the newest "omics" sciences, metabolomics focuses on the systematic study of the small exogenous and endogenous metabolites involved in extensive biochemical metabolic pathways of living system. In good agreement with the systemic perspective of medicinal plants, metabolomics offers a new insight into the efficacy assessment and action mechanism investigation of medicinal plants as adjuvant therapeutics for GIC therapy. In this review, the metabolomics investigations on metabolism-targeting therapies for GIC in the recent 10 years were systematically reviewed from five aspects of carbohydrate, lipid, amino acid, and nucleotide metabolisms, as well as other altered metabolisms (microbial metabolism, inflammation, and oxidation), with particular attention to the potential of active compounds, extracts, and formulae from medicinal plants. Meanwhile, the current perspectives and future challenges of metabolism-targeting therapies of medicinal plants for GIC were also discussed. In conclusion, the understanding of the action mechanisms of medicinal plants in GIC from the metabolomics perspective will contribute to the clinical application of potential candidates from the resourceful medicinal plants as novel and efficient adjuvant therapeutics for GIC therapy.
    Keywords:  adjuvant therapeutics; cancer metabolism; gastrointestinal cancers; medicinal plants (herbal drugs); metabolomics
    DOI:  https://doi.org/10.3389/fphar.2022.909755
  37. Adv Drug Deliv Rev. 2022 Jul 07. pii: S0169-409X(22)00309-X. [Epub ahead of print] 114419
    Upconversion Nanomaterials and Delivery Systems for Smart Photonic Medicines and Healthcare Devices.
    Gibum Lee, Hye Eun Choi, Sang Hoon Hong, Min-Ji Choi, Dong-Wook Han, Junmin Lee, Ki Su Kim, Sei Kwang Hahn.
      In the past decade, upconversion (UC) nanomaterials have been extensively investigated for the applications to photomedicines with their unique features including biocompatibility, near-infrared (NIR) to visible conversion, photostability, controllable emission bands, and facile multi-functionality. These characteristics of UC nanomaterials enable versatile light delivery for deep tissue biophotonic applications. Among various stimuli-responsive delivery systems, the light-responsive delivery process has been greatly advantageous to develop spatiotemporally controllable on-demand "smart" photonic medicines. UC nanomaterials are classified largely to two groups depending on the photon UC pathway and compositions: inorganic lanthanide-doped UC nanoparticles and organic triplet-triplet annihilation UC (TTA-UC) nanomaterials. Here, we review the current-state-of-art inorganic and organic UC nanomaterials for photo-medicinal applications including photothermal therapy (PTT), photodynamic therapy (PDT), photo-triggered chemo and gene therapy, multimodal immunotherapy, NIR mediated neuromodulations, and photochemical tissue bonding (PTB). We also discuss the future research direction of this field and the challenges for further clinical development.
    Keywords:  Delivery system; Healthcare device; Photomedicine; Upconversion nanomaterial
    DOI:  https://doi.org/10.1016/j.addr.2022.114419
  38. J Colloid Interface Sci. 2022 Jun 25. pii: S0021-9797(22)01107-9. [Epub ahead of print]626 719-728
    Ferrocene-based multifunctional nanoparticles for combined chemo/chemodynamic/photothermal therapy.
    Jiahui Yang, Liu Yang, Qin Li, Liangke Zhang.
      Ferrocene and its derivatives have great potential for biomedical applications, but few related studies have been reported. In this study, copper ions and ferrocene derivatives were used for the first time to construct the ferrocene-based nanoparticles (Cu-Fc) with a hydrated particle size of approximately 220 nm. Their good photothermal conversion properties were verified in vitro and in vivo for the first time, indicating that they could be used as a novel photothermal agent for tumor treatment. In addition, the nanoparticles exhibited efficient Fenton effect under weakly acidic conditions, indicating that they can generate hydroxyl radicals (OH) to kill tumors in the weakly acidic environment of the tumor-specific microenvironment. More importantly, the nanoparticles can deplete glutathione (GSH), thus further enhancing Fenton effect-mediated chemodynamic therapy (CDT). Multifunctional ferrocene-based nanoparticles (DOX@Cu-Fc) were obtained after loading the chemotherapeutic drug doxorubicin hydrochloride (DOX). The results of in vitro and in vivo experiments showed that DOX@Cu-Fc could enhance tumor treatment by the combination of chemo/CDT/photothermal therapy (PTT).
    Keywords:  Chemodynamic therapy; Ferrocene; Photothermal therapy; Tumor
    DOI:  https://doi.org/10.1016/j.jcis.2022.06.117
  39. Drug Deliv. 2022 Dec;29(1): 2269-2282
    Flexible nano-liposomes-based transdermal hydrogel for targeted delivery of dexamethasone for rheumatoid arthritis therapy.
    Yi-Pu Zhao, Jiang-Fan Han, Fei-Yue Zhang, Tian-Tian Liao, Ren Na, Xiao-Feng Yuan, Guang-Bin He, Weiliang Ye.
      Rheumatoid arthritis (RA) is an inflammatory immune-mediated disease that can lead to synovitis, cartilage destruction, and even joint damage. Dexamethasone (DEX) is a commonly used agent for RA therapy on inflammation manage. However, the traditional administering DEX is hampered by low efficiency and obvious adverse effects. Therefore, in order to efficiently deliver DEX to RA inflamed joints and overcome existing deficiencies, we developed transdermal formation dextran sulfate (DS) modified DEX-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel), validated their transdermal efficiency, evaluated its ability to target activated macrophages, and its anti-inflammatory effect. The DS-FLs/DEX exhibited excellent biocompatibility, sustainable drug release, and high uptake by lipopolysaccharide (LPS)-activated macrophages. Furthermore, the DS-FLs/DEX hydrogel showed desired skin permeation as compared with regular liposome hydrogel (DS-RLs/DEX hydrogel) due to its good deformability. In vivo, when used the AIA rats as RA model, the DS-FLs/DEX hydrogel can effectively penetrate and accumulate in inflamed joints, significantly improve joint swelling in RA rats, and reduce the destructive effect of RA on bone. Importantly, the expression of inflammatory cytokines in joints was inhibited and the system toxicity did not activate under DS-FLs/DEX hydrogel treatment. Overall, these data revealed that the dextran sulfate (DS) modified DEX-loaded flexible liposome hydrogel (DS-FLs/DEX hydrogel) can prove to be an excellent drug delivery vehicle against RA.
    Keywords:  Transdermal drug delivery system; dextran sulfate; flexible liposome; rheumatoid arthritis
    DOI:  https://doi.org/10.1080/10717544.2022.2096718
  40. Transl Lung Cancer Res. 2022 Jun;11(6): 1199-1216
    The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target-a narrative review.
    Alessia Spagnuolo, Paolo Maione, Cesare Gridelli.
       Background and Objective: The genetic nature of cancer provides the rationale to support the need for molecular diagnosis and patient selection for individualised antineoplastic treatments that are the best in both tolerability and efficacy for each cancer patient, including non-small cell lung cancer (NSCLC) patients. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent the prevalent oncogenic driver in NSCLC, being detected in roughly one-third of cases and KRAS G12C is the most frequent mutation found in approximately 13% of patients.
    Methods: This paper gives an overview of the numerous scientific efforts in recent decades aimed at KRAS inhibition.
    Key Content and Findings: Sotorasib is the first approved KRAS G12C inhibitor that has been shown to provide a durable clinical benefit in patients with pre-treated NSCLC with KRAS G12C mutation. Together with the development of new targeted drugs, the development of strategies to control resistance mechanisms is one of the major drivers of research that is exploring the use of KRAS inhibitors not only alone, but also in combination with other targeted therapies, chemotherapy and immunotherapy.
    Conclusions: This review will describe the major therapeutic developments in KRAS mutation-dependent NSCLC and will analyse future perspectives to maximise benefits for this group of patients.
    Keywords:  Adagrasib; KRAS G12C; non-small cell lung cancer (NSCLC); resistance; sotorasib
    DOI:  https://doi.org/10.21037/tlcr-21-948
  41. J Control Release. 2022 Jul 09. pii: S0168-3659(22)00419-9. [Epub ahead of print]
    Microenvironment-tailored micelles restrain carcinoma-astrocyte crosstalk for brain metastasis.
    Zhenhao Zhao, Yujie Zhang, Chao Li, Xuwen Li, Yongchao Chu, Qin Guo, Yiwen Zhang, Weiyi Xia, Peixin Liu, Hongyi Chen, Yu Wang, Chufeng Li, Tao Sun, Chen Jiang.
      Breast-to-brain metastatic cells can interact with the surrounding cells, including astrocytes and microglia, to generate a pro-tumorigenic niche. Breast-to-brain metastasis can be treated using a dual strategy of eliminating metastatic tumor cells and normalizing their localized microenvironment. The effective accumulation of drugs at the action site of metastasis is crucial to realizing the above strategy, especially when dealing with the blood-brain barrier (BBB)-penetrating and tumor-targeting tactics. Here, we establish an in-situ microenvironment-tailored micelle (T-M/siRNA) to co-deliver therapeutic siRNA and paclitaxel (PTX) into the breast-to-brain metastasis. Anchored with a D-type cyclic peptide, T-M/siRNA can penetrate the BBB and subsequently target the brain metastases. Upon internalization by metastatic tumor cells, T-M/siRNA can release PTX in the high-level glutathione (GSH), resulting in killing cancer cells. Meanwhile, the micellar structure is dissociated, resulting in lowering the charge density to release the loaded siRNA that can targeted downregulate the expression of protocadherin 7 (PCDH7). Treatment of model mice revealed that T-M/siRNA can inhibit the abnormal activation of astrocytes and immunosuppressive activation of microglia, resulting in significantly enhanced synergistic anti-tumor efficacy. This study indicates that the micelle system can serve as a hopeful strategy to treat breast-to-brain metastasis.
    Keywords:  Breast-to-brain metastasis; Micelle; Microenvironment; Paclitaxel; Protocadherin 7
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.009
  42. BMC Biol. 2022 Jul 15. 20(1): 163
    Proton export upregulates aerobic glycolysis.
    Shonagh Russell, Liping Xu, Yoonseok Kam, Dominique Abrahams, Bryce Ordway, Alex S Lopez, Marilyn M Bui, Joseph Johnson, Tamir Epstein, Epifanio Ruiz, Mark C Lloyd, Pawel Swietach, Daniel Verduzco, Jonathan Wojtkowiak, Robert J Gillies.
       INTRODUCTION: Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the "Warburg Effect." It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell.
    RESULTS: To test this hypothesis, we stably transfected lowly glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton-exporting systems: either PMA1 (plasma membrane ATPase 1, a yeast H+-ATPase) or CA-IX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher-grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden.
    CONCLUSIONS: Therefore, cancer cells which increase export of H+ equivalents subsequently increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards an upregulation of aerobic glycolysis, a Warburg phenotype. Overall, we have shown that the traditional understanding of cancer cells favoring glycolysis and the subsequent extracellular acidification is not always linear. Cells which can, independent of metabolism, acidify through proton exporter activity can sufficiently drive their metabolism towards glycolysis providing an important fitness advantage for survival.
    Keywords:  CA-IX; Cancer; Glycolysis; Metastasis; PMA1; Proton; Warburg; pH
    DOI:  https://doi.org/10.1186/s12915-022-01340-0
  43. Drug Deliv. 2022 Dec;29(1): 2177-2189
    Acoustic triggered nanobomb for US imaging guided sonodynamic therapy and activating antitumor immunity.
    Mengmeng Li, Ya Zhu, Chao Yang, Mi Yang, Haitao Ran, Yefeng Zhu, Wei Zhang.
      We fabricated an ultrasound activated 'nanobomb' as a noninvasive and targeted physical therapeutic strategy for sonodynamic therapy and priming cancer immunotherapy. This 'nanobomb' was rationally designed via the encapsulation of indocyanine green (ICG) and perfluoropentane (PFP) into cRGD peptide-functionalized nano-liposome. The resulting Lip-ICG-PFP-cRGD nanoparticle linked with cRGD peptide could actively targeted ID8 and TC-1 cells and elicits ROS-mediated apoptosis after triggered by low-intensity focused ultrasound (LIFU). Moreover, the phase change of PFP (from droplets to microbubbles) under LIFU irradiation can produce a large number of microbubbles, which act as intra-tumoral bomber and can detonate explode tumor cells by acoustic cavitation effect. Instant necrosis of tumor cells further induces the release of biologically active damage-associated molecular patterns (DAMPs) to facilitate antitumor immunity. More important, the 'nanobomb' in combination with anti-PD-1checkpoint blockade therapy can significantly improve the antitumor efficacy in a subcutaneous model. In addition, the liposomes may also be used as an imaging probe for ultrasound (US) imaging after being irradiated with LIFU. In summary, the US imaging-guided, LIFU activated ROS production and explosion 'nanobomb' might significantly improve the antitumor efficacy and overcome drug resistance through combination of SDT and immunotherapy, we believe that this is a promising approach for targeted therapy of solid tumor including ovarian cancer.
    Keywords:  Sonodynamic; cancer therapy; immunogenic cell death; nanobomb; reactive oxygen species
    DOI:  https://doi.org/10.1080/10717544.2022.2095058
  44. Int J Biol Sci. 2022 ;18(9): 3747-3761
    Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest.
    Jinyu Shi, Li Zhou, Hui-Si Huang, Liyuan Peng, Na Xie, Edouard Nice, Li Fu, Cen Jiang, Canhua Huang.
      Colorectal cancer (CRC) is one of the most common malignancies worldwide, yet successful treatment still remains a challenge. In this study, we found that oxiconazole (OXI), a broad-spectrum antifungal agent, exhibits certain anti-tumor effect against CRC. Autophagy arrest and subsequent apoptosis are characterized as pivotal events involving OXI-induced growth suppression of CRC cells. Mechanistically, OXI downregulates the protein levels of peroxiredoxin-2 (PRDX2), an antioxidant enzyme, for reactive oxygen species (ROS) detoxication, to initiate autophagy by inactivating the Akt/mTOR pathway and inhibiting RAB7A-mediated fusion of autophagosome and lysosome, which lead to extreme accumulation of autophagosomes and subsequent growth suppression of CRC cells. Consistently, interfering with autophagy or overexpressing PRDX2 significantly impedes OXI-induced growth suppression of CRC cells. Moreover, OXI plus oxaliplatin, a mainstay drug for CRC treatment, achieves an improved anti-tumor effect. Taken together, our findings bring novel mechanistic insights into OXI-induced autophagy arrest and the growth inhibitory effect on CRC cells, and suggest a promisingly therapeutic role of OXI for CRC treatment.
    Keywords:  PRDX2; RAB7A; apoptosis; autophagy arrest; colorectal cancer; oxiconazole
    DOI:  https://doi.org/10.7150/ijbs.70679
  45. J Pharm Anal. 2022 Jun;12(3): 380-393
    Natural product-based radiopharmaceuticals: Focus on curcumin and its analogs, flavonoids, and marine peptides.
    Hendris Wongso.
      Natural products provide a bountiful supply of pharmacologically relevant precursors for the development of various drug-related molecules, including radiopharmaceuticals. However, current knowledge regarding the importance of natural products in developing new radiopharmaceuticals remains limited. To date, several radionuclides, including gallium-68, technetium-99m, fluorine-18, iodine-131, and iodine-125, have been extensively studied for the synthesis of diagnostic and therapeutic radiopharmaceuticals. The availability of various radiolabeling methods allows the incorporation of these radionuclides into bioactive molecules in a practical and efficient manner. Of the radiolabeling methods, direct radioiodination, radiometal complexation, and halogenation are generally suitable for natural products owing to their simplicity and robustness. This review highlights the pharmacological benefits of curcumin and its analogs, flavonoids, and marine peptides in treating human pathologies and provides a perspective on the potential use of these bioactive compounds as molecular templates for the design and development of new radiopharmaceuticals. Additionally, this review provides insights into the current strategies for labeling natural products with various radionuclides using either direct or indirect methods.
    Keywords:  Curcumin; Flavonoids; Marine peptides; Natural products; Radiolabeling; Radiopharmaceuticals
    DOI:  https://doi.org/10.1016/j.jpha.2021.07.006
  46. Expert Opin Drug Metab Toxicol. 2022 Jul 11.
    Strategies for enhancing the oral bioavailability of cannabinoids.
    Ayala Bar-Hai, Abraham J Domb, Amnon Hoffman.
       INTRODUCTION: Oral administration of cannabinoids is a convenient route of administration in many cases. To enhance the poor and variable bioavailability of cannabinoids, selected strategies utilizing proper delivery systems have been designed. Low solubility in the GI aqueous media is the first and most critical barrier. Thereafter, cannabinoids can reach the systemic blood circulation via the portal vein that is associated with significant hepatic first pass metabolism (FPM) or bypass it via lymphatic absorption.
    AREAS COVERED: The solubility obstacle of cannabinoids is mainly addressed with lipid-based formulations such as self-nanoemulsifying drug delivery systems (SNEDDS). Certain lipids are used to overcome the solubility issue. Surfactants and other additives in the formulation have additional impact on several barriers, including dictating the degree of lymphatic bioavailability and hepatic FPM. Gastro-retentive formulation is also plausible.
    EXPERT OPINION: Comparison of the role of the same SNEDDS formulation, cyclosporine vs. cannabinoids, when used to elevate the oral bioavailability of different compounds, is presented. It illustrates some similarities and major mechanistic differences obtained by the same SNEDDS. Thus, the different influence over the absorption pathway illuminates the importance of understanding the absorption mechanism and its barriers to properly select appropriate strategies to achieve enhanced oral bioavailability.
    Keywords:  Absorption enhancer; CBD; LBDDS; Lymphatic absorption; SNEDDS; THC; bioavailability; cannabinoids; chylomicrons; cyclosporine; first pass metabolism; piperine
    DOI:  https://doi.org/10.1080/17425255.2022.2099837
  47. Biomater Sci. 2022 Jul 14.
    Delivery of enzalutamide via nanoparticles for effectively inhibiting prostate cancer progression.
    Ze Gao, Jun Huang, Zhaoxiang Xie, Peikun Xin, Hao Huang, Tao Du, Jun Wu, Hai Huang.
      Androgen deprivation therapy has been used as a standard clinical treatment for prostate cancer, but the disease generally progresses to castration-resistant prostate cancer in a very short time. Enzalutamide (ENZ) is an emerging second-generation androgen receptor (AR) antagonist used for the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC). However, due to the rapid onset of drug resistance, it provides only a modest increase in survival. Here, we propose a convenient and effective androgen receptor antagonist drug delivery strategy, that is, the use of a biocompatible nanoparticle (NP) drug delivery system for drug delivery to improve its bioavailability and therapeutic performance. Although the particle size of the phenylpropyl polymer (8P4) nanoparticles is small, it has a high drug-carrying capacity. ENZ-8P4 NPs can increase drug delivery efficiency, enhance drug cytotoxicity, and reduce the half-inhibitory concentration (IC50) of the drug. In addition, in vivo experiments confirmed that ENZ-8P4 preferentially accumulates in the tumor and significantly inhibits tumor growth. Hence, the 8P4 drug delivery system loaded with enzalutamide has excellent potential for the treatment of prostate cancer.
    DOI:  https://doi.org/10.1039/d2bm00697a
  48. Nutr Cancer. 2022 Jul 11. 1-13
    Complexity of Tumor Microenvironment: Therapeutic Role of Curcumin and Its Metabolites.
    Sahdeo Prasad, Priyanka Saha, Bilash Chatterjee, Anis Ahmad Chaudhary, Rajiv Lall, Amit K Srivastava.
      The tumor microenvironment (TME) is a complex network of cellular and non-cellular components surrounding the tumor. The cellular component includes fibroblasts, adipocytes, endothelial cells, and immune cells, while non-cellular components are tumor vasculature, extracellular matrix and signaling molecules. The tumor cells have constant close interaction with their surrounding TME components that facilitate their growth, survival, and metastasis. Targeting a complex TME network and its interaction with the tumor can offer a novel strategy to disrupt cancer cell progression. Curcumin, from turmeric rhizome, is recognized as a safe and effective natural therapeutic agent against multiple diseases including cancer. Here the effects of curcumin and its metabolites on tumor-TME interaction modulating ability have been described. Curcumin and its metabolites regulate TME by inhibiting the growth of its cellular components such as cancer-associated adipocytes, cancer-associated fibroblast, tumor endothelial cells, tumor-stimulating immune cells, and inducing anticancer immune cells. They also inhibit the interplay of tumor cells to TME by suppressing non-cellular components such as extracellular matrix, and associated tumor promoting signaling-pathways. In addition, curcumin inhibits the inflammatory environment, suppresses angiogenic factors, and increases antioxidant status in TME. Overall, curcumin has the capability to regulate TME components and their interaction with tumor cells.
    DOI:  https://doi.org/10.1080/01635581.2022.2096909
  49. Evid Based Complement Alternat Med. 2022 ;2022 5957378
    Genistein: Therapeutic and Preventive Effects, Mechanisms, and Clinical Application in Digestive Tract Tumor.
    Shenglin Hou.
      Genistein is one of the numerous recognized isoflavones that may be found in a variety of soybeans and soy products, including tofu and tofu products. The chemical name for genistein is 4', 5, 7-trihydroxyisoflavone, and it is found in plants. In recent years, the scientific world has become more interested in genistein because of its possible therapeutic effects on many forms of cancer. It has been widely investigated for its anticancer properties. The discovery of genistein's mechanism of action indicates its potential for apoptosis induction and cell cycle arrest in gastrointestinal cancer, especially gastric and colorectal cancer. Genistein's pharmacological activities as determined by the experimental studies presented in this review lend support to its use in the treatment of gastrointestinal cancer; however, additional research is needed in the future to determine its efficacy, safety, and the potential for using nanotechnology to increase bioavailability and therapeutic efficacy.
    DOI:  https://doi.org/10.1155/2022/5957378
  50. Adv Exp Med Biol. 2022 Jul 14.
    Pharmacological Effects of Caffeic Acid and Its Derivatives in Cancer: New Targeted Compounds for the Mitochondria.
    Haydeé Bastidas, Gabriel Araya-Valdés, Gonzalo Cortés, José A Jara, Mabel Catalán.
      Cancer is a complex pathology of great heterogeneity and difficulty that makes the constant search for new therapies necessary. A major advance on the subject has been made by focusing on the development of new drugs aimed to alter the metabolism of cancer cells, by generating a disruption of mitochondrial function. For this purpose, several new compounds with specific mitochondrial action have been tested, leading successfully to cell death. Recently, attention has centered on a group of natural compounds present in plants named polyphenols, among which is caffeic acid, a polyphenol that has proven to be a powerful antitumoral agent and a prominent compound for studies focused on the development of new therapies against cancer.In this review, we revised the antitumoral capacity and mechanisms of action of caffeic acid and its derivatives, with special emphasis in a new class of caffeic acid derivatives that target mitochondria by chemical binding to the lipophilic cation triphenylphosphonium.
    Keywords:  Caffeic acid; Cancer; Cancer therapy; Mitochondria; Triphenylphosphonium cation
    DOI:  https://doi.org/10.1007/5584_2022_718
  51. Curr Top Med Chem. 2022 Jul 13.
    Traditonal Uses, Pharmacological, and Phytochemical Studies of Euphorbia: a Review.
    Smail Amtaghri, Mourad Akdad, Miloudia Slaoui, Mohamed Eddouks.
       ETHNOPHARMACOLOGICAL RELEVANCE: Plants of the genus Euphorbia have long been used as traditional medicine in China, Europe, America, Turkey, India, Africa, Iran, and Pakistan for their great medicinal value and health benefits. Their stems, leaves, roots, latex are widely used to treat respiratory infections, body and skin irritations, digestive disorders, inflammatory infections, body pain, snake or scorpion bites, pregnancy, sensory disturbances, microbial and anti-cancer diseases.
    OBJECTIVE: This review aimed to provide updated information on the genus Euphorbia, including traditional medicinal uses, valuation and exploitation of medicinal plants, phytochemistry, botanical characterization, pharmacological and toxicological research focused on the medicinal properties of several Euphorbias in particular their antibacterial, anti-tumor, and cell manifestations, in addition to the effect of each isolated bioactive molecule from these species and their pharmacological use including preclinical evaluation of new drugs.
    MATERIALS AND METHODS: This work was conducted using scientific databases such as: PubMed, Google scholar, Scopus, Science Direct, etc. In addition, ChemDraw software has been used for the drawing of chemical molecules. The correct names of the plants were confirmed from plantlist.org. The results of this review research were interpreted, analyzed and documented based on the bibliographical information obtained.
    RESULTS: Among all the species of the Euphorbiaceae family, 15 species have been demonstrated to exhibit anticancer activity, 21 species have antibacterial activity and 10 species have cytotoxic activity. The majority of the chemical constituents of this plant include triterpenoid glycosides, diterpenoids, flavonoids, and the 4α-methyl steroids. Among them, the main bioactive constituents are present in the diterpenoid fraction. The study of more than 33 steroid plants identified more than 104 compounds. Pharmacological research proved that the crude extracts and some pure compounds obtained from Euphorbia had activities for the treatment of different diseases. The objective of the present study was focused on cytotoxic, antibacterial and antitumor diseases. The study of the phytochemistry of the Euphorbia families led to the conclusion that all the plants studied had active compounds, of which 27 plants characterized by their cytotoxic effects, 7 had antibacterial effects and 10 plants had anti-tumor activities. Therefore, the safety of Euphorbia herbal medicine should be considered a top priority in the early stages of development and clinical trials.
    CONCLUSIONS: Many previous studies have validated many traditional uses of Euphorbia species. The latex of some Euphorbia species seems to be toxic however studies dealing with safety and quality of these species are still incomplete. Extensive studies are needed on the Euphorbia plants before it can be fully used in clinics as a potent drug candidate, as researchers are focusing mainly on diterpenoids and triterpenoids, while there are many other types of compounds that may possess new biological activities.
    Keywords:  Anti-tumor; Antibacterial; Cytotoxicity; Euphorbiaceae; Medicinal properties; Pharmacology; Phytochemistry.; Traditional use
    DOI:  https://doi.org/10.2174/1568026622666220713143436
  52. Theranostics. 2022 ;12(10): 4734-4752
    Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy.
    Dannielle H Upton, Caitlin Ung, Sandra M George, Maria Tsoli, Maria Kavallaris, David S Ziegler.
      Despite significant advances in research, the prognosis for both primary and secondary brain cancers remains poor. The blood-brain barrier (BBB) is a complex and unique semi-permeable membrane that serves as a protective structure to maintain homeostasis within the brain. However, it presents a significant challenge for the delivery of therapeutics into the brain and tumor. Some brain tumors are known to compromise BBB integrity, producing a highly heterogeneous vasculature known as the blood-tumor-barrier (BTB). Identifying strategies to bypass these obstacles to improve the penetrability of anticancer therapeutics has been the focus of research in this area. In this review, we discuss the strategies that have been investigated to evade or alter the cellular and molecular barriers of both the BBB and the BTB and detail the methods currently under preclinical or clinical investigation, including molecular, biological, and physical processes to overcome the BBB or BTB. Increased understanding of the BBB and BTB and the current methods of overcoming these barriers will enable the development of new and more effective treatment strategies for brain tumors.
    Keywords:  BBB disruption; CNS malignancies; blood brain barrier; brain tumors; drug delivery systems
    DOI:  https://doi.org/10.7150/thno.69682
  53. J Biomater Sci Polym Ed. 2022 Jul 12. 1-18
    Fabrication of novel ruthenium loaded silk fibroin nanomaterials for fingolimod release improved antitumor efficacy in hepatocellular carcinoma.
    Dong Li, Chenmei Xia, Xia Chen, Qianqian Li, Jian Li, Xiaoqi Qian.
      Cancer targeted nanomaterials-based drug delivery systems have been described as promising. In this work, we employed silk fibroin (SF), ruthenium nanomaterials (RuNMs), heptapeptide (T7), and fingolimod (FTY720) to construct a pH-responsive smart nanomaterials drug delivery system. They were spherical with a mean size of around 120 nm, which may have contributed to the improved penetration and retention of the NMs in tumour areas. T7-FTY720@SF-RuNMs had an encapsulation efficiency (EE) of 72.51 ± 4.02%. When the pH of an environment is acidic, the release of FTY720 from nanocarriers is enhanced. T7-FTY720@SF-RuNMs demonstrated increased cellular uptake selective and anticancer efficacy for hepatocellular cancer in both in vitro and in vivo experiments. Additionally, the in vivo biodistribution investigation showed that T7-FTY720@SF-RuNMs could efficiently aggregate in the tumour location, improving their in vivo potential to kill cancer cells. T7-FTY720@SF-RuNMs demonstrated little toxicity to tumour-bearing animals in investigations of histology and immunohistochemistry, showing that the fabricated NMs are biocompatible in vivo. For the treatment of hepatocellular cancer, the T7-FTY720@SF-RuNMs delivery method offers significant promise.
    Keywords:  Fingolimod; T7 peptide; hepatocellular carcinoma; ruthenium; silk fibroin
    DOI:  https://doi.org/10.1080/09205063.2022.2090348
  54. Front Oncol. 2022 ;12 936054
    The Phytochemical Potential for Brain Disease Therapy and the Possible Nanodelivery Solutions for Brain Access.
    Yang Liu, Zhouchun Chen, Aijie Li, Runhan Liu, Haoying Yang, Xue Xia.
      Plant-derived phytochemicals have gifted humans with vast therapeutic potentials. Yet, the unique features of the blood-brain barrier significantly limit their accession to the target tissue and thus clinical translation in brain disease treatment. Herein, we explore the medicinal outcomes of both the rare examples of phytochemicals that can easily translocate across the blood-brain barrier and most of the phytochemicals that were reported with brain therapeutic effects, but a bizarre amount of dosage is required due to their chemical nature. Lastly, we offer the nanodelivery platform that is capable of optimizing the targeted delivery and application of the non-permeable phytochemicals as well as utilizing the permeable phytochemicals for boosting novel applications of nanodelivery toward brain therapies.
    Keywords:  blood–brain barrier; brain diseases; nanodelivery; phytochemicals; therapeutics development
    DOI:  https://doi.org/10.3389/fonc.2022.936054
  55. Phytother Res. 2022 Jul 15.
    Medicinal herbs in treating chemotherapy-induced nausea and vomiting: A review.
    Reza Rajabalizadeh, Mahboobeh Ghasemzadeh Rahbardar, Hossein Hosseinzadeh.
      Cancer development entangles with mutation and selection for cells that progressively increase capacity for proliferation and metastasis at the cellular level. Surgery, chemotherapy, and radiotherapy are the standard treatments to manage several types of cancer. Chemotherapy is toxic for both normal and cancer cells and can induce unfavorable conditions, such as chemotherapy-induced nausea and vomiting (CINV), that reduce patients' quality of life. Emesis after chemotherapy is categorized into two classes acute and delayed. Since ancient times, herbal medicines have been used in various cultures to manage stomachache, vomiting, and nausea. In this manuscript, the antiemetic mechanisms of several herbal medicines and their preparations such as Zingiber officinale (5-HT, NK-1 receptor and muscarinic antagonist activity), Mentha spicata (5-HT antagonist activity), Scutellaria baicalensis (antioxidant activity), Persumac (useful in delayed phase through antioxidant, anti-inflammatory, and anti-contractile properties) and Rikkunshito (supportive in acute and delayed phase through 5-HT receptor antagonist activity) have been reviewed to show their potential effects on decreasing CINV and attract scientists attention to formulate more herbal medicine to alleviate CINV in cancer patients. However, it is crucial to say that additional high-quality investigations are required to firmly verify the clinical effectiveness and safety of each plant/compound.
    Keywords:  cancer; chemotherapy; complementary medicine; herbal medicine; nausea; vomiting
    DOI:  https://doi.org/10.1002/ptr.7563
  56. Front Oncol. 2022 ;12 891652
    Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches.
    Talha Bin Emran, Asif Shahriar, Aar Rafi Mahmud, Tanjilur Rahman, Mehedy Hasan Abir, Mohd Faijanur-Rob Siddiquee, Hossain Ahmed, Nova Rahman, Firzan Nainu, Elly Wahyudin, Saikat Mitra, Kuldeep Dhama, Mahmoud M Habiballah, Shafiul Haque, Ariful Islam, Mohammad Mahmudul Hassan.
      Cancer is one of the leading causes of death worldwide. Several treatments are available for cancer treatment, but many treatment methods are ineffective against multidrug-resistant cancer. Multidrug resistance (MDR) represents a major obstacle to effective therapeutic interventions against cancer. This review describes the known MDR mechanisms in cancer cells and discusses ongoing laboratory approaches and novel therapeutic strategies that aim to inhibit, circumvent, or reverse MDR development in various cancer types. In this review, we discuss both intrinsic and acquired drug resistance, in addition to highlighting hypoxia- and autophagy-mediated drug resistance mechanisms. Several factors, including individual genetic differences, such as mutations, altered epigenetics, enhanced drug efflux, cell death inhibition, and various other molecular and cellular mechanisms, are responsible for the development of resistance against anticancer agents. Drug resistance can also depend on cellular autophagic and hypoxic status. The expression of drug-resistant genes and the regulatory mechanisms that determine drug resistance are also discussed. Methods to circumvent MDR, including immunoprevention, the use of microparticles and nanomedicine might result in better strategies for fighting cancer.
    Keywords:  cancer; immuno-prevention; intracellular and extracellular ATP; microRNA; multidrug resistance
    DOI:  https://doi.org/10.3389/fonc.2022.891652
  57. Crit Rev Food Sci Nutr. 2022 Jul 14. 1-24
    A comprehensive review of flaxseed (Linum usitatissimum L.): health-affecting compounds, mechanism of toxicity, detoxification, anticancer and potential risk.
    Abdul Mueed, Sahar Shibli, Muhammad Jahangir, Saqib Jabbar, Zeyuan Deng.
      Flaxseed consumption (Linum usitatissimum L.) has increased due to its potential health benefits, such as protection against inflammation, diabetes, cancer, and cardiovascular diseases. However, flaxseeds also contains various anti-nutritive and toxic compounds such as cyanogenic glycosides, and phytic acids etc. In this case, the long-term consumption of flaxseed may pose health risks due to these non-nutritional substances, which may be life threatening if consumed in high doses, although if appropriately utilized these may prevent/treat various diseases by preventing/inhibiting and or reversing the toxicity induced by other compounds. Therefore, it is necessary to remove or suppress the harmful and anti-nutritive effects of flaxseeds before these are utilized for large-scale as food for human consumption. Interestingly, the toxic compounds of flaxseed also undergoes biochemical detoxification in the body, transforming into less toxic or inactive forms like α-ketoglutarate cyanohydrin etc. However, such detoxification is also a challenge for the development, scalability, and real-time quantification of these bioactive substances. This review focuses on the health affecting composition of flaxseed, along with health benefits and potential toxicity of its components, detoxification methods and mechanisms with evidence supported by animal and human studies.
    Keywords:  Flaxseed consumption; anti-nutritional ingredients; anti-tumor activities; cyanogenic compounds; detoxification; potential risk
    DOI:  https://doi.org/10.1080/10408398.2022.2092718
  58. J Pharm Anal. 2022 Jun;12(3): 365-379
    Nanomagnet-facilitated pharmaco-compatibility for cancer diagnostics: Underlying risks and the emergence of ultrasmall nanomagnets.
    Divya S Parimi, Yamini Gupta, Sreekar Marpu, Chandra S Bhatt, Tharun K Bollu, Anil K Suresh.
      Cancer therapy is a fast-emerging biomedical paradigm that elevates the diagnostic and therapeutic potential of a nanovector for identification, monitoring, targeting, and post-treatment response analysis. Nanovectors of superparamagnetic iron oxide nanoparticles (SPION) are of tremendous significance in cancer therapy because of their inherited high surface area, high reactivity, biocompatibility, superior contrast, and magnetic and photo-inducibility properties. In addition to a brief introduction, we summarize various progressive aspects of nanomagnets pertaining to their production with an emphasis on sustainable biomimetic approaches. Post-synthesis particulate and surface alterations in terms of pharmaco-affinity, liquid accessibility, and biocompatibility to facilitate cancer therapy are highlighted. SPION parameters including particle contrast, core-fusions, surface area, reactivity, photosensitivity, photodynamics, and photothermal properties, which facilitate diverse cancer diagnostics, are discussed. We also elaborate on the concept of magnetism to selectively focus chemotherapeutics on tumors, cell sorting, purification of bioentities, and elimination of toxins. Finally, while addressing the toxicity of nanomaterials, the advent of ultrasmall nanomagnets as a healthier alternative with superior properties and compatible cellular interactions is reviewed. In summary, these discussions spotlight the versatility and integration of multi-tasking nanomagnets and ultrasmall nanomagnets for diverse cancer theragnostics.
    Keywords:  Biomimetics; Cancer theragnostics; Core-fusion; Magnetization; Nanomagnets; Utrasmall-SPIONs
    DOI:  https://doi.org/10.1016/j.jpha.2021.11.002
  59. Food Res Int. 2022 Aug;pii: S0963-9969(22)00565-8. [Epub ahead of print]158 111507
    High dietary methionine intake may contribute to the risk of nonalcoholic fatty liver disease by inhibiting hepatic H2S production.
    Yuhui Yang, Manman Lu, Yuncong Xu, Jing Qian, Guowei Le, Yanli Xie.
      Methionine, an essential sulfur-containing amino acid, is associated with hepatic lipid accumulation; however, the underlying mechanism is unknown. This study aimed to investigate the effects of different dietary methionine levels on hepatic lipid accumulation in mice and clarify the possible mechanisms involved. The Institute of Cancer Research (ICR) mice were fed a normal diet (ND, 0.86% methionine), high-methionine diet (HMD, 2.58% methionine), or methionine-restricted diet (MRD, 0.17% methionine) for 11 consecutive weeks. Our results showed that HMD increased the liver weight and liver index, plasma and hepatic lipid profiles, and hepatic fatty infiltration area and perirenal fat volume. In addition, HMD promoted lipid synthesis, inhibited lipid catabolism and glycolysis metabolism, reduced the activities of mitochondrial respiratory chain enzyme complexes (Ⅰ and Ⅴ) and adenosine triphosphate (ATP) production, and elevated oxidative stress and inflammation in the liver. Moreover, HMD inhibited homocysteine metabolism and significantly decreased the expression and activity of cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), thereby reducing endogenous H2S production in the liver. Interestingly, MRD reversed these adverse effects, and promoted endogenous H2S production. In conclusion, inhibition of hepatic H2S production may be the mechanism behind an increased risk of nonalcoholic fatty liver disease (NAFLD) associated with high dietary methionine intake. Therefore, it is necessary to reduce methionine intake in the daily diet to prevent NAFLD and maintain good physical health.
    Keywords:  Excess methionine; Fatty liver; Hepatic lipid accumulation; Hydrogen sulfide; Methionine; Methionine restriction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.foodres.2022.111507
  60. Drug Dev Ind Pharm. 2022 Jul 12. 1-18
    PEGylated drug delivery systems in the pharmaceutical field: past, present and future perspective.
    Eva Sanchez Armengol, Alexander Unterweger, Flavia Laffleur.
      Target-site drug delivery systems are gaining interest in the pharmaceutical field due to their great advantages, such as higher drug dosing capacity and better bioavailability. However, some existing problems need to be overcome. As an example, interaction between blood proteins and drug delivery systems. A potent candidate to approach the mentioned problem is based on polyethylene glycol (PEG) surface modifications. This polymer acts as a protector towards the external possible interactions with other compounds, making targeted delivery possible. Diseases such as cancer, diabetes, haemophilia and pain treatment can benefit from these new systems.This review aims to give an overview of drug delivery systems based on PEGylation as surface modification as pharmaceutical approach. Moreover, a deeper insight of the properties of PEG and its advantages is given, as well as brief overview of present therapies based on this technology.
    Keywords:  Cancer; Conjugate; Diabetes; Haemophilia; PEGylation; Therapy
    DOI:  https://doi.org/10.1080/03639045.2022.2101062
  61. Expert Opin Drug Deliv. 2022 Jul 13.
    Thermosensitive liposomes: A promising step towards locsalised chemotherapy.
    Maryam Chaudhry, Paul Lyon, Constantin Coussios, Robert Carlisle.
       INTRODUCTION: Many small molecules and biologic therapeutics have been developed for solid tumor therapy. However, the unique physiology of tumors makes the actual delivery of these drugs into the tumor mass inefficient. Such delivery requires transport from blood vessels, across the vasculature and into and through interstitial space within a tumor. This transportation is dependent on the physiochemical properties of the therapeutic agent and the biological properties of the tumour. It was hoped the application of nanoscale drug carrier systems would solve this problem. However, issues with poor tumor accumulation and limited drug release have impeded clinical impact. In response, these carrier systems have been redesigned to be paired with targetable external mechanical stimuli which can trigger much enhanced drug release and deposition.
    AREAS COVERED: The pre-clinical and clinical progress of thermolabile drug carrier systems and the modalities used to trigger the release of their cargo, is assessed.
    EXPERT OPINION: Combined application of mild hyperthermia and heat-responsive liposomal drug carriers has great potential utility. Clinical trials continue to progress this approach and serve to refine the technologies, dosing regimens and exposure parameters that will provide optimal patient benefit.
    Keywords:  Clinical trials; Liposomes; drug release; hyperthermia; pre-clinical; solid tumours; thermosensitive
    DOI:  https://doi.org/10.1080/17425247.2022.2099834
  62. J Biomed Mater Res B Appl Biomater. 2022 Jul 11.
    Development of branched polyphenolic poly(beta amino esters) to facilitate post-synthesis processing.
    Kelley Wiegman, Nicolas J Briot, J Zach Hilt, Aron J Huckaba, Thomas D Dziubla.
      Given their versatility and formability, polymers have proven to be a viable platform facilitating a controlled and tuned release for a variety of therapeutic agents. One growing area of polymer drug delivery is polymeric prodrugs, which covalently link active pharmaceutical ingredients to a polymeric form to enhance stability, delivery, and pharmacology. One such class of polymeric prodrugs, poly(beta amino esters) (PβAEs) can be synthesized into crosslinked, or "thermoset," networks which greatly limits their processability. An antioxidant-PβAE polymer prodrug that is soluble in organic solutions would permit enhanced processability, increasing their utility and manufacturability. Curcumin PβAEs were synthesized to be soluble in organic solvents while retaining the release and activity properties. To demonstrate the polymer processability, curcumin PβAEs were further synthesized into nanoparticles and thin films. Control over nanoparticle size and film thickness was established through variance of dope solution concentration and withdrawal speed, respectively. Layering of polymeric films was demonstrated through inkjet printing of thin films. Polymer function was characterized through curcumin release and antioxidant activity. The processing of the polymer had a drastic impact on the curcumin release profiles indicating the polymer degradation was influenced by surface area and porosity of the final product. Previously, release was controlled primarily through the hydrophobicity of the polymer. Here, we demonstrate a novel method for further tuning the degradation by processing the polymer.
    Keywords:  antioxidant; controlled release; poly(beta amino ester) (PβAE)
    DOI:  https://doi.org/10.1002/jbm.b.35123
  63. Biomed Res Int. 2022 ;2022 1659338
    Recent Progress in Development of Dressings Used for Diabetic Wounds with Special Emphasis on Scaffolds.
    Ankit Awasthi, Monica Gulati, Bimlesh Kumar, Jaskiran Kaur, Sukriti Vishwas, Rubiya Khursheed, Omji Porwal, Aftab Alam, Arya Kr, Leander Corrie, Rajan Kumar, Ankit Kumar, Monika Kaushik, Niraj Kumar Jha, Piyush Kumar Gupta, Dinesh Kumar Chellappan, Gaurav Gupta, Kamal Dua, Saurabh Gupta, Rohit Gundamaraju, Pasupuleti Visweswara Rao, Sachin Kumar Singh.
      Diabetic wound (DW) is a secondary application of uncontrolled diabetes and affects about 42.2% of diabetics. If the disease is left untreated/uncontrolled, then it may further lead to amputation of organs. In recent years, huge research has been done in the area of wound dressing to have a better maintenance of DW. These include gauze, films, foams or, hydrocolloid-based dressings as well as polysaccharide- and polymer-based dressings. In recent years, scaffolds have played major role as biomaterial for wound dressing due to its tissue regeneration properties as well as fluid absorption capacity. These are three-dimensional polymeric structures formed from polymers that help in tissue rejuvenation. These offer a large surface area to volume ratio to allow cell adhesion and exudate absorbing capacity and antibacterial properties. They also offer a better retention as well as sustained release of drugs that are directly impregnated to the scaffolds or the ones that are loaded in nanocarriers that are impregnated onto scaffolds. The present review comprehensively describes the pathogenesis of DW, various dressings that are used so far for DW, the limitation of currently used wound dressings, role of scaffolds in topical delivery of drugs, materials used for scaffold fabrication, and application of various polymer-based scaffolds for treating DW.
    DOI:  https://doi.org/10.1155/2022/1659338
  64. Int J Pharm. 2022 Jul 06. pii: S0378-5173(22)00545-2. [Epub ahead of print] 121990
    Piperine-loaded electrospun nanofibers, an implantable anticancer controlled delivery system for postsurgical breast cancer treatment.
    Delaram Babadi, Simin Dadashzadeh, Zahra Shahsavari, Soraya Shahhosseini, Timo L M Ten Hagen, Azadeh Haeri.
      Tumorectomy followed by radiotherapy, hormone, and chemotherapy, are the current mainstays for breast cancer treatment. However, these strategies have systemic toxicities and limited treatment outcomes. Hence, there is a crucial need for a novel controlled release delivery system for implantation following tumor resection to effectively prevent recurrence. Here, we fabricated polycaprolactone (PCL)-based electrospun nanofibers containing piperine (PIP), known for chemopreventive and anticancer activities, and also evaluated the impact of collagen (Coll) incorporation into the matrices. In addition to physicochemical characterization such as morphology, hydrophilicity, drug content, release properties, and mechanical behaviors, fabricated nanofibers were investigated in terms of cytotoxicity and involved mechanisms in MCF-7 and 4T1 breast tumor cell lines. In vivo antitumor study was performed in 4T1 tumor-bearing mice. PIP-PCL75-Coll25 nanofiber was chosen as the optimum formulation due to sustained PIP release, good mechanical performance, and superior cytotoxicity. Demonstrating no organ toxicity, animal studies confirmed the superiority of locally administered PIP-PCL75-Coll25 nanofiber in terms of inhibition of growth tumor, induction of apoptosis, and reduction of cell proliferation compared to PIP suspension, blank nanofiber, and the control. Taken together, we concluded that PIP-loaded nanofibers can be introduced as a promising treatment for implantation upon breast tumorectomy.
    Keywords:  Breast cancer; PCL; collagen; implant; nanofiber; piperine
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121990
  65. Chem Commun (Camb). 2022 Jul 14.
    An active tumor-targeting organic photochemotherapy agent with naproxen for enhanced cancer therapy.
    Chang Xu, Jinjie Chang, Yanhua Li, Kaiye Wang, Wei Pan, Hongyu Wang, Na Li, Bo Tang.
      An active tumor-targeting organic photochemotherapy agent via the combination of a an organic photothermal material and a naproxen prodrug was developed to precisely kill cancer cells and suppress the inflammatory response induced by cell necrosis; in vitro, and in vivo experiments illustrated its low cytotoxicity and excellent tumor inhibitory effect.
    DOI:  https://doi.org/10.1039/d2cc01729f
  66. J Pharm Pharmacol. 2022 Jul 14. pii: rgac048. [Epub ahead of print]
    Docetaxel in combination with metformin enhances antitumour efficacy in metastatic breast carcinoma models: a promising cancer targeting based on PEGylated liposomes.
    Roghayyeh Vakili-Ghartavol, Amin Mehrabian, Farshad Mirzavi, Seyed Mahdi Rezayat, Mohammad Mashreghi, Leila Farhoudi, Sharmin Kharrazi, Kayvan Sadri, Mahmoud Reza Jaafari.
       OBJECTIVES: Metformin has been shown to kill cancer stem-like cells in genetically various types of breast carcinoma. With the aim to simultaneously eradicate the bulk population of tumour cells and the rare population of cancer stem-like cells in breast cancer tissues, we used the combination chemotherapy of docetaxel (DTX) with metformin (MET). Furthermore, we introduce an active loading method based on ammonium sulphate 250 mM (SA) for encapsulating docetaxel into liposomes.
    METHODS: Docetaxel and metformin encapsulated into PEGylated liposomes with two different methods based on remote or passive loading methods, respectively. The size and surface charge of the liposomes were characterized. DTX content in the nanoliposomes was measured by the high-performance liquid chromatography method. The drug release profiles were evaluated in phosphate-buffered dextrose 5% with the pH of 6.5 and 7.4. We examined the antitumour activity of Taxotere (TAX), and liposomal formulation of DTX and MET as a monotherapy or combination therapy. The biodistribution of liposomes was also investigated using 99mTc hexamethyl propylene amine oxime method in BALB/c mice bearing 4T1 breast carcinoma tumours.
    KEY FINDINGS: The final formulations were prepared according to the best physicochemical characteristics which were HSPC/mPEG2000-DSPE/Chol (DTX liposomes) and HSPC/DPPG/mPEG2000-DSPE/Chol (MET liposomes), at molar ratios of 85/5/10 and (55/5/5/35), respectively. In vivo experiments showed that when free or liposomal metformin used in combination with liposomal docetaxel, they prolonged median survival time (MST) from 31 in the control group to 46 days, which demonstrates their promising effects on the survival of the 4T1 breast carcinoma mice models. Moreover, combination therapies could significantly increase life span in comparison with phosphate-buffered saline (PBS) and Taxotere groups at the same dose. Furthermore, in the combination therapy study, treatment with DTX liposomes prepared by ammonium sulphate 250 mM buffer alone resulted in similar therapeutic efficacy to combination therapy. The biodistribution study exhibited significant accumulation of DTX liposomes in the tumours due to the Enhanced Permeability and Retention effect.
    CONCLUSIONS: This study also showed that metformin-based combinatorial chemotherapies have superior efficacy versus their corresponding monotherapy counterparts at same doses. The findings confirm that liposomes based on ammonium sulphate 250 mM could be as a promising formulation for efficient DTX delivering and cancer targeting and therefore merit further investigations.
    Keywords:  combination chemotherapy; docetaxel; liposome; metformin
    DOI:  https://doi.org/10.1093/jpp/rgac048
  67. Biomed Res Int. 2022 ;2022 7337261
    Synergistic Effect of Conventional Medicinal Herbs against Different Pharmacological Activity.
    Huma Ali, Daoud Ali, Bader O Almutairi, Gokhlesh Kumar, Gizachew Assefa Karga, Chandran Masi, Venkatesa Prabhu Sundramurthy.
      Triticum aestivum (Family: Poaceae), Ocimum sanctum (Family: Lamiaceae), and Tinospora cordifolia (Family: Menispermaceae) are commonly known as wheatgrass, tulsi, and giloy, respectively, which are the plants used as medicines for the treatment of various diseases. All three medicinal plants possess phenolic compounds with other important chemical constituents such as polysaccharides, aliphatic compounds, and alkaloids. The extract of these plants has been prepared and investigated for antioxidant, total phenolic content, total flavonoid content, and antimicrobial study in order to discover potential sources for new pharmaceutical formulations. To determine the antioxidant activity, a free radical scavenging assay for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide was performed using ascorbic acid as the standard. The R 2 value of the prepared extract was found to be 0.9964 and 0.990 in DPPH and hydrogen peroxide scavenging activity, respectively. The phenolic and flavonoid content was found to be 87.50 μl/ml and 58.00 μl/ml, respectively. The diffusion method was used to screen the antimicrobial activity of the prepared extract sample against various microorganisms. This extract showed better results for antioxidant and antimicrobial activity.
    DOI:  https://doi.org/10.1155/2022/7337261
  68. Front Immunol. 2022 ;13 915985
    The Effect of Hypoxia-Induced Exosomes on Anti-Tumor Immunity and Its Implication for Immunotherapy.
    Wenwen Guo, Tianyun Qiao, Bingwei Dong, Tian Li, Qiang Liu, Xiaofeng Xu.
      Hypoxia is a critical feature of solid tumors and is considered to be a key factor in promoting tumorigenesis and progression. Beyond inducing metabolic reprogramming of tumor cells to adapt to the hypoxia tumor microenvironment (TME), hypoxia can also promote tumor growth by affecting the secretion of exosomes. Exosomes are nano-sized (30-150 nm in diameter) extracellular vesicles that can carry numerous substances including lipids, proteins, nucleic acids, and metabolites. Notably, hypoxia-induced exosomes alterations not only exist in tumor cells, but also in various TME cells including stromal cells and immune cells. Besides promoting tumor invasion, angiogenesis, and drug resistance, the secretion of these altered exosomes has recently been found to negatively regulate anti-tumor immune responses. In this review, we focus on the hypoxia-induced changes in exosome secretion and found it can contributes to immune evasion and cancer progression by recruiting protumor immune cells into TME, as well as inhibiting antitumor immune cells. Next, we also describe the recent advances of exosomes in immunotherapy and future direction. In conclusion, ongoing discoveries in this field have brought new insights into hypoxia exosome-led immunosuppression, enabling the development of exosome-based therapeutics and elucidating their potential in immunotherapy.
    Keywords:  anti-tumor immunity; exosomes; hypoxia; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.915985
  69. Photodiagnosis Photodyn Ther. 2022 Jul 09. pii: S1572-1000(22)00297-6. [Epub ahead of print] 103011
    Curcumin-loaded multifunctional chitosan gold nanoparticles: An enhanced PDT/PTT dual-modal phototherapeutic and pH-responsive antimicrobial agent.
    Ying Zhang, Peiyuan Li, Rixiang Su, Fangzhou Wen, Zhiruo Jia, Yingbin Lv, Jinyun Cai, Wei Su.
      Overuse of antibiotics has led to the emergence of multidrug resistant (MDR) bacteria in recent years. Photothermal (PTT) and photodynamic therapy (PDT) have been proven to be effective alternatives for antibiotics in the treatment of bacterial infections. In this study, based on chitosan (CS)-coated gold nanoparticles, a pH stimulus-responsive drug delivery system was developed, which can anchor to the cell membrane for photodynamic therapy and photothermal therapy, and enhance the therapeutic potential of curcumin (Cur). Release experiments showed that AuNPs/CS-Cur nanocomposites released curcumin in a pH-dependent manner, which may facilitate the drug to be delivered to the acidic bacterial infection environment. CS as the outer layer covered on gold nanoparticles could improve the dispersibility of Cur in aqueous solution, gold nanoparticles prevent rapid photobleaching of curcumin, thus ensuring the yield of singlet oxygen under irradiation, and enhance the electrostatic binding with bacteria cell membrane. Under light conditions, AuNPs/CS-Cur can produce a large amount of reactive oxygen species and heat to kill S. aureus and E. coli. Compared with free Cur-mediated PDT, the complex significantly improved the synergistic PTT/PDT photoinactivation ability against S. aureus and E. coli. In addition, AuNPs/CS-Cur had good biocompatibility. Therefore, AuNPs/CS-Cur possessed the characteristics of electrostatic targeting, photodynamic and photothermal antibacterial therapy, which would become an efficient and safe antibacterial nano-platform and provide new ideas for the treatment of bacterial infection.
    Keywords:  antibacterial; chitosan; curcumin; gold nanoparticles; photodynamic; photothermal
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103011
  70. Nanoscale. 2022 Jul 12.
    Low-dose exposure to phytosynthesized gold nanoparticles combined with glutamine deprivation enhances cell death in the cancer cell line HeLa via oxidative stress-mediated mitochondrial dysfunction and G0/G1 cell cycle arrest.
    Abhinav Prasad, Ashapurna Khatua, Yugal Kishore Mohanta, Muthupandian Saravanan, Ramovatar Meena, Ilora Ghosh.
      Cancer cells use nutrients like D-glucose (Glc) and L-glutamine (Q) more efficiently for their development. This increased nutritional dependency of malignant cells has been commonly employed in various in vitro and in vivo models of anticancer therapies. This study utilized a combination of a low dose (25 μg mL-1) of S2, a phytosynthesized gold nanoparticle (AuNP) that was previously proven to be non-toxic, and deprivation of extracellular glutamine as an anticancer strategy in the human cervical cancer cell line HeLa. We discovered that 24 h Q deprivation led to a less significant decrease in the viability of HeLa cells while a low dose of S2 caused a non-significant reduction in the viability of HeLa cells. However, combining these two treatments resulted in highly significant inhibition of cell growth, as measured by the MTT test and morphological examination. Glutamine starvation in HeLa cells was found to induce cellular uptake of S2 via clathrin-mediated endocytosis, thus facilitating the improved antitumor effects of the combined treatment. Flow cytometry-based assays using fluorescent probes H2DCFDA and MitoSOX Red confirmed that this combination therapy involved the development of oxidative stress conditions owing to a surplus of cytosolic reactive oxygen species (cytoROS) and mitochondrial superoxide (mtSOX) generation. Furthermore, the investigated combinatorial treatment also indicated mitochondrial inactivity and disintegration, as evidenced by the drop in the mitochondrial membrane potential (Δψm) and the decrease in the mitochondrial mass (mtMass) in a flow-cytometric assay utilizing the probes. Tetramethylrhodamine ethyl ester and MitoTracker Green FM, respectively. Cell cycle arrest in the G0/G1 phase, induction of cell death via apoptosis/necrosis, and inhibition of migration capacities of HeLa cells were also seen after the combined treatment. Thus, this research provides insight into a new combinatorial approach for reducing the dose of nanoparticles and increasing their efficacy to better inhibit the growth of human cervical cancer cells by leveraging their extracellular glutamine dependence.
    DOI:  https://doi.org/10.1039/d2nr02150a
  71. Exp Ther Med. 2022 Aug;24(2): 520
    3-Bromopyruvic acid regulates glucose metabolism by targeting the c-Myc/TXNIP axis and induces mitochondria-mediated apoptosis in TNBC cells.
    Jiachen Li, Jianmin Pan, Yang Liu, Xiaohui Luo, Cheng Yang, Wangfa Xiao, Qishang Li, Lihui Yang, Xiaodong Zhang.
      Aerobic glycolysis is commonly observed in tumor cells, including triple-negative breast cancer (TNBC) cells, and the rate of aerobic glycolysis is higher in TNBC cells than in non-TNBC cells. Hexokinase 2 (HK2) is a key enzyme in the glycolytic pathway and a target of the transcription factor c-Myc, which is highly expressed in TNBC and promotes aerobic glycolysis by enhancing HK2 expression. As an inhibitor of HK2, 3-bromopyruvic acid (3-BrPA) exhibits good therapeutic efficacy in intrahepatic and extrahepatic tumors and inhibits the proliferation of human tumor cells with high expression levels of c-Myc in vivo and in vitro. In addition, 3-BrPA combines with photodynamic therapy to inhibit TNBC cell migration. Thioredoxin-interacting protein (TXNIP) competes with c-Myc to reduce glucose consumption in tumor cells to restrain cell proliferation. A comparative analysis was performed in the present study in TNBC (HCC1143) and non-TNBC (MCF-7) cell lines to explore the effect of 3-BrPA on energy metabolism in TNBC cells and to investigate the possible mechanism of action. Cell viability and apoptosis were detected through Cell Counting Kit-8 and flow cytometry assays, respectively. Expression levels of HK2, glucose transporter 1, TXNIP, c-Myc and mitochondria-regulated apoptosis pathway proteins were measured through western blotting. 3-BrPA inhibited cell proliferation, downregulated c-Myc and HK2 expression, and upregulated TXNIP expression in TNBC cells, but it doesn't have the same effect on non-TNBC cells. Furthermore, 3-BrPA induced the typical manifestations of mitochondrial-mediated apoptosis such as decreasing Bcl-2 expression and increasing Bax, Cyt-C and Caspase-3 expression. The present results suggested that 3-BrPA promoted TXNIP protein expression and reduced HK2 expression in TNBC cells by downregulating c-Myc expression, inhibiting glycolysis including suppressing lactate generation, intracellular ATP generation and HK activity, inducing mitochondrial-mediated apoptosis and eventually suppressing TNBC cell proliferation. These findings may reveal a novel therapeutic target for the clinical treatment of TNBC.
    Keywords:  3-bromopyruvic acid; aerobic glycolysis; c-Myc; thioredoxin-interacting protein; triple-negative breast cancer
    DOI:  https://doi.org/10.3892/etm.2022.11447
  72. Front Aging. 2021 ;2 707372
    The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging.
    Stephanie A Fernandes, Constantinos Demetriades.
      The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.
    Keywords:  aging; amino acids; dietary restriction; mTORC1; nutrient sensing
    DOI:  https://doi.org/10.3389/fragi.2021.707372
  73. AAPS PharmSciTech. 2022 Jul 13. 23(6): 195
    Alpha Tocopherol Loaded Polymeric Nanoparticles: Preparation, Characterizations, and In Vitro Assessments Against Oxidative Stress in Spinal Cord Injury Treatment.
    Aayushi Laliwala, Amita Daverey, Sandeep K Agrawal, Alekha K Dash.
      Spinal cord injury (SCI) is characterized by mechanical injury or trauma to the spinal cord. Currently, SCI treatment requires extremely high doses of neuroprotective agents, which in turn, causes several adverse effects. To overcome these limitations, the present study focuses on delivery of a low but effective dose of a naturally occurring antioxidant, α-tocopherol (α-TP). Calcium alginate nanoparticles (CA-NP) and poly D,L-lactic-co-glycolic acid nanoparticles (PLGA-NP) prepared by ionotropic gelation and solvent evaporation technique had particle size of 21.9 ± 11.19 and 152.4 ± 10.6 nm, respectively. Surface morphology, surface charge, as well as particle size distribution of both nanoparticles were evaluated. Entrapment of α-TP into CA-NP and PLGA-NP quantified by UPLC showed entrapment efficiency of 4.00 ± 1.63% and 76.6 ± 11.4%, respectively. In vitro cytotoxicity profiles on human astrocyte-spinal cord (HA-sp) showed that blank CA-NP at high concentrations reduced the cell viability whereas blank PLGA-NP showed relatively safer cytotoxic profiles. In addition, PLGA nanoparticles encapsulated with α-TP (α-TP-PLGA-NP) in comparison to α-TP alone at high concentrations were less toxic. Pretreatment of HA-sp cells with α-TP-PLGA-NP showed two-fold higher anti-oxidative protection as compared to α-TP alone, when oxidative stress was induced by H2O2. In conclusion, CA-NP were found to be unsuitable for treatment of SCI due to their cytotoxicity. Comparatively, α-TP-PLGA-NP were safer and showed high degree of protection against oxidative stress than α-TP alone.
    Keywords:  Calcium alginate; Human astrocyte-spinal cord cells; PLGA; Pretreatment; Vitamin E
    DOI:  https://doi.org/10.1208/s12249-022-02345-2
  74. Crit Rev Food Sci Nutr. 2022 Jul 11. 1-20
    Molecular bases for the use of functional foods in the management of healthy aging: Berries, curcumin, virgin olive oil and honey; three realities and a promise.
    María D Navarro-Hortal, Jose M Romero-Márquez, Victoria Jiménez-Trigo, Jianbo Xiao, Francesca Giampieri, Tamara Y Forbes-Hernández, Giuseppe Grosso, Maurizio Battino, Cristina Sánchez-González, José L Quiles.
      As the number of older people has grown in recent decades, the search for new approaches to manage or delay aging is also growing. Among the modifiable factors, diet plays a crucial role in healthy aging and in the prevention of age-related diseases. Thus, the interest in the use of foods, which are rich in bioactive compounds such as functional foods with anti-aging effects is a growing market. This review summarizes the current knowledge about the molecular mechanisms of action of foods considered as functional foods in aging, namely berries, curcumin, and virgin olive oil. Moreover, honey is also analyzed as a food with well-known healthy benefits, but which has not been deeply evaluated from the point of view of aging. The effects of these foods on aging are analyzed from the point of view of molecular mechanisms including oxidative stress, mitochondrial dysfunction, inflammation, genomic stability, telomere attrition, cellular senescence, and deregulated nutrient-sensing. A comprehensive study of the scientific literature shows that the aforementioned foods have demonstrated positive effects on certain aspects of aging, which might justify their use as functional foods in elderly. However, more research is needed, especially in humans, designed to understand in depth the mechanisms of action through which they act.
    Keywords:  Dietary fat; hydroxytyrosol; monounsaturated fatty acids; nutraceutics; strawberry; turmeric
    DOI:  https://doi.org/10.1080/10408398.2022.2098244
  75. Methods Mol Biol. 2022 ;2525 21-34
    Reactive Oxygen Species-Responsive and Self-Illuminating Nanoparticles for Inflammation and Tumor Imaging.
    Xiaoqiu Xu, Qi Li, Jianxiang Zhang.
      Reactive oxygen species (ROS) play a key role in various physiological and pathological processes. Abnormally elevated ROS levels are generally related to the pathogenesis of inflammatory diseases and tumors. Real-time imaging and quantification of ROS can not only provide new insight into mechanistic understanding of diseases associated with ROS but also facilitate high-throughput and high-content drug screening for these diseases. Here, the present protocol introduces ROS-responsive and self-illuminating nanoparticles with chemiluminescence (CL) and fluorescence (FL) properties that can serve as an effective nanoprobe for imaging of pathophysiology, including inflammation and tumor.
    Keywords:  Chemiluminescence imaging (CLI); Inflammation; Nanoparticles (NPs); Reactive oxygen species; Self-illuminating; Tumor
    DOI:  https://doi.org/10.1007/978-1-0716-2473-9_3
  76. Front Bioeng Biotechnol. 2022 ;10 929536
    Assembling p53 Activating Peptide With CeO2 Nanoparticle to Construct a Metallo-Organic Supermolecule Toward the Synergistic Ferroptosis of Tumor.
    Jingmei Wang, Wenguang Yang, Xinyuan He, Zhang Zhang, Xiaoqiang Zheng.
      Inducing lipid peroxidation and subsequent ferroptosis in cancer cells provides a potential approach for anticancer therapy. However, the clinical translation of such therapeutic agents is often hampered by ferroptosis resistance and acquired drug tolerance in host cells. Emerging nanoplatform-based cascade engineering and ferroptosis sensitization by p53 provides a viable rescue strategy. Herein, a metallo-organic supramolecular (Nano-PMI@CeO2) toward p53 restoration and subsequent synergistic ferroptosis is constructed, in which the radical generating module-CeO2 nanoparticles act as the core, and p53-activator peptide (PMI)-gold precursor polymer is in situ reduced and assembled on the CeO2 surface as the shell. As expected, Nano-PMI@CeO2 effectively reactivated the p53 signaling pathway in vitro and in vivo, thereby downregulating its downstream gene GPX4. As a result, Nano-PMI@CeO2 significantly inhibited tumor progression in the lung cancer allograft model through p53 restoration and sensitized ferroptosis, while maintaining favorable biosafety. Collectively, this work develops a tumor therapeutic with dual functions of inducing ferroptosis and activating p53, demonstrating a potentially viable therapeutic paradigm for sensitizing ferroptosis via p53 activation. It also suggests that metallo-organic supramolecule holds great promise in transforming nanomedicine and treating human diseases.
    Keywords:  anticancer therapy; p53; peptide; protein–protein interactions; supramolecular
    DOI:  https://doi.org/10.3389/fbioe.2022.929536
  77. Front Pharmacol. 2022 ;13 886981
    Biocompatible Supramolecular Mesoporous Silica Nanoparticles as the Next-Generation Drug Delivery System.
    Farahidah Mohamed, May K Oo, Bappaditya Chatterjee, Batoul Alallam.
      Supramolecular mesoporous silica nanoparticles (MSNs) offer distinct properties as opposed to micron-sized silica particles in terms of their crystal structure, morphology-porosity, toxicity, biological effects, and others. MSN biocompatibility has touched the pharmaceutical realm to exploit its robust synthesis pathway for delivery of various therapeutic molecules including macromolecules and small-molecule drugs. This article provides a brief review of MSN history followed by special emphasis on the influencing factors affecting morphology-porosity characteristics. Its applications as the next-generation drug delivery system (NGDDS) particularly in a controlled release dosage form via an oral drug delivery system are also presented and shall be highlighted as oral delivery is the most convenient route of drug administration with the economical cost of development through to scale-up for clinical trials and market launch.
    Keywords:  insulin; mesoporous; nanoparticles; oral; pharmaceutical; silica
    DOI:  https://doi.org/10.3389/fphar.2022.886981
  78. Front Oncol. 2022 ;12 921983
    Nanomaterial Technology and Soft Tissue Sarcomas.
    Changkai Zhou, Xue Chen, Ying Huang, Qi Zhang, Shu Zhu, Wei Fu.
      Soft tissue sarcomas (STSs) are relatively rare heterogeneous solid tumors of the mesenchymal origin. They account for approximately 1% of all malignant tumors in adults and have more than 70 histological subtypes. Consequently, the rarity and heterogeneity of STSs make their diagnosis and treatment very challenging. Nanotechnology has attracted increasing attention from researchers due to the unique physicochemical and biological properties of nanomaterials with potential medical applications as nanoprobes, drug delivery systems, photosensitizers, radioenhancers, antitumor agents, and their combinations for cancer diagnosis and treatment. This review discusses the progress made in the use of nanotechnology for the diagnosis and treatment of STSs and highlights future prospects of the STS multimodality therapy.
    Keywords:  cancer diagnosis; drug delivery; nanotechnology; photodynamic therapy; radiotherapy; soft tissue sarcoma
    DOI:  https://doi.org/10.3389/fonc.2022.921983
  79. Phytomedicine. 2022 Jul 03. pii: S0944-7113(22)00385-3. [Epub ahead of print]104 154306
    Role of curcumin in the treatment of acute kidney injury: research challenges and opportunities.
    Yi Cai, Chaoming Huang, Mengyu Zhou, Shiqi Xu, Yongwan Xie, Shuhan Gao, Yantianyu Yang, Zirong Deng, Libei Zhang, Jicheng Shu, Tingdong Yan, Chunpeng Craig Wan.
       BACKGROUND: Acute kidney injury (AKI) is a common complication in clinical inpatients, and it continues a high morbidity and mortality rate despite many clinical treatment measures. AKI is triggered by infections, surgery, heavy metal exposure and drug side effects, but current chemical drugs often fall short of expectations for AKI treatment and have toxic side effects. Therefore, finding new interventions and treatments, especially of natural origin, is of remarkable clinical significance and application. The herbal monomer curcumin is a natural phenolic compound extracted from the plant Curcuma longa and showed various biological activities, including AKI. Furthermore, recent studies have shown that curcumin restores renal function by modulating the immune system and the release of inflammatory mediators, scavenging oxygen free radicals, reducing apoptosis and improving mitochondrial dynamics. However, curcumin has a low bioavailability, which limits its clinical application. For this reason, it is essential to investigate the therapeutic effects and molecular mechanisms of curcumin in AKI, as well as to improve its bioavailability for curcumin formulation development and clinical application.
    PURPOSE: This review summarizes the sources, pharmacokinetics, and limitations in the clinical application of curcumin and explores methods to optimize its bioavailability using nanotechnology. In particular, the therapeutic effects and molecular mechanisms of curcumin on AKI are highlighted to provide a theoretical basis for AKI treatment in clinical practices.
    METHODS: This review was specifically searched by means of a search of three databases (Web of Science, PubMed and Science Direct), till December 2021. Search terms were "Curcumin", "Acute kidney injury", "AKI", " Pharmacokinetics", "Mitochondria" and "Nano formulations". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review) RESULTS: Studies have shown that curcumin responded to AKI-induced renal injury and restored renal tubular epithelial cell function by affecting multiple signaling pathways in AKI models induced by factors such as cisplatin, lipopolysaccharide, ischemia/reperfusion, gentamicin and potassium dichromate. Curcumin was able to affect NF-κB signaling pathway and reduce the expression of IL-1β, IL-6, IL-8 and TNF-α, thus preventing renal inflammatory injury. In the prevention of renal tubular oxidative damage, curcumin reduced ROS production by activating the activity of Nrf2, HO-1 and PGC-1α. In addition, curcumin restored mitochondrial homeostasis by upregulating OPA1 and downregulating DRP1 expression, while reducing apoptosis by inhibiting the caspase-3 apoptotic pathway. In addition, due to the low bioavailability and poor absorption of curcumin in vivo, curcumin nanoformulations including nanoparticles, liposomes, and polymeric micelles are formulated to improve the bioavailability.
    CONCLUSION: This review provides new ideas for the use of curcumin in the prevention and treatment of AKI by modulating the molecular targets of several different cellular signaling pathways.
    Keywords:  Acute kidney injury; Curcumin; Mitochondria; Nano formulations; Pharmacokinetics
    DOI:  https://doi.org/10.1016/j.phymed.2022.154306
  80. J Cosmet Dermatol. 2022 Jul 14.
    Herbal nanocosmeceuticals: A review on cosmeceutical innovations.
    Purva Vaishampayan, Meenal M Rane.
       BACKGROUND: Cosmeceuticals are drugs, cosmetics, or a combination of both. Cosmeceuticals are personal care products that not only beautify but need to have healing, therapeutic, and disease-fighting characteristics. For decades, phytocompounds have been employed in cosmeceuticals and have shown promise in applications such as moisturizing, sunscreen, antiaging, and hair-based therapy. The inability of phytocompounds to easily penetrate through the skin and instability limit their usage in cosmetic products. This can be overcome by incorporating nanotechnology into cosmetic products for a more stable and long-lasting release. Nanotechnology's substantial impact on the cosmetics industry is due to the improved properties attained by particles at the nano scale, such as colour, solubility, and transparency. Liposomes, solid lipid nanoparticles, niosomes, and many varieties of nanoparticulate systems are commonly used in cosmetics. Safety concerns for the usage of nanomaterials in cosmeceuticals have been raised lately, hence causing the restriction on the use of nanomaterials by cosmetic companies and enforcing laws demanding thorough safety testing prior to market entry.
    AIM: This review focuses on the types of nanomaterials used in Phyto-cosmetics, along with the potential hazards they pose to human life and the environment, and what legislation has been enacted or can be enacted to address them.
    METHODS: For relevant literature, a literature search was conducted using PubMed, ScienceDirect, and Google Scholar. Nanotechnology, cosmeceuticals, herbal cosmetics, and other related topics were researched and evaluated in articles published between 2016 and 2022.
    RESULTS: Herbal drugs provide a tremendous range of therapeutic benefits. And when nanoparticles were introduced to the personal care industry, the quality of the final product containing Phyto-compounds continued to rise. Unfortunately, because these nano components can permeate intact skin barriers and create unwanted consequences, this revolution comes with a slew of health risks.
    CONCLUSION: The cosmeceutical industry's expansion and growth in the application of herbal compounds, as well as the entrance of nanotechnology into the cosmeceuticals business, entail the urgent need for scientific research into their efficacy, safety profile, and use.
    Keywords:  Cosmetic Regulation; Herbal Cosmetics; Nanocosmeceuticals; Nanotechnology; Phytoconstituents
    DOI:  https://doi.org/10.1111/jocd.15238
  81. Front Pharmacol. 2022 ;13 917266
    Recent Advances and Perspectives on the Health Benefits of Urolithin B, A Bioactive Natural Product Derived From Ellagitannins.
    Peng Chen, Zhiei Guo, Fuchao Chen, Yue Wu, Benhong Zhou.
      Urolithin (Uro) B is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranates, raspberries, blueberries and chestnuts. Uro B has recently garnered considerable attention owing to its wide range of nutraceutical effects and relatively high potency. According to several studies, Uro B prevents the development of hyperlipidemia, cardiovascular disease (CVD) and tumors due to its strong antioxidant and anti-inflammatory properties. Many reviews have systematically summarized the health benefits and pharmacological activities of ETs, EA and urolithins (especially Uro A) while available reviews or detailed summaries on the positive impact of Uro B are rarer. Here, we sought to review the pharmacological activity, mechanism of action, regulation of immune function and its associated diseases and preventive potential of Uro B to elucidate its function as a nutritional agent in humans.
    Keywords:  anti-aging; antioxidant; biological effect; nutritional agent; urolithin B
    DOI:  https://doi.org/10.3389/fphar.2022.917266
  82. Liver Int. 2022 Jul 14.
    KRAS mutation in intrahepatic cholangiocarcinoma: linkage with metastasis-free survival and reduced E-cadherin expression.
    Mariko Tanaka, Akiko Kunita, Makoto Yamagishi, Hiroto Katoh, Shumpei Ishikawa, Hiroyuki Yamamoto, Jun Abe, Junichi Arita, Kiyoshi Hasegawa, Tatsuhiro Shibata, Tetsuo Ushiku.
       BACKGROUND & AIMS: Although KRAS mutations are the major driver of intrahepatic cholangiocarcinoma (ICC), their role remains unexplored. This study aimed to elucidate the prognostic effects, association with clinicopathologic characteristics and potent functions of KRAS mutations in ICC.
    METHODS: 107 resected stage I-III ICCs were analyzed for KRAS mutation status and its link with clinicopathological features. An independent validation cohort (n = 138) was included. In vitro analyses using KRAS-mutant ICC cell lines were performed.
    RESULTS: KRAS mutation was significantly associated with worse overall survival in stage I-III ICCs, which was validated in an independent cohort. Recurrence-free survival did not significantly differ between cases with and without KRAS mutations, but if limited to recurrence with extrahepatic metastasis, KRAS-mutant cases showed significantly worse distant metastasis-free survival than KRAS-wild cases showed. KRAS mutations were associated with frequent tumor budding with reduced E-cadherin expression. In vitro, KRAS depletion caused marked inhibition of cell growth and migration together with E-cadherin upregulation in KRAS-mutant ICC cells. RNA sequencing assay revealed that KRAS depletion caused MYC pathway downregulation and interferon pathway upregulation.
    CONCLUSIONS: Our observations suggest that KRAS mutations are associated with aggressive behavior of ICC, especially the development of extrahepatic metastasis. Mutant KRAS is likely to change the adhesive status of ICC cells, affect the responsiveness of tumor cells to interferon immune signals, and consequently promote extrahepatic metastasis. KRAS mutation status, which predicts the prognoses of patients with ICC after surgical resection, is expected to help stratify patients better for individual postoperative treatment strategies.
    Keywords:   KRAS ; E-cadherin; cholangiocarcinoma; distant metastasis; intrahepatic
    DOI:  https://doi.org/10.1111/liv.15366
  83. Phytomedicine. 2022 Jun 25. pii: S0944-7113(22)00365-8. [Epub ahead of print]104 154286
    Untapping the protective role of carotenoids against respiratory diseases.
    Janani Manochkumar, Anuma Singh, Thomas Efferth, Siva Ramamoorthy.
       BACKGROUND: Recent studies revealed a substantial role of carotenoids to treat respiratory diseases. This review aimed to give an updated overview of the investigational evidence on the preventive properties of carotenoids against respiratory diseases both in vitro and in vivo along with their pathophysiology and mechanisms of action.
    HYPOTHESIS: Carotenoids as a potential therapeutic class of bioactive compounds to treat respiratory diseases.
    RESULTS: Carotenoids such as β-carotene, lycopene, crocin, bixin, lutein, and astaxanthin show beneficial effects against chronic lung diseases (e.g., asthma, emphysema, fibrosis, COPD, acute lung injury, and lung cancer). Moreover, in vitro and in vivo studies also supported the preventive role of carotenoids. These carotenoids showed a beneficial role by activation of the NRF2/HO-1 pathway and inhibition of the NF-кB, MAPK, JAK/STAT-3, and PI3K/AKT pathways. Additionally, epidemiological studies also showed that dietary intake of carotenoids lowers the risk of lung diseases.
    CONCLUSION: Carotenoids may be used as drugs or can be given in combination with other drugs to prevent and treat respiratory diseases. Although in vitro and in vivo results are encouraging, further well-conducted randomized clinical trials are required to approve carotenoids as drug candidates.
    Keywords:  Carotenoids; In vitro and in vivo models; NRF2/HO-1 pathway; Phytochemicals; Respiratory diseases; Terpenoids
    DOI:  https://doi.org/10.1016/j.phymed.2022.154286
  84. Adv Healthc Mater. 2022 Jul 12. e2200742
    Inhibition of Mitochondrial Biosynthesis using a "Right-Side-Out" Membrane Camouflaged Micelle to Facilitate the Therapeutic Effects of Shikonin on Triple-Negative Breast Cancer.
    Jianqing Peng, Xiaoxia Hu, Shuangqin Fan, Jia Zhou, Shuang Ren, Runbin Sun, Yi Chen, Xiangchun Shen, Yan Chen.
      The mitochondria represent a potential target for the treatment of triple-negative breast cancer (TNBC) and shikonin (SK) has shown remarkable therapeutic effects on TNBC. Herein, we found that SK possesses potent inhibitory effects on mitochondrial biogenesis via targeting polymerase gamma (POLG). However, its application is restricted by its poor aqueous solubility and stability and therefore, we have designed a biomimetic micelle to aid with tumor lesion accumulation and mitochondria-targeted delivery of SK. A folic acid (FA) conjugated polyethylene glycol derivative (FA-PEG-FA) was inserted onto the external membranes of red blood cells (FP-RBCm) to prepare a "right-side-out" RBCm camouflaged cationic micelle (ThTM/SK@FP-RBCm). Both FP-RBCm coating and a triphenylphosphine (TPP) moiety on the periphery of micelles contributed to tumor lesion distribution, receptor-mediated cellular uptake, and electrostatic attraction-dependent mitochondrial targeting, thereby maximizing inhibitory effects on mitochondrial biosynthesis in TNBC cells. Intravenous administration of ThTM/SK@FP-RBCm led to profound inhibition of tumor growth and lung metastasis in a TNBC mouse model with no obvious toxicity. Our work highlights the mitochondria-targeted delivery of SK using a "right-side-out" membrane camouflaged micelle for the inhibition of mitochondrial biogenesis and enhanced therapeutic effects on TNBC. This article is protected by copyright. All rights reserved.
    Keywords:  Biomimetic; Micelles; Mitochondrial biogenesis; Shikonin; Triple-negative breast cancer
    DOI:  https://doi.org/10.1002/adhm.202200742
  85. Oncol Lett. 2022 Aug;24(2): 286
    Organic extract of Geodia cydonium induces cell cycle block in human mesothelioma cells.
    Francesco Di Meo, Roberta Esposito, Rossana Cuciniello, Gregorio Favale, Mario Arenga, Nadia Ruocco, Genoveffa Nuzzo, Angelo Fontana, Stefania Filosa, Stefania Crispi, Maria Costantini.
      The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species Geodia cydonium represents a potential source of these type of products with considerable biotechnological interest as pharmaceutical agents. The present study demonstrated the antiproliferative effect of an organic G. cydonium extract (GEOCYDO) against three human mesothelioma cell lines, MSTO-211H (MSTO), NCI-H2452 (NCI) and Ist-Mes2 (Mes2), which differ in their sensitivity (MSTO and NCI) and resistance (Mes2) to standard combined treatment with cisplatin and piroxicam. To this aim, the activity of the extract was evaluated by analyzing its effects on cell viability, cancer properties and cell cycle progression by means of colony formation assay, cell cycle analysis and protein expression analysis. The results revealed, in mesothelioma, this extract was able to reduce self-renewal, cell migration and it could induce cell cycle arrest in G0/G1 stage, thus blocking cell proliferation. In conclusion, to the best of our knowledge, the present results indicated for the first time that GEOCYDO can contain active compounds able to affect cell proliferation in mesothelioma, suggesting that it could be considered as a potential novel drug source for cancer treatment.
    Keywords:  Geodia cydonium extract; antiproliferative effect; cell cycle block; mesothelioma; solid-phase extraction
    DOI:  https://doi.org/10.3892/ol.2022.13406
  86. Food Chem. 2022 Jul 06. pii: S0308-8146(22)01596-5. [Epub ahead of print]395 133634
    Enhancing the bioaccessibility of vitamin D using mixed micelles - An in vitro study.
    Steven L Mulrooney, Graham J O'Neill, Dermot F Brougham, Dolores O'Riordan.
      Vitamin-D deficiency is a global issue and a food fortification strategy may reduce deficiency levels. Mixed micelles (MM) are crucial to vitamin-D absorption in vivo and may enhance vitamin-D food fortification. This study compared the ability of MM based delivery systems to oil-in-water emulsions to improve vitamin-D bioaccessibility in vitro. Vitamin-D loaded emulsions were formed with olive or coconut oil alone or with added l-α-phosphatidylcholine, as well as two MM based systems. Particle size throughout digestion, fatty acid release, and vitamin-D bioaccessibility were measured. After digestion, particles in the MM size range (∼6-10 nm) were observed for emulsions but not for MM based systems. The bioaccessibility of vitamin-D in olive and coconut emulsions was 75% and 78%, respectively, and ∼ 90% with added l-α-phosphatidylcholine. Bioaccessibility for the MM alone was 93% and 90% when mixed with a protein/lactose base. Overall, MM show good potential as a delivery system for vitamin-D in vitro.
    Keywords:  Bioaccessibility; In vitro; Infogest; Mixed micelles; Vitamin D
    DOI:  https://doi.org/10.1016/j.foodchem.2022.133634
  87. Front Oncol. 2022 ;12 910963
    The Role and Therapeutic Perspectives of Sirtuin 3 in Cancer Metabolism Reprogramming, Metastasis, and Chemoresistance.
    QingYi Zhao, Jing Zhou, Feng Li, Sen Guo, Liang Zhang, Jing Li, Qin Qi, Yin Shi.
      Sirtuin 3 (SIRT3), the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, acts as a metabolic modulator mainly located in mitochondria via regulating the process of the relevant biochemical processes by targeting crucial mediators. Recently, owing to its dual role in cancer, SIRT3 has attracted extensive attention. Cancer cells have different metabolic patterns from normal cells, and SIRT3-mediated metabolism reprogramming could be critical in the cancer context, which is closely related to the mechanism of metabolism reprogramming, metastasis, and chemoresistance in tumor cells. Therefore, it is crucial to elucidate the relevant pathological mechanisms and take appropriate countermeasures for the progression of clinical strategies to inhibit the development of cancer. In this review, existing available data on the regulation of cancer metabolism reprogramming, metastasis, and chemoresistance progression of SIRT3 are detailed, as well as the status quo of SIRT3 small molecule modulators is updated in the application of cancer therapy, aiming to highlight strategies directly targeting SIRT3-mediated tumor-suppressing and tumor-promoting, and provide new approaches for therapy application. Furthermore, we offer an effective evidence-based basis for the evolvement of potential personalized therapy management strategies for SIRT3 in cancer settings.
    Keywords:  activator; cancer; chemoresistance; inhibitor; metabolism reprogramming; metastasis; sirtuin 3; therapy
    DOI:  https://doi.org/10.3389/fonc.2022.910963
  88. Front Immunol. 2022 ;13 938439
    Enhanced Therapeutic Efficacy of Combining Losartan and Chemo-Immunotherapy for Triple Negative Breast Cancer.
    Qing Zhao, Xuexin He, Xiyi Qin, Yu Liu, Han Jiang, Jing Wang, Shuang Wu, Rui Zhou, Congcong Yu, Suling Liu, Hong Zhang, Mei Tian.
      Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, which is relatively resistant to anti-programmed cell death-1 (α-PD1) therapy, characterized as non-immunogenic, dense stroma and accumulation of M2 tumor-associated macrophages (TAMs). Despite progress in strategies to deplete extracellular matrix (ECM) and enhance tumor-cell immunogenicity, the combinatorial anti-cancer effects with α-PD1 need to be explored. Here, we applied doxorubicin hydrochloride liposome (Dox-L) as immunogenic cell death (ICD)-inducing nano-chemotherapy and used losartan as stroma-depleting agent to improve α-PD1 efficacy (Losartan + Dox-L + α-PD1). The results showed that losartan could cause ECM reduction, facilitating enhanced delivery of Dox-L and further dendritic cell (DC) maturation. Additionally, losartan could also alleviate hypoxia for TNBC, thus reprogramming pro-cancer M2 TAMs to anti-cancer M1 TAMs, successfully overcoming immune-suppressive microenvironment. These modifications led to a significant increase in T cells' infiltration and augmented anti-tumor immunity as exemplified by the notable reduction in tumor size and lung metastases. In summary, our findings support that combined treatment of losartan with Dox-L normalizes immunological-cold microenvironment, improves immuno-stimulation and optimizes the efficacy of TNBC immunotherapy. A novel combinational strategy with FDA-approved compounds proposed by the study may potentially be useful in TNBC clinical treatment.
    Keywords:  chemotherapy; extracellular matrix; immunotherapy; positron emission tomography (PET); triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fimmu.2022.938439
  89. Eur J Pharm Biopharm. 2022 Jul 07. pii: S0939-6411(22)00140-0. [Epub ahead of print]
    Co-delivery of Interleukin-12 and Doxorubicin Loaded Nano-delivery System for Enhanced Immunotherapy with Polarization toward M1-type Macrophages.
    Tushuai Li, Zhihong Liu, Xiao Fu, Yongquan Chen, Shenglong Zhu, Jie Zhang.
      Chemo-immunotherapy has gained increasing attention as one of the most promising combination therapy strategies to battle cancer. In this study, the therapeutic nanoparticles (TNPs) co-delivering doxorubicin (DOX) and IL-12 (IL-12) were developed for chemo-immunotherapy combination therapy on liver cancer. TNPs were synthesized based on the ionic interactions between cationic chitosan (Ch) and anionic poly-(glutamic acid) (PGA). DOX and IL-12 loaded in TNPs presented prolonged circulation in blood, efficient accumulation in tumors, and internalization in tumor cells. After that, DOX and IL-12 were co-released in the tumor microenvironment. The locally responsive property of TNPs could subsequently re-educate macrophages. More significantly, TNPs with no obvious side effects can remarkably inhibit the H22 tumor growth in vivo. A low dosage of loaded IL-12 in TNPs can effectively polarize macrophages toward the M1 phenotype to reduce tumor burden, further enhancing the antitumor efficacy. Our results suggest that the self-stabilized TNPs could be a secure and effective drug carrier for intravenous administration when deprived of protective agents.
    Keywords:  Chemo-immunotherapy; M1 phenotype; drug carrier; macrophages; microenvironment-responsive
    DOI:  https://doi.org/10.1016/j.ejpb.2022.07.002
  90. J Proteomics. 2022 Jul 11. pii: S1874-3919(22)00207-X. [Epub ahead of print] 104683
    Proteomic alterations in Paracoccidioides brasiliensis caused by exposure to curcumin.
    Olivia Basso Rocha, Kleber Santiago Freitas E Silva, Marcos Antônio Batista de Carvalho Junior, Dayane Moraes, Antônio Alonso, Laís Alonso, Lívia do Carmo Silva, Celia Maria Almeida Soares, Maristela Pereira.
      Paracoccidioides spp. are the etiological agent of paracoccidioidomycosis, a disease that causes skin lesions and affect the lungs and other organs. The current management of the disease is long and has several side effects that often lead the patient to give up the treatment, sequelae and even death. The search for new forms of treatment that minimize these drawbacks is very important. Thus, natural compounds are targets of great interest. Curcumin is one of the main components of the tubers of Curcuma longa, presenting medicinal effects well described in the literature, including the antifungal effect on Paracocidioides brasiliensis. Nevertheless, the mechanisms related to the antifungal effect of such compound are still unknown, so the objective of the present research is to understand what changes occur in the metabolism of P. brasiliensis after exposure to curcumin and to identify the main targets of the compound. Proteomic analysis as based on nanoUPLC-MS analysis and the functional classification of the identified proteins. The main metabolic processes that were being regulated were biologically validated through assays such as fluorescence microscopy, EPR and phagocytosis. Proteomic analysis revealed that curcumin regulates several metabolic processes of the fungus, including important pathways for energy production, such as the glycolytic pathway, beta oxidation and the glyoxylate cycle. Protein synthesis was down-regulated in fungi exposed to curcumin. The electron transport chain and the tricarboxylic acid cycle were also down-regulated, indicating that both the mitochondrial membrane and the mitochondrial activity were compromised. Plasma membrane and cell wall structure were altered following exposure to the compound. The fungus' ability to survive the phagocytosis process by alveolar macrophages was reduced. Thus, curcumin interferes with several metabolic pathways in the fungus that causes paracoccidioidomycosis. BIOLOGICAL SIGNIFICANCE: The challenges presented by the current treatment of paracoccidioidomycosis often contributing to patients' withdrawal from treatment, leading to sequelae or even death. Thus, the search for new treatment options against this disease is growing. The discovery that curcumin is active against Paracoccidioides was previously reported by our study group. Here, we clarify how the compound acts on the fungus causing its growth inhibition and decreased viability. Understanding the mechanisms of action of curcumin on P. brasiliensis elucidates how we can seek new alternatives and which metabolic pathways and molecular targets we should focus on in this incessant search to bring the patient a treatment with fewer adverse effects.
    Keywords:  Paracoccidioidomycosis, Curcuma longa; Proteomic profile
    DOI:  https://doi.org/10.1016/j.jprot.2022.104683
  91. Int J Nanomedicine. 2022 ;17 3013-3041
    Estrone-Conjugated PEGylated Liposome Co-Loaded Paclitaxel and Carboplatin Improve Anti-Tumor Efficacy in Ovarian Cancer and Reduce Acute Toxicity of Chemo-Drugs.
    Huan Tang, Yizhuo Xie, Ming Zhu, Juan Jia, Rui Liu, Yujia Shen, Yucui Zheng, Xin Guo, Dongfanghui Miao, Jin Pei.
       Purpose: Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages.
    Methods: ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP.
    Results: Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC50 values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs.
    Conclusion: ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.
    Keywords:  combination therapy; drug delivery system; estrogen receptor; liposome; ovarian cancer
    DOI:  https://doi.org/10.2147/IJN.S362263
  92. BMC Musculoskelet Disord. 2022 Jul 14. 23(1): 670
    Effect of chitosan and curcumin nanoparticles against skeletal muscle fibrosis at early regenerative stage of glycerol-injured rat muscles.
    Mohamed A A Mahdy, Mohamed A Akl, Fatma A Madkour.
       INTRODUCTION: Chitosan and curcumin are natural products that have a wide range of beneficial effects including wound healing. However, their high molecular weight and poor water solubility limit their applications.
    AIMS: Therefore, the current study aims to evaluate the effects of chitosan (Cs) and curcumin (Cn) nanoparticles (NPs) on fibrosis and regeneration of glycerol-injured muscle.
    METHODS: Muscle injury was induced by intramuscular injection of glycerol into the tibialis anterior muscle of rats. Cs-NPs and Cn-NPs were administered at different doses intraperitoneally after injury. Injured muscles were collected at day 7 after injury, and muscle fibrosis and regeneration were assessed.
    RESULTS: The present results revealed that Cs-NPs and Cn-NPs treatment significantly decreased fibrosis index and increased the average myotube diameter with shifting of the distribution of myotube diameters towards larger diameters in a dose-dependent manner. Immunohistochemical analysis revealed that Cs-NPs and Cn-NPs treatment significantly decreased the number of CD-68+ cells and Col-1+ area. Results showed that Cn-NPs had a higher protective effect, in the form of attenuating muscle fibrosis and inflammation, and enhancing muscle regeneration, than that of Cs-NPs.
    CONCLUSIONS: To our knowledge, this is the first study to document the effects of Cs-NPs in injured muscles. The results of study might be a novel approach to attenuate muscle fibrosis in humans using curcumin and chitosan nanoparticles.
    Keywords:  Chitosan; Curcumin; Fibrosis; Glycerol injury; Nanoparticles
    DOI:  https://doi.org/10.1186/s12891-022-05633-x
  93. J Ethnopharmacol. 2022 Jul 06. pii: S0378-8741(22)00560-8. [Epub ahead of print]296 115521
    Research on the progress of Traditional Chinese medicine components and preparations on histone deacetylase inhibitors - Like effects in the course of disease treatment.
    Yuxin Wei, Yuyan Guo, Shaowa Lv.
       ETHNOPHARMACOLOGICAL RELEVANCE: During the treatment of diseases, histone deacetylases (HDAC) may have side effects such as strong immune inhibition and drug resistance, which may lead to damage of heart, liver and kidney. Traditional Chinese medicine (TCM) is a valuable and unique resource in China, which has good efficacy and safety. At present, it has been found that Chinese herbal compounds and active ingredients can effectively inhibit the expression of HDAC. Moreover, pharmacological studies have shown that these TCMs have shown therapeutic effects in the treatment of cancer, cardiovascular and cerebrovascular diseases, orthopedic diseases and skin diseases.
    AIM OF THE REVIEW: This article reviews the mechanism of action of HDAC, and introduces the epigenetic correlation between TCM and HDAC. We expounded the histone deacetylase inhibitor (HDACi)-like inhibitory effect and clinical application of natural drugs, and summarized the research progress of TCM on HDAC in recent years.
    MATERIALS AND METHODS: We collected relevant information published before March 2022 by searching the literature in various online databases such as PubMed, CNKI, Wanfang Database, Elsevier, Web of Science and China Biomedical Database. Search terms include "HDAC" or "HDACi", as well as "herb" or "herbal ingredient".
    RESULTS: A large number of studies have proved that many TCMs and their chemical components have the effect of inhibiting HDAC activity, which is highly selective, acts on different HDAC subtypes, and plays a certain therapeutic effect in cancer, cardiovascular and cerebrovascular diseases, orthopedic diseases, skin diseases and other diseases by inhibiting the process of HDAC.
    DISCUSSION AND CONCLUSIONS: The review of this paper is helpful to understand and excavate the active components of TCM, further explore the role of plant drugs with HDACi-like effect in diseases, and provide ideas for the development of new HDACi.
    Keywords:  Cance; Cardiovascular and cerebrovascular diseases; Dermatosis; Epigenetics; HDAC; HDACi; Herb; Orthopedic diseases
    DOI:  https://doi.org/10.1016/j.jep.2022.115521
  94. Cell Mol Biol (Noisy-le-grand). 2022 Feb 04. 67(5): 151-156
    Nanoformulations of curcumin and quercetin with silver nanoparticles for inactivation of bacteria.
    Mehran Alavi, Nareen Arif Adulrahman, Azad Abduljabar Haleem, Ahmed Diyar Hussein Al-Râwanduzi, Ameer Khusro, Mohamed A Abdelgawad, Mohammed M Ghoneim, Gaber El-Saber Batiha, Danial Kahrizi, Fleming Martinez, Niranjan Koirala.
      Antibiotic resistance in pathogenic bacteria to various types of antibiotics has resulted in the necessity of new effective strategies to get around this problem. In recent investigations, metal or metal oxide nanoparticles specifically silver nanoparticles (AgNPs) have been employed successfully to hinder antibiotic-resistant Gram-negative and Gram-positive bacteria. However, AgNPs at high concentrations have cytotoxicity for eukaryotic cells which, application of other biocompatible materials particularly plant secondary metabolites of curcumin and quercetin to reduce cytotoxicity is a critical affair. These compounds may be used directly or indirectly to produce AgNPs. In this regard, modified NPs by curcumin and quercetin have shown an increased therapeutic effect and biocompatibility and biodegredibility properties. Therefore, here, recent advances and challenges about antibacterial and biocompatibility properties of nanoformulation of AgNPs with curcumin and quercetin are presented.
    DOI:  https://doi.org/10.14715/cmb/2021.67.5.21
  95. Mol Biol Rep. 2022 Jul 12.
    Therapeutic potential of autophagy activators and inhibitors in lung and breast cancer- a review.
    Priyanka Mudaliar, Apoorva Nalawade, Shine Devarajan, Jyotirmoi Aich.
      Autophagy is a cellular process that eliminates damaged components of cytoplasm via the lysosome. Autophagy supports cells and tissues to remain healthy by recycling old or damaged cellular organelles and proteins with new ones. The breakdown products that follow are directed into cellular metabolism, where they are utilized to produce energy as well as for maintaining homeostasis and stability of the genome. In many cancers, autophagy modulation carries out a dual role in cancer development and suppression. Autophagy suppresses the proliferation of cancer cells by bringing about cell death and limiting cancer cell development, although it also promotes tumorigenesis by encouraging cancer cell growth and formation. Nevertheless, autophagy's implication in cancer remains a paradox. While several autophagy activators, and inhibitors, such as SAH-EJ2, Gefitinib, Ampelopsin hydroxychloroquine and chloroquine, are utilized to regulate autophagy in chemoprevention, the exact intrinsic system of autophagy in cancer deserves further investigation. Despite improved treatment regimens, the incidence rate of both breast and lung cancer has grown, as has the number of recurrence cases. Hence, this review offers a wide overview of autophagy's underlying role in lung and breast cancer, particularly focusing on the various autophagy activators and inhibitors in both cancers, as well as the use of various organic compounds, regular drugs, and natural products in cancer prevention and treatment.
    Keywords:  Activators; Autophagy; Breast Cancer; Inhibitors; Lung Cancer
    DOI:  https://doi.org/10.1007/s11033-022-07711-8
  96. Iran J Allergy Asthma Immunol. 2022 Jun 18. 21(3): 313-321
    Eugenol: A New Option in Combination Therapy with Sorafenib for the Treatment of Undifferentiated Thyroid Cancer.
    Pedram Talezadeh Shirazi, Shirin Farjadian, Mohammad Hossein Dabbaghmanesh, Hossein Jonaidi, Ali Alavianmehr, Mehdi Kalani, Ladan Emadi.
      Thyroid cancer (TC) is the most common endocrine malignancy. Thyroidectomy and radiotherapy are common treatment modalities for patients with undifferentiated TC (UTC), and sorafenib is usually recommended to prevent a recurrence. However, malignant cells may evade chemotherapy-induced apoptosis, and combination therapy was developed to achieve better outcomes. This study investigated whether eugenol in combination with sorafenib was more effective than either substance individually in triggering apoptosis in the UTC. The IC50 of sorafenib and eugenol was determined in a UTC cell line (8305C) by MTT assay, and their synergistic effect in combination therapy was investigated. Flow cytometry was used to evaluate the rate of apoptosis in treated cells. To confirm that cell death occurred through apoptosis, immunoblotting was used to determine the relative cleavage of caspase-8 and caspase-9. The IC50 of sorafenib was 20 µM, and that of eugenol was 2100 µM. The sorafenib-eugenol combination (1:105) showed synergistic effects at concentrations equal to or less than their IC50. The rate of apoptosis induction was higher in cells treated with eugenol or the eugenol-sorafenib combination compared to sorafenib-treated cells. The relative intensity of cleaved/un cleaved forms of caspase-8 increased in eugenol-treated cells compared to sorafenib-treated cells.Sorafenib and eugenol at concentrations equal to or less than their IC50 had a synergistic effect in 8305C cells. The most potent apoptotic effect was achieved with sorafenib and eugenol at their IC50. Lower doses of sorafenib could be used with eugenol to improve its efficacy while reducing its side effects.
    Keywords:  Apoptosis; Drug synergism; Eugenol; Sorafenib; Thyroid neoplasms
    DOI:  https://doi.org/10.18502/ijaai.v21i3.9804
  97. Front Pharmacol. 2022 ;13 906038
    Differentiating Cannabis Products: Drugs, Food, and Supplements.
    Arash Salehi, Keely Puchalski, Yalda Shokoohinia, Behzad Zolfaghari, Sedigheh Asgary.
      "Hemp" refers to non-intoxicating, low delta-9 tetrahydrocannabinol (Δ9-THC) cultivars of Cannabis sativa L. "Marijuana" refers to cultivars with high levels of Δ9-THC, the primary psychoactive cannabinoid found in the plant and a federally controlled substance used for both recreational and therapeutic purposes. Although marijuana and hemp belong to the same genus and species, they differ in terms of chemical and genetic composition, production practices, product uses, and regulatory status. Hemp seed and hemp seed oil have been shown to have valuable nutritional capacity. Cannabidiol (CBD), a non-intoxicating phytocannabinoid with a wide therapeutic index and acceptable side effect profile, has demonstrated high medicinal potential in some conditions. Several countries and states have facilitated the use of THC-dominant medical cannabis for certain conditions, while other countries continue to ban all forms of cannabis regardless of cannabinoid profile or low psychoactive potential. Today, differentiating between hemp and marijuana in the laboratory is no longer a difficult process. Certain thin layer chromatography (TLC) methods can rapidly screen for cannabinoids, and several gas and liquid chromatography techniques have been developed for precise quantification of phytocannabinoids in plant extracts and biological samples. Geographic regulations and testing guidelines for cannabis continue to evolve. As they are improved and clarified, we can better employ the appropriate applications of this uniquely versatile plant from an informed scientific perspective.
    Keywords:  HEMP; cannabis; cbd; marijuana; thc
    DOI:  https://doi.org/10.3389/fphar.2022.906038
  98. Food Res Int. 2022 Aug;pii: S0963-9969(22)00598-1. [Epub ahead of print]158 111540
    A comprehensive review on bioavailability, safety and antidepressant potential of natural bioactive components from tea.
    Jie Shao, Yang Wei, Xinlin Wei.
      Depression is a global public health issue with high morbidity and mortality, which tends to cause fatigue, inability to concentrate, insomnia, and loss of appetite, especially represented by major depressive disorder (MDD). Pathologically, depression is associated with hyperactivity of hypothalamic-pituitaryadrenal (HPA) axis, inflammation, loss of monoaminergic system, and disturbance of gut microbiota. Epidemiological studies have shown that regular tea drinking can reduce the risk of depression. Tea bioactive compounds (L-theanine, catechin, tea pigment and GABA) can regulate depression by inhibiting hyperactive HPA axis, reducing the inflammatory response, restoring the monoaminergic system, inhibiting monoamine oxidase levels, increasing the enrichment of intestinal flora and promoting microbial-gut-brain axis activity. This review discusses the composition, structure, bioavailability and safety of bioactive components from tea, and focuses on exploring the possible pathways of tea bioactive compounds in the regulation of depression. In addition, the low bioavailability of natural bioactive compounds from tea limits the efficacy on depression. Emerging technologies (such as metabolomics, proteomics, and genomics) and nano-encapsulation can be utilized to improve the stability and bioavailability of tea active ingredients, and reduce the potential biotoxicity. The review provides a theoretical basis of utilization of tea active compounds for formulating the prevention and treatment of depression.
    Keywords:  Bioactive compounds; Bioavailbility; Depression; Gut microbiota; HPA axis; Imflammation; Tea
    DOI:  https://doi.org/10.1016/j.foodres.2022.111540
  99. Aliment Pharmacol Ther. 2022 Jul;56 Suppl 1 S38-S48
    Review article: Dietary management of coeliac disease.
    Anne R Lee.
      As the gluten-free diet is currently the only treatment for coeliac disease and one that needs to applied in the long term, this review aims to explore the various issues confronting an individual and discuss the importance of ongoing dietary management. The process of dietary counselling has shifted from one that focuses on just foods to avoid to one that evaluates the multiple life factors (social, cultural, environmental, biological) that affect the individual's food choices and dietary behaviour. The nutritional quality of a gluten-free diet continues to affect vitamin, mineral and weight status of individuals with coeliac disease. There are many barriers to dietary adherence including increased cost and limited availability of gluten-free products, as well as the negative impact on an individual's social domain of quality of life. Therefore, assessment, education and counselling by a coeliac specialist dietitian should be the cornerstone of dietary management.
    DOI:  https://doi.org/10.1111/apt.16974
  100. Biomaterials. 2022 Jul 08. pii: S0142-9612(22)00313-1. [Epub ahead of print]287 121673
    Vitamin C supramolecular hydrogel for enhanced cancer immunotherapy.
    Han Zhang, Kai Liu, Yimou Gong, Wenjun Zhu, Jiafei Zhu, Feng Pan, Yu Chao, Zhishen Xiao, Yanbin Liu, Xianwen Wang, Zhuang Liu, Yang Yang, Qian Chen.
      Vitamin C (VitC) has shown great promise to promote cancer immunotherapy, however, its high hydrophilicity makes it quickly excreted, leading to limited therapeutic efficiency even with frequent high-dose administration. Herein, we provide a pioneering report about the employment of VitC amphiphile self-assembled nanofiber hydrogels for enhanced cancer immunotherapy. Specifically, driven by hydrogen bonding and hydrophobic interactions, the synthesized VitC amphiphile, consisting of a hydrophilic VitC headgroup and a hydrophobic alkyl chain, could self-assemble into an injectable nanofiber hydrogel with self-healing properties. The formed VitC hydrogel not only serves as a reservoir for VitC but also acts as an effective delivery platform for stimulator of interferon genes (STING) agonist-4 (SA). Interestingly, the VitC hydrogel itself exhibits antitumor effects by upregulating genes related to interferon (IFN) signaling, apoptotic signaling and viral recognition and defense. Moreover, the SA-encapsulated VitC hydrogel (SA@VitC hydrogel) synergistically activated the immune system to inhibit the progression of both local and abscopal tumors.
    Keywords:  Cancer immunotherapy; Drug delivery; Self-assembly; Supramolecular hydrogel; Vitamin C
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121673
  101. Int J Biol Sci. 2022 ;18(9): 3636-3652
    Daidzein Synergizes with Gefitinib to Induce ROS/JNK/c-Jun Activation and Inhibit EGFR-STAT/AKT/ERK Pathways to enhance Lung Adenocarcinoma cells chemosensitivity.
    Thomas Gabriel Mhone, Ming-Cheng Chen, Chia-Hua Kuo, Tzu-Ching Shih, Chung-Min Yeh, Tso-Fu Wang, Ray-Jade Chen, Yu-Chun Chang, Wei-Wen Kuo, Chih-Yang Huang.
      Lung cancer is the major cause of cancer associated mortality. Mutations in EGFR have been implicated in lung cancer pathogenesis. Gefitinib (GF) is a RTKI (receptor tyrosine kinase inhibitor) first-choice drug for EGFR mutated advanced lung cancer. However, drug toxicity and cancer cell resistance lead to treatment failure. Consequently, new therapeutic strategies are urgently required. Therefore, this study was aimed at identifying tumor suppressive compounds that can synergistically improve Gefitinib chemosensitivity in the lung cancer treatment. Medicinal plants offer a vast platform for the development of novel anticancer agents. Daidzein (DZ) is an isoflavone compound extracted from soy plants and has been shown to possess many medicinal benefits. The anticancer potential of GF and DZ combination treatment was investigated using MTT, western blot, fluorescent microscopy imaging, flow cytometry and nude mice tumor xenograft techniques. Our results demonstrate that DZ synergistically induces c-Jun nuclear translocation through ROS/ASK1/JNK and downregulates EGFR-STAT/AKT/ERK pathways to activate apoptosis and a G0/G1 phase cell cycle blockade. In in-vivo, the combination treatment significantly suppressed A549 lung cancer cells tumor xenograft growth without noticeable toxicity. Daidzein supplements with current chemotherapeutic agents may well be an alternative strategy to improve the treatment efficacy of lung adenocarcinoma.
    Keywords:  Apoptosis; Chemosensitivity; Daidzein; ROS; Synergistic; c-Jun
    DOI:  https://doi.org/10.7150/ijbs.71870
  102. Int J Pharm. 2022 Jul 09. pii: S0378-5173(22)00561-0. [Epub ahead of print] 122006
    Design, Characterization and In Vivo Performance of Solid Lipid Nanoparticles (SLNs)-Loaded Mucoadhesive Buccal Tablets for Efficient Delivery of Lornoxicam in Experimental Inflammation.
    Moataz B Zewail, Gihan F Asaad, Salma M Swellam, Sama M Abd-Allah, Sahar K Hosny, Salma K Sallah, Jehan E Eissa, Salma S Mohamed, Walaa A El-Dakroury.
      Lornoxicam (LRX) is a potent nonsteroidal anti-inflammatory drug (NSAID) used extensively to manage pain and inflammatory conditions. However, the drug possesses poor aqueous solubility (i.e., BCS class II) and a short half-life (3-4h). Mucoadhesive buccal tablets containing LRX -loaded solid lipid nanoparticles (SLNs) were developed to enhance the drug solubility and bioavailability and achieve a controlled release pattern for a better anti-inflammatory effect. Different LRX-loaded SLNs were prepared using the hot homogenization /ultra-sonication technique and evaluated using size analysis and entrapment efficiency (EE%). Optimized LRX -loaded SLNs formulation showed particle size of 216± 7.4 nm, zeta potential of -27.3±4.6 mV, and entrapment efficiency of 92.56± 2.3 %. Dried LRX-loaded SLNs alongside mucoadhesive polymers blend (PVP K30 /HPMC K15) were compressed to prepare the mucoadhesive buccal tablets. The tablets showed proper physicochemical properties, good mucoadhesive strength, long mucoadhesive time, suitable pH surface, good swelling capacity, and controlled drug release profile. Furthermore, Fourier transform-infrared (FTIR) spectroscopy, Powder X-Ray diffraction (PXRD), and Scanning electron microscopy (SEM) studies were carried out. The in vivo anti-inflammatory effect of pure LRX, market LRX and optimized mucoadhesive buccal tablet of LRX -loaded SLNs (T3) against carrageenan-induced models were evaluated. T3 showed a significant and early anti-inflammatory response after 1 and 2 h (63.62 - 77.84 % inhibition) as well as an extended effect after 4 h as compared to pure and market LRX. In parallel, T3 showed the best amelioration of PGE2, COX2, and TNF-α serum levels after 4 h of carrageenan injection.
    Keywords:  Lornoxicam; buccal tablets; mucoadhesive; solid lipid nanoparticles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122006
  103. Methods Mol Biol. 2022 ;2473 385-396
    Generation of Hybrid Extracellular Vesicles by Fusion with Functionalized Liposomes.
    Max Piffoux, Amanda Karine Andriola Silva, Florence Gazeau, David Tareste.
      Extracellular vesicles (EVs) and liposomes are natural and synthetic drug delivery systems, respectively, with their own advantages and limitations. EV/liposome fusion allows the generation of hybrid EVs that benefit from both the versatility of liposomes (tunable lipid and protein composition, surface functionalization, lumen loading, etc.) and the functionality of EVs (natural targeting properties, low immunogenicity, anti-inflammatory properties, etc.). Here, we describe the methods to (1) produce EVs and liposomes, (2) induce and monitor their fusion, and (3) purify the obtained hybrid EVs.
    Keywords:  Extracellular vesicles; Fluorescence resonance energy transfer; Liposomes; Membrane fusion; Polyethylene glycol; Ultracentrifugation
    DOI:  https://doi.org/10.1007/978-1-0716-2209-4_24
  104. Nutrition. 2022 Jun 03. pii: S0899-9007(22)00177-0. [Epub ahead of print]102 111764
    Review Effects of time-restricted feeding with different feeding windows on metabolic health: A systematic review of human studies.
    Zhibo Xie, Zhangyuting He, Yuqian Ye, Yilei Mao.
      Time-restricted feeding (TRF), a feasible form of intermittent fasting, has been proven to benefit metabolic health in animal models and humans. TRF restricts the daily feeding window to 3 to 12 h for eating ad libitum, with fasting for the rest of the day. To our knowledge, specific guidance on the appropriate time period for eating during TRF has not yet been promoted. Therefore, the aim of the present review was to summarize the current literature on the effects of TRF with different eating windows in humans and compare their effects on metabolic health-related markers. Early TRF (which restricts food intake during the early period of the day) and delayed TRF (which restricts food intake during the later period of the day) studies have shown that both TRF regimens improve metabolic health in terms of reducing energy intake, decreasing body weight, improving insulin sensitivity, reducing blood pressure, and reducing oxidative stress. Differences between the consequences of early and delayed TRF were found, including differences in changes in blood lipid factors. These preliminary findings may help to provide guidance for choosing suitable eating windows during TRF. Future studies with rigorous designs and direct comparisons between the effects of TRF regimens with different eating windows on metabolic health markers are still needed.
    Keywords:  Cadian rhythm; Feeding window; Metabolic health; Time-restricted feeding
    DOI:  https://doi.org/10.1016/j.nut.2022.111764
  105. Redox Biol. 2022 08;pii: S2213-2317(22)00158-6. [Epub ahead of print]54 102386
    Vitamin A aldehyde-taurine adducts function in photoreceptor cells.
    Hye Jin Kim, Jin Zhao, Janet R Sparrow.
      To facilitate the movement of retinoids through the visual cycle and to limit nonspecific chemical reaction, multiple mechanisms are utilized to handle these molecules when not contained within the binding pocket of opsin. Vitamin A aldehyde is sequestered by reversible Schiff base formation with phosphatidylethanolamine (PE) and subsequently undergoes NADPH-dependent reduction. Otherwise inefficient handling of retinaldehyde can lead to the formation of fluorescent di-retinal compounds within the outer segments of photoreceptor cells. These bisretinoid fluorophores initiate photooxidative processes having adverse consequences for retina. Various carrier proteins confer water solubility and maintain the 11-cis-retinoid configuration. Mechanisms for sequestration of retinoid include the formation of a reversible Schiff base between retinaldehyde and taurine (A1-taurine, A1T), the most abundant amino acid in photoreceptor cells. Here we have undertaken to examine the effects of taurine depletion using the transport inhibitors guanidinoethyl sulfonate (GES) and β-alanine. Oral treatment of BALB/cJ mice with β-alanine reduced ocular A1T and the mice exhibited significantly lower scotopic and photopic a-wave amplitudes. As a secondary effect of retinal degeneration, A1T was not detected and taurine was significantly reduced in mice carrying a P23H opsin mutation. The thinning of ONL that is indicative of reduced photoreceptor cell viability in albino Abca4-/- mice was more pronounced in β-alanine treated mice. Treatment of agouti and albino Abca4-/- mice with β-alanine and GES was associated with reduced bisretinoid measured chromatographically. Consistent with a reduction in carbonyl scavenging activity by taurine, methylglyoxal-adducts were also increased in the presence of β-alanine. Taken together these findings support the postulate that A1T serves as a reservoir of vitamin A aldehyde, with diminished A1T explaining reduced photoreceptor light-sensitivity, accentuated ONL thinning in Abca4-/- mice and attenuated bisretinoid formation.
    Keywords:  Bisretinoids; Retina; Retinaldehyde; Taurine; Vitamin A
    DOI:  https://doi.org/10.1016/j.redox.2022.102386
  106. Semin Cancer Biol. 2022 Jul 09. pii: S1044-579X(22)00175-4. [Epub ahead of print]
    'Warburg effect' controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives.
    J Pouysségur, Marchiq, S K Parks, J Durivault, M Ždralević, M Vucetic.
      The evolutionary pressure for life transitioning from extended periods of hypoxia to an increasingly oxygenated atmosphere initiated drastic selections for a variety of biochemical pathways supporting the robust life currently present on the planet. First, we discuss how fermentative glycolysis, a primitive metabolic pathway present at the emergence of life, is instrumental for the rapid growth of cancer, regenerating tissues, immune cells but also bacteria and viruses during infections. The 'Warburg effect', activated via Myc and HIF-1 in response to growth factors and hypoxia, is an essential metabolic and energetic pathway which satisfies nutritional and energetic demands required for rapid genome replication. Second, we present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via monocarboxylate transporting proteins (i.e. MCT1/4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumour microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. Third, we revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumours (melanoma B16-F10, human adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumour growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1/4 suppressed glycolysis, mTORC1, and tumour growth as a result of intracellular acidosis. Finally, we briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future cancer clinical applications.
    Keywords:  BASIGIN; CRISPR-cas9; GPI; LDHA; LDHB; MCT1; MCT4; OXPHOS; Warburg effect; acidosis; bacteria; cancer; fermentative glycolysis; glycogen; immune evasion; immunity; lactate; pathogens; viruses
    DOI:  https://doi.org/10.1016/j.semcancer.2022.07.004
  107. Cell Metab. 2022 Jul 07. pii: S1550-4131(22)00228-5. [Epub ahead of print]
    Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells.
    Ilaria Elia, Jared H Rowe, Sheila Johnson, Shakchhi Joshi, Giulia Notarangelo, Kiran Kurmi, Sarah Weiss, Gordon J Freeman, Arlene H Sharpe, Marcia C Haigis.
      The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.
    Keywords:  T cells; cancer metabolism; lactate; pyruvate; succinate; tumor immunity
    DOI:  https://doi.org/10.1016/j.cmet.2022.06.008
  108. Eur J Nutr. 2022 Jul 13.
    Effect of curcumin supplementation on exercise-induced muscle damage: a narrative review.
    K Nanavati, K Rutherfurd-Markwick, S J Lee, N C Bishop, A Ali.
      Curcumin, a natural polyphenol extracted from turmeric, is a potent antioxidant and anti-inflammatory agent. In the past few decades, curcumin's ability to impact chronic inflammatory conditions such as metabolic syndrome, arthritis, and cancer has been widely researched, along with growing interest in understanding its role in exercise-induced muscle damage (EIMD). EIMD impacts individuals differently depending on the type (resistance exercise, high-intensity interval training, and running), intensity, and duration of the exercise. Exercise disrupts the muscles' ultrastructure, raises inflammatory cytokine levels, and can cause swelling in the affected limb, a reduction in range of motion (ROM), and a reduction in muscular force-producing capacity. This review focuses on the metabolism, pharmacokinetics of various brands of curcumin supplements, and the effect of curcumin supplementation on EIMD regarding muscle soreness, activity of creatine kinase (CK), and production of inflammatory markers. Curcumin supplementation in the dose range of 90-5000 mg/day can decrease the subjective perception of muscle pain intensity, increase antioxidant capacity, and reduce CK activity, which reduces muscle damage when consumed close to exercise. Consumption of curcumin also improves muscle performance and has an anti-inflammatory effect, downregulating the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-8. Curcumin may also improve oxidative capacity without hampering training adaptations in untrained and recreationally active individuals. The optimal curcumin dose to ameliorate EIMD is challenging to assess as its effect depends on the curcumin concentration in the supplement and its bioavailability.
    Keywords:  Antioxidant; Curcumin; Inflammation; Muscle soreness; Oxidative stress; Pharmacokinetics
    DOI:  https://doi.org/10.1007/s00394-022-02943-7
  109. J Mater Chem B. 2022 Jul 12.
    Targeted intelligent mesoporous polydopamine nanosystems for multimodal synergistic tumor treatment.
    Jiaxin Yang, Weinan Zeng, Xiaoxue Fu, Lu Chen, Xiaojuan Yu, Ping Xu, Wenyan Huang, Feng Leng, Chao Yu, Zhangyou Yang.
      Developing intelligent responsive platforms to carry out high-performance therapy is of great interest for the treatment of tumors and their metastases. However, effective drug loading, activity maintenance, off-target leakage, and response to collaborative therapy remain great challenges. Herein, a targeted intelligent responsive mesoporous polydopamine (MPDA) nanosystem was reported for use in gene-mediated photochemotherapy for synergistic tumor treatment. First, the MPDA was surface modified to maintain a positive charge near the surface and to impart active targeting. Then, gambogic acid (GA) was encapsulated in the MPDA, solidified by phase change materials (PCMs), and finally loaded with siRNA by electrostatic interactions to obtain the smart nanodelivery system (PPMD@GA/si). In vitro and in vivo experiments showed that it not only effectively avoids siRNA inactivation and accidental release of GA, but also possesses potential for targeted accumulation to tumor tissue and mild-temperature photothermal therapy and chemotherapy via near infrared (NIR) radiation. Additionally, the release of siRNA could also effectively inhibit tumor invasion and metastasis to realize multimodal synergistic therapy. Overall, our studies provide a promising idea for synergistic tumor and metastasis treatment based on vector construction.
    DOI:  https://doi.org/10.1039/d2tb00973k
  110. Evid Based Complement Alternat Med. 2022 ;2022 5649156
    Investigating Polyphenol Nanoformulations for Therapeutic Targets against Diabetes Mellitus.
    Fahadul Islam, Jannatul Fardous Khadija, Md Rezaul Islam, Sheikh Shohag, Saikat Mitra, Saad Alghamdi, Ahmad O Babalghith, Abdulrahman Theyab, Mohammad Tauhidur Rahman, Aklima Akter, Abdullah Al Mamun, Fahad A Alhumaydhi, Talha Bin Emran.
      Diabetes mellitus (DM) is a fatal metabolic disorder, and its prevalence has escalated in recent decades to a greater extent. Since the incidence and severity of the disease are constantly increasing, plenty of therapeutic approaches are being considered as a promising solution. Many dietary polyphenols have been reported to be effective against diabetes along with its accompanying vascular consequences by targeting multiple therapeutic targets. Additionally, the biocompatibility of these polyphenols raises questions about their use as pharmacological mediators. Nevertheless, the pharmacokinetic and biopharmaceutical properties of these polyphenols limit their clinical benefit as therapeutics. Pharmaceutical industries have attempted to improve compliance and therapeutic effects. However, nanotechnological approaches to overcome the pharmacokinetic and biopharmaceutical barriers associated with polyphenols as antidiabetic medications have been shown to be effective to improve clinical compliance and efficacy. Therefore, this review highlighted a comprehensive and up-to-date assessment of polyphenol nanoformulations in the treatment of diabetes and vascular consequences.
    DOI:  https://doi.org/10.1155/2022/5649156
  111. ACS Appl Mater Interfaces. 2022 Jul 14.
    Reactive Oxygen Species Scavenging Functional Hydrogel Delivers Procyanidins for the Treatment of Traumatic Brain Injury in Mice.
    Xuyang Huang, Yongqing Ye, Jianyong Zhang, Xuefeng Zhang, Hongwei Ma, Yongkang Zhang, Xianhua Fu, JiaJia Tang, Ning Jiang, Yuhan Han, Hongmei Liu, Honglin Chen.
      Traumatic brain injury (TBI) is accompanied by the overload of reactive oxygen species (ROS), which can result in secondary brain injury. Although procyanidins (PCs) have a powerful free radical scavenging capability and have been widely studied in the treatment of TBI, conventional systemic drug therapy cannot make the drug reach the targeted area in the early stage of TBI and will cause systemic side effects because of the presence of the blood-brain barrier (BBB). To address this tissue, we designed and fabricated a ROS-scavenging functional hydrogel loaded PC (GelMA-PPS/PC) to deliver the drug by responding to the traumatic microenvironment. In situ injection of the GelMA-PPS/PC hydrogel effectively avoided the BBB and was directly applied to the surface of brain tissue to target the traumatic area. Hydrophobic poly(propylene sulfide)60 (PPS60), an ROS quencher and H2O2-responsive substance, was covalently bound to GelMA and exposed in response to the trauma microenvironment. At the same time, the H2O2 response of PPS60 further caused the structure of the hydrogel to degrade and release the encapsulated PC. Then PC could regulate the oxidative stress response in the cells and synergistically deplete ROS to play a neurotrophic protective role. This work suggests a novel method for the treatment of secondary brain injury by inhibiting the oxidative stress response after TBI.
    Keywords:  ROS scavenger; brain protection; functional hydrogel; procyanidins; traumatic brain injury
    DOI:  https://doi.org/10.1021/acsami.2c04930
  112. Curr Drug Deliv. 2022 Jul 14.
    Targeted Delivery of Doxorubicin as a Potential Chemotherapeutic Agent.
    Tanmay S Markandeywar, Raj Kumar Narang, Dilpreet Singh, Vineet Kumar Rai.
      Cancer is the world's fifth-most significant cause of related death, and the second most commonly diagnosed malignancy among women and men. Some of its types like brain cancer, colon cancer, and breast cancer are threatened and considered fatal. These cancers are more prevalent in developed and underdeveloped countries. Still, doxorubicin is considered a gold standard drug and the only molecule which has been used in multiple types of cancer. However, the toxicity and biopharmaceutical hindrances like poor solubility, poor permeability, and high in vivo fate of drug cause low systematic circulation. The creation of a multifunctional nanocarrier for targeted medication delivery that can transport and accumulate drugs at cancer sites should help to lessen the likelihood of side effects. These nanocarriers improve the targetability of infected tissue and improve the therapeutic circulation of drugs. Hence, the present review focused on the improved targetability of doxorubicin using different nanocarriers and its possible outcomes in different types of cancer. Moreover, the prior art also discussed various challenges and future prospects of improved doxorubicin delivery and its therapeutic outcomes.
    Keywords:  Doxorubicin; brain cancer; breast cancer; cervical cancer; colorectal cancer; prostate cancer
    DOI:  https://doi.org/10.2174/1567201819666220714101952
  113. Comput Biol Med. 2022 Jul 06. pii: S0010-4825(22)00580-7. [Epub ahead of print]148 105819
    Exploration and validation of Taraxacum mongolicum anti-cancer effect.
    Jumin Xie, Ruxi Chen, Qingzhi Wang, Hui Mao.
      Taraxacum mongolicum gained a lot of concern and was applied in 93 formulas in China due to its fame as a traditional Chinese medicine. The earliest recorded application of Taraxacum mongolicum was traced back to the Han dynasty. Generations of doctors boosted the usage and enriched the pharmacological mechanism. Clinical application of the Taraxacum mongolicum is flourishing as it treats multiple diseases. This study aims to explore the anti-cancer effect, retrieve the active ingredients and screen the key targets of Taraxacum mongolicum in cancer therapy. We collected and evaluated 10 key active compounds to investigate the anti-cancer effect via 69 significant targets and a variety of biological processes and pathways. Gene Ontology (GO) enrichment analysis uncovered targets associated with protein phosphorylation, cell proliferation and apoptotic processes via regulation of kinases, ATP and enzyme binding activities. Half of the top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were directly involved in cancer. Based on standard selection criteria, seven hub targets were obtained. These targets functioned through distinct patterns and pathways in realizing the anti-cancer effect. Molecular docking was conducted to validate the potential combination between compounds and hub targets to explore the pharmacological mechanism of key compounds in Taraxacum mongolicum against cancer. In summary, our findings indicate that the famous and widely used Chinese herb, Taraxacum mongolicum, shows good anti-cancer effect through its active compounds, targeted genes, and multiple involved biological processes. The results may provide a theoretical basis for subsequent experimental validation and drug development of Taraxacum mongolicum extract against cancer.
    Keywords:  Anti-cancer; Molecular docking; Network pharmacology; Taraxacum mongolicum
    DOI:  https://doi.org/10.1016/j.compbiomed.2022.105819
  114. Cell Mol Biol (Noisy-le-grand). 2022 Feb 27. 67(6): 200-212
    Gene Expression of Antioxidant Metabolic Enzymes in Grape Extracts.
    Huitian Cai, Yi Zhang, Zhehan Qiu, Peihuan Luo.
      Fruit can use its structural characteristics to stabilize the excess electrons of free radicals and prevent cell aging, which is the main source of antioxidants supplementation. In the current study, the expression of antioxidant metabolic genes was evaluated in fruit extract. Seventy mice were divided into one control group and six experimental groups. Six experimental groups were fed 0.1g of grape extract daily for 3, 7, 10, 14, 21, 24 and 30 days, respectively. The antioxidant activity of fruit extract was tested by antioxidant metabolic enzyme gene expression in the liver and kidney of different experimental groups. The results showed that grape extract could effectively enhance SOD activity, LPL relative expression and FAS relative expression in mice liver tissue; grape extract could effectively increase SOD relative expression, TrxR2 relative expression and CAT relative expression in mice kidney tissue; grape extract could effectively reduce MDA activity in mice liver tissue, and increase and decrease the extent of MDA activity and the duration of feeding in mice. The proportion of fruit extracts showed that fruit extracts could effectively improve the antioxidant performance of the body.
    DOI:  https://doi.org/10.14715/cmb/2021.67.6.27
  115. J Photochem Photobiol B. 2022 Jun 17. pii: S1011-1344(22)00114-2. [Epub ahead of print]234 112500
    Metallated phthalocyanines and their hydrophilic derivatives for multi-targeted oncological photodynamic therapy.
    Photodynamic Therapy Study Group
       BACKGROUND AND AIM: A photosensitizer (PS) delivery and comprehensive tumor targeting platform was developed that is centered on the photosensitization of key pharmacological targets in solid tumors (cancer cells, tumor vascular endothelium, and cellular and non-cellular components of the tumor microenvironment) before photodynamic therapy (PDT). Interstitially targeted liposomes (ITLs) encapsulating zinc phthalocyanine (ZnPC) and aluminum phthalocyanine (AlPC) were formulated for passive targeting of the tumor microenvironment. In previous work it was established that the PEGylated ITLs were taken up by cultured cholangiocarcinoma cells. The aim of this study was to verify previous results in cancer cells and to determine whether the ITLs can also be used to photosensitize cells in the tumor microenvironment and vasculature. Following positive results, rudimentary in vitro and in vivo experiments were performed with ZnPC-ITLs and AlPC-ITLs as well as their water-soluble tetrasulfonated derivatives (ZnPCS4 and AlPCS4) to assemble a research dossier and bring this platform closer to clinical transition.
    METHODS: Flow cytometry and confocal microscopy were employed to determine ITL uptake and PS distribution in cholangiocarcinoma (SK-ChA-1) cells, endothelial cells (HUVECs), fibroblasts (NIH-3T3), and macrophages (RAW 264.7). Uptake of ITLs by endothelial cells was verified under flow conditions in a flow chamber. Dark toxicity and PDT efficacy were determined by cell viability assays, while the mode of cell death and cell cycle arrest were assayed by flow cytometry. In vivo systemic toxicity was assessed in zebrafish and chicken embryos, whereas skin phototoxicity was determined in BALB/c nude mice. A PDT efficacy pilot was conducted in BALB/c nude mice bearing human triple-negative breast cancer (MDA-MB-231) xenografts.
    RESULTS: The key findings were that (1) photodynamically active PSs (i.e., all except ZnPCS4) were able to effectively photosensitize cancer cells and non-cancerous cells; (2) following PDT, photodynamically active PSs were highly toxic-to-potent as per anti-cancer compound classification; (3) the photodynamically active PSs did not elicit notable systemic toxicity in zebrafish and chicken embryos; (4) ITL-delivered ZnPC and ZnPCS4 were associated with skin phototoxicity, while the aluminum-containing PSs did not exert detectable skin phototoxicity; and (5) ITL-delivered ZnPC and AlPC were equally effective in their tumor-killing capacity in human tumor breast cancer xenografts and superior to other non-phthalocyanine PSs when appraised on a per mole administered dose basis.
    CONCLUSIONS: AlPC(S4) are the safest and most effective PSs to integrate into the comprehensive tumor targeting and PS delivery platform. Pending further in vivo validation, these third-generation PSs may be used for multi-compartmental tumor photosensitization.
    Keywords:  In vitro pharmacokinetics; Interstitially targeted liposomes; Mode of cell death; Mouse xenograft tumor model; Pharmacodynamics; Photonanomedicine; Skin phototoxicity; Therapeutic efficacy; Toxicity
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112500
  116. Food Res Int. 2022 Aug;pii: S0963-9969(22)00614-7. [Epub ahead of print]158 111556
    Bioactive potential of beetroot (Beta vulgaris).
    Sneh Punia Bangar, Nitya Sharma, Nikita Sanwal, Jose M Lorenzo, J K Sahu.
      Beetroot (Beta vulgaris) is the most well-known and commonly cultivated fruit from the Chenopodiaceae family. Beetroot is a rich source of nutrients including vitamins (B complex and C), minerals, fibre, proteins, and a variety of bioactive phenolic substances, which are chiefly composed of betalains, and other components possessing antioxidant activity, such as coumarins, carotenoids, sesquiterpenoids, triterpenes, and flavonoids (astragalin, tiliroside, rhamnocitrin, kaempferol, rhamnetin). Beetroot and its value-added products provide a variety of health advantages and may help prevent and manage various ailments and diseases due to bioactive components. Beetroot's phytochemical diversity makes them potential sources of nutraceutical chemicals that can be used to build functional foods. Pharmacologically, beetroot has the potential to be an antioxidant, antimicrobial, anticancerous, hypocholesterolemic, and anti-inflammatory agent. In a comprehensive analysis, this review first provides an overview of the bioactive compounds present in beetroot and its parts, followed by a specific description of the current evidence on this bioactive potential of beetroot and its parts, highlighting the biochemical mechanisms involved. Additionally, the factors affecting the concentration and activity of the beetroot bioactives and the best possible method to conserve its bioactivity has also been discussed in this review.
    Keywords:  Beetroot bioactive compunds; Beetroot bioactivities; Betalains; Nitrates; ROS scavenging
    DOI:  https://doi.org/10.1016/j.foodres.2022.111556
  117. Light Sci Appl. 2022 Jul 13. 11(1): 222
    Nanocomposites based on lanthanide-doped upconversion nanoparticles: diverse designs and applications.
    Kaimin Du, Jing Feng, Xuan Gao, Hongjie Zhang.
      Lanthanide-doped upconversion nanoparticles (UCNPs) have aroused extraordinary interest due to the unique physical and chemical properties. Combining UCNPs with other functional materials to construct nanocomposites and achieve synergistic effect abound recently, and the resulting nanocomposites have shown great potentials in various fields based on the specific design and components. This review presents a summary of diverse designs and synthesis strategies of UCNPs-based nanocomposites, including self-assembly, in-situ growth and epitaxial growth, as well as the emerging applications in bioimaging, cancer treatments, anti-counterfeiting, and photocatalytic fields. We then discuss the challenges, opportunities, and development tendency for developing UCNPs-based nanocomposites.
    DOI:  https://doi.org/10.1038/s41377-022-00871-z
  118. Cell Death Dis. 2022 Jul 12. 13(7): 603
    Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR.
    Boah Lee, Seung Ju Park, Seulgi Lee, Jinwook Lee, Eunbeol Lee, Eun-Seon Yoo, Won-Suk Chung, Jong-Woo Sohn, Byung-Chul Oh, Seyun Kim.
      Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-022-05039-6
  119. Colloids Surf B Biointerfaces. 2022 Jul 07. pii: S0927-7765(22)00361-7. [Epub ahead of print]217 112678
    Improving the oral delivery of benznidazole nanoparticles by optimizing the formulation parameters through a design of experiment and optimization strategy.
    Eva C Arrua, Olga Hartwig, Brigitta Loretz, Héctor Goicoechea, Xabier Murgia, Claus-Michael Lehr, Claudio J Salomon.
      Chagas disease is a neglected tropical disease affecting the American continent and also some regions of Europe. Benznidazole, approved by FDA, is a drug of choice but its poor aqueous solubility may lead to a low bioavailability and efficacy. Therefore, the aim of this study was to formulate nanoparticles of benznidazole for improving its solubility, dissolution and permeability. A Plackett-Burman design was applied to identify the effect of 5 factors over 4 responses. Then, a Central Composite design was applied to estimate the values of the most important factors leading to the best compromise between highest nanoprecipitation efficiency, drug solubility and lower particle size. The optimized nanoparticles were evaluated for in vitro drug release in biorelevant media, stability studies and transmission electron microscopy. Biocompatibility and permeability of nanoparticles were evaluated on the Caco-2 cell line. The findings of the optimization process indicated that concentration of drug and stabilizer influenced significantly the particle size while concentration of stabilizer and organic/water phase volume ratio mainly influenced the drug solubility. Stability studies suggested that benznidazole nanoparticles were stable after 12 months at different temperatures. Minimal interactions of those nanoparticles and mucin glycoproteins suggested favorable properties to address the intestinal mucus barrier. Cell viability studies confirmed the safety profile of the optimized formulation and showed an increased permeation through the Caco-2 cells. Thus, this study confirmed the suitability of the design of experiment and optimization approach to elucidate critical parameters influencing the quality of benznidazole nanoparticles, which could lead to a more efficient management of Chagas disease by oral route.
    Keywords:  Benznidazole; Design of experiment and optimization; Mucus interactions; Nanoparticles; Stabilizer
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112678
  120. Trends Biotechnol. 2022 Jul 11. pii: S0167-7799(22)00147-0. [Epub ahead of print]
    Immunostimulation in experimental gas plasma therapy for breast cancer.
    Sander Bekeschus.
      Gas plasma is a partially ionized gas operated at body temperature, expelling various reactive oxygen species (ROS) in chorus. While the technology's anticancer potential is generally appreciated, exciting progress in experimental gas plasma therapy for breast cancer has been made recently, particularly in empowering anticancer immunity.
    Keywords:  antitumor immunity; cold physical plasma; combination therapy; plasma oncology; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.tibtech.2022.06.007
  121. Crit Rev Food Sci Nutr. 2022 Jul 11. 1-55
    Underutilized green leafy vegetables: frontier in fortified food development and nutrition.
    Tanmay Sarkar, Molla Salauddin, Sarita Roy, Runu Chakraborty, Maksim Rebezov, Mohammad Ali Shariati, Muthu Thiruvengadam, Kannan R R Rengasamy.
      From the ancient period, Green leafy vegetables (GLV) are part of the daily diet and were believed to have several health beneficial properties. Later it has been proved that GLV has outstanding nutritional value and can be used for medicinal benefits. GLV is particularly rich in minerals like iron, calcium, and zinc. These are also rich in vitamins like beta carotene, vitamin E, K, B and vitamin C. In addition, some anti-nutritional elements in GLV can be reduced if it is grown properly and processed properly before consumption. Tropical countries have a wide variety of these green plants such as Red Spinach, Amaranth, Malabar Spinach, Taro Leaf, Fenugreek leaf, Bengal Gram Leaves, Radish Leaves, Mustard Leaves, and many more. This review focuses on listing this wide range of GLVs (in total 54 underutilized GLVs) and their compositions in a comparative manner. GLV also possesses medicinal activities due to its rich bioactive and nutritional potential. Different processing techniques may alter the nutritional and bioactive potential of the GLVs significantly. The GLVs have been considered a food fortification agent, though not explored widely. All of these findings suggest that increasing GLV consumption could provide nutritional requirements necessary for proper growth as well as adequate protection against diseases caused by malnutrition.
    Keywords:  Bioactive compounds; health benefits; nutritional and anti-nutritional factors; processing techniques
    DOI:  https://doi.org/10.1080/10408398.2022.2095555
  122. Drug Dev Ind Pharm. 2022 Jul 14. 1-31
    In vitro and in vivo activity of thermosensitive liposomes loaded with doxorubicin and cisplatin.
    Hamzah Maswadeh, Arif Khan, Mohammed S Alorainy, Naser A Al-Wabel, Costas Demetzos.
      Thermosensitive liposomes loaded with cisplatin and doxorubicin composed of DPPC, DSPC, and DPPE-PEG5000 with different ratios were prepared by thin film hydration method. The Differential Scanning Calorimetry (DSC) curves showed that the liposomes composed of DPPC-DSPC-DPPE-PEG5000 with phospholipid ratio 95:5:0.05 w/w were a suitable formulation as thermosensitive liposomes with a DSC peak at 42.1 °C. The effect of doxorubicin and cisplatin encapsulated non-thermosensitive and thermosensitive liposomes on cellular proliferation and IC50 in SKBR3 & MDA-MB-231 breast cancer and PC-3 & LNcaP prostate cancer cell lines was investigated. The results showed that doxorubicin loaded into thermosensitive liposomes showed 20-fold decrease in the IC50 at 42 °C while comparing it with the same at 37 °C. Also, the results showed a more than 35-fold and 12-fold decrease in the IC50 of cisplatin thermosensitive liposomes at 42 °C, while compared with free cisplatin and cisplatin thermosensitive liposomes at any temperature. The in vivo results showed that the effect of doxorubicin encapsulated thermosensitive liposomes at hyperthermic conditions during the treatment as the tumor growth inhibition was measured 1.5-fold higher than any of the liposomal formulations of doxorubicin. It was also noticed that the tumor volume reduced to 150 mm3 in doxorubicin thermosensitive liposomes (G8) after 3 weeks during the treatment, but increased to 196 mm3 after 4 weeks. The Kaplan-Meir curve showed the 100% survival of the animals from G8 (thermosensitive liposomes containing doxorubicin plus hyperthermia) after 12 weeks. The flow cytometry data revealed more than 25% apoptotic cells and 6.25% necrotic cells in the tumor cells from the tissues of the G8 group of the animals. The results clearly indicate the superior efficacy of doxorubicin and cisplatin containing thermosensitive liposomes treatment during hyperthermia.
    Keywords:  Breast cancer; Cisplatin; Doxorubicin; Fibrosarcoma; Prostate cancer; Thermosensitive liposomes
    DOI:  https://doi.org/10.1080/03639045.2022.2102648
  123. Transl Lung Cancer Res. 2022 Jun;11(6): 1185-1198
    Comparative characteristics of small cell lung cancer and Ewing's sarcoma: a narrative review.
    Gerhard Hamilton.
       Background and Objective: Small cell lung cancer (SCLC) and Ewing's sarcoma (ES) at the disseminated stage are not amenable to therapy and have a dismal prognosis with low survival rates. Despite representing different tumor entities, treatment for both malignancies relies on cytotoxic chemotherapy that has not considerably changed for the past decades. The genomic background has been extensively studied and found to comprise inactivation of p53 and RB1 in case of SCLC and EWSR1/FLI1 rearrangement in case of ES resulting in aggressive tumors in adults with heavy tobacco consumption and as bone tumor in juveniles, respectively. New therapeutic modalities are urgently needed to improve the outcomes of both tumor entities, especially in patients with metastatic disease or recurrences. This review summarizes the common cell biologic and clinical characteristics of difficult-to-treat SCLC and ES and discusses their refractoriness and options to improve the therapeutic efficacy.
    Methods: PubMed and Euro PMC were searched from January 1st, 2012 to January 16th, 2022 using the following key words: "SCLC", "Ewing´s sarcoma", "Genomics" and "Chemoresistance" as well as own work.
    Key Content and Findings: Therapy of SCLC and ES involves the use of undirected cytotoxic drugs in multimodal chemotherapy and administration of topotecan for 2nd line SCLC regimens. Despite highly aggressive chemotherapies, outcomes are dismal for patients with disseminated tumors. A host of unrelated drugs and targeted therapeutics have failed to result in progress for the patients and the underlying mechanisms of chemoresistance are still not clear. Identification of chemoresistance-reversing modulators in vitro and patient-derived xenografts of SCLC and ES has not translated into new therapies.
    Conclusions: The global chemoresistance of SCLC and ES may be explained by physiological resistance at the tumor level and formation of larger spheroids that contain quiescent and hypoxic tumor cells in regions that occlude therapeutics. This type of chemoresistance is difficult to overcome and prevent the accumulation of effective drug concentration at the tumor cell level to a significant degree leaving therapeutic interventions of any kind ineffective.
    Keywords:  Ewing’s sarcoma (ES); Small cell lung cancer (SCLC); chemoresistance; spheroids
    DOI:  https://doi.org/10.21037/tlcr-22-58
  124. PeerJ. 2022 ;10 e13606
    Sea urchins: an update on their pharmacological properties.
    Dulce María Moreno-García, Monica Salas-Rojas, Eduardo Fernández-Martínez, Ma Del Rocío López-Cuellar, Carolina G Sosa-Gutierrez, Armando Peláez-Acero, Nallely Rivero-Perez, Adrian Zaragoza-Bastida, Deyanira Ojeda-Ramírez.
      Sea urchins are a group of benthic invertebrates characterized by having rigid globose bodies, covered in spines, and have an innate immune system that has allowed them to survive in the environment and defend against many pathogens that affect them. They are consumed for their unique flavor, but also for possessing a rich source of bioactive compounds which make them a source for a wide array of medicinal properties. Thus, these may be used to discover and develop new drugs such as anti-bacterials, anti-carcinogenics and anti-virals. Precisely for those reasons, this revision is centered on the known biological activities in various sea urchin species. Recently, the potential pharmacological benefits of nine sea urchin species [Diadema antillarum (Philippi 1845), Echinometra mathaei (de Blainville), Evechinus chloroticus (Valenciennes), Mesocentrotus nudus (Agassiz, 1863), Paracentrotus lividus (Lamarck, 1816), Scaphechinus mirabilis (Agazzis, 1863), Stomopneustes variolaris (Lamarck, 1816), Tripneustes depressus (Agassiz, 1863), and Tripneustes ventricosus (Lamarck, 1816)] have been evaluated. Our work includes a comprehensive review of the anti-fungal, anti-parasitic, anti-inflammatory, hepatoprotective, anti-viral, anti-diabetic, anti-lipidemic, gastro-protective and anti-cardiotoxic effects. Furthermore, we revised the compounds responsible of these pharmacological effects. This work was intended for a broad readership in the fields of pharmacology, drugs and devices, marine biology and aquaculture, fisheries and fish science. Our results suggest that organic extracts, as well as pure compounds obtained from several parts of sea urchin bodies are effective in vitro and in vivo pharmacological models. As such, these properties manifest the potential use of sea urchins to develop emergent active ingredients.
    Keywords:  Bioactive compounds; Echinoderms; Naftoquinones; PUFAs; Sea urchin; Terpenes
    DOI:  https://doi.org/10.7717/peerj.13606
  125. Front Bioeng Biotechnol. 2022 ;10 939158
    Manganese-Based Prussian Blue Nanocatalysts Suppress Non-Small Cell Lung Cancer Growth and Metastasis via Photothermal and Chemodynamic Therapy.
    Danruo Fang, Zeyu Liu, Hansong Jin, Xiulin Huang, Yongxin Shi, Suqin Ben.
      Based on the safety of prussian blue (PB) in biomedical application, we prepared manganese-based prussian blue (MnPB) nanocatalysts to achieve enhanced photothermal therapy and chemodynamic therapy. And we conducted a series of experiments to explore the therapeutic effects of MnPB nanoparticles (NPs) on non-small cell lung cancer (NSCLC) in vivo and in vitro. For in vitro experiments, the MnPB NPs suppressed growth of A549 cells by reactive oxygen species upregulation and near-infrared irradiation. Moreover, the MnPB NPs could inhibit lung cancer metastasis through downregulating the matrix metalloproteinase (MMP)-2 and MMP-9 expression in A549 cells. And for in vivo experiments, the MnPB NPs inhibited the growth of xenografted tumor effectively and were biologically safe. Meanwhile, Mn2+ as a T1-weighted agent could realize magnetic resonance imaging-guided diagnosis and treatment. To sum up, the results in this study clearly demonstrated that the MnPB NPs had remarkable effects for inhibiting the growth and metastasis of NSCLC and might serve as a promising multifunctional nanoplatform for NSCLC treatment.
    Keywords:  MnPB nanoparticles; chemodynamic therapy; metastatic lung cancer; non-small cell lung cancer; photothermal therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.939158
  126. Ann Surg Oncol. 2022 Jul 13.
    Patient-Derived Sarcoma Organoids Offer a Novel Platform for Personalized Precision Medicine.
    Adrian Sanchez-Fdez, Ashwyn K Sharma, Herve Tiriac, Jason K Sicklick.
      
    DOI:  https://doi.org/10.1245/s10434-022-12152-5
  127. Front Chem. 2022 ;10 888673
    Chicoric Acid: Natural Occurrence, Chemical Synthesis, Biosynthesis, and Their Bioactive Effects.
    Min Yang, Chao Wu, Tianxi Zhang, Lei Shi, Jian Li, Hongbao Liang, Xuzhen Lv, Fengtang Jing, Lu Qin, Tianlun Zhao, Chenxi Wang, Guangxu Liu, Shuai Feng, Feng Li.
      Chicoric acid has been widely used in food, medicine, animal husbandry, and other commercial products because of its significant pharmacological activities. However, the shortage of chicoric acid limits its further development and utilization. Currently, Echinacea purpurea (L.) Moench serves as the primary natural resource of chicoric acid, while other sources of it are poorly known. Extracting chicoric acid from plants is the most common approach. Meanwhile, chicoric acid levels vary in different plants as well as in the same plant from different areas and different medicinal parts, and different extraction methods. We comprehensively reviewed the information regarding the sources of chicoric acid from plant extracts, its chemical synthesis, biosynthesis, and bioactive effects.
    Keywords:  bioactive effects; biosynthesis; chemical synthesis; chicoric acid; content detection; natural occurrence
    DOI:  https://doi.org/10.3389/fchem.2022.888673
  128. J Conserv Dent. 2022 May-Jun;25(3):25(3): 241-245
    Antioxidant, anti-inflammatory activity of Thymus vulgaris-mediated selenium nanoparticles: An in vitro study.
    Indumathy Pandiyan, Sakthi D Sri, Meignana Arumugham Indiran, Pradeep Kumar Rathinavelu, Jayashri Prabakar, S Rajeshkumar.
       Background: Nanotechnology is the specialty associated with material science and biology, rather than a particular field. It entails the method of particles at nanoscale called Nanoparticles, wherein they have control over bulk macroscopic properties of the identical material. The "drug nanocarrier," selenium possesses strong antibacterial, antioxidant and anti-cancer as well as anti-inflammatory properties. As the medicinal plant Thymus vulgaris possesses a lot of phytochemicals, this study was conducted to assess the anti-inflammatory and antioxidant activity of selenium nanoparticles (SeNps) reinforced with T. vulgaris.
    Materials and Methods: Anti-inflammatory activity, antioxidant activity of SeNps reinforced with T. vulgaris extract were assessed using bovine serum albumin and 2, 2-diphenyl-1-picrylhydrazyl assay, respectively, at 10, 20, 30, 40, and 50 μL.
    Results: The values for anti-inflammatory property of nanoparticles were higher than the standard values at 30, 40, and 50 μL concentrations. Percentage of inhibition was highest at 40 μL (87.7%) and 50 μL (92.6%). The values for antioxidant property of nanoparticles were found to be higher than the standard values at 10, 20, and 30 μL concentrations. Percentage of inhibition was highest at 30 μL (68.3%).
    Conclusion: SeNps reinforced with T. vulgaris extract have a potential as an anti-inflammatory and antioxidant agent and can be used as an alternative to commercially available products.
    Keywords:  Anti-inflammatory; Thymus vulgaris; antioxidant; selenium nanoparticles
    DOI:  https://doi.org/10.4103/JCD.JCD_369_21
  129. Crit Rev Food Sci Nutr. 2022 Jul 11. 1-17
    Dietary flavonoids prevent diabetes through epigenetic regulation: advance and challenge.
    Shuai Han, Yi Luo, Bo Liu, Tianyi Guo, Dandan Qin, Feijun Luo.
      The pathophysiology of diabetes has been studied extensively in various countries, but effective prevention and treatment methods are still insufficient. In recent years, epigenetics has received increasing attention from researchers in exploring the etiology and treatment of diabetes. DNA methylation, histone modifications, and non-coding RNAs play critical roles in the occurrence, maintenance, and progression of diabetes and its complications. Therefore, preventing or reversing the epigenetic alterations that occur during the development of diabetes may reduce the individual and societal burden of the disease. Dietary flavonoids serve as natural epigenetic modulators for the discovery of biomarkers for diabetes prevention and the development of alternative therapies. However, there is limited knowledge about the potential beneficial effects of flavonoids on the epigenetics of diabetes. In this review, the multidimensional epigenetic effects of different flavonoid subtypes in diabetes were summarized. Furthermore, it was discussed that parental flavonoid diets might reduce diabetes incidence in offspring, which represent a promising opportunity to prevent diabetes in the future. Future work will depend on exploring anti-diabetic effects of different flavonoids with different epigenetic regulation mechanisms and clinical trials. Highlights• "Epigenetic therapy" could reduce the burden of diabetic patients• "Epigenetic diet" ameliorates diabetes• Targeting epigenetic regulations by dietary flavonoids in the diabetes prevention• Dietary flavonoids prevent diabetes via transgenerational epigenetic inheritance.
    Keywords:  Diabetes; dietary flavonoids; epigenetics; transgenerational epigenetic inheritance
    DOI:  https://doi.org/10.1080/10408398.2022.2097637
  130. Int J Nanomedicine. 2022 ;17 2995-3012
    A Cosmeceutical Topical Water-in-Oil Nanoemulsion of Natural Bioactives: Design of Experiment, in vitro Characterization, and in vivo Skin Performance Against UVB Irradiation-Induced Skin Damages.
    Carol Yousry, Mona M Saber, Wessam H Abd-Elsalam.
       Introduction: Damage to human skin occurs either chronologically or through repetitive exposure to ultraviolet (UV) radiation, where collagen photodegradation leads to the formation of wrinkles and skin imperfections. Consequently, cosmeceutical products containing natural bioactives to restore or regenerate collagen have gained a remarkable attention as an ameliorative remedy.
    Methods: This study aimed to develop and optimize collagen-loaded water-in-oil nanoemulsion (W/O NE) through a D-optimal mixture design to achieve an ideal multifunctional nanosystem containing active constituents. Vit E was included as a constituent of the formulation for its antioxidant properties to minimize the destructive impact of UV radiation. The formulated systems were characterized in terms of their globule size, optical clarity, and viscosity. An optimized system was selected and evaluated for its physical stability, in vitro wound healing properties, and in vivo permeation and protection against UV radiation. In addition, the effect of collagen-loaded NE was compared to Vit C-loaded NE and collagen-/Vit C-loaded NEs mixture as Vit C is known to enhance collagen production within the skin.
    Results: The optimized NE was formulated with 25% oils (Vit E: safflower oil, 1:3), 54.635% surfactant/cosurfactant (Span 80: Kolliphor EL: Arlasolve, 1:1:1), and 20.365% water. The optimized NE loaded with either collagen or Vit C exhibited a skin-friendly appearance with boosted permeability, and improved cell viability and wound healing properties on fibroblast cell lines. Moreover, the in vivo study and histopathological investigations confirmed the efficacy of the developed system to protect the skin against UV damage. The results revealed that the effect of collagen-/Vit C-loaded NEs mixture was more pronounced, as both drugs reduced the skin damage to an extent that it was free from any detectable alterations.
    Conclusion: NE formulated using Vit E and containing collagen and/or Vit C could be a promising ameliorative remedy for skin protection against UVB irradiation.
    Keywords:  UVB irradiation; collagen; fibroblast; vitamin C; vitamin E; water-in-oil nanoemulsion
    DOI:  https://doi.org/10.2147/IJN.S363779
  131. Cell Biochem Funct. 2022 Jul 13.
    Bile acid-based advanced drug delivery systems, bilosomes and micelles as novel carriers for therapeutics.
    Mohadeseh Nemati, Anahita Fathi-Azarbayjani, Hani Al-Salami, Elmira Roshani Asl, Yousef Rasmi.
      Diabetes mellitus affects almost half a billion patients worldwide and results from either destruction of β-cells responsible for insulin secretion or increased tissue resistance to insulin stimulation and the reduction of glycemic control. Novel drug delivery systems can improve treatment efficacy in diabetic patients. The low aqueous solubility of most oral antidiabetic drugs decreases drug bioavailability; therefore, there is a demand for the use of novel methods to overcome this issue. The application of bile acids mixed micelles and bilosomes can provide an enhancement in drug efficacy. Bile acids are amphiphilic steroidal molecules that contain a saturated tetracyclic hydrocarbon cyclopentanoperhydrophenanthrene ring, and consist of three 6-membered rings and a 5-membered ring, a short aliphatic side chain, and a tough steroid nucleus. This review offers a comprehensive and informative data focusing on the great potential of bile acid, their salts, and their derivatives for the development of new antidiabetic drug delivery system.
    Keywords:  antidiabetic drug; bile acid; bilosome; drug delivery; micelle
    DOI:  https://doi.org/10.1002/cbf.3732
  132. Int J Biol Sci. 2022 ;18(9): 3714-3730
    Isovalerylspiramycin I suppresses non-small cell lung carcinoma growth through ROS-mediated inhibition of PI3K/AKT signaling pathway.
    Zeyu Liu, Moli Huang, Yue Hong, Shaoyang Wang, Yongle Xu, Cheng Zhong, Jingyuan Zhang, Zhengping Zhuang, Shan Shan, Tao Ren.
      Novel drugs are required for non-small cell lung cancer (NSCLC) treatment urgently. Repurposing old drugs as new treatments is a practicable approach with time and cost savings. Some studies have shown that carrimycin, a Chinese Food and Drug Administration (CFDA)-approved macrolide antibiotic, possesses potent anti-tumor effects against oral squamous cell carcinoma. However, its detailed component and underlying mechanisms in anti-NSCLC remain unknown. In our study, isovalerylspiramycin I (ISP-I) was isolated from carrimycin and demonstrated a remarkable anti-NSCLC efficacy in vitro and in vivo with a favorable safety profile. It has been proven that in NSCLC cell lines H460 and A549, ISP-I could induce G2/M arrest and apoptosis, which was mainly attributed to ROS accumulation and subsequently PI3K/AKT signaling pathway inhibition. Numerous downstream genes including mTOR and FOXOs were also changed correspondingly. An observation of NAC-induced reverse effect on ISP-I-leading cell death and PI3K/AKT pathway inhibition, emphasized the necessity of ROS signaling in this event. Moreover, we identified ROS accumulation and PI3K/AKT pathway inhibition in tumor xenograft models in vivo as well. Taken together, our study firstly reveals that ISP-I is a novel ROS inducer and may act as a promising candidate with multi-target and low biological toxicity for anti-NSCLC treatment.
    Keywords:  G2/M arrest; Isovalerylspiramycin I (ISP-I); Non-small cell lung cancer (NSCLC); PI3K/AKT signaling pathway; ROS; apoptosis
    DOI:  https://doi.org/10.7150/ijbs.69989
  133. Alzheimers Dement. 2022 Jul 13.
    The landscape of metabolic brain alterations in Alzheimer's disease.
    Alzheimer's Disease Metabolomics Consortium (ADMC)
       INTRODUCTION: Alzheimer's disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in the brain has been missing.
    METHODS: We metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures.
    RESULTS: We observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation, and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than amyloid beta pathology.
    DISCUSSION: This work provides a comprehensive reference map of metabolic brain changes in AD that lays the foundation for future mechanistic follow-up studies.
    Keywords:  Alzheimer's disease; bioenergetic pathways; brain; cholesterol metabolism; metabolic landscape; metabolism; multi-omic integration; neuroinflammation; neurotransmission; osmoregulation
    DOI:  https://doi.org/10.1002/alz.12714
  134. J Pharm Anal. 2022 Jun;12(3): 406-414
    Physicochemical degradation of phycocyanin and means to improve its stability: A short review.
    Aïda Adjali, Igor Clarot, Zilin Chen, Eric Marchioni, Ariane Boudier.
      The cyanobacterium Arthrospira platensis, spirulina, is a source of pigments such as phycobiliprotein and phycocyanin. Phycocyanin is used in the food, cosmetics, and pharmaceutical industries because of its antioxidant, anti-inflammatory, and anticancer properties. The different steps involved in extraction and purification of this protein can alter the final properties. In this review, the stability of phycocyanin (pH, temperature, and light) is discussed, considering the physicochemical parameters of kinetic modeling. The optimal working pH range for phycocyanin is between 5.5 and 6.0 and it remains stable up to 45 °C; however, exposure to relatively high temperatures or acidic pH decreases its half-life and increases the degradation kinetic constant. Phycobiliproteins are sensitive to light; preservatives such as mono- and di-saccharides, citric acid, or sodium chloride appear to be effective stabilizing agents. Encapsulation within nano- or micro-structured materials such as nanofibers, microparticles, or nanoparticles, can also preserve or enhance its stability.
    Keywords:  Arthrospira platensis; Encapsulation; Phycocyanin stability; Preservatives; Spirulina
    DOI:  https://doi.org/10.1016/j.jpha.2021.12.005
  135. Biomed Res Int. 2022 ;2022 2051017
    Nutraceuticals: Pharmacologically Active Potent Dietary Supplements.
    Subhash Chandra, Sarla Saklani, Pramod Kumar, Bonglee Kim, Henrique D M Coutinho.
      A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nutraceuticals, up today, do not have a specific definition distinct from those of other food-derived categories, e.g., food supplements, herbal products, functional foods, and fortified foods. They have, however, a pharmacological beneficial effect on health. Many studies have been recently addressed to assess their safety, efficacy, and regulation. The object of writing this review article is that we need to pay more attention to natural and organic foods. The bases of nutraceutical components (food supplements) are known for potent and powerful clinical evidence effects on the treatment of hypertension and type 2 diabetes.
    DOI:  https://doi.org/10.1155/2022/2051017
  136. Womens Health Rep (New Rochelle). 2022 ;3(1): 563-572
    Dietary Drivers and Challenges of Australian Breast Cancer Survivors: A Qualitative Study.
    Daniel G Coro, Amanda D Hutchinson, Siobhan Banks, Alison M Coates.
       Purpose: Cancer survivors often make long-term dietary changes, and nutrition is important for survivorship outcomes. Many survivors experience persisting cognitive difficulties, which can impact health behaviors. This study aimed to identify perceived drivers of eating habit changes, and the barriers to making intentional dietary changes, among breast cancer survivors with persisting self-reported cancer-related cognitive impairment.
    Materials and Methods: A qualitative framework explored survivors' perceptions of dietary habit changes. Thirteen Australian breast cancer survivors (M.time since diagnosis: 23.6 months, standard deviation [SD] 15.3; M.time since completing primary treatment: 14.7 months, SD 15.3) completed semistructured interviews. Questions related to dietary changes since diagnosis and treatment. Major themes were identified from interview transcripts using thematic analysis.
    Results: While most individuals perceived their diet to be broadly similar to prediagnosis, several changes to diet and eating habits were identified, which were often meaningful to these survivors. Themes relating to survivors' eating habit changes included the following: (1) meal timing and frequency shifts, (2) more plant-based eating, and (3) less variety and more convenience. Changes in eating habits were attributed to the following: (1) persisting treatment-related changes, (2) help and support from others, (3) old treatment habits, (4) preventative health and self-care, and (5) changes to work schedule. Barriers to making intentional dietary changes included the following: (1) too much time and effort, (2) food cravings and enjoyment, and (3) lacking dietary ideas and resources.
    Conclusions: Many survivors reported long-term changes in dietary habits, some of which align with current recommendations. Causes of dietary habit changes, and barriers to engaging in healthier dietary habits, involved multiple biopsychosocial elements. Additional resources or strategies that assist navigating survivorship challenges and their effects on dietary habits are needed. Future studies should explore whether post-treatment nutritional review with a qualified dietary health professional is helpful for survivors who experience long-term cancer-related cognitive impairment.
    Keywords:  barriers; cancer survivors; cognition; diet; nutrition; qualitative
    DOI:  https://doi.org/10.1089/whr.2021.0133
  137. Photodiagnosis Photodyn Ther. 2022 Jul 07. pii: S1572-1000(22)00290-3. [Epub ahead of print] 103004
    Identification and pharmacological modification of resistance mechanisms to protoporphyrin-mediated photodynamic therapy in human cutaneous squamous cell carcinoma cell lines.
    Nicole Schary, Ben Novak, Laura Kämper, Aisha Yousf, Hermann Lübbert.
       BACKGROUND: Photodynamic therapy (PDT) is clinically approved to treat neoplastic skin diseases such as precursors of cutaneous squamous cell carcinoma (cSCC). In PDT, 5-aminolevulinic acid (5-ALA) drives the selective formation of the endogenous photosensitizer protoporphyrin IX (PpIX). Although 5-ALA PDT is clinically highly effective, resistance might occur due to decreased accumulation of PpIX in certain tumors. Such resistance may be caused by any fundamental step of PpIX accumulation: 5-ALA uptake, PpIX synthesis and PpIX efflux.
    METHODS: We investigated PpIX accumulation and photodynamically induced cell death in PDT refractory SCC-13, PDT susceptible A431, and normal human epidermal keratinocytes (NHEK). Expression of genes associated with cellular PpIX kinetics was investigated on mRNA and protein level. PpIX accumulation and cell death upon illumination were pharmacologically manipulated using drugs targeting 5-ALA uptake, PpIX synthesis or efflux.
    RESULTS: The experiments indicate that taurine transporter (SLC6A6) is the major pathway for 5-ALA uptake in cSCC cells, while being less important in NHEK. Downregulation of PpIX synthesis enzymes in SCC-13 was counteracted by methotrexate (MTX) treatment, which restored PpIX formation and cell death. PpIX efflux inhibitors targeting ABC transporters led to significantly increased PpIX accumulation in SCC-13, thereby fully overcoming resistance.
    CONCLUSIONS: The results indicate a conserved threshold for PpIX accumulation with respect to resistance at 1.5 nM. Selective uptake of 5-ALA via taurine transporters in tumor cells is novel but unrelated to resistance. MTX can partially abrogate resistance by enzyme induction, while efflux mechanisms via ABC transporters seem the main driving force and promising drug targets.
    Keywords:  5-aminolevulinic acid; ABC transporters; photodynamic therapy; protoporphyrin IX; resistance; squamous cell carcinoma
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103004
  138. Biomater Transl. 2020 ;1(1): 46-57
    Hydroxyethyl starch and its derivatives as nanocarriers for delivery of diagnostic and therapeutic agents towards cancers.
    Ronghua Tan, Ying Wan, Xiangliang Yang, Rt, Yw, Xy.
      Many types of drugs and agents used for cancer diagnosis and therapy often have low bioavailability and insufficient efficacy, as well as causing various side effects due to their nonspecific delivery. Nanocarriers with purposely-designed compositions and structures have shown varying degrees of abilities to deliver these compounds towards cancers in passive or active manners. Despite the availability of a variety of materials for the construction of nanocarriers, natural polymers with good biocompatibility and biodegradability are preferable for such usage because of their high in vivo safety as well as easy removal of degradation products. Among the natural polymers intended for building nanocarriers, hydroxyethyl starch and its derivatives have gained tremendous attention in the field of drug delivery in the form of nanomedicines over the last decade. There is growing optimism that ever more hydroxyethyl starch-based nanomedicines will be a significant addition to the armoury currently used for cancer diagnosis and therapy.
    Keywords:  anticancer treatment; chemical modification; diagnostic and therapeutic agents; hydroxyethyl starch; nanocarriers; prodrug
    DOI:  https://doi.org/10.3877/cma.j.issn.2096-112X.2020.01.005
  139. Int J Biol Macromol. 2022 Jul 07. pii: S0141-8130(22)01442-8. [Epub ahead of print]216 558-570
    Chitosan IR806 dye-based polyelectrolyte complex nanoparticles with mitoxantrone combination for effective chemo-photothermal therapy of metastatic triple-negative breast cancer.
    S B Alvi, P S Rajalakshmi, A B Jogdand, B Nazia, V Bantal, A K Rengan.
      Chemo-photothermal therapy is one of the emerging therapies for treating triple-negative breast cancer. In this study, we have used ionotropic gelation method to fabricate chitosan and IR806 dye-based polyelectrolyte complex (CIR-PEx) nanoparticles. These nano-complexes were in size range of 125 ± 20 nm. The complexation of IR 806 dye with chitosan improved photostability, photothermal transduction, and showed excellent biocompatibility. Cancer cells treated with CIR-PEx NPs enhanced intracellular uptake within 5 h of incubation and also displayed mitochondrial localization. With the combination of CIR-PEx NPs and a chemotherapeutic agent (i.e., mitoxantrone, MTX), a significant decline in cancer cell viability was observed in both 2D and 3D cell culture models. The chemo-photothermal effect of CIR-PEx NPs + MTX augmented apoptosis in cancer cells when irradiated with NIR light. Furthermore, when tested in the 4 T1-tumor model, the chemo-photothermal therapy showed a drastic decline in tumor volume and inhibited metastatic lung nodules. The localized hyperthermia caused by photothermal therapy reduced the primary tumor burden, and the chemotherapeutic activity of mitoxantrone further complemented by inhibiting the spread of cancer cells. The proposed chemo-photothermal therapy combination could be a promising strategy for treating triple-negative metastatic breast cancer.
    Keywords:  Breast cancer; Chemo-photothermal therapy; Chitosan nanosystems; IR806; Metastasis; Mitoxantrone
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.018
  140. Physiol Rep. 2022 Jul;10(13): e15375
    Low-carbohydrate diet score is associated with improved blood pressure and cardio-metabolic risk factors among obese adults.
    Mohammad Sadegh Pour Abbasi, Niloofar Shojaei, Mahdieh Abbasalizad Farhangi.
      Obesity is associated with numerous co-morbidities and diet, is one of the modifiable risk factors for prevention against these obesity-related metabolic disorders. In the current study, we aimed to evaluate the association between adherence to low carbohydrate diet (LCD) score and serum lipids, glycemic markers, blood pressure, and anthropometric parameters among obese individuals. The current cross-sectional study is a combination of two projects with total participants of 359 obese individuals (body mass index [BMI] ≥ 30 kg/m2 ) aged 20-50 years were included. Dietary intake was assessed by a validated semi-quantitative food frequency questionnaire (FFQ) of 132 food items. Low carbohydrate diet score was estimated by deciles of dietary intakes. Metabolic syndrome (MetS) was defined based on the guidelines of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III). Enzymatic methods were used to assess serum lipids, glucose, and insulin concentrations. Blood pressure was measured by sphygmomanometer and body composition with bioelectrical impedance analysis (BIA). Higher adherence to LCD score was associated with significantly lower DBP and triglyceride (TG) concentrations and increased high density lipoprotein (HDL)-C levels after adjustment for the confounders (p < 0.05). A non-significant reduction in systolic blood pressure (SBP) and total cholesterol (TC) values were also observed. Also, high adherence to LCD score was associated with reduced prevalence of metabolic syndrome (p < 0.05). Higher BMI, fat mass, and lower fat-free mass were also accompanied with higher adherence to LCD score. According to our study, low carbohydrate diet score was associated with more favorable cardio-metabolic risk factors independent of some confounders like age, BMI, sex, and physical activity level. Further studies in different communities will help for generalization of our findings.
    Keywords:  cardio-metabolic risk factors; low carbohydrate diet; metabolic syndrome; obesity
    DOI:  https://doi.org/10.14814/phy2.15375
  141. Biomater Sci. 2022 Jul 15.
    A novel active mitochondrion-selective fluorescent probe for the NIR fluorescence imaging and targeted photodynamic therapy of gastric cancer.
    Jie Ding, Xing Kang, Min Feng, Jiangkun Tan, Qingzhao Feng, Xingzhou Wang, Jiafeng Wang, Jiang Liu, Zan Li, Wenxian Guan, Tong Qiao.
      The annual morbidity and mortality due to gastric cancer are still high across the world, posing a serious threat to public health. Improving the diagnosis rate of gastric cancer and exploring new treatments are urgent issues in the clinical field. In recent years, photosensitizer (PS)-based photodynamic therapy (PDT) has proven to be an effective cancer treatment strategy and can be used to treat a variety of cancers. Developing PSs with tumor-targeting ability and high singlet oxygen yield (Φ(1O2)) is the key to improving the PDT effect. Herein, we developed a novel diagnosis and treatment system (Cy1395-NPs). Our active thio-photosensitizer is based on the sulfur substitution strategy as it can reduce the S1-T1 energy gap, which can promote the process of intersystem crossing (ISC), thus resulting in high ROS generation efficiency. Cy1395-NPs exhibited stable spectral characteristics, satisfactory biocompatibility and high 1O2 yield under laser irradiation due to the introduction of the sulfur atom. In cellular studies, Cy1395-NPs could specifically target MKN45 cells via integrin αvβ3-mediated cRGD endocytosis and selectively aggregate in the mitochondria. Cy1395-NPs had no obvious cytotoxicity for MKN45 cells and exerted obvious phototoxicity due to the production of 1O2 under laser irradiation. The in vivo results showed that the fluorescence signal from the tumor site was obviously enhanced in 16-48 h, and Cy1395-NPs could selectively target solid tumors with a retention time of about 32 h. Under laser irradiation, Cy1395-NPs significantly inhibited tumor growth and led to significant tumor suppression and apoptosis. In summary, the developed Cy1395-NPs could actively target tumors and exert mitochondrial selectivity, showing an excellent fluorescence imaging effect. Under the irradiation of an 808 nm laser, Cy1395-NPs achieved good inhibition of gastric cancer cells both in vitro and in vivo, thus displaying the functions of tumor targeting, mitochondrial selectivity, fluorescence imaging and tumor inhibition. Our strategy provides a new diagnostic and treatment method for gastric cancers in clinical settings.
    DOI:  https://doi.org/10.1039/d2bm00684g
  142. Nanomedicine. 2022 Jul 08. pii: S1549-9634(22)00067-3. [Epub ahead of print]44 102581
    Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment.
    Zhang Ye, Lun Gao, Jiayang Cai, Yixuan Wang, Yong Li, Shiao Tong, Tengfeng Yan, Qian Sun, Yangzhi Qi, Yang Xu, Hongxiang Jiang, Si Zhang, Linyao Zhao, Shenqi Zhang, Qianxue Chen.
      Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood-brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.
    Keywords:  CXCR4; GBM; PLGA nanoparticle; Prodrug; Tandutinib
    DOI:  https://doi.org/10.1016/j.nano.2022.102581
  143. Cancer Res. 2022 Jul 15. pii: CAN-22-0887. [Epub ahead of print]
    The mechanisms of action of Tumor Treating Fields.
    Justin C Moser, Ellaine Salvador, Karina Deniz, Kenneth Swanson, Jack Tusynski, Kristen W Carlson, Narasimha Kumar Karanam, Chirag B Patel, Michael Story, Emil Lou, Carsten Hagemann.
      Tumor Treating Fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While anti-mitotic effects were the first recognized biological anti-cancer activity of TTFields, data have shown that tumor treating fields achieve their anti-cancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0887
  144. Iran J Allergy Asthma Immunol. 2022 Jun 18. 21(3): 287-299
    Immunosuppressive Effects and Potent Anti-tumor Efficacy of mTOR Inhibitor Everolimus in Breast Tumor-bearing Mice.
    Davoud Rostamzadeh, Mohammad Reza Haghshenas, Mahdi Samadi, Zahra Mojtahedi, Zohreh Babaloo, Abbas Ghaderi.
      To investigate the effects of everolimus, a mechanistic/mammalian target of rapamycin (mTOR) inhibitor, on tumor growth and immune response in a mouse model of breast cancer. Human hormone receptor-positive (HR+)/human epidermal growth receptor 2-negative (HER2-) MC4-L2 cell line was used to establish a mouse model of breast cancer. The inhibitory effects of high (10 mg/kg) and low (5 mg/kg) doses of everolimus were investigated on tumor growth. Additionally, the frequency of CD4+Foxp3+ regulatory T cells (Tregs), CD8+Foxp3+ Tregs, and CD4+ and CD8+ T cells expressing cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) was explored by flow cytometry in bone marrow, lymph nodes, and spleen. Our results showed that both 10 mg/kg and 5 mg/kg doses of everolimus efficiently inhibited tumor growth, resulting in reduced breast tumor volume. In addition, it was revealed that everolimus-treated mice induced a higher frequency of CD4+Foxp3+ Tregs, CD8+Foxp3+ Tregs, and CD4+Foxp3+CTLA-4+ Tregs as well as CD4+ and CD8+ T cells expressing CTLA-4 in their bone marrow, lymph nodes, and spleen compared with standard control (vehicle-treated) in a dose-dependent manner. Furthermore, we found that everolimus treatment with 10 mg/kg and 5 mg/kg increased the frequency of Helios+Foxp3+ Tregs in the bone marrow of treated mice compared with the control group. Our results indicate that treatment with everolimus not only inhibits tumor growth but also exerts an immunomodulatory effect by inducing Tregs in the lymphoid organs of breast cancer-bearing mice. The combination of therapy with other anti-cancer agents may negate immune suppression and improve the efficacy of mTOR-targeted breast cancer therapy.
    Keywords:  CTLA-4 antigen; Everolimus; Regulatory T-lymphocytes
    DOI:  https://doi.org/10.18502/ijaai.v21i3.9802
  145. Physiol Rev. 2022 Jul 14.
    Complex Physiology and Clinical Implications of Time-restricted Eating.
    Max C Petersen, Molly R Gallop, Stephany Flores Ramos, Amir Zarrinpar, Josiane L Broussard, Maria Chondronikola, Amandine Chaix, Samuel Klein.
      Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we: i) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; ii) discuss the interaction between circadian molecular metabolism and TRE; iii) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; iv) summarize other time-related dietary interventions that have been studied in people; and v) identify current gaps in knowledge and provide a framework for future research directions.
    Keywords:  Chrononutrition; Intermittent fasting; Nutrition; Obesity; Time-restricted eating
    DOI:  https://doi.org/10.1152/physrev.00006.2022
  146. Adv Funct Mater. 2021 Feb 10. pii: 2007017. [Epub ahead of print]31(7):
    FAP-Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts.
    Shiyi Zhou, Zipeng Zhen, Amy V Paschall, Lijun Xue, Xueyuan Yang, Anne-Gaelle Bebin-Blackwell, Zhengwei Cao, Weizhong Zhang, Mengzhe Wang, Yong Teng, Gang Zhou, Zibo Li, Fikri Y Avci, Wei Tang, Jin Xie.
      Cancer-associated fibroblasts (CAFs) are present in many types of tumors and play a pivotal role in tumor progression and immunosuppression. Fibroblast-activation protein (FAP), which is overexpressed on CAFs, has been indicated as a universal tumor target. However, FAP expression is not restricted to tumors, and systemic treatment against FAP often causes severe side effects. To solve this problem, a photodynamic therapy (PDT) approach was developed based on ZnF16Pc (a photosensitizer)-loaded and FAP-specific single chain variable fragment (scFv)-conjugated apoferritin nanoparticles, or αFAP-Z@FRT. αFAP-Z@FRT PDT efficiently eradicates CAFs in tumors without inducing systemic toxicity. When tested in murine 4T1 models, the PDT treatment elicits anti-cancer immunity, causing suppression of both primary and distant tumors, i.e. abscopal effect. Treatment efficacy is enhanced when αFAP-Z@FRT PDT is used in combination with anti-PD1 antibodies. Interestingly, it is found that the PDT treatment not only elicits a cellular immunity against cancer cells, but also stimulates an anti-CAFs immunity. This is supported by an adoptive cell transfer study, where T cells taken from 4T1-tumor-bearing animals treated with αFAP PDT retard the growth of A549 tumors established on nude mice. Overall, our approach is unique for permitting site-specific eradication of CAFs and inducing a broad spectrum anti-cancer immunity.
    Keywords:  cancer associated fibroblast; fibroblast activation protein; immunomodulation; immunotherapy; photodynamic therapy
    DOI:  https://doi.org/10.1002/adfm.202007017
  147. Theranostics. 2022 ;12(10): 4791-4801
    Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives.
    Karolin Roemhild, Helena C Besse, Bi Wang, Quim Peña, Qingxue Sun, Daiki Omata, Burcin Ozbakir, Clemens Bos, Hans W Scheeren, Gert Storm, Josbert M Metselaar, Haijun Yu, Ruth Knüchel-Clarke, Fabian Kiessling, Chrit T W Moonen, Roel Deckers, Yang Shi, Twan Lammers.
      Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer.
    Keywords:  Cancer; Focused ultrasound; HIFU; Prodrugs; β-glucuronidase
    DOI:  https://doi.org/10.7150/thno.69168
  148. Transl Cancer Res. 2022 Jun;11(6): 1781-1794
    Hesperetin ameliorates glioblastoma by inhibiting proliferation, inducing apoptosis, and suppressing metastasis.
    Qian Cheng, Lianzhi Mao, Hongxiang Huang, Longguang Tang, Hongyan Jiang, Yufei Zhang, Qingchun Mu.
       Background: Glioblastoma is the most common type of malignant tumor of the brain. Despite substantial improvements in therapy, the 5-year survival rate of patients with glioblastoma remains low. Antitumor drug development has encountered considerable obstacles, which can be attributed to metastasis and the blood-brain barrier (BBB). Hesperetin (HSP), derived from citrus fruits, exhibits several biological properties, including anticancer and anti-inflammatory activities. In addition, in vitro models have shown that HSP can easily cross the BBB. The purpose of the present study was to explore the effects and underlying mechanisms of HSP on glioblastoma cells.
    Methods: GL261 cell were cultured and treated with different dose HSP. The cell viability was assessed with Cell Counting Kit-8 (CCK-8) assay. The cell apoptosis was determined using an Annexin V/propidine iodide (PI) staining and Hoechst staining and detection assay, cell migration and invasion were observed on GL261 cells using Matrigel-coated Transwells and Wound-Healing assay. The expression of proteins was detected by Western blotting.
    Results: HSP suppressed cell proliferation and could induce apoptosis, the latter of which might be regulated through the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor-kappa B (NF-κB) pathways. Furthermore, HSP inhibited cell migration and invasion by downregulating the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and inhibited epithelial-mesenchymal transition (EMT) by upregulating the expression of E-cadherin while downregulating N-cadherin and vimentin expression.
    Conclusions: These findings suggest HSP to be an alternative preventive and therapeutic antiglioblastoma drug that may be especially useful for patients with recurrent glioblastoma.
    Keywords:  Hesperetin; apoptosis; epithelial-mesenchymal transition (EMT); metastasis
    DOI:  https://doi.org/10.21037/tcr-22-1497
  149. Plant Foods Hum Nutr. 2022 Jul 14.
    The Edible Plant Crithmum maritimum Shows Nutraceutical Properties by Targeting Energy Metabolism in Hepatic Cancer.
    Davide Gnocchi, Carlo Sabbà, Antonio Mazzocca.
      In the past few years, evidence has supported the role of plants as a valuable tool for the development of promising therapeutic support options for many diseases, including cancer. We recently discovered that the edible wild plant Crithmum maritimum L. effectively inhibits the growth of hepatocellular carcinoma (HCC) cells and we provide insights into the biological mechanisms involved. Here, we aimed to characterize the effect of ethyl acetate extract of Crithmum maritimum on the bioenergetic phenotype of HCC cells and if this is associated with the anti-tumour effect we previously described. Results show that Crithmum maritimum significantly increases cellular respiration and reduces lactic fermentation in HCC cells, and that this reduction of the fermentative glycolytic phenotype is linked to inhibition of HCC growth. These data provide new preclinical evidence supporting the role of Crithmum maritimum L. as a nutraceutical option to expand the therapeutic opportunities in the management of HCC.
    Keywords:  Anticancer activity; Bioenergetic phenotype; Crithmum maritimum L.; Edible wild plants; Hepatocellular carcinoma; Plant extracts
    DOI:  https://doi.org/10.1007/s11130-022-00986-z
  150. J Biomol Struct Dyn. 2022 Jul 13. 1-10
    Promising disruptors of p53-MDM2 dimerization from some medicinal plant phytochemicals: a molecular modeling study.
    Abdul-Quddus Kehinde Oyedele, Temitope Isaac Adelusi, Abdeen Tunde Ogunlana, Mojeed Ashiru Ayoola, Rofiat Oluwabusola Adeyemi, Musa Oladayo Babalola, James Babatunde Ayorinde, Josiah Ayoola Isong, Toheeb Olakunle Ajasa, Ibrahim Damilare Boyenle.
      Cancer is a major global health issue that has a high mortality rate. p53, which functions as a tumor suppressor, is critical in preventing tumor development by regulating the cell cycle and inducing apoptosis in damaged cells. However, the tumor suppressor function of p53 is effectively inhibited by its direct interaction with the hydrophobic cleft of MDM2 protein via multiple mechanisms As a result, restoring p53 activity by blocking the p53-MDM2 protein-protein interaction has been proposed as a compelling therapeutic strategy for cancer treatment. The use of molecular docking and phytochemical screening procedures are appraised to inhibit MDM2's hydrophobic cleft and disrupt the p53-MDM2 interaction. For this purpose, a library of 51 bioactive compounds from 10 medicinal plants was compiled and subjected to structure-based virtual screening. Out of these, only 3 compounds (Atalantoflavone, Cudraxanthone 1, and Ursolic acid) emerged as promising inhibitors of MDM2-p53 based on their binding affinities (-9.1 kcal/mol, -8.8 kcal/mol, and -8.8 kcal/mol respectively) when compared to the standard (-8.8 kcal/mol). Moreover, these compounds showed better pharmacokinetic and drug-like profiling than the standard inhibitor (Chromonotriazolopyrimidine 1). Finally, the 100 ns MD simulation analysis confirmed no significant perturbation in the conformational dynamics of the simulated binary complexes when compared to the standard. In particular, Ursolic acid was found to satisfy the molecular enumeration the most compared to the other inhibitors. Our overall molecular modeling finding shows why these compounds may emerge as potent arsenals for cancer therapeutics. Nonetheless, extensive experimental and clinical research is needed to augment their use in clinics.Communicated by Ramaswamy H. Sarma.
    Keywords:  ADMET evaluation; Cancer therapy; MDM2-p53 inhibitors; Molecular dynamics simulation; virtual screening
    DOI:  https://doi.org/10.1080/07391102.2022.2097313
  151. Food Res Int. 2022 Aug;pii: S0963-9969(22)00559-2. [Epub ahead of print]158 111501
    Dietary strategies with anti-aging potential: Dietary patterns and supplements.
    Hui Duan, Jiani Pan, Min Guo, Jinwei Li, Leilei Yu, Liuping Fan.
      Dietary intervention is a safe, broad-spectrum, and low-cost preventive strategy for slow aging. The Okinawan, Mediterranean, and Dietary approaches to stop hypertension (DASH) diets, as well as caloric restriction (CR) and intermittent fasting (IF), are classic and reliable dietary patterns that slow aging by regulating nutrient-sensing pathways, gut microbiota, metabolism, and immunity. Moreover, the proportion of the three macronutrients (carbohydrate, protein and fat) is also vital for slowing aging, but the debates about the appropriate proportion, especially the ratio of carbohydrates and proteins, remain unknown. Strict and lifelong adherence to these regimens is difficult, thereby promoting the emergence of various dietary supplements, including natural CR mimics, probiotics, natural senolytics, vitamins and essential minerals. Combinations of different dietary patterns and supplements with distinct pathways may have additive effects. Individuals' aging speed and dietary response are highly variable, thus highlighting the need for precise anti-aging dietary intervention. Nutrigenomics plays an important role in personalized dietary strategies. Therefore, this review critically compares the anti-aging effects of various dietary patterns and supplements, analyzes their mechanisms and combined use, and proposes future research directions to achieve personalized dietary strategies for slowing aging.
    Keywords:  Aging; Dietary patterns; Dietary supplements; Gut microbiota; Probiotics
    DOI:  https://doi.org/10.1016/j.foodres.2022.111501
  152. Drug Deliv Transl Res. 2022 Jul 11.
    Management of bone diseases: looking at scaffold-based strategies for drug delivery.
    Myriam Bordone, Ana Bettencourt.
      The bone tissue can regenerate itself completely and continuously; however, large-scale bone defects may overpower this self-regenerative process. Furthermore, the aging population, the increment in obesity incidence, and the sedentary lifestyles are serious risk factors for bone diseases' development which are associated with the self-regenerative process's failure, high morbidity, and mortality rates. Thus, there is an ever-growing need for strategic approaches targeting bone replacement, its remodelling, and its regeneration. Bone scaffolds have successfully been used as synthetic bone grafts for many years, yet recent bone tissue engineering strategies attempt to explore their multifunctionality by investigating them as drug delivery systems. Bone diseases' treatments can be substantially difficult due to the avascular nature of the surrounding cartilage; thus, targeted drug delivery to the bone can be advantageous: it provides local high drug concentrations and minimizes adverse effects while securing a space for new, healthy tissue growth. Despite the promising scientific progress, studies underlining bone scaffolds' use as local drug delivery systems are not abundant. Hence, this work reviews bone scaffolds' therapeutic interest for local drug delivery in five distinct bone disorders-osteomyelitis, osteoporosis, osteoarthritis, osteosarcoma, and cancer bone metastasis. Additionally, it presents the challenges of this possible therapeutic approach and its future perspectives. Albeit bone scaffolds present therapeutic benefits by acting as drug delivery systems, further pre-clinical and clinical assessments are needed to strengthen their understanding and enable research evidence translation into clinical practice. The mismatch between scientific evolution and regulatory frameworks remains one of the major future challenges.
    Keywords:  Bone diseases; Bone regeneration; Local drug delivery; Scaffolds
    DOI:  https://doi.org/10.1007/s13346-022-01191-w
  153. Adv Drug Deliv Rev. 2022 Jul 08. pii: S0169-409X(22)00333-7. [Epub ahead of print] 114443
    Decorated bacteria and the application in drug delivery.
    Feng Wu, Jinyao Liu.
      The use of living bacteria either as therapeutic agents or drug carriers has shown great potential in treating a multitude of intractable diseases. However, cells are often fragile to unfriendly environmental stressors and limited by inadequately therapeutic responses, leading to unwanted cell death and a decline in treatment efficacy. Surface decoration of bacteria has emerged as a simple yet useful strategy that not only confers bacteria with extra capacity to resist environmental threats but also endows them with exogenous characteristics that are neither inherent nor naturally achievable. In this review, we systematically introduce the advancements of physicochemical and biological technologies for surface modification of bacteria, especially the single-cell surface decoration strategies of individual bacteria. We highlight the recent progress on surface decoration that aims to improve the bioavailability and efficacy of therapeutic bacterial agents and also to achieve enhanced and targeted delivery of conventional drugs. The promises along with challenges of surface-decorated bacteria as drug delivery systems for applications in cancer therapy, intestinal disease treatment, bioimaging, and diagnosis are further discussed with respect to future clinical translation. This review offers an overview of the advances of decorated bacteria for drug delivery applications and would contribute to the development of the next generation of advanced bacterial-based therapies.
    Keywords:  Bacteria; Drug carrier; Drug delivery; Living therapeutics; Surface decoration
    DOI:  https://doi.org/10.1016/j.addr.2022.114443
  154. Int J Surg Case Rep. 2022 Jul 09. pii: S2210-2612(22)00644-7. [Epub ahead of print]97 107398
    Synchronous breast cancer and non-Hodgkin lymphoma: A case report.
    Salman Ardi Syamsu, Rino Setiady, Nilam Smaradania, Prihantono, Febie Irsandy, Muhammad Faruk.
       INTRODUCTION: Among women, breast cancer (BC) is the most prevalent type of cancer and the top cause of cancer deaths. Although non-Hodgkin lymphoma (NHL) is the most prevalent hematological cancer, it is rarely reported synchronous with BC. Moreover, which malignancy appears first can rarely be explained because they are usually detected incidentally while diagnosing and treating other malignancies. This paper reports a case of invasive ductal carcinoma (IDC) concomitant with NHL.
    PRESENTATION OF CASE: A 35-year-old woman presented with simultaneous IDC in the left breast and NHL in a lymph node in the neck. The patient underwent a modified radical mastectomy for stage IIIA IDC and received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for stage I NHL.
    CLINICAL DISCUSSION: Treating BC and NHL remains challenging due to their significantly different management, the lack of guidelines for treating BC and lymphoma simultaneously, and uncertainty about whether synchronous tumors should be treated separately as distinct clinical entities or as one disease with treatment covering both. Therefore, the best approach continues to be focusing on the most biologically aggressive malignancies.
    CONCLUSION: The enlargement of lymph nodes not in the lymphatic drainage of the primary tumor should be suspected of indicating multiple primary malignancies until proven otherwise. For patients with luminal-B BC, NHL chemotherapy can involve receiving the R-CHOP regimen, including doxorubicin and cyclophosphamide, which can help to mitigate BC.
    Keywords:  Breast cancer; Case report; Chemotherapy drug; Mastectomy; Non-Hodgkin lymphoma; Synchronous malignancy
    DOI:  https://doi.org/10.1016/j.ijscr.2022.107398
  155. BMJ Nutr Prev Health. 2022 ;5(1): 118-133
    Dietary factors that affect the risk of pre-eclampsia.
    Abigail Perry, Anna Stephanou, Margaret P Rayman.
      Pre-eclampsia affects 3%-5% of pregnant women worldwide and is associated with a range of adverse maternal and fetal outcomes, including maternal and/or fetal death. It particularly affects those with chronic hypertension, pregestational diabetes mellitus or a family history of pre-eclampsia. Other than early delivery of the fetus, there is no cure for pre-eclampsia. Since diet or dietary supplements may affect the risk, we have carried out an up-to-date, narrative literature review to assess the relationship between nutrition and pre-eclampsia. Several nutrients and dietary factors previously believed to be implicated in the risk of pre-eclampsia have now been shown to have no effect on risk; these include vitamins C and E, magnesium, salt, ω-3 long-chain polyunsaturated fatty acids (fish oils) and zinc. Body mass index is proportionally correlated with pre-eclampsia risk, therefore women should aim for a healthy pre-pregnancy body weight and avoid excessive gestational and interpregnancy weight gain. The association between the risk and progression of the pathophysiology of pre-eclampsia may explain the apparent benefit of dietary modifications resulting from increased consumption of fruits and vegetables (≥400 g/day), plant-based foods and vegetable oils and a limited intake of foods high in fat, sugar and salt. Consuming a high-fibre diet (25-30 g/day) may attenuate dyslipidaemia and reduce blood pressure and inflammation. Other key nutrients that may mitigate the risk include increased calcium intake, a daily multivitamin/mineral supplement and an adequate vitamin D status. For those with a low selenium intake (such as those living in Europe), fish/seafood intake could be increased to improve selenium intake or selenium could be supplemented in the recommended multivitamin/mineral supplement. Milk-based probiotics have also been found to be beneficial in pregnant women at risk. Our recommendations are summarised in a table of guidance for women at particular risk of developing pre-eclampsia.
    Keywords:  blood pressure lowering; dietary patterns; nutrient deficiencies; nutritional treatment; weight management
    DOI:  https://doi.org/10.1136/bmjnph-2021-000399
  156. J Sci Food Agric. 2022 Jul 14.
    Protective effect of surfactant modified phytosterol oleogels on loaded curcumin.
    Junhua Li, Jiali Zhai, Cuihua Chang, Yanjun Yang, Calum J Drummond, Charlotte E Conn.
       BACKGROUND: Oleogels represent one of the most important carriers for the delivery of lipophilic nutraceuticals. Phytosterols (PS), plant-derived natural sterol compounds, are preferred for oleogel preparation due to their self-assembly properties and health function. However, the relationship between the physical properties of PS-based oleogels and the chemical stability of loaded bioactive compounds is still unclear.
    RESULTS: The influence of lecithin (LC) and glycerol monostearate (GMS) on the physical properties of PS-based oleogels made of liquid coconut oil and the stability of curcumin as a model bioactive loaded in the oleogels was investigated. Results showed that the flow consistency index was much higher for GMS-containing oleogels than that for LC-containing oleogels. The optical microscopy and X-ray scattering analysis showed that the addition of GMS in the PS oleogels promoted the formation of crystal mixture with different crystal polymorph structures, whereas LC addition promoted the formation of needle-like crystals of PS. Using curcumin as a model lipophilic nutraceutical, the GMS-enriched PS oleogels with high crystallinity and flow consistency index exhibited good retention ratio and scavenging activity of the loaded curcumin when stored at room temperature.
    CONCLUSION: This study shows that enhancing the firmness of oleogels made from PS and liquid coconut oil is beneficial to the retention and chemical stability of loaded bioactive (curcumin). The findings of the study will boost the development of PS-based oleogel formulations for lipophilic nutraceutical delivery. This article is protected by copyright. All rights reserved.
    Keywords:  curcumin stability; glycerol monostearate; lecithin; oleogels; physical properties; phytosterol
    DOI:  https://doi.org/10.1002/jsfa.12122
  157. Nutrition. 2022 Jun 09. pii: S0899-9007(22)00183-6. [Epub ahead of print]102 111770
    Efficacy of front-of-pack nutrition labels in improving health status.
    Lorenzo Maria Donini, Claudia Penzavecchia, Luca Muzzioli, Eleonora Poggiogalle, Anna Maria Giusti, Andrea Lenzi, Alessandro Pinto.
      Nutrition labels advise consumers about the nutritional value of packaged foods and their contribution to the overall composition of the diet. They have been proposed as an instrument for the promotion of healthy diets and as a fundamental tool in the prevention of obesity and diet-related non-communicable diseases (NCDs). The aim of this review is to discuss the effectiveness of front-of-pack nutrition labels (FOPNLs) in improving health status, the concern about focusing on single nutrients/foods rather than on eating patterns to prevent obesity and NCDs, and the strength of positive rather than negative messages to promote a healthy and sustainable diet. Although nutrition science investigates individual foods or nutrients, when communicating to the public most of the significant evidence of the favorable health effect largely depends on dietary patterns and not on a single food component or individual nutrient. Therefore, we suggest that a new tool based on positive communication should be developed and implemented to highlight the importance of the diet as a complex matrix.
    Keywords:  Eating pattern; Front-of-pack nutrition label; Healthy diet; Mediterranean diet; Positive nutrition
    DOI:  https://doi.org/10.1016/j.nut.2022.111770
  158. Apoptosis. 2022 Jul 12.
    Anticancer effect and apoptosis induction by azaflavanone derivative in human prostate cancer cells.
    Ganesh Kumar Raut, Genji Sukumar, Moumita Chakrabarti, Jolly Janette Mendonza, Srihari Pabbaraja, B Jagan Mohan Reddy, Ramakrishna Sistla, Sai Balaji Andugulapati, Manika Pal Bhadra.
      Polyphenols are naturally occurring organic compounds with varying structures represented by four major groups: flavonoids, phenolic acids, lignans and stilbenes. Several studies suggested that these secondary metabolites have health benefits due to its anti-tumorigenic effect. Therefore, substantial effort has been put forward to isolate and characterize these natural compounds and synthesize analogues that may serve as potential anti-cancer therapeutics. This present study is aimed at designing and synthesis of azaflavanone derivative and in understanding its mechanism of action in vitro and in vivo. Molecular docking studies predicted that the compound can potentially bind strongly to the Cyclin E1-Cdk2 complex which is a key mediator of the cell cycle progression indicating a biological interference in aggressive prostate cancer. Further downstream studies to understand its cytotoxicity and mechanism of action showed this azaflavanone derivative markedly inhibits viability of prostate cancer cells (DU145) showing an IC50 value of 0.4 μM compared to other cancer cells. The pharmacological ROS insult using the azaflavanone derivative increases the oxidative damage leading to high expression of apoptotic markers with increasing concentration. On compound treatment, the cells lose the metabolic flexibility accompanied by mitochondrial dysfunction leading to cell cycle arrest and apoptosis. Further, no compound mediated toxicity was observed in xenograft mouse model of prostate cancer at a concentration as high as 5 mg/kg. The tumor burden was reduced to 60% rendering the azaflavanone derivative a potential candidate in cancer therapeutics. Collectively, the compound triggers cell cycle arrest and ROS mediated oxidative stress sensitizing the cancerous cells towards apoptosis.
    Keywords:  Apoptosis; Aza-derivative; Cell migration and invasion; Cytotoxicity; OCR and ROS
    DOI:  https://doi.org/10.1007/s10495-022-01745-w
  159. Cell Death Discov. 2022 Jul 09. 8(1): 312
    Gankyrin modulated non-small cell lung cancer progression via glycolysis metabolism in a YAP1-dependent manner.
    Tong Yu, Yanyan Liu, Junwen Xue, Xiang Sun, Di Zhu, Lu Ma, Yingying Guo, Tongzhu Jin, Huiying Cao, Yingzhun Chen, Tong Zhu, Xuelian Li, Haihai Liang, Zhimin Du, Hongli Shan.
      Non-small cell lung cancer (NSCLC) is highly malignant and heterogeneous form of lung cancer and involves various oncogene alterations. Glycolysis, an important step in tumor metabolism, is closely related to cancer progression. In this study, we investigated the biological function and mechanism of action of Gankyrin in glycolysis and its association with NSCLC. Analyzed of data from The Cancer Genome Atlas as well as NSCLC specimens and adjacent tissues demonstrated that Gankyrin expression was upregulated in NSCLC tissues compared to adjacent normal tissues. Gankyrin was found to significantly aggravate cancer-related phenotypes, including cell viability, migration, invasion, and epithelial mesenchymal transition (EMT), whereas Gankyrin silencing alleviated the malignant phenotype of NSCLC cells. Our results reveal that Gankyrin exerted its function by regulating YAP1 expression and increasing its nuclear translocation. Importantly, YAP1 actuates glycolysis, which involves glucose uptake, lactic acid production, and ATP generation and thus might contribute to the tumorigenic effect of Gankyrin. Furthermore, the Gankyrin-accelerated glycolysis in NSCLC cells was reversed by YAP1 deficiency. Gankyrin knockdown reduced A549 cell tumorigenesis and EMT and decreased YAP1 expression in a subcutaneous xenograft nude mouse model. In conclusion, both Gankyrin and YAP1 play important roles in tumor metabolism, and Gankyrin-targeted inhibition may be a potential anti-cancer therapeutic strategy for NSCLC.
    DOI:  https://doi.org/10.1038/s41420-022-01104-3
  160. Pharmacol Res. 2022 Jul 11. pii: S1043-6618(22)00297-3. [Epub ahead of print] 106352
    Saponins and their derivatives: potential candidates to alleviate anthracycline-induced cardiotoxicity and multidrug resistance.
    Pei-Rong Qu, Zhi-Lin Jiang, Ping-Ping Song, Lan-Chun Liu, Mi Xiang, Jie Wang.
      Anthracyclines (ANTs) continue to play an irreplaceable role in oncology treatment. However, the clinical application of ANTs has been limited. In the first place, ANTs can cause dose-dependent cardiotoxicity such as arrhythmia, cardiomyopathy, and congestive heart failure. In the second place, the development of multidrug resistance (MDR) leads to their chemotherapeutic failure. Oncology cardiologists are urgently searching for agents that can both protect the heart and reverse MDR without compromising the antitumor effects of ANT. Based on in vivo and in vitro data, we found that natural compounds, including saponins, may be active agents for other both natural and chemical compounds in the inhibition of anthracycline-induced cardiotoxicity (AIC) and the reversal of MDR. In this review, we summarize the work of previous researchers, describe the mechanisms of AIC and MDR, and focus on revealing the pharmacological effects and potential molecular targets of saponins and their derivatives in the inhibition of AIC and the reversal of MDR, aiming to encourage future research and clinical trials.
    Keywords:  23-Hydroxybetulinic acid(Pubchem CID:12305768); Anthracycline-induced cardiotoxicity; Astragaloside II (Pubchem CID: 13996693); Astragaloside IV(Pubchem CID: 13943297); Dioscin(Pubchem CID: 119245); Doxorubicin; Ginsenoside Rg1(Pubchem CID: 441923); Ginsenoside Rg3(Pubchem CID: 9918693); Ginsenoside Rh2(Pubchem CID: 119307); Heart failure; Multidrug resistance; Natural compounds; Ocotillol(Pubchem CID: 102058355); Saikosaponin-D(Pubchem CID: 107793); Saponins; Ursolic acid(Pubchem CID: 64945)
    DOI:  https://doi.org/10.1016/j.phrs.2022.106352
  161. J Photochem Photobiol B. 2022 Jul 05. pii: S1011-1344(22)00123-3. [Epub ahead of print]234 112509
    The response of the canine mammary simple carcinoma and carcinosarcoma cells to 5-aminolaevulinic acid-based photodynamic therapy: An in vitro study.
    Gamze Guney Eskiler, Ozge Turna, Asuman Deveci Ozkan, Aslihan Baykal, Hazal Ozturk Gurgen, Beyzanur Erk, Elif Ilkay Armutak, Hyun Soo Lim.
       BACKGROUNDS: Canine mammary gland tumors (CMGTs) are heterogeneous tumors and share many similar features with human breast cancer. Despite the improvement of current treatment options, new treatment modalities are required to effectively kill tumor cells without general toxicity in the treatment of CMGTs. Photodynamic therapy (PDT) is a promising method for cancer treatment. However, there is a limited study evaluating the therapeutic efficacy of PDT in the treatment of CMGTs.
    METHODS: In this context, we, for the first time, investigated the therapeutic potential of 5-aminolaevulinic acid (5-ALA) mediated PDT at 6 and 12 J/cm2 in two different subtypes [Tubulopapillary carcinoma (TPC) and carcinosarcoma (CS)] cells via different molecular analysis. The cytotoxic effects of 5-ALA/PDT on these cells were analyzed by intracellular PpIX level, WST-1 and ROS analysis. Furthermore, the underlying moleculer mechanism of 5-ALA/PDT mediated apoptotic effects on TPC and CS cells were evaluated Annexin V, AO/PI, RT-PCR and western blot analysis.
    RESULTS: The 5-ALA/PDT treatment upon irradiation considerably inhibited the viability of both TPC and CS cells (p<0.01) and caused apoptotic death through elevated ROS levels, the activation of Caspase-9, and Caspase-3, and the overexpression of Bax. However, the response of TPC and CS cells to 5-ALA/PDT was different.
    CONCLUSIONS: Our preliminary in vitro findings provide novel insights into the molecular mechanisms underlying 5-ALA/PDT mediated apoptosis in both TPC and CS cells. However, the therapeutic response of CMGT cells to 5-ALA/PDT is limited.
    Keywords:  5-aminolaevulinic acid; Apoptosis; Canine mammary gland tumor; Carcinoma; Carcinosarcoma; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112509
  162. Regen Biomater. 2022 ;9 rbac041
    Iron oxide nanoparticles with photothermal performance and enhanced nanozyme activity for bacteria-infected wound therapy.
    Jiaxin Guo, Wenying Wei, Yanan Zhao, Honglian Dai.
      Metal-based nanomaterials usually have broad-spectrum antibacterial properties, low biological toxicity and no drug resistance due to their intrinsic enzyme-like catalytic properties and external field (magnetic, thermal, acoustic, optical and electrical) responsiveness. Herein, iron oxide (Fe3O4) nanoparticles (IONPs) synthesized by us have good biosafety, excellent photothermal conversion ability and peroxidase-like catalytic activity, which can be used to construct a photothermal-enzymes combined antibacterial treatment platform. IONPs with peroxide-like catalytic activity can induce H2O2 to catalyze the production of •OH in a slightly acidic environment, thus achieving certain bactericidal effects and increasing the sensitivity of bacteria to heat. When stimulated by near-infrared light, the photothermal effect could destroy bacterial cell membranes, resulting in cleavage and inactivation of bacterial protein, DNA or RNA. Meanwhile, it can also improve the catalytic activity of peroxidase-like and promote IONPs to catalyze the production of more •OH for killing bacteria. After IONPs synergistic treatment, the antibacterial rate of Escherichia coli and Staphylococcus aureus reached nearly 100%. It also has an obvious killing effect on bacteria in infected wounds of mice and can effectively promote the healing of S. aureus-infected wounds, which has great application potential in clinical anti-infection treatment.
    Keywords:  antibacterial; catalytic therapy; peroxidase-like; photothermal therapy
    DOI:  https://doi.org/10.1093/rb/rbac041
  163. EPMA J. 2022 Jul 08. 1-26
    Anti-prostate cancer protection and therapy in the framework of predictive, preventive and personalised medicine - comprehensive effects of phytochemicals in primary, secondary and tertiary care.
    Alena Mazurakova, Marek Samec, Lenka Koklesova, Kamil Biringer, Erik Kudela, Raghad Khalid Al-Ishaq, Martin Pec, Frank A Giordano, Dietrich Büsselberg, Peter Kubatka, Olga Golubnitschaja.
      According to the GLOBOCAN 2020, prostate cancer (PCa) is the most often diagnosed male cancer in 112 countries and the leading cancer-related death in 48 countries. Moreover, PCa incidence permanently increases in adolescents and young adults. Also, the rates of metastasising PCa continuously grow up in young populations. Corresponding socio-economic burden is enormous: PCa treatment costs increase more rapidly than for any other cancer. In order to reverse current trends in exploding PCa cases and treatment costs, pragmatic decisions should be made, in favour of advanced populational screening programmes and effective anti-PCa protection at the level of the health-to-disease transition (sub-optimal health conditions) demonstrating the highest cost-efficacy of treatments. For doing this, the paradigm change from reactive treatments of the clinically manifested PCa to the predictive approach and personalised prevention is essential. Phytochemicals are associated with potent anti-cancer activity targeting each stage of carcinogenesis including cell apoptosis and proliferation, cancer invasiveness and metastatic disease. For example, their positive effects are demonstrated for stabilising and restoring mitochondrial health quality, which if compromised is strongly associated with sub-optimal health conditions and strong predisposition to aggressive PCa sub-types. Further, phytochemicals significantly enhance response of cancer cells to anti-cancer therapies including radio- and chemotherapy. Evident plant-based mitigation of negative side-effects frequently observed for conventional anti-cancer therapies has been reported. Finally, dual anti-cancer and anti-viral effects of phytochemicals such as these of silibinin have been demonstrated as being highly relevant for improved PCa management at the level of secondary and tertiary care, for example, under pandemic conditions, since PCa-affected individuals per evidence are highly vulnerable towards COVID-19 infection. Here, we present a comprehensive data analysis towards clinically relevant anti-cancer effects of phytochemicals to be considered for personalised anti-PCa protection in primary care as well as for an advanced disease management at the level of secondary and tertiary care in the framework of predictive, preventive and personalised medicine.
    Keywords:  Anti-cancer protection; COVID-19; Clinical trials; Cost-efficacy; Health policy; Health-to-disease transition; Metastatic disease; Mitochondrial health; Molecular mechanisms; Phenotyping; Phytochemicals; Plant-based food; Predictive Preventive Personalised Medicine (PPPM/3PM); Primary secondary tertiary care; Prostate cancer management; ROS; Radiation and chemotherapy; Risk assessment; Silibinin; Stress; Sub-optimal health condition; Tailored treatments
    DOI:  https://doi.org/10.1007/s13167-022-00288-z
  164. J Colloid Interface Sci. 2022 Jun 30. pii: S0021-9797(22)01124-9. [Epub ahead of print]626 453-465
    Macromolecular conjugated cyanine fluorophore nanoparticles for tumor-responsive photo nanotheranostics.
    Quan Cheng, Huiping Dang, Youliang Tian, Changchang Teng, Dalong Yin, Lifeng Yan.
      For photothermal therapy (PTT), the improved targeting can decrease the dosage and promote the therapeutic function of photothermal agents, which would effectively improve the antitumor effect. The tumor microenvironment (TME) and cells are targets in designing intelligent and responsive theranostics. However, most of these schemes have been limited to the traditional visible and first near-infrared (NIR-I) regions, eager to expand to the second near-infrared (NIR-II) window. We designed and synthesized a polyethylene glycol conjugated and disulfide-modified macromolecule fluorophore (MPSS). MPSS could self-assemble into core-shell micelles in an aqueous solution (MPSS-NPS), while the small molecule probes were in a high aggregation arrangement inside the nanoparticle. The pronounced aggregation quenching (ACQ) effect caused them to the "sleeping" state. After entering the tumor cells, the disulfide bonds in MPSS-NPS broke in response to a high concentration of glutathione (GSH) in TME, and the molecule probes were released. The highly aggregated state was effectively alleviated, resulting in distinct absorption enhancement in the near-infrared region. Therefore, the fluorescence signal was recovered, and the photothermal performance was triggered. In vitro and in vivo studies reveal that the Nano-system is efficient for the smart NIR-II fluorescence imaging-guided PTT, even at a low dosage and density of irradiation.
    Keywords:  Glutathione (GSH); NIR-II fluorescence; Phototheranostics; Photothermal therapy (PTT); Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.jcis.2022.06.134
  165. Med Oncol. 2022 Jul 14. 39(10): 142
    Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells.
    Shane O'Grady, John Crown, Michael J Duffy.
      TP53 (p53) is mutated in 80-90% of cases of triple-negative breast cancer (TNBC). Statins, which are widely used to treat elevated cholesterol, have recently been shown to degrade mutant p53 protein and exhibit anti-cancer activity. The aim of this work was to evaluate the potential of statins in the treatment of TNBC. The anti-proliferative effects of 2 widely used statins were investigated on a panel of 15 cell lines representing the different molecular subtypes of breast cancer. Significantly lower IC50 values were found in triple-negative (TN) than in non-TN cell lines (atorvastatin, p < 0.01; simvastatin p < 0.05) indicating greater sensitivity. Furthermore, cell lines containing mutant p53 were more responsive to both statins than cell lines expressing wild-type p53, suggesting that the mutational status of p53 is a potential predictive biomarker for statin response. In addition to inhibiting proliferation, simvastatin was also found to promote cell cycle arrest and induce apoptosis. Using an apoptosis array capable of detecting 43 apoptosis-associated proteins, a novel protein shown to be upregulated by simvastatin was the IGF-signalling modulator, IGBP4, a finding we confirmed by Western blotting. Finally, we found synergistic growth inhibition between simvastatin and the IGF-1R inhibitor, OSI-906 as well as between simvastatin and doxorubicin or docetaxel. Our work suggests repurposing of statins for clinical trials in patients with TNBC. Based on our findings, we suggest that these trials investigate statins in combination with either doxorubicin or docetaxel and include p53 mutational status as a potential predictive biomarker.
    Keywords:  Breast cancer; Statins; Treatment; Triple-negative; p53
    DOI:  https://doi.org/10.1007/s12032-022-01733-9
  166. Front Nutr. 2022 ;9 883672
    The Association Between Fasting Blood Sugar and Index of Nutritional Quality in Adult Women.
    Farkhondeh Alami, Golsa Khalatbari Mohseni, Mina Ahmadzadeh, Farhad Vahid, Maryam Gholamalizadeh, Mohammad Masoumvand, Soheila Shekari, Atiyeh Alizadeh, Hanieh Shafaei, Saeid Doaei.
       Aim: It's unclear whether diet quality affects glycemic management. The index of nutritional quality (INQ) can examine diets both quantitatively and qualitatively (INQ). Hence, this study aimed to determine whether INQ and fasting blood sugar (FBS) are related among Iranian women.
    Methods: This cross-sectional study was conducted on 360 adult Iranian women. Data were collected on the participants' general characteristics, medical history, anthropometric indices, physical activity, and dietary intake. For nutrient intake assessment, a valid food frequency questionnaire (FFQ) was used, and INQ was then calculated using the daily nutrient intake.
    Results: After adjusting for age, FBS was significantly inverse associated with INQ for vitamins A (B = -0.193, p < 0.01), magnesium (B = -0.137, p < 0.01), phosphor (B = -0.175, p < 0.01), zinc (B = -0.113, p < 0.01), vitamin K (B = -0.197, p < 0.01), manganese (B = -0.111, p < 0.01) and selenium (B = -0.123, p < 0.01). The association between FBS and INQ for Se and Mn was disappeared after further adjustment for gender, body mass index (BMI), menopausal status, and total energy intake.
    Conclusion: There was a significant inverse relationship between FBS and the INQ of vitamin A, manganese, phosphor, zinc, vitamin K, magnesium, and selenium. Prospective cohort studies should be conducted to establish a causal relationship between FBS and INQ.
    Keywords:  dietary intake; fasting blood sugar; glycemic control; index of nutritional quality; medical history
    DOI:  https://doi.org/10.3389/fnut.2022.883672
  167. Elife. 2022 Jul 11. pii: e73245. [Epub ahead of print]11
    Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context.
    Samuel Kerk, Lin Lin, Amy L Myers, Damien J Sutton, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Yaqing Zhang, Jennifer A Jiménez, Barbara S Nelson, Brandon Chen, Anthony Robinson, Galloway Thurston, Samantha B Kemp, Nina G Steele, Megan T Hoffman, Hui-Ju Wen, Daniel Long, Sarah E Ackenhusen, Johanna Ramos, Xiaohua Gao, Zeribe C Nwosu, Stefanie Galban, Christopher J Halbrook, David B Lombard, David R Piwnica-Worms, Haoqiang Ying, Marina Pasca di Magliano, Howard C Crawford, Yatrik M Shah, Costas A Lyssiotis.
      Mitochondrial glutamate-oxaloacetate (GOT2) is part of the malate-aspartate shuttle (MAS), a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance induced by GOT2 KD, permitting sustained proliferation. Despite a strong in vitro inhibitory phenotype, loss of GOT2 had no effect on tumor growth in xenograft PDA or autochthonous mouse models. We show that cancer-associated fibroblasts (CAFs), a major component of the pancreatic tumor microenvironment (TME), release the redox active metabolite pyruvate, and culturing GOT2 KD cells in CAF conditioned media (CM) rescued proliferation in vitro. Furthermore, blocking pyruvate import or pyruvate-to-lactate reduction prevented rescue of GOT2 KD in vitro by exogenous pyruvate or CAF CM. However, these interventions failed to sensitize xenografts to GOT2 KD in vivo, demonstrating the remarkable plasticity and differential metabolism deployed by PDA cells in vitro and in vivo. This emphasizes how the environmental context of distinct pre-clinical models impacts both cell-intrinsic metabolic rewiring and metabolic crosstalk with the tumor microenvironment (TME).
    Keywords:  biochemistry; cancer biology; chemical biology; human; mouse
    DOI:  https://doi.org/10.7554/eLife.73245
  168. J Control Release. 2022 Jul 12. pii: S0168-3659(22)00413-8. [Epub ahead of print]349 367-378
    TRAIL & EGFR affibody dual-display on a protein nanoparticle synergistically suppresses tumor growth.
    Heejin Jun, Eunjung Jang, Hansol Kim, Mirae Yeo, Seong Guk Park, Jaehyeok Lee, Kyeong Jin Shin, Young Chan Chae, Sebyung Kang, Eunhee Kim.
      The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer drug candidate because it selectively binds to the proapoptotic death receptors, which are frequently overexpressed in a wide range of cancer cells, subsequently inducing strong apoptosis in these cells. However, the therapeutic benefit of TRAIL has not been clearly proven, mainly because of its poor pharmacokinetic characteristics and frequent resistance to its application caused by the activation of a survival signal via the EGF/epidermal growth factor receptor (EGFR) signaling pathway. Here, a lumazine synthase protein cage nanoparticle isolated from Aquifex aeolicus (AaLS) was used as a multiple ligand-displaying nanoplatform to display polyvalently both TRAIL and EGFR binding affibody molecules (EGFRAfb) via a SpyTag/SpyCatcher protein-ligation system, to form AaLS/TRAIL/EGFRAfb. The dual-ligand-displaying AaLS/TRAIL/EGFRAfb exhibited a dramatically enhanced cytotoxicity on TRAIL-resistant and EGFR-overexpressing A431 cancer cells in vitro, effectively disrupting the EGF-mediated EGFR survival signaling pathway by blocking EGF/EGFR binding as well as strongly activating both the extrinsic and intrinsic apoptotic pathways synergistically. The AaLS/TRAIL/EGFRAfb selectively targeted A431 cancer cells in vitro and actively reached the tumor sites in vivo. The A431 tumor-bearing mice treated with AaLS/TRAIL/EGFRAfb exhibited a significant suppression of the tumor growth without any significant side effects. Collectively, these findings showed that the AaLS/TRAIL/EGFRAfb could be used as an effective protein-based therapeutic for treating EGFR-positive cancers, which are difficult to manage using mono-therapeutic approaches.
    Keywords:  Dual-ligand display; EGFR affibody; Lumazine synthase; Protein ligation; TRAIL
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.004
  169. J Exp Clin Cancer Res. 2022 Jul 15. 41(1): 222
    Targeting purinergic pathway to enhance radiotherapy-induced immunogenic cancer cell death.
    Xuhui Bao, Liyi Xie.
      Emerging evidence has demonstrated that radiotherapy (RT) can not only cause direct damage to cancer cells but also lead to immunogenic cell death (ICD), which involves the activation of host antitumor immune response in tumor immune microenvironment (TIME). RT-induced ICD comprises the release of damage-associated molecular patterns (DAMPs) from dying cancer cells that result in the activation of tumor-specific immunity to elicit long-term antitumor efficacy in both original and abscopal tumor sites. Adenosine triphosphate (ATP), as an important DAMP released by irradiated cancer cells and an essential factor within purinergic pathway, can be further hydrolyzed to adenosine (ADO) by two key ectonucleotidases, CD39 and CD73, to further modulate the antitumor immunity in TIME through purinergic signaling via the interaction to its specific receptors such as adenosine 2A receptor (A2AR) and A2BR widely expressed on the surface of the components in TIME, including cancer cells and many immune effector cells. In this review, we first introduced key components in purinergic pathway including ATP, ADO, their receptors, and essential ectonucleotidases. Then we reviewed the regulation of ATP and ADO levels and their main mechanisms by which they promote tumor growth and broadly suppress antitumor immunity through inhibiting the pro-inflammatory response of dendritic cells, cytotoxic T lymphocytes, and natural killer cells, while improving the anti-inflammatory response of regulatory T cells, macrophages, and myeloid-derived suppressor cells in TIME, especially after irradiation. Finally, we presented an overview of dozens of promising therapeutics including pharmacological antagonists and specific antibodies targeting ADO receptors and ectonucleotidases CD39 or CD73 investigated in the clinic for cancer treatment, especially focusing on the preclinical studies and clinical trials being explored for blocking the purinergic signaling to enhance RT as a combination antitumor therapeutic strategy, which has a robust potential to be translated to the clinic in the future.
    Keywords:  Cancer; Immunogenic cell death; Immunotherapy; Purinergic pathway; Radiotherapy
    DOI:  https://doi.org/10.1186/s13046-022-02430-1
  170. Cell Mol Biol (Noisy-le-grand). 2022 Feb 27. 67(6): 117-124
    Experimental study on anti angiogenesis of recombinant mouse angiostatin gene in mice with gallbladder carcinoma.
    Chunlin Wang, Tao Jiang, Yunxie Zhu.
      Gallbladder cancer is one of the gastrointestinal tumors with an extremely poor prognosis. Its incidence rate is gradually increasing worldwide, and the rate of radical resection surgery is extremely low. Not sensitive to radiotherapy and chemotherapy, with a very poor prognosis. This study aimed to investigate whether the recombinant mouse angiostatin gene transfected anti-angiogenic gallbladder cancer cells can express angiostatin protein with the activity of inhibiting the growth of vascular endothelial cells and the inhibitory effect on the growth of gallbladder cancer. The recombinant mouse angiostatin gene eukaryotic expression plasmid was transfected into the gallbladder cancer cell line by applying liposome LIPOFECTAMINE 2000, and its activity was detected by vascular endothelial cell proliferation analysis. The results show that angiostatin can inhibit the growth of transplanted gallbladder cancer, and as the number of injections increases, the inhibition rate of gallbladder cancer growth also increases. At the end of the experiment, the total inhibition rate of gallbladder cancer growth reached 95% 5%, 20%, 30%, 40% gradually increase. Therefore, angiostatin has potential clinical application value in gene therapy of gallbladder cancer.
    DOI:  https://doi.org/10.14715/cmb/2021.67.6.16
  171. Int J Biol Macromol. 2022 Jul 08. pii: S0141-8130(22)01423-4. [Epub ahead of print]216 475-486
    A poloxamer/hyaluronic acid/chitosan-based thermosensitive hydrogel that releases dihydromyricetin to promote wound healing.
    Yingchun Zhao, Xinglong Liu, Xiaojuan Peng, Yinan Zheng, Zhiqiang Cheng, Shuwen Sun, Qiteng Ding, Wencong Liu, Chuanbo Ding.
      Wounds caused by accidents and surgery are inevitable, and inflammation and microbial infection during the healing process are serious clinical challenges, resulting in slow wound healing. In this study, we created a 37 °C-sensitive hydrogel using poloxamer, chitosan and hyaluronic acid, loaded with the active substance dihydromyricetin, and further evaluated its potential for wound healing. The hydrogels were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction and thermogravimetric analysis for their micromorphological structure, characteristic functional groups, crystal structure and thermal stability, and in vitro drug release assays showed that the hydrogel could slowly release dihydromyricetin. In addition, the hydrogels were found to exhibit good biocompatibility and significant in vitro antioxidant and anti-inflammatory activity according to hemolysis, in vitro antioxidant and anti-inflammatory tests. Methyl thiazolyl tetrazole cytotoxicity tests verified that the film was non-toxic to human keratinocyte (HaCaT) cells, while in vivo experiments showed that this hydrogel could promote skin repair by promoting skin-associated growth factor expression and inhibiting nuclear factor kappa B-mediated cellular inflammatory factors. These results demonstrated that the temperature-sensitive hydrogels loaded with dihydromyricetin could serve as potential candidates for guided skin repair.
    Keywords:  Dihydromyricetin; Inflammation; Temperature sensitive hydrogel; Wound healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.06.210
  172. Biomed Res Int. 2022 ;2022 6491771
    Effect of Dihydroquercetin on Energy Metabolism in LPS-Induced Inflammatory Mice.
    Xiaoying Yu, Saddam Hussein, Lijia Li, Qingyu Liu, Zhibin Ban, Hailong Jiang.
      This study investigated the effects and alterations of dihydroquercetin on the growth performance, nutriment metabolism, antioxidant and immune function, and energy substrate utilization in lipopolysaccharide-challenged mice. A total of 0, 50, and 200 mg/kg of dihydroquercetin were intragastrically administered once a day for 21 days. After the pretreatment with dihydroquercetin, each group was subjected to a lipopolysaccharide challenge (except for the control group). After lipopolysaccharide injection, food intake, body weight, metabolic indexes of blood and liver nutrients, blood inflammatory factors, and liver oxidative stress indexes were measured at 6, 12, 24, and 48 h, respectively. Indirect calorimetry analysis was performed by respiratory gas analysis for 48 h to calculate the energy substrate metabolism of carbohydrate, fat, and protein. Urinary nitrogen excretion was measured to evaluate the urinary protein metabolism to calculate the substrate utilization. The results showed that dihydroquercetin pretreatment can significantly increase the weight gain and average food intake and decrease the mortality rate in lipopolysaccharide-induced inflammation mice. Furthermore, dihydroquercetin pretreatment can alleviate the negative effects of lipopolysaccharides by increasing levels of superoxide dismutase and glutathione peroxidase and by decreasing the malondialdehyde and serum inflammatory cytokines (interleukin-1β, nuclear factor κB, and interleukin-6). Dihydroquercetin pretreatment also can relieve nutrient metabolic disorder by increasing blood glucose, serum total protein, and liver glycogen levels and reducing serum and liver triglycerides, serum cholesterol, serum lactate dehydrogenase, and serum urea nitrogen levels. Meanwhile, it increases the relative utilization of carbohydrate, reducing relative utilization of protein and lipid, alleviating the change in energy metabolism pattern from glucose-predominant to lipid-predominant caused by lipopolysaccharide stimulation. In addition, the degree of metabolic pattern transformation depends on the dose of dihydroquercetin supplement. Finally, according to principal component analysis, we found that the inflammation was strongest in the mice at 24 h and was subsequently relieved in the LPS-stimulated group, whereas in the dihydroquercetin-pretreated group, the inflammation was initially relieved. To summarize, dihydroquercetin pretreatment can improve energy metabolism disorder and attenuate the negative effects of lipopolysaccharide challenge in mice from the initial stage of inflammation.
    DOI:  https://doi.org/10.1155/2022/6491771
  173. Acta Biomater. 2022 Jul 06. pii: S1742-7061(22)00392-0. [Epub ahead of print]
    Skin-Targeted Delivery of Extracellular Vesicle-Encapsulated Curcumin Using Dissolvable Microneedle Arrays.
    Saigopalakrishna S Yerneni, Ezgi P Yalcintas, Jason D Smith, Saadyah Averick, Phil G Campbell, O Burak Ozdoganlar.
      Therapeutic benefits of curcumin for inflammatory diseases have been demonstrated. However, curcumin's potential as a clinical therapeutic has been hindered due to its low solubility and stability in vivo. We hypothesized that a hybrid curcumin carrier that incorporates albumin-binding and extracellular vesicle (EV) encapsulation could effectively address the current challenges of curcumin delivery. We further postulated that using dissolvable microneedle arrays (dMNAs) for local delivery of curcumin-albumin-EVs (CA-EVs) could effectively control skin inflammation in vivo. Mild sonication was used to encapsulate curcumin and albumin into EVs, and the resulting CA-EVs were integrated into tip-loaded dMNAs. In vitro and in vivo studies were performed to assess the stability, cellular uptake, and anti-inflammatory bioactivity of dMNA-delivered CA-EVs. Curcumin in CA-EVs exhibited at least five-fold higher stability in vitro than naïve curcumin or curcumin-EVs without albumin. Incorporating CA-EVs into dMNAs did not alter their cellular uptake or anti-inflammatory bioactivity. The dMNA embedded CA-EVs retained their bioactivity when stored at room temperature for at least 12 months. In rat and mice models, dMNA delivered CA-EVs suppressed and significantly reduced lipopolysaccharide and Imiquimod-triggered inflammation. We conclude that dMNA delivery of CA-EVs has the potential to become an effective local-delivery strategy for inflammatory skin diseases. STATEMENT OF SIGNIFICANCE: : We introduce and evaluate a skin-targeted delivery system for curcumin that incorporates albumin association, extracellular-vesicle encapsulation, and dissolvable microneedle arrays (dMNAs) for delivery. In vitro, curcumin-albumin encapsulated extracellular vesicles (CA-EVs) inhibit and reverse the LPS-triggered expression of inflammatory transcription factor NF-kB. The integration of CA-EVs into dMNAs does not affect them physically or functionally. Importantly, dMNAs extend EV storage stability up to 12 months at room temperature with minimal loss in their bioactivity. We demonstrate that dMNA delivered CA-EVs effectively block and reverse skin inflammation in vivo in mouse and rat models.
    Keywords:  Microneedle arrays; curcumin; drug delivery; exosomes; extracellular vesicles; inflammation
    DOI:  https://doi.org/10.1016/j.actbio.2022.06.046
  174. ACS Nano. 2022 Jul 12.
    Targeting the Mitochondria with Pseudo-Stealthy Nanotaxanes to Impair Mitochondrial Biogenesis for Effective Cancer Treatment.
    Lulu Ren, Peirong Xu, Jie Yao, Zihan Wang, Kewei Shi, Weidong Han, Hangxiang Wang.
      The clinical success of anticancer therapy is usually limited by drug resistance and the metastatic dissemination of cancer cells. Mitochondria are essential generators of cellular energy and play a crucial role in sustaining cell survival and metastatic escape. Selective drug strategies targeting mitochondria are able to rewire mitochondrial metabolism and may provide an alternative paradigm to treat many aggressive cancers with high efficiency and low toxicity. Here, we present a pseudo-stealthy mitochondria-targeted pro-nanotaxane and test it against recurrent and metastatic tumor xenografts. The nanoparticle encapsulates a mitochondria-targetable pro-taxane agent, which can be converted into the chemically unmodified cabazitaxel drug, with further surface cloaking with a low-density lipophilic triphenylphosphonium cation. The resultant nanotaxane could be effectively taken up by cells and consequently specifically localized to the mitochondria. The in situ activated cabazitaxel causes mitochondrial dysfunction and ultimately results in potent cell apoptosis. After intravenous administration to animals, pro-nanotaxane mimics the stealthy behavior of polyethylene glycol-cloaked nanoparticles to provide a long circulation time. The antitumor efficacy of this mitochondria-targeted system was validated in multiple preclinical drug-resistant tumor models. Notably, in a patient-derived metastatic melanoma model that was initially pretreated with cabazitaxel, nanotaxane administration not only produced durable tumor reduction but also substantially suppressed metastatic recurrence. Taken together, these results demonstrate that this combination of a pseudo-stealthy platform with a rationally designed pro-drug is an attractive approach to target mitochondria and enhance drug efficacy.
    Keywords:  drug resistance; metastasis; mitochondrial delivery; pro-drug engineering; pseudo-stealthy nanotaxane
    DOI:  https://doi.org/10.1021/acsnano.1c08008
  175. Front Oncol. 2022 ;12 900985
    Drug Repurposing by Tumor Tissue Editing.
    Florian Lüke, Dennis Christoph Harrer, Pan Pantziarka, Tobias Pukrop, Lina Ghibelli, Christopher Gerner, Albrecht Reichle, Daniel Heudobler.
      The combinatory use of drugs for systemic cancer therapy commonly aims at the direct elimination of tumor cells through induction of apoptosis. An alternative approach becomes the focus of attention if biological changes in tumor tissues following combinatory administration of regulatorily active drugs are considered as a therapeutic aim, e.g., differentiation, transdifferentiation induction, reconstitution of immunosurveillance, the use of alternative cell death mechanisms. Editing of the tumor tissue establishes new biological 'hallmarks' as a 'pressure point' to attenuate tumor growth. This may be achieved with repurposed, regulatorily active drug combinations, often simultaneously targeting different cell compartments of the tumor tissue. Moreover, tissue editing is paralleled by decisive functional changes in tumor tissues providing novel patterns of target sites for approved drugs. Thus, agents with poor activity in non-edited tissue may reveal new clinically meaningful outcomes. For tissue editing and targeting edited tissue novel requirements concerning drug selection and administration can be summarized according to available clinical and pre-clinical data. Monoactivity is no pre-requisite, but combinatory bio-regulatory activity. The regulatorily active dose may be far below the maximum tolerable dose, and besides inhibitory active drugs stimulatory drug activities may be integrated. Metronomic scheduling often seems to be of advantage. Novel preclinical approaches like functional assays testing drug combinations in tumor tissue are needed to select potential drugs for repurposing. The two-step drug repurposing procedure, namely establishing novel functional systems states in tumor tissues and consecutively providing novel target sites for approved drugs, facilitates the systematic identification of drug activities outside the scope of any original clinical drug approvals.
    Keywords:  PPAR γ; anakoinosis; biomodulation; mTOR; metronomic chemotherapy; molecular diagnostics; pioglitazone; umbrella trial
    DOI:  https://doi.org/10.3389/fonc.2022.900985
  176. Anim Biotechnol. 2022 Jul 15. 1-10
    Phytosterol: nutritional significance, health benefits, and its uses in poultry and livestock nutrition.
    Mahzaib Munawar, Muhammad Sajjad Khan, Muhammad Saeed, Umair Younas, Mayada R Farag, Alessandro Di Cerbo, Nahed El-Shall, Anna Rita Loschi, Kuldeep Dhama, Mahmoud Alagawany.
      Medicinal plants with active ingredients have shown great potential as natural and sustainable additives in livestock and poultry diets as growth promoters, performance, feed conversion ratio, digestibility of nutrient enhancers, and antioxidants and immune system modulators. Among active ingredients, phytosterols, which are plant-based bio-factors that may be found in seeds, fruits, grains, vegetables and legumes, are thought to be involved in the aforementioned activities but are also widely known in human medicine due to their efficacy in treating diabetes, coronary heart disease, and tumors. Nevertheless, phytosterols can also promote carcinogens production, angiogenesis inhibition, metastasis, infiltration, and cancer cells proliferation. This review focuses on the deepening of the biological role and health benefits of phytosterols and their new potential application in poultry and livestock nutrition.
    Keywords:  Phytosterols; beneficial effects; mechanism of action; poultry; sources
    DOI:  https://doi.org/10.1080/10495398.2022.2099882
  177. Front Nutr. 2022 ;9 890730
    The Interaction Between Dietary Fructose and Gut Microbiota in Hyperuricemia and Gout.
    Xin-Yu Fang, Liang-Wei Qi, Hai-Feng Chen, Peng Gao, Qin Zhang, Rui-Xue Leng, Yin-Guang Fan, Bao-Zhu Li, Hai-Feng Pan, Dong-Qing Ye.
      With the worldwide epidemics of hyperuricemia and associated gout, the diseases with purine metabolic disorders have become a serious threat to human public health. Accumulating evidence has shown that they have been linked to increased consumption of fructose in humans, we hereby made a timely review on the roles of fructose intake and the gut microbiota in regulating purine metabolism, together with the potential mechanisms by which excessive fructose intake contributes to hyperuricemia and gout. To this end, we focus on the understanding of the interaction between a fructose-rich diet and the gut microbiota in hyperuricemia and gout to seek for safe, cheap, and side-effect-free clinical interventions. Furthermore, fructose intake recommendations for hyperuricemia and gout patients, as well as the variety of probiotics and prebiotics with uric acid-lowering effects targeting the intestinal tract are also summarized to provide reference and guidance for the further research.
    Keywords:  fructose; gout; gut microbiota; hyperuricemia; interaction
    DOI:  https://doi.org/10.3389/fnut.2022.890730
  178. J Colloid Interface Sci. 2022 Jul 01. pii: S0021-9797(22)01164-X. [Epub ahead of print]626 803-814
    Nanoscale Hf-hematoporphyrin frameworks for synergetic sonodynamic/radiation therapy of deep-seated tumors.
    Zhaojie Wang, Nuo Yu, Jiulong Zhang, Qian Ren, Maoquan Li, Zhigang Chen.
      Most of tumors are located in deep-depth of animals, and the therapy of deep-seated tumors remains a severe challenge due to the performance reduction of promising technologies including phototherapy. To solve the problem, herein we have developed a hafnium-hemoporfin frameworks (HfHFs) as multifunctional theranostic nanoplatforms for synergetic sonodynamic therapy (SDT) and radiation therapy (RT) of deep-seated tumors. HfHFs are constructed by a sonication-assisted assembly route with hematoporphyrin monomethyl ether (HMME) sonosensitizer molecules as bridging linkers and Hf4+ as metal nodes. The resulting HfHFs sample is composed of spherical nanoparticles with size of 90-130 nm, and then surface-modified with DSPE-PEG to improve the water-dispersity. Under ultrasound (US) irradiation, HMME ligands in HfHFs can be motivated to produce singlet oxygen (1O2) due to sonodynamic effect. When the HfHFs sample is exposed by X-ray, the high atomic-number Hf4+ in the HfHFs can effectively absorb X-ray to increase RT effect by producing hydroxyl radicals (•OH). When HfHFs dispersion is intravenously injected in the tumor-bearing mice, the tumor can be monitored by CT imaging. Moreover, the deep-seated tumors coated by tissue barriers can be suppressed effectively by the synergistic SDT and RT, which is better than that of SDT or RT alone. Therefore, HfHFs can be employed as a novel nanoagent for the SDT-RT of deep-seated tumors.
    Keywords:  Deep-seated tumors; Hf-hematoporphyrin frameworks; Radiation therapy; Sonodynamic therapy
    DOI:  https://doi.org/10.1016/j.jcis.2022.06.174
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