bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–07–24
132 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Light triggered release of a triple action porphyrin-cisplatin conjugate evokes stronger immunogenic cell death for chemotherapy, photodynamic therapy and cancer immunotherapy.
  2. Anticancer effects of natural phytochemicals in anaplastic thyroid cancer (Review).
  3. Curcumin- and resveratrol-co-loaded nanoparticles in synergistic treatment of hepatocellular carcinoma.
  4. Emerging roles of fatty acid metabolism in cancer and their targeted drug development.
  5. Anti-CD44 and EGFR Dual-Targeted Solid Lipid Nanoparticles for Delivery of Doxorubicin to Triple-Negative Breast Cancer Cell Line: Preparation, Statistical Optimization, and In Vitro Characterization.
  6. Research progress on the interaction between long non‑coding RNAs and RNA‑binding proteins to influence the reprogramming of tumor glucose metabolism (Review).
  7. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).
  8. Biodegradable disulfide crosslinked chitosan/stearic acid nanoparticles for dual drug delivery for colorectal cancer.
  9. The role of dietary polyphenols in alternating DNA methylation in cancer.
  10. Synergistic hydroxyl radical formation, system XC- inhibition and heat shock protein crosslinking tango in ferrotherapy: A prove-of-concept study of "sword and shield" theory.
  11. Polymeric Nanoparticles in Cancer Chemotherapy: A Narrative Review.
  12. Evaluation of thermosensitive chitosan hydrogel containing gefitinib loaded cellulose acetate butyrate nanoparticles in a subcutaneous breast cancer model.
  13. Potential of Black Phosphorus in Immune-Based Therapeutic Strategies.
  14. Synthetic antioxidants from a natural source can overtake the oncogenic stress management system and activate the stress‑sensitized death of KSHV‑infected cancer cells.
  15. Formulation Development and Characterization of pH Responsive Polymeric Nano-Pharmaceuticals for Targeted Delivery of Anti-Cancer Drug (Methotrexate).
  16. Effects and mechanisms of resveratrol for prevention and management of cancers: An updated review.
  17. Integrating Au and ZnO nanoparticles onto graphene nanosheet for enhanced sonodynamic therapy.
  18. Ferrocene and glucose oxidase-installed multifunctional hydrogel reactors for local cancer therapy.
  19. Recent advances in smart nanoplatforms for tumor non-interventional embolization therapy.
  20. Recent Progress in Bio-Responsive Drug Delivery Systems for Tumor Therapy.
  21. Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy.
  22. Cancer depends on fatty acids for ATP production: a possible link between cancer and obesity.
  23. Fucoidan-based nanoparticles: Preparations and applications.
  24. Nanozyme Hydrogels for Self-Augmented Sonodynamic/Photothermal Combination Therapy.
  25. Release of bioactive compounds from delivery systems by stimuli-responsive approaches; triggering factors, mechanisms, and applications.
  26. A Nanounit Strategy Disrupts Energy Metabolism and Alleviates Immunosuppression for Cancer Therapy.
  27. Nanocarriers for Smart Therapeutic Strategies to Treat Drug-Resistant Tumors: A Review.
  28. Anticancer effect of selenium/chitosan/polyethylene glycol/allyl isothiocyanate nanocomposites against diethylnitrosamine-induced liver cancer in rats.
  29. Zwitterionic polymer coated sorafenib-loaded Fe3O4 composite nanoparticles induced ferroptosis for cancer therapy.
  30. O-GlcNAcylation of ZEB1 facilitated mesenchymal pancreatic cancer cell ferroptosis.
  31. Role of oxidative stress in angiogenesis and the therapeutic potential of antioxidants in breast cancer.
  32. Advances, challenge and prospects in cell-mediated nanodrug delivery for cancer therapy: a review.
  33. Radiodynamic therapy with CsI(na)@MgO nanoparticles and 5-aminolevulinic acid.
  34. Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance.
  35. The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors.
  36. Advances in Nano-formulated Polyphenols for Protection against Cardiovascular diseases.
  37. Intracellular K+-Responsive Block Copolymer Micelles for Targeted Drug Delivery of Curcumin.
  38. A New Gold Nanoparticles and Paclitaxel Co-Delivery System for Enhanced Anti-Cancer Effect Through Chemo-Photothermal Combination.
  39. Simvastatin-Loaded Lipid Emulsion Nanoparticles: Characterizations and Applications.
  40. Effect of Fasting on Cancer: A narrative review of scientific evidence.
  41. A multi-hit therapeutic nanoplatform for hepatocellular carcinoma: Dual stimuli-responsive drug release, dual-modal imaging, and in situ oxygen supply to enhance synergistic therapy.
  42. Research Progress on the Anticancer Activities and Mechanisms of Polysaccharides From Ganoderma.
  43. Combination of Ashwagandha Water Extract and Intermittent Fasting as a Therapy to Overcome Cisplatin Resistance in Breast Cancer: An in vitro and in vivo Study.
  44. Cell Metabolomics Study on Synergistic anti-Hepatocellular Carcinoma Effect of Aidi Injection Combined with Doxorubicin.
  45. Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy.
  46. Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer.
  47. Boric acid exert anti-cancer effect in poorly differentiated hepatocellular carcinoma cells via inhibition of AKT signaling pathway.
  48. Coacervate-mediated novel pancreatic cancer drug Aleuria Aurantia lectin delivery for augmented anticancer therapy.
  49. Nanofabrication of PLGA- PEG-Chitosan-Folic acid Systems for Delivery of Colchicine to HT-29 Cancer Cells.
  50. Alendronate modified mPEG-PLGA nano-micelle drug delivery system loaded with astragaloside has anti-osteoporotic effect in rats.
  51. Review On the Effects Curcumin on Tumors of the Reproductive System: Curcumin and Reproductive Tumors.
  52. Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity.
  53. Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.
  54. Formulation and evaluation of a smart drug delivery system of 5-fluorouracil for pH-sensitive chemotherapy.
  55. Anti-cancer properties of cannflavin A and potential synergistic effects with gemcitabine, cisplatin, and cannabinoids in bladder cancer.
  56. KRAS Mutation: Characterization and Its Impact on Survival Outcome of Patients with Metastatic Colorectal Cancer.
  57. Recent advances in multifunctional dendrimer-based nanoprobes for breast cancer theranostics.
  58. Fabrication, GSH-responsive drug release, and anticancer properties of thioctic acid-based intelligent hydrogels.
  59. Mitochondrial Function and Microbial Metabolites as Central Regulators of Intestinal Immune Responses and Cancer.
  60. Plant Extracts and Phytochemicals, a Promising Strategy Against Oral Lichen Planus: a review on Clinical Trials.
  61. Mechanisms of cancer cell death induction by paclitaxel: an updated review.
  62. Recent developments in chitosan hydrogels carrying natural bioactive compounds.
  63. Polysaccharide-based hydrogels containing herbal extracts for wound healing applications.
  64. The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications.
  65. Combinatorial delivery of Ribociclib and Green tea extract mediated nanostructured lipid carrier for oral delivery for the treatment of breast cancer synchronizing in silico, in vitro, and in vivo studies.
  66. Interplay between Cellular Metabolism and DNA viruses.
  67. Selenium nanoparticles: Enhanced nutrition and beyond.
  68. Co-Delivery of Erlotinib and Resveratrol via Nanostructured Lipid Carriers: A Synergistically Promising Approach for Cell Proliferation Prevention and ROS-Mediated Apoptosis Activation.
  69. Mechanisms Linking Vitamin D Deficiency to Impaired Metabolism: An Overview.
  70. Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer.
  71. Amphiphilic nano-delivery system based on modified-chitosan and ovalbumin: Delivery and stability in simulated digestion.
  72. Targeted Therapy of Lung Adenocarcinoma by the Nanoplatform Based on Milk Exosomes Loaded with Paclitaxel.
  73. Protection of Hair Color With Pomegranate Peel Extract Loaded Liposomal Formulation: Preparation, Characterization and Ex-vivo Activity Studies.
  74. Anti-angiogenic nano-delivery system promotes tumor vascular normalizing and micro-environment reprogramming in solid tumor.
  75. Preparation and evaluation of the anti-cancer properties of RGD-modified curcumin-loaded chitosan/perfluorohexane nanocapsules in vitro.
  76. Cu-Hemin Nanosheets and Indocyanine Green Co-Loaded Hydrogel for Photothermal Therapy and Amplified Photodynamic Therapy.
  77. New insights into anti-diabetes effects and molecular mechanisms of dietary saponins.
  78. Novel antibacterial hydrogels based on gelatin/polyvinyl-alcohol and graphene oxide/silver nanoconjugates: formulation, characterization, and preliminary biocompatibility evaluation.
  79. The Effects of Vitamin D Fortified Products on Bone Biomarkers: A Systematic Review and Meta-Analysis.
  80. Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers.
  81. Stability Characterization for Pharmaceutical Liposome Product Development with Focus on Regulatory Considerations: An Update.
  82. Remodeling "cold" tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona.
  83. Laboratory scale medicinal plants mediated green synthesis of biocompatible nanomaterials and their versatile biomedical applications.
  84. Nonlinear Multi-Objective Flux Balance Analysis of the Warburg Effect.
  85. Cyclodextrin-based delivery systems in parenteral formulations: a critical update review.
  86. Editorial: Metabolic Intervention Based on Functional Biomaterial Strategy to Potentiate Cancer Immunotherapy, Volume I.
  87. Curcumin, thymoquinone, and 3, 3'-diindolylmethane combinations attenuate lung and liver cancers progression.
  88. Extrinsic hyaluronic acid induction differentially modulates intracellular glutamine metabolism in breast cancer stem cells.
  89. Selenium Status and Its Antioxidant Role in Metabolic Diseases.
  90. Statins and angiogenesis in non-cardiovascular diseases.
  91. Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology.
  92. Oxidative stress-mediated synergistic deleterious effects of nano- and microplastics in the hypoxia-conditioned marine rotifer Brachionus plicatilis.
  93. Resveratrol Nanoparticles Suppresses Migration and Invasion of Renal Cell Carcinoma Cells by Inhibiting Matrix Metalloproteinase 2 Expression and Extracellular Signal-Regulated Kinase Pathway.
  94. Targeting Autophagy in Thyroid Cancer: EMT, Apoptosis, and Cancer Stem Cells.
  95. Natural Products in Redox Toxicology.
  96. Herb and Spices in Colorectal Cancer Prevention and Treatment: A Narrative Review.
  97. Administration of 4‑hexylresorcinol increases p53‑mediated transcriptional activity in oral cancer cells with the p53 mutation.
  98. [Research progress of nanomaterials for intra-articular targeted drug delivery in treatment of osteoarthritis].
  99. Formulation Design, Characterization and In-Vivo Assessment of Cefixime Loaded Binary Solid Lipid Nanoparticles to Enhance Oral Bioavailability.
  100. Bioactive Properties of Bread Formulated with Plant-based Functional Ingredients Before Consumption and Possible Links with Health Outcomes After Consumption- A Review.
  101. Antitumor activity of the combination of artemisinin and epirubicin in human leukemia cells.
  102. Biological fate and interaction with cytochromes P450 of the nanocarrier material, d-α-tocopheryl polyethylene glycol 1000 succinate.
  103. High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer.
  104. Carrier-Free Nanomedicine for Cancer Immunotherapy.
  105. Review of Shikonin and Derivatives: Isolation, Chemistry, Biosynthesis, Pharmacology and Toxicology.
  106. [Exercise Therapy for Cancer Cachexia].
  107. A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound.
  108. A comprehensive analysis of meloxicam particles produced by nanosecond laser ablation as a wet milling technique.
  109. A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9.
  110. An Endogenous H2S-Activated Nanoplatform for Triple Synergistic Therapy of Colorectal Cancer.
  111. Antitumor effects of pyrrole-imidazole polyamide modified with alkylating agent on prostate cancer cells.
  112. Injectable Self-Healing Adhesive Chitosan Hydrogel with Antioxidative, Antibacterial, and Hemostatic Activities for Rapid Hemostasis and Skin Wound Healing.
  113. Target-based in-silico screening of basil polysaccharides against different epigenetic targets responsible for breast cancer.
  114. Anti-inflammatory effect of simvastatin by impeding TNF-α and interleukin-1ß pathways: antiangiogenic activity of simvastatin and simvastatin-loaded silver nanoparticles.
  115. Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.
  116. Combination of Focused Ultrasound, Immunotherapy, and Chemotherapy: New Perspectives in Breast Cancer Therapy.
  117. Functionalized FcRn-targeted nanosystems for oral drug delivery: A new approach to colorectal cancer treatment.
  118. The role of imaging in targeted delivery of nanomedicine for cancer therapy.
  119. Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
  120. Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management.
  121. Effect of Meloxicam on the Proliferation and Apoptosis of the Raji Cell Line: an In Vitro Study.
  122. Effects of Vitamin E Supplementation to Metabolic Markers on Diet-Induced Obesity in Mice.
  123. Examining the role of systemic chronic inflammation in diet and sleep relationship.
  124. Therapeutic Efficacy of Polyphenol-Rich Fraction of Boesenbergia rotunda in Diabetic Rats: A Focus on Hypoglycemic, Antihyperlipidemic, Carbohydrate Metabolism, Antioxidant, Anti-Inflammatory and Pancreato-Protective Activities.
  125. Protective effects of resveratrol against genotoxicity induced by nano and bulk hydroxyapatite in Drosophila melanogaster.
  126. [Professional activity and cancer].
  127. Neuropharmacological Study of Posaconazole for Glioblastoma: A Phase 0 Clinical Trial Protocol.
  128. Drug independence and the curability of cancer by combination chemotherapy.
  129. Therapeutic ultrasound: The future of epilepsy surgery?
  130. Effects of Ketogenic Diet on Neuroinflammation in Neurodegenerative Diseases.
  131. Advanced Hydrogels With Nanoparticle Inclusion for Cartilage Tissue Engineering.
  132. Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy.
  1. J Nanobiotechnology. 2022 Jul 16. 20(1): 329
    Light triggered release of a triple action porphyrin-cisplatin conjugate evokes stronger immunogenic cell death for chemotherapy, photodynamic therapy and cancer immunotherapy.
    Haiqin Song, Zhenghao Cai, Juyi Li, Haihua Xiao, Ruogu Qi, Minhua Zheng.
      Photodynamic therapy (PDT) has emerged as an attractive therapeutic approach which can elicit immunogenic cell death (ICD). However, current ICD inducers are still very limited as the representative ICD induces of photosensitizers can only evoke insufficient ICD to achieve unsatisfactory cancer immunotherapy. Herein, we demonstrated the use of a triple action cationic porphyrin-cisplatin conjugate (Pt-1) for drug delivery by a reactive oxygen species (ROS) sensitive polymer as nanoparticles (NP@Pt-1) for combined chemotherapy, PDT and immunotherapy. This unique triple action Pt-1 contains both chemotherapeutic Pt drugs and Porphyrin as a photosensitizer to generate ROS for PDT. Moreover, the ROS generated by Pt-1 can on the one hand degrade polymer carriers to release Pt-1 for chemotherapy and PDT. On the other hand, the ROS generated by Pt-1 subsequently triggered the ICD cascade for immunotherapy. Taken together, we demonstrated that NP@Pt-1 were the most effective and worked in a triple way. This study could provide us with new insight into the development of nanomedicine for chemotherapy, PDT as well as cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Cisplatin; Immunogenic cell death; Nanoparticles; Photodynamic therapy; Porphyrin
    DOI:  https://doi.org/10.1186/s12951-022-01531-5
  2. Oncol Rep. 2022 Sep;pii: 156. [Epub ahead of print]48(3):
    Anticancer effects of natural phytochemicals in anaplastic thyroid cancer (Review).
    Yitian Li, Jing Zhang, Huihui Zhou, Zhen Du.
      Anaplastic thyroid cancer (ATC) is an aggressive and lethal malignancy having a dismal prognosis. Phytochemicals are bioactive components obtained from plants that have been proven useful to treat numerous diseases. Phytochemicals are also an important source of novel anticancer drugs and an important area of research due to the numerous available candidates that can potentially treat cancers. This review discusses naturally occurring phytochemicals and their derivatives that show promising anticancer effects in anaplastic thyroid cancer. Anticancer effects include cell growth inhibition, induction of apoptosis, promoting cell cycle arrest, suppressing angiogenesis, modulating autophagy, and increasing the production of reactive oxygen species. Phytochemicals are not only prospective candidates in the therapy of anaplastic thyroid cancer but also exhibit potential as adjuvants to improve the anticancer effects of other drugs. Although some phytochemicals have excellent anticancer properties, drug resistance observed during the use of resveratrol and artemisinin in different anaplastic thyroid cancer cell lines is still a problem. Anaplastic thyroid cancer cells have several biological, clinical, and drug‑resistance features that differ from differentiated thyroid cancer cells. Phytochemicals such as resveratrol and quercetin exhibit different biological effects in anaplastic thyroid cancer and differentiated thyroid cancer. Tumor cells depend on increased aerobic glycolysis by mitochondrial oxidative phosphorylation to provide energy for their rapid growth, invasiveness, and drug resistance. Phytochemicals can alter signaling cascades, modulate the metabolic properties of cancer cells, and influence the mitochondrial membrane potential of anaplastic thyroid cancer cells. These findings enrich our knowledge of the anticancer effects of phytochemicals and highlight alternative therapies to prevent drug resistance in anaplastic thyroid cancer.
    Keywords:  adjuvant; anaplastic thyroid cancer; drug resistance; phytochemicals; resveratrol
    DOI:  https://doi.org/10.3892/or.2022.8368
  3. J Nanobiotechnology. 2022 Jul 20. 20(1): 339
    Curcumin- and resveratrol-co-loaded nanoparticles in synergistic treatment of hepatocellular carcinoma.
    Yongshun Zheng, Ran Jia, Jun Li, Xiaohe Tian, Yeben Qian.
       BACKGROUND: Currently, systemic therapies for patients with advanced-stage hepatocellular carcinoma (HCC) rely mainly on systemic drugs. However, traditional systemic drugs have a high rate of serious adverse events, and the curative effects of some potential anticancer drugs, such as curcumin (CUR) and resveratrol (RSV), are less apparent due to their poor bioavailability. Therefore, it is urgent to develop a highly effective therapy to improve patient prognosis. Herein, an injectable HCC-targeted nanoparticle (NP) was designed to deliver CUR and RSV to hepatoma cells.
    RESULTS: The molecular self-assembled NPs showed higher tumour retention through the enhanced permeability and retention (EPR) effect of the NPs and surface modification with the HCC-specific peptide moiety SP94 to effectively treat HCC. These HCC-targeted NPs led to a significant reduction in the drug dosage, delayed the rate of drug release and improved the bioavailability of the encapsulated drugs. The drug concentrations in the vicinity of the tumour increased, and a good therapeutic effect was observed without obvious side effects.
    CONCLUSIONS: These SP94-mediated NPs allowed large amounts of antitumor drugs to accumulate in tumours, providing a novel strategy for innovative HCC therapy. This nanoplatform also offers an idea for exploring other potential chemotherapeutics.
    Keywords:  Chemotherapy; Curcumin; HCC; Nanoparticles; Resveratrol; Tumour-specific targeting
    DOI:  https://doi.org/10.1186/s12951-022-01554-y
  4. Eur J Med Chem. 2022 Jul 16. pii: S0223-5234(22)00515-3. [Epub ahead of print]240 114613
    Emerging roles of fatty acid metabolism in cancer and their targeted drug development.
    Qi An, Rui Lin, Dongmei Wang, Chuan Wang.
      Metabolic reprogramming is now considered as one of hallmark of tumor cells and provides them with a selective survival/growth advantage to resist harsh micro-environmental stress. Fatty acid (FA) metabolism of tumor cells supports the biosynthetic needs and provides fuel sources for energy supply. Since FA metabolic reprogramming is a critical link in tumor metabolism, its various roles in tumors have attracted increasing interest. Herein, we review the mechanisms through which cancer cells rewire their FA metabolism with a focus on the pathway of FA metabolism and its targeting drug development. The failure and successful cases of targeting tumor FA metabolism are expected to bypass the metabolic vulnerability and improve the efficacy of targeted therapy.
    Keywords:  Fatty acid; Metabolic reprograming; Targeted drug; Tumor metabolism
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114613
  5. Biomed Res Int. 2022 ;2022 6253978
    Anti-CD44 and EGFR Dual-Targeted Solid Lipid Nanoparticles for Delivery of Doxorubicin to Triple-Negative Breast Cancer Cell Line: Preparation, Statistical Optimization, and In Vitro Characterization.
    Farnosh Darabi, Massoud Saidijam, Fatemeh Nouri, Reza Mahjub, Meysam Soleimani.
       Background: Despite being more aggressive than other types of breast cancer, there is no suitable treatment for triple-negative breast cancer (TNBC). Here, we designed doxorubicin-containing solid lipid nanoparticles (SLNs) decorated with anti-EGFR/CD44 dual-RNA aptamers, which are overexpressed in TNBC. For more efficiency in the nuclear delivery of doxorubicin, dexamethasone (Dexa) was chemically attached to the surface of nanoparticles.
    Methods: To prepare the cationic SLNs, 6-lauroxyhexyl BOC-ornithine (LHON) was synthesized and was chemically attached to dexamethasone to form Dexa-LHON complexes. The doxorubicin-containing SLNs were prepared via double emulsification (w/o/w) and the solvent evaporation technique. The preparation of SLNs was statistically optimized using the central composite response surface methodology. Independent factors were the GMS/lecithin concentration ratio and the amount of Tween 80, while responses considered were particle size, polydispersity index, and entrapment efficiency of the nanoparticles. The optimized nanoparticles were studied morphologically using transmission electron microscopy, and in vitro release of doxorubicin from nanoparticles was studied in phosphate-buffered saline. Then, the designated aptamers were attached to the surface of nanoparticles using electrostatic interactions, and their cytotoxicity was assessed in vitro.
    Results: The size, PDI, zeta potential, EE%, and LE% of the prepared nanoparticles were 101 ± 12.6 nm, 0.341 ± 0.005, +13.6 ± 1.83 mV, 69.98 ± 7.54%, and 10.2 ± 1.06%, respectively. TEM images revealed spherical nanoparticles with no sign of aggregation. In vitro release study exhibited that 96.1 ± 1.97% of doxorubicin was released within 48 h of incubation. The electrostatic attachment of the designated aptamers to the nanoparticles' surface was confirmed by reducing the zeta potential to -15.6 ± 2.07 mV. The in vitro experiments revealed that the SLNs/DOX/Dexa/CD44 or EGFR aptamers were substantially more successful than SLNs/DOX/Dexa at inhibiting cell proliferation. Using the MDA-MB-468 cell line, we discovered that SLN/DOX/Dexa/CD44/EGFR aptamers were more effective than other constructs in inhibiting cell proliferation (p < 0.001). The reduction of cell viability using this construct suggests that targeting numerous proliferation pathways is effective.
    Conclusion: Overall, the finding of this investigation suggested that SLNs/DOX/Dexa/CD44/EGFR could be a promising new enhanced anticancer delivery system and deserved further preclinical consideration.
    DOI:  https://doi.org/10.1155/2022/6253978
  6. Oncol Rep. 2022 Sep;pii: 153. [Epub ahead of print]48(3):
    Research progress on the interaction between long non‑coding RNAs and RNA‑binding proteins to influence the reprogramming of tumor glucose metabolism (Review).
    Weizheng Wu, Kunming Wen.
      As epigenetic regulators, long non‑coding RNAs (lncRNAs) are involved in various important regulatory processes and typically interact with RNA‑binding proteins (RBPs) to exert their core functional effects. An increasing number of studies have demonstrated that lncRNAs can regulate the occurrence and development of cancer through a variety of complex mechanisms and can also participate in tumor glucose metabolism by directly or indirectly regulating the Warburg effect. As one of the metabolic characteristics of tumor cells, the Warburg effect provides a large amount of energy and numerous intermediate products to meet the consumption demands of tumor metabolism, providing advantages for the occurrence and development of tumors. The present review article summarizes the regulatory effects of lncRNAs on the reprogramming of glucose metabolism after interacting with RBPs in tumors. The findings discussed herein may aid in the better understanding of the pathogenesis of malignancies, and may provide novel therapeutic targets, as well as new diagnostic and prognostic markers for human cancers.
    Keywords:  RNA‑binding protein; Warburg effect; glycolysis; glycolytic enzyme; long non‑coding RNA; tumor
    DOI:  https://doi.org/10.3892/or.2022.8365
  7. Nat Chem Biol. 2022 Jul 21.
    Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).
    Ziyang Zhang, Keelan Z Guiley, Kevan M Shokat.
      Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.
    DOI:  https://doi.org/10.1038/s41589-022-01065-9
  8. Carbohydr Polym. 2022 Oct 15. pii: S0144-8617(22)00738-X. [Epub ahead of print]294 119833
    Biodegradable disulfide crosslinked chitosan/stearic acid nanoparticles for dual drug delivery for colorectal cancer.
    Ankur Sood, Aastha Gupta, Ravi Bharadwaj, Pavana Ranganath, Neal Silverman, Garima Agrawal.
      Herein, redox responsive chitosan/stearic acid nanoparticles (CSSA NPs) (≈200 nm) are developed for dual drug delivery. These degradable nanoparticles are prepared based on disulfide (SS) crosslinking chemistry avoiding the use of any external crosslinking agent. CSSA NPs are further loaded with both DOX (hydrophilic) and curcumin (hydrophobic) drugs with ≈86 % and ≈82 % encapsulation efficiency respectively. This approach of combining anticancer therapeutics having different mode of anticancer action allows to develop systems for cancer therapy with enhanced efficacy. In vitro drug release experiments clearly exhibit the low leakage of drug under physiological conditions while ≈98 % DOX and ≈96 % curcumin is released after 136 h under GSH reducing conditions. The cytotoxicity experiments against HCT116 cells demonstrate higher cytotoxicity of dual drug loaded CSSA NPs. In vivo biodistribution experiments with c57bl/6j mice confirms the retention of CSSA NPs in the colon area up to 24 h exhibiting their potential for colorectal cancer therapy.
    Keywords:  Chitosan; Colorectal cancer; Dual drug delivery; Nanoparticles; Redox responsive
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119833
  9. Crit Rev Food Sci Nutr. 2022 Jul 18. 1-14
    The role of dietary polyphenols in alternating DNA methylation in cancer.
    Nadir Mustafa Qadir Nanakali, Parisa Maleki Dana, Fatemeh Sadoughi, Zatollah Asemi, Mehran Sharifi, Reza Asemi, Bahman Yousefi.
      Natural products such as curcumin, quercetin, and resveratrol have been shown to have antitumor effectsand several studies have examined their role in treating cancer, either alone or in combination with other chemotherapeutic drugs. These compounds are capable of affecting different cancer-related mechanisms, such as proliferation, inflammation, invasion, and metastasis. Along with all of the benefits of these agents, affecting epigenetic processes is one of the most important aspects of their impact. Epigenetic modifications can be categorized into three main processes that include DNA methylation, histone modification, and regulation of small non-coding RNAs. Therefore, targeting DNA methylation can be used as a cancer treatment strategy by identifying or developing methylation modulators. Herein, we take a look into the studies investigating the role of natural products (e.g. curcumin, resveratrol, epigallocatechin gallate (EGCG), and quercetin) in alternating the DNA methylation status of various cancer cells. We discuss how these compounds reduce the expression of enzymes mediating the methylation of tumor suppressor genes and thereby, increasing the expression of tumor suppressors while reactivating antitumor signaling pathways.
    Keywords:  Curcumin; DNA methylation; DNMT; EGCG; quercetin; resveratrol
    DOI:  https://doi.org/10.1080/10408398.2022.2100313
  10. Mater Today Bio. 2022 Dec;16 100353
    Synergistic hydroxyl radical formation, system XC- inhibition and heat shock protein crosslinking tango in ferrotherapy: A prove-of-concept study of "sword and shield" theory.
    Li Xie, Wenjie Chen, Qifang Chen, Yang Jiang, Erqun Song, Xiaokang Zhu, Yang Song.
      Ferroptosis provide new insights into designing nanomedicines for enhanced cancer therapy; however, its antitumor efficacy is relatively low, mainly due to self-protective mechanism of cancer cells, e.g., heat shock protein (HSP) overexpression. Since HSPs can be modified/inhibited by lipid peroxidation (LPO) ending products, we construct a nanoplatform, namely MPDA@Fe3O4-Era, to amplify intracellular reactive oxygen species (ROS) and LPO for synergistic ferrotherapy. Upon tumor acidic microenvironment and local near-infrared stimuli, this nanoplatform releases Fe3O4 and reacts with intracellular hydrogen peroxide (H2O2) to promote Fenton reaction, and yields significant intracellular ROS (specifically hydroxyl radical, •OH) and LPO. In turn, LPO ending products crosslink HSPs to destroy self-preservation pathways of cancer cells to enhance anticancer effect. Meanwhile, the released erastin inhibits system XC - signal pathway to depletes glutathione. Fe3O4 loading further provides magnetic resonance imaging T2-weighted signal to guide anti-tumor treatment. Together, this nanoplatform not only provides •OH (as a "sword" to attack tumor cells), but also inhibits system XC - signal pathway and crosslinks HSP (break down the "shield" of tumor cells) to maximize synergistic ferro-therapeutic effect. MPDA@Fe3O4-Era plus laser irradiation possessed highly efficient tumor suppression with magnified the levels of •OH and inactive glutathione peroxidase 4 (GPX4), which can promote the development of precise cooperative cancer therapy.
    Keywords:  Ferroptosis; HSP; LPO; ROS; System XC−
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100353
  11. Iran J Public Health. 2022 Feb;51(2): 226-239
    Polymeric Nanoparticles in Cancer Chemotherapy: A Narrative Review.
    Hossein Ali Yousefi Rizi, Dong Hoon Shin, Shima Yousefi Rizi.
      Chemotherapy is a common treatment technique that uses chemical drugs to kill cancer cells. This technique affects normal healthy tissues being unspecific and has toxic adverse effects. Nowadays, nanotechnology applications in cancer chemotherapy have helped to solve the uncontrolled problems involving distribution of medicine particles and other side effects. Nanoparticles (NPs) can offer significant advantages over conventional drug delivery to have magnificent properties such as controlled mode of action, various methods of administration, and the ability to transport both organic/inorganic drug particles. Special ligands containing polymeric NPs preferentially hit the tumour site because of their chemical affinity to malignant tissues. This article, reviews the fabrication, characterization, and applications of NPs being used in chemotherapy. Furthermore, different forms of polymeric and especially polymeric chemotherapy were also explored and discussed to understand better the effects of NPs on cancer chemotherapy.
    Keywords:  Cancer therapy; Chemotherapy; Drug delivery; Magnetic nanoparticles; Polymeric nanoparticles
    DOI:  https://doi.org/10.18502/ijph.v51i2.8677
  12. Int J Pharm. 2022 Jul 19. pii: S0378-5173(22)00591-9. [Epub ahead of print] 122036
    Evaluation of thermosensitive chitosan hydrogel containing gefitinib loaded cellulose acetate butyrate nanoparticles in a subcutaneous breast cancer model.
    Zahra Karimi, Somayeh Taymouri, Mohsen Minaiyan, Mina Mirian.
      In the present study, gefitinib loaded cellulose acetate butyrate nanoparticles (Gnb-NPs) were prepared and then incorporated into thermo-sensitive chitosan/ß-glycerophosphate hydrogels for intratumoral administration in mice bearing breast cancer. Accordingly, Gnb-NPs were prepared using the solvent evaporation process and optimized by applying a two-level fractional factorial design. Properties of NPs, including particle size, zeta potential (ZP), polydispersity index (PdI), encapsulation efficiency (EE) % and drug loading (DL) %, were investigated; the optimized Gnb-NPs were then loaded in chitosan hydrogels (Gnb-NPs-Hydrogel). The formulated Gnb-NPs-Hydrogel was assessed in terms of gelling time, release behavior, injectability, swelling and degradation behavior. The anti-cancer efficacy of Gnb-NPs-Hydrogel was evaluated in vitro against the 4T1 breast cancer cell line and in vivo in breast tumor bearing mice. The optimized formulation showed spherical particles with the size of 156.50 ± 2.40 nm, PdI of 0.20 ± 0.002, ZP of -4.90 ± 0.04 mV, EE of 99.77 ± 0.09% and DL of 20.59± 0.05%. Incorporating Gnb-NPs into the hydrogel led to the decrease of the drug release rate. Gnb-NPs-Hydrogel displayed a greater cytotoxic effect in comparison to the free Gnb and Gnb-Hydrogel in 4T1 cancer cells. Furthermore,intratumorallyinjectedGnb-NPs-Hydrogel showed the strongest antitumor efficacy in vivo. The superior performance of Gnb-NPs-Hydrogel, thus, demonstrated its potential for the treatment of breast cancer.
    Keywords:  Breast cancer; Gefitinib; Intratumoral administration; Targeted delivery; Thermosensitive hydrogel
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122036
  13. Bioinorg Chem Appl. 2022 ;2022 3790097
    Potential of Black Phosphorus in Immune-Based Therapeutic Strategies.
    Wenjuan Dong, Hu Wang, Hailin Liu, Chunqiao Zhou, Xuelin Zhang, Song Wang, Lin He.
      Black phosphorus (BP) consists of phosphorus atoms, an essential element of bone and nucleic acid, which covalently bonds to three adjacent phosphorus atoms to form a puckered bilayer structure. With its anisotropy, band gap, biodegradability, and biocompatibility properties, BP is considered promising for cancer therapy. For example, BP under irradiation can convert near-infrared (NIR) light into heat and reactive oxygen species (ROS) to damage cancer cells, called photothermal therapy (PTT) and photodynamic therapy (PDT). Compared with PTT and PDT, the novel techniques of sonodynamic therapy (SDT) and photoacoustic therapy (PAT) exhibit amplified ROS generation and precise photoacoustic-shockwaves to enhance anticancer effect when BP receives ultrasound or NIR irradiation. Based on the prospective phototherapy, BP with irradiation can cause a "double-kill" to tumor cells, involving tumor-structure damage induced by heat, ROS, and shockwaves and a subsequent anticancer immune response induced by in situ vaccines construction in tumor site, which is referred to as photoimmunotherapy (PIT). In conclusion, BP shows promise in natural antitumor biological activity, biological imaging, drug delivery, PTT/PDT/SDT/PAT/PIT, nanovaccines, nanoadjuvants, and combination immunotherapy regimens.
    DOI:  https://doi.org/10.1155/2022/3790097
  14. Int J Mol Med. 2022 Sep;pii: 117. [Epub ahead of print]50(3):
    Synthetic antioxidants from a natural source can overtake the oncogenic stress management system and activate the stress‑sensitized death of KSHV‑infected cancer cells.
    Piyanki Das, Goutam Brahmachari, Koustav Chatterjee, Tathagata Choudhuri.
      Synthetic and modified natural derivatives are reported as potential bioactive compounds and are being used therapeutically against various diseases in a widespread manner nowadays. Cancerous cells exhibit high levels of reactive oxygen species (ROS) internally, and thus successfully manage to sustain themselves and proliferate via antioxidative mechanisms that maintain a redox balance. On this note, various antioxidants are applied as anticancer compounds, which strategically affects the ongoing oncogenic stress management system in both a pro‑ and antioxidative manner, resulting in cancer restriction, as well as sustaining cell proliferation via antioxidative mechanisms that promote cancer progression. Alike non‑viral cancers, viral cancers exhibit varying levels of ROS during different stages of cancer progression. Hence, successful stress balance should be addressed, depending on the cancer cell stress response during the therapeutic management. The application of antioxidants is crucial and needs to be carefully designed in such cases; the respective underlying mechanisms are less understood. The role of antioxidants controlling the varied levels of stress response at different stages of Kaposi's sarcoma‑associated herpes virus malignancy have not been fully reported. Therefore, the present study aimed to analyze the activity of certain antioxidants in KSHV‑infected oncogenic cells. For this purpose, two naturally derived flavonoid‑based antioxidants (theaflavin and novel curcumin derivatives) were selected and tested in different KSHV‑infected cell lines. The findings presented herein demonstrate that these compounds can successfully induce the death of different KSHV‑positive cells and can restrict the growth of KSHV‑infected cell lines restricting viral reactivation by counteracting the oncogenic stress management system.
    Keywords:  Kaposi's sarcoma‑associated herpes virus/human herpesvirus 8‑associated malignancy; antioxidants; autophagy‑apoptosis; cellular stress balance; oncogenic stress
    DOI:  https://doi.org/10.3892/ijmm.2022.5173
  15. Front Pharmacol. 2022 ;13 911771
    Formulation Development and Characterization of pH Responsive Polymeric Nano-Pharmaceuticals for Targeted Delivery of Anti-Cancer Drug (Methotrexate).
    Farhad Ullah, Zafar Iqbal, Amjad Khan, Saeed Ahmad Khan, Lateef Ahmad, Amal Alotaibi, Riaz Ullah, Muhammad Shafique.
      Oral administration of pH sensitive/stimuli responsive nanoparticles are gaining importance because of the limited side effects, minimum dose and controlled drug release. The objective of this study was to develop and evaluate pH sensitive polymeric nanoparticles for methotrexate with the aim to maximize the drug release at target site. In the presented study, pH sensitive polymeric nanoparticles of methotrexate were developed through modified solvent evaporation technique using polymer Eudragit S100. Different process parameters like drug to polymer ratio, speed of sonication, concentration of surfactant and time of sonication were optimized by evaluating their effects on particle size, PDI, zeta potential, entrapment/encapsulation efficiency. The developed formulations were evaluated for their size, polydispersity (PDI), zeta potential, encapsulation efficiency, XRD, scanning electron microscopy, in-vitro drug release and stability studies. Best results were obtained with poloxamer-407 and PVA and were selected as surfactants. Physicochemical characterization of the developed formulations showed that the particle size lies in the range 165.7 ± 1.85-330.4 ± 4.19, PDI 0.119 ± 0.02-0.235 ± 0.008, zeta potential -0.163 ± 0.11--5.64 ± 0.36 mV, and encapsulation efficiency more than 61%. The results of scanning electron microscopy revealed that nanoparticles have regular geometry with spherical shape. Initially the drug release occur through diffusion followed by erosion. The present studies showed that MTX-ES100 nanoparticles prepared during this study have the desired physicochemical properties, surface morphology and release characteristics used to target the desired organs.
    Keywords:  Eudragit; methotrexate; polymeric nanoparticles; solvent evaporation method; targeted drug delivery
    DOI:  https://doi.org/10.3389/fphar.2022.911771
  16. Crit Rev Food Sci Nutr. 2022 Jul 19. 1-19
    Effects and mechanisms of resveratrol for prevention and management of cancers: An updated review.
    Si-Xia Wu, Ruo-Gu Xiong, Si-Yu Huang, Dan-Dan Zhou, Adila Saimaiti, Cai-Ning Zhao, Ao Shang, Yun-Jian Zhang, Ren-You Gan, Hua-Bin Li.
      Cancer is a severe public health problem. Resveratrol is a famous natural compound that has various bioactivities, such as antioxidant, anti-inflammatory, antidiabetic and antiaging activities. Especially, resveratrol could prevent and treat various cancers, such as oral, thyroid, breast, lung, liver, pancreatic, gastric, colorectal, bladder, prostate and ovarian cancers. The underlying mechanisms have been widely studied, such as inhibiting cell proliferation, suppressing metastasis, inducing apoptosis, stimulating autophagy, modulating immune system, attenuating inflammation, regulating gut microbiota and enhancing effects of other anticancer drugs. In this review, we summarize effects and mechanisms of resveratrol on different cancers. This paper is helpful to develop resveratrol, crude extract containing resveratrol, or foods containing resveratrol into functional food, dietary supplements or auxiliary agents for prevention and management of cancers.
    Keywords:  Resveratrol; anticancer; apoptosis; mechanism; metastasis; proliferation
    DOI:  https://doi.org/10.1080/10408398.2022.2101428
  17. Nano Res. 2022 Jul 11. 1-11
    Integrating Au and ZnO nanoparticles onto graphene nanosheet for enhanced sonodynamic therapy.
    Fei Wang, Boyu Wang, Wei You, Guang Chen, Ye-Zi You.
      Sonodynamic therapy has attracted widespread attention for cancer treatment because of its noninvasiveness and high tissue-penetration ability. Generally, ultrasound irradiation of sonosensitizers produces separated electrons (e-) and holes (h+), which inhibits cancer by producing reactive oxygen species (ROS). However, the separated electrons (e-) and holes (h+) could easily recombine, lowering the yield of ROS and hindering the application of sonodynamic therapy (SDT). Herein, we present a highly efficient sonosensitizer system for enhanced sonodynamic therapy built on reduced graphene oxide (rGO) nanosheets, bridged ZnO and Au nanoparticles, coated with polyvinyl pyrrolidone (PVP). The ultrasound irradiation activates ZnO nanoparticles to generate separated electron-hole (e--h+) pairs, and the rGO nanosheets facilitate electron transfer from ZnO to Au nanoparticles because of the narrow band gap of rGO, which could efficiently restrain the recombination of the e--h+ pairs, thereby significantly augmenting the production of ROS to kill cancer cells, such as U373MG, HeLa, and CT26 cells. Moreover, rGO nanosheets integrated with Au nanoparticles could catalyze the endogenous decomposition of H2O2 into O2, which can alleviate hypoxic tumor microenvironment (TME). Therefore, the rational design of Au-rGO-ZnO@PVP nanomaterials can not only improve the efficiency of sonodynamic therapy, but also mitigate the hypoxic tumor microenvironment, which would provide a new perspective in the development of efficient sonosensitizers.
    Electronic Supplementary Material: Supplementary material (the UV-vis-NIR absorption spectra of the DPBF and the RhB, biological effect assessment of the Au-rGO-ZnO@PVP, and the inhibition rate of tumor under different treatments during the animal study) is available in the online version of this article at 10.1007/s12274-022-4599-5.
    Keywords:  reactive oxygen species; reduced graphene oxide; sonodynamic therapy; tumor
    DOI:  https://doi.org/10.1007/s12274-022-4599-5
  18. J Control Release. 2022 Jul 19. pii: S0168-3659(22)00427-8. [Epub ahead of print]
    Ferrocene and glucose oxidase-installed multifunctional hydrogel reactors for local cancer therapy.
    Song Yi Lee, JiHye Park, Da In Jeong, ChaeRim Hwang, Junmin Lee, KangJu Lee, Han-Jun Kim, Hyun-Jong Cho.
      A hyaluronic acid (HA)-based one-pot hydrogel reactor with single syringe injection and immediate gelation was developed for starvation therapy (ST), chemodynamic therapy (CDT), ferroptosis, and photothermal therapy (PTT) against breast cancer. A rheologically tuned hydrogel network, composed of HA-phenylboronic acid (HP) and HA-dopamine (HD), was designed by introducing a boronate ester linkage (phenylboronic acid-dopamine interaction) and polydopamine bond (pH control). Ferrocene (Fc)-conjugated HP (Fc-HP) was synthesized to achieve ferroptosis, Fenton reaction-involved toxic hydroxyl radical (•OH) generation, and photothermal ablation in cancer therapy. Glucose oxidase (GOx) was entrapped in the pH-modulated Fc-HP (Fc-HP°)/HD hydrogel network for converting intracellular glucose to H2O2 to enable its own supply. The GOx/Fc combination-installed hydrogel reactor system can provide sustained ST/CDT/PTT functions along with ferroptosis. Injection of Fc-HP°/HD/GOx hydrogel with single-syringe injectability, shear-thinning feature, and self-healing capability offered a slow biodegradation rate and high safety profiles. Peritumorally injected Fc-HP°/HD/GOx hydrogel also efficiently suppressed the growth of breast cancer based on multifunctional therapeutic approaches with reduced dosing frequency. Hyperthermia induced by near-infrared (NIR) laser absorption may amplify the therapeutic effects of free radicals. It is expected that this Fc-HP°/HD/GOx hydrogel system can be applied to local cancer therapy with high efficacy and safety profiles.
    Keywords:  Cancer; Chemodynamic therapy; Ferroptosis; Hydrogel; Photothermal therapy; Starvation therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.017
  19. J Nanobiotechnology. 2022 Jul 20. 20(1): 337
    Recent advances in smart nanoplatforms for tumor non-interventional embolization therapy.
    Heng Dong, Dongliang Yang, Yanling Hu, Xuejiao Song.
      Tumor embolization therapy has attracted great attention due to its high efficiency in inhibiting tumor growth by cutting off tumor nutrition and oxygen supply by the embolic agent. Although transcatheter arterial embolization (TAE) is the mainstream technique in the clinic, there are still some limitations to be considered, especially the existence of high risks and complications. Recently, nanomaterials have drawn wide attention in disease diagnosis, drug delivery, and new types of therapies, such as photothermal therapy and photodynamic therapy, owing to their unique optical, thermal, convertible and in vivo transport properties. Furthermore, the utilization of nanoplatforms in tumor non-interventional embolization therapy has attracted the attention of researchers. Herein, the recent advances in this area are summarized in this review, which revealed three different types of nanoparticle strategies: (1) nanoparticles with active targeting effects or stimuli responsiveness (ultrasound and photothermal) for the safe delivery and responsive release of thrombin; (2) tumor microenvironment (copper and phosphate, acidity and GSH/H2O2)-responsive nanoparticles for embolization therapy with high specificity; and (3) peptide-based nanoparticles with mimic functions and excellent biocompatibility for tumor embolization therapy. The benefits and limitations of each kind of nanoparticle in tumor non-interventional embolization therapy will be highlighted. Investigations of nanoplatforms are undoubtedly of great significance, and some advanced nanoplatform systems have arrived at a new height and show potential applications in practical applications.
    Keywords:  Combination therapy; Smart nanoplatforms; Tumor non-interventional embolization therapy; Tumor vascular occlusion; thrombus
    DOI:  https://doi.org/10.1186/s12951-022-01548-w
  20. Front Bioeng Biotechnol. 2022 ;10 916952
    Recent Progress in Bio-Responsive Drug Delivery Systems for Tumor Therapy.
    Xiufeng Cong, Jun Chen, Ran Xu.
      Spatially- and/or temporally-controlled drug release has always been the pursuit of drug delivery systems (DDSs) to achieve the ideal therapeutic effect. The abnormal pathophysiological characteristics of the tumor microenvironment, including acidosis, overexpression of special enzymes, hypoxia, and high levels of ROS, GSH, and ATP, offer the possibility for the design of stimulus-responsive DDSs for controlled drug release to realize more efficient drug delivery and anti-tumor activity. With the help of these stimulus signals, responsive DDSs can realize controlled drug release more precisely within the local tumor site and decrease the injected dose and systemic toxicity. This review first describes the major pathophysiological characteristics of the tumor microenvironment, and highlights the recent cutting-edge advances in DDSs responding to the tumor pathophysiological environment for cancer therapy. Finally, the challenges and future directions of bio-responsive DDSs are discussed.
    Keywords:  bio-responsiveness; cancer therapy; drug delivery system; pathophysiological characteristics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fbioe.2022.916952
  21. Acta Pharm Sin B. 2022 Apr;12(4): 2103-2119
    Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy.
    Yongrong Yao, Huachao Chen, Ninghua Tan.
      Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments, but its clinical implementation has been restricted by the low host antitumor response rate. Recently, chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication. The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism. Herein, a synergistic antitumor platform (designated as BMS/RA@CC-Liposome) was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug (RA-V) and PD-1/PD-L1 blockade inhibitor (BMS-202) to remarkably enhance antitumor immunity. In this study, the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem. To achieve the cell-specific targeting drug delivery, the combination therapy nanosystem was functionalized with cancer cell membrane camouflage. The biomimetic drug delivery system perfectly disguised as endogenous substances, and realized elongated blood circulation due to anti-phagocytosis capability. Moreover, the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells. The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response, RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells. Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically, demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.
    Keywords:  Antitumor immune response; Cancer-cell-biomimetic nanoparticles; Checkpoint blockade-based immunotherapy; Chemotherapy; Combination therapy nanosystem; Cyclopeptide RA-V; PD-1/PD-L1 pathway; Synergetic mechanism
    DOI:  https://doi.org/10.1016/j.apsb.2021.10.010
  22. Semin Cancer Biol. 2022 Jul 19. pii: S1044-579X(22)00176-6. [Epub ahead of print]
    Cancer depends on fatty acids for ATP production: a possible link between cancer and obesity.
    Ho Lee, Sang Myung Woo, Hyonchol Jang, Mingyu Kang, Soo-Youl Kim.
      Several metabolic pathways for the supply of adenosine triphosphate (ATP) have been proposed; however, the major source of reducing power for ADP in cancer remains unclear. Although glycolysis is the source of ATP in tumors according to the Warburg effect, ATP levels do not differ between cancer cells grown in the presence and absence of glucose. Several theories have been proposed to explain the supply of ATP in cancer, including metabolic reprograming in the tumor microenvironment. However, these theories are based on the production of ATP by the TCA-OxPhos pathway, which is inconsistent with the Warburg effect. We found that blocking fatty acid oxidation (FAO) in the presence of glucose significantly decreased ATP production in various cancer cells. This suggests that cancer cells depend on fatty acids to produce ATP through FAO instead of glycolysis. We observed that cancer cell growth mainly relies on metabolic nutrients and oxygen systemically supplied through the bloodstream instead of metabolic reprogramming. In a spontaneous mouse tumor model (KrasG12D; Pdx1-cre), tumor growth was 2-fold higher in mice fed a high-fat diet (low-carbo diet) that caused obesity, whereas a calorie-balanced, low-fat diet (high-carbo diet) inhibited tumor growth by 3-fold compared with that in mice fed a control/normal diet. This 5-fold difference in tumor growth between mice fed low-fat and high-fat diets suggests that fat-induced obesity promotes cancer growth, and tumor growth depends on fatty acids as the primary source of energy.
    Keywords:  ATP production; cancer energy metabolism; fatty acid oxidation; obesity
    DOI:  https://doi.org/10.1016/j.semcancer.2022.07.005
  23. Int J Biol Macromol. 2022 Jul 13. pii: S0141-8130(22)01498-2. [Epub ahead of print]217 652-667
    Fucoidan-based nanoparticles: Preparations and applications.
    Jayachandran Venkatesan, Sesha Subramanian Murugan, Gi Hun Seong.
      Nanoparticle-based therapy has gained much attention in the pharmaceutical industry. Fucoidan is a sulfated polysaccharide naturally derived from marine brown algae and is widely used for medical applications. We explore preparation of fucoidan-based nanoparticles and their biomedical applications in the current review. The fucoidan-based nanoparticles have been synthesized using microwave, emulsion, solvent evaporation, green synthesis, polyelectrolyte self-assembly, precipitation, and ultrasonication methods. The synthesized nanoparticles have particle sizes ranging from 100 to 400 nm. Therefore, fucoidan-based nanoparticles have a variety of potential therapeutic applications, including drug delivery, cancer therapies, tissue engineering, antimicrobial applications, magnetic resonance imaging contrast, and atherothrombosis imaging. For example, fucoidan nanoparticles have been used to deliver curcumin, dextran, gentamicin, epigallocatechin gallate, and cisplatin for cancer therapies. Furthermore, fucoidan nanoparticles coupled with metal nanoparticles have been used to target and recognize clinical conditions for diagnostic purposes. Hence, fucoidan-based nanoparticles have been helpful for biomedical applications.
    Keywords:  Cancer therapies; Drug delivery; Fucoidan; Magnetic resonance imaging contrast agent; Tissue engineering
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.068
  24. Front Oncol. 2022 ;12 888855
    Nanozyme Hydrogels for Self-Augmented Sonodynamic/Photothermal Combination Therapy.
    Shuntao Wang, Ning Zeng, Qi Zhang, Mingzhu Chen, Qinqin Huang.
      Sonosensitizer-mediated sonodynamic therapy (SDT) has emerged as a promising anti-tumor strategy. However, this strategy of continuous oxygen consumption further exacerbates the hypoxic tumor microenvironment, which limits its therapeutic efficacy. In this study, we designed a multifunctional hydrogel (PB+Ce6@Hy) that simultaneously co-delivers nanozyme prussian blue (PB) and sonosensitizer chlorin e6 (Ce6) for the realization of photothermal therapy (PTT) and enhanced SDT. When the hydrogel reaches the tumor tissue through local injection, the 808 nm laser can induce the hydrogel to warm up and soften, thereby triggering the release of PB and Ce6. PB can interact with endogenous H2O2 in situ and generate sufficient oxygen to promote the Ce6-mediated SDT effect. Besides, due to the good encapsulation ability of the hydrogel, the nanomaterials can be released in a controlled manner by changing laser parameter, irradiation time, etc. The experimental results show that the PB+Ce6@Hy system we developed can generate a large amount of reactive oxygen species (ROS), which can be combined with the photothermal effect to kill tumor cells, as a result, tumor proliferation has been adequately inhibited. This combined PTT/SDT dynamic strategy provides a new perspective for Ce6-induced cancer therapy, showing great potential for clinical application.
    Keywords:  chlorin e6; oxygen regulation; photothermal therapy; prussian blue; sonodynamic therapy
    DOI:  https://doi.org/10.3389/fonc.2022.888855
  25. Adv Colloid Interface Sci. 2022 Jul 06. pii: S0001-8686(22)00130-0. [Epub ahead of print]307 102728
    Release of bioactive compounds from delivery systems by stimuli-responsive approaches; triggering factors, mechanisms, and applications.
    Atefe Rezaei, Fatemeh Rafieian, Safoura Akbari-Alavijeh, Mohammad Saeed Kharazmi, Seid Mahdi Jafari.
      Recent advances in emerging nanocarriers and stimuli-responsive (SR) delivery systems have brought about a revolution in the food and pharmaceutical industries. SR carriers are able to release the encapsulated bioactive compounds (bioactives) upon an external trigger. The potential of releasing the loaded bioactives in site-specific is of great importance for the pharmaceutical industry and medicine that can deliver the cargo in an appropriate condition. For the food industry, release of encapsulated bioactives is considerably important in processing or storage of food products and can be used in their formulation or packaging. There are various stimuli to control the favorite release of bioactives. In this review, we will shed light on the effect of different stimuli such as temperature, humidity, pH, light, enzymatic hydrolysis, redox, and also multiple stimuli on the release of encapsulated cargo and their potential applications in the food and pharmaceutical industries. An overview of cargo release mechanisms is also discussed. Furthermore, various alternatives to manipulate the controlled release of bioactives from carriers and the perspective of more progress in these SR carriers are highlighted.
    Keywords:  Bioactive compounds; Controlled release; Food; Pharmaceuticals; Stimuli-responsive
    DOI:  https://doi.org/10.1016/j.cis.2022.102728
  26. Nano Lett. 2022 Jul 20.
    A Nanounit Strategy Disrupts Energy Metabolism and Alleviates Immunosuppression for Cancer Therapy.
    Yang Luo, Yingmin Li, Zhengjie Huang, Xinyang Li, Yi Wang, Jianwen Hou, Shaobing Zhou.
      Aberrant energy metabolism not only endows tumor cells with unlimited proliferative capacity but also contributes to the establishment of the glucose-deficient/lactate-rich immunosuppressive tumor microenvironment (ITM) impairing antitumor immunity. Herein, a novel metabolic nanoregulator (D/B/CQ@ZIF-8@CS) was developed by enveloping 2-deoxy-d-glucose (2-DG), BAY-876, and chloroquine (CQ) into zeolitic imidazolate framework-8 (ZIF-8) to simultaneously deprive the energy/nutrition supply of tumor cells and relieve the ITM for synergetic tumor starvation-immunotherapy. Aerobic glycolysis, glucose uptake, and autophagy flux could be concurrently blocked by D/B/CQ@ZIF-8@CS, cutting off the nutrition/energy supply and the source of lactate. Furthermore, inhibition of glucose uptake and aerobic glycolysis could effectively reverse the glucose-deficient/lactate-rich ITM, thus functionally inactivating regulatory T cells and augmenting anti-CTLA-4 immunotherapy. Such a two-pronged strategy would provide new insights for the design of metabolic intervention-based synergistic cancer therapy.
    Keywords:  autophagy blockage; glycolysis inhibition; immunosuppressive; regulatory T cells; starvation-immunotherapy
    DOI:  https://doi.org/10.1021/acs.nanolett.2c02475
  27. Assay Drug Dev Technol. 2022 Jul;20(5): 191-210
    Nanocarriers for Smart Therapeutic Strategies to Treat Drug-Resistant Tumors: A Review.
    Abdulsalam A Alqahtani, Hira Aslam, Shazia Shukrullah, Hareem Fatima, Muhammad Yasin Naz, Saifur Rahman, Mater H Mahnashi, Muhammad Irfan.
      Combination therapy has become much more effective in treating cancer because it produces combinatorial anticancer results, lowers specific drug-related toxicities, and inhibits multidrug resistivity through several modes of action. Combined drug delivery (CDD) to cancerous tissues, primarily based on nanotechnology, has developed as a viable method in recent years, surpassing various biomedical, biophysical, and biological obstacles that the body erects to prevent antitumor drugs from reaching their target tissues. In a combined strategy, the prolonged, regulated, and targeted administration of chemotherapeutic medicines improves therapeutic anticancer benefits while reducing drug-related adverse effects. CDD systems have several advantages over traditional drug systems, such as improved solubility, higher permeability for traveling through biomembranes, a significantly longer half-life to expand the treatment time, and low cytotoxicity. CDDs are mostly used to treat neurological, cardiovascular, neoplastic, infectious, and inflammatory diseases. Many CDDs are designed to enhance hydrophilicity to improve transportation inside or across biomembranes, particularly the cornea and skin. CDDs could be delivered to particular cells, organs, or tissues, resulting in increased bioavailability. The most widely utilized nanocarriers for CDDs of anticancer medicines are summarized in this review. This study also covers the chemical or enzymatic decomposition of CDDs and their bioactivity and pharmacokinetics. Additional clinical trials will enhance the usefulness of CDDs in treating drug-resistant tumors.
    Keywords:  drug delivery; drug-resistant tumors; nanocarriers; smart therapeutic strategies
    DOI:  https://doi.org/10.1089/adt.2022.025
  28. Saudi J Biol Sci. 2022 May;29(5): 3354-3365
    Anticancer effect of selenium/chitosan/polyethylene glycol/allyl isothiocyanate nanocomposites against diethylnitrosamine-induced liver cancer in rats.
    Cheng Li, Saleh H Salmen, Tahani Awad Alahmadi, Vishnu Priya Veeraraghavan, Krishna Mohan Surapaneni, Nandakumar Natarajan, Senthilkumar Subramanian.
       Background: Nano-based drug delivery systems have shown several advantages in cancer treatment like specific targeting of cancer cells, good pharmacokinetics, and lesser adverse effects. Liver cancer is a fifth most common cancer and third leading cause of cancer-related mortalities worldwide.
    Objective: The present study focusses to formulate the selenium (S)/chitosan (C)/polyethylene glycol (Pg)/allyl isothiocyanate (AI) nanocomposites (SCPg-AI-NCs) and assess its therapeutic properties against the diethylnitrosamine (DEN)-induced liver cancer in rats via inhibition of oxidative stress and tumor markers.
    Methodology: The SCPg-AI-NCs were synthesized by ionic gelation technique and characterized by various characterization techniques. The liver cancer was induced to the rats by injecting a DEN (200 mg/kg) on the 8th day of experiment. Then DEN-induced rats treated with 10 mg/kg of formulated SCPg-AI-NCs an hour before DEN administration for 16 weeks. The 8-hydroxy-2' -deoxyguanosine (8-OHdG) content, albumin, globulin, and total protein were examined by standard methods. The level of glutathione (GSH), vitamin-C & -E, and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) activities were examined using assay kits. The liver marker enzymes i.e., alanine transaminase (ALT), aspartate tansaminase (AST), γ-glutamyl transaminase (GGT), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) activities, alpha fetoprotein (AFP) and carcinoembryonic antigen (CEA), Bax, and Bcl-2 levels, and caspase-3&9 activities was examined using assay kits and the liver histopathology was assessed microscopically by hematoxylin and eosin staining method. The effect of formulated SCPg-AI-NCs on the viability and apoptotic cell death on the HepG2 cells were examined using MTT and dual staining assays, respectively.
    Results: The results of different characterization studies demonstrated the formation of SCPg-AI-NCs with tetragonal shape, narrowed distribution, and size ranging from 390 to 450 nm. The formulated SCPg-AI-NCs treated liver cancer rats indicated the reduced levels of 8-OHdG, albumin, globulin, and total protein. The SCPg-AI-NCs treatment appreciably improved the GSH, vitamin-C & -E contents, and SOD, CAT, GPx, and GR activities in the serum of liver cancer rats. The SCPg-AI-NCs treatment remarkably reduced the liver marker enzyme activities in the DEN-induced rats. The SCPg-AI-NCs treatment decreased the AFP and CEA contents and enhanced the Bax and caspase 3&9 activities in the DEN-induced rats. The SCPg-AI-NCs effectively decreased the cell viability and induced apoptosis in the HepG2 cells.
    Conclusion: The present findings suggested that the formulated SCPg-AI-NCs remarkably inhibited the DEN-induced liver carcinogenesis in rats. These findings provide an evidence that SCPg-AI-NCs can be a promising anticancer nano-drug in the future to treat the liver carcinogenesis.
    Keywords:  8-Hydroxy-2′-deoxyguanosine; Allyl isothiocyanate; Diethylnitrosamine; Liver cancer; Nano-drug delivery
    DOI:  https://doi.org/10.1016/j.sjbs.2022.02.012
  29. J Mater Chem B. 2022 Jul 21.
    Zwitterionic polymer coated sorafenib-loaded Fe3O4 composite nanoparticles induced ferroptosis for cancer therapy.
    Jingbo Lin, Jiaxin Zhang, Kuang Wang, Shengdi Guo, Wuli Yang.
      Ferroptosis, as a form of cell death different from apoptosis, is very promising for the treatment of cancer in nonapoptotic systems. Since iron is a key component in the induction of ferroptosis in cells, the use of iron-based nanomaterials in treating cancer through ferroptosis is of great significance. Therefore, in this study, magnetic nanoparticles (MNP) were coated with the zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), and then loaded with sorafenib (SRF) to obtain drug-loaded composite nanoparticles MNP@PMPC-SRF. Fe3O4 provided a large number of ferric/ferrous ions as an iron source, releasing Fe2+ for the regulation of the ferroptosis process and enhancing the effect of the induced cellular ferroptosis on the treatment of colon cancer with SRF. The zwitterionic polymer PMPC effectively extended the blood circulation time, resulting in an enhanced tumor accumulation of the nanodrug. MNP@PMPC-SRF exhibited good biocompatibility for in vivo application and showed an excellent tumor inhibitory effect on HCT116 tumor-bearing nude mice.
    DOI:  https://doi.org/10.1039/d2tb01242a
  30. Int J Biol Sci. 2022 ;18(10): 4135-4150
    O-GlcNAcylation of ZEB1 facilitated mesenchymal pancreatic cancer cell ferroptosis.
    Xin Wang, Mengqi Liu, Yue Chu, Yanfang Liu, Xiongfeng Cao, Han Zhang, Yao Huang, Aihua Gong, Xiang Liao, Dongqing Wang, Haitao Zhu.
      Background: Mesenchymal cancer cells, resistant to the traditional regulated cell death, are exquisitely vulnerable to ferroptosis. However, the underlying mechanism has been rarely studied. While glycolipid metabolism rewiring is a critical determination of both cancer cell mesenchymal phenotype and cell death resistance, we are interested in the underlying cross talk between glycolipid metabolism and mesenchymal cancer cell ferroptosis sensitivity. Methods: CCK-8, western blot and clone forming assay were used to access the effect of glucose on mesenchymal cancer cell ferroptosis susceptibility and O-GlcNAcylation level. GEPIA database, shRNA knockdown and various pharmacological inhibitors were used to analyze the relationship between O-GlcNAcylation and mesenchymal cancer cell ferroptosis in vitro and in vivo. A series of experiments were conducted to investigate the underlying mechanisms of glucose induced ZEB1 O-GlcNAcylation on mesenchymal cancer cell ferroptosis susceptibility. Results: Mesenchymal pancreatic cancer cells O-GlcNAcylation level and ferroptosis cell death was significantly increased under high glucose condition in vitro and in vivo. O-GlcNAcylation of ZEB1, rather than other transcription factors, was involved in this process. Mechanistically, glucose triggered ZEB1 O-GlcNAcylation at Ser555 site enhanced its stabilization and nuclear translocation, induced lipogenesis associated genes, FASN and FADS2, transcription activity, which ultimately resulted in lipid peroxidation dependent mesenchymal pancreatic cancer cell ferroptosis. Conclusions: These results identify a novel role of glycolipid metabolism and O-GlcNAcylation in mesenchymal cancer cells ferroptosis susceptibility, which broaden the molecular mechanism of ferroptosis and suggested a potential clinical therapeutic strategy for refractory tumors.
    Keywords:  Ferroptosis; Glycolipid metabolism; Mesenchymal pancreatic cancer cell; O-GlcNAcylation; ZEB1
    DOI:  https://doi.org/10.7150/ijbs.71520
  31. Eur Rev Med Pharmacol Sci. 2022 Jul;pii: 29192. [Epub ahead of print]26(13): 4677-4692
    Role of oxidative stress in angiogenesis and the therapeutic potential of antioxidants in breast cancer.
    B Mdkhana, S Goel, M A Saleh, R Siddiqui, N A Khan, A B Elmoselhi.
      The escalation of cancer cases globally, especially breast cancer, is of concern. Angiogenesis is hallmark of cancer pathogenesis and plays an important role in cancer progression and metastasis. Pro-angiogenic agents, secreted by tumor cells, form new blood vessels, and produce reactive oxygen species (ROS). ROS promote angiogenesis via two major pathways: namely Vascular Endothelial Growth Factor (VEGF) dependent and non-VEGF dependent pathways. As a consequence of unbalanced ROS overproduction and low antioxidants levels, oxidative stress occurs and promotes angiogenesis in breast cancer tissues. Thus, the potential use of antioxidants as a preventive therapy in breast cancer. Preclinical studies depict that vitamins A and E may counter oxidative stress resulting in reduction of metastasis and viability of breast cancer. Furthermore, clinical studies demonstrate a decline in breast cancer risk in postmenopausal women upon the consumption of antioxidants. Herein, we discuss various pro-angiogenic agents that may play an important role in breast cancer angiogenesis. Moreover, the contribution of oxidative stress in inducing the angiogenic process is extensively reviewed here. Furthermore, the findings of pre-clinical and clinical studies on the use of antioxidants, namely vitamins A and E, in breast cancer are deliberated upon, along with the role of angiogenesis in cancer therapy.
    DOI:  https://doi.org/10.26355/eurrev_202207_29192
  32. J Drug Target. 2022 Jul 20. 1-27
    Advances, challenge and prospects in cell-mediated nanodrug delivery for cancer therapy: a review.
    Wei Wuhao, Yuansheng Zhang, Zhizhe Lin, Xin Wu, Wei Fan, Jianming Chen.
      Nanomedicine offers considerable opportunities to improve drugability and reduce toxicity for tumour therapy. However, the application of nanomedicine has achieved little success in clinical trials due to multiple physiological barriers to drug delivery. Circulating cells are expected to improve the physical distribution of drugs and enhance the therapeutic effect by overcoming various biological barriers in collaboration with nano-drug delivery systems owing to excellent biocompatibility, low immunogenicity, and a long-circulation time and strong binding specificity. Nonetheless, we have noticed some limitations in implementing the strategy. In this article, we intend to introduce the latest progress in research and application of circulating cell-mediated nano-drug delivery systems, describe the main cell-related drug delivery modes, sum up the relevant points of the transport systems in the process of loading, transport and release, and lastly discuss the advantages, challenges and future development trends in cell-mediated nano-drug delivery.
    Keywords:  Cancer; Circulating cells; Nanoparticles;Drug delivery system
    DOI:  https://doi.org/10.1080/1061186X.2022.2104299
  33. J Nanobiotechnology. 2022 Jul 16. 20(1): 330
    Radiodynamic therapy with CsI(na)@MgO nanoparticles and 5-aminolevulinic acid.
    Fangchao Jiang, Chaebin Lee, Weizhong Zhang, Wen Jiang, Zhengwei Cao, Harrison Byron Chong, Wei Yang, Shuyue Zhan, Jianwen Li, Yong Teng, Zibo Li, Jin Xie.
       BACKGROUND: Radiodynamic therapy (RDT) holds the potential to overcome the shallow tissue penetration issue associated with conventional photodynamic therapy (PDT). To this end, complex and sometimes toxic scintillator-photosensitizer nanoconjugates are often used, posing barriers for large-scale manufacturing and regulatory approval.
    METHODS: Herein, we report a streamlined RDT strategy based on CsI(Na)@MgO nanoparticles and 5-aminolevulinic acid (5-ALA). 5-ALA is a clinically approved photosensitizer, converted to protoporphyrin IX (PpIX) in cancer cells' mitochondria. CsI(Na)@MgO nanoparticles produce strong ~ 410 nm X-ray luminescence, which matches the Soret band of PpIX. We hypothesize that the CsI(Na)@MgO-and-5-ALA combination can mediate RDT wherein mitochondria-targeted PDT synergizes with DNA-targeted irradiation for efficient cancer cell killing. Because scintillator nanoparticles and photosensitizer are administered separately, the approach forgoes issues such as self-quenching or uncontrolled release of photosensitizers.
    RESULTS: When tested in vitro with 4T1 cells, the CsI(Na)@MgO and 5-ALA combination elevated radiation-induced reactive oxygen species (ROS), enhancing damages to mitochondria, DNA, and lipids, eventually reducing cell proliferation and clonogenicity. When tested in vivo in 4T1 models, RDT with the CsI(Na)@MgO and 5-ALA combination significantly improved tumor suppression and animal survival relative to radiation therapy (RT) alone. After treatment, the scintillator nanoparticles, made of low-toxic alkali and halide elements, were efficiently excreted, causing no detectable harm to the hosts.
    CONCLUSIONS: Our studies show that separately administering CsI(Na)@MgO nanoparticles and 5-ALA represents a safe and streamlined RDT approach with potential in clinical translation.
    Keywords:  Cancer; Nanoparticles; Photodynamic therapy; Radiation therapy; Scintillator
    DOI:  https://doi.org/10.1186/s12951-022-01537-z
  34. Drug Deliv. 2022 Dec;29(1): 2072-2085
    Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance.
    Muhammad Umair Amin, Sajid Ali, Muhammad Yasir Ali, Dominik C Fuhrmann, Imran Tariq, Benjamin S Seitz, Eduard Preis, Jana Brüßler, Bernhard Brüne, Udo Bakowsky.
      Hypoxia, an oxygen-deprived condition of the tumor, is one of the major reasons for resistance to chemotherapy. Carbonic anhydrases are generally involved in pH homeostasis in normal conditions, but in solid tumors having a strong relation with hypoxia, the carbonic anhydrase IX (CA-IX) enzyme is overexpressed and results in an extracellular acidic environment. For most weakly basic anticancer drugs, including doxorubicin (Dox), the ionization in an acidic environment limits their cellular uptake, and consequently, the tumor exposure to the drug at sub-therapeutic concentration comes out as chemoresistance. Herein, a combined drug delivery system of liposomes and mesoporous silica nanoparticles (MSNPs) was developed for the co-delivery of the CA-IX enzyme inhibitor and Dox in hypoxic condition. The unique structure of MSNPs with higher surface area was utilized for higher drug loading and sustained release of Dox. Additionally, the biocompatible nature of liposomal coating as a second loading site for the CA-IX enzyme inhibitor has provided gatekeeping effects at pore opening to avoid premature drug release. Lipid coated MSNPs as a co-delivery system for Dox and the CA-IX inhibitor have synergistic cytotoxic effects against MDA-MB 231 breast cancer cells in hypoxic conditions. These findings assure the potential of this drug delivery system to overcome hypoxia-related chemoresistance.
    Keywords:  CA-IX enzyme inhibition; Hypoxia; co-delivery; liposomes; mesoporous silica nanoparticles
    DOI:  https://doi.org/10.1080/10717544.2022.2092234
  35. Cell Mol Biol Lett. 2022 Jul 22. 27(1): 58
    The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors.
    Samaneh Mostafavi, Hamidreza Zalpoor, Zuhair Mohammad Hassan.
      Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.
    Keywords:  Cancer-associated fibroblasts; Lactic acid; Metformin; Myofibroblasts; Stromal cells; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s11658-022-00356-2
  36. J Cardiovasc Pharmacol. 2022 Jul 18.
    Advances in Nano-formulated Polyphenols for Protection against Cardiovascular diseases.
    Prasanti Sharma, Neelima Sharma.
       ABSTRACT: In the past decade, a plethora of research has revealed numerous biological effects of polyphenols, most significantly anti-cancer and anti-microbial. These versatile, naturally occurring compounds have attracted growing interest among researchers owing to their crucial role in modifying disease progression associated with almost all of the body's vital systems, including the cardiovascular, neurological, and gastrointestinal systems. However, poor water solubility and rapid metabolism result in low bioavailability, which is a critical limitation to their clinical use. Nanotechnology is one promising approach that has served to maximize the therapeutic potential of polyphenols. Incorporation of sensitive polyphenolic compounds into nanocarriers protects them from physiological degradation, facilitates prolonged release, improves bioavailability and allows targeted drug delivery. There is emerging evidence that nanomedicine could provide a solution to the poor pharmacokinetics of polyphenols and enhance their treatment efficacy. This review focuses on the various nanoparticle-based delivery systems that have been developed for the entrapment of these hydrophobic molecules and circumvent the pitfalls of poor systemic availability with an emphasis on their application in cardiovascular disorders. It elucidates recent developments in nanotechnology that could not only be imperative to cardiovascular disease alleviation but also in resolving issues of safety and specificity associated with these molecules. It also highlights the improved physicochemical properties and possible molecular mechanisms of some major polyphenols administered as nano-formulations and describes the results of in-vitro and in-vivo studies carried out in animal models of cardiovascular diseases (CVDs).
    DOI:  https://doi.org/10.1097/FJC.0000000000001335
  37. Front Bioeng Biotechnol. 2022 ;10 919189
    Intracellular K+-Responsive Block Copolymer Micelles for Targeted Drug Delivery of Curcumin.
    Mingyue Jiang, Le Chen, Bo Chen, Qinghua Yu, Xianming Zhang, Weihong Jing, Limei Ma, Tao Deng, Zhangyou Yang, Chao Yu.
      Curcumin (CUR) is a natural bioactive compound that has attracted attention as a "golden molecule" due to its therapeutic properties against several types of tumors. Nonetheless, the antitumor application of CUR is hampered due to its extremely low aqueous solubility and chemical instability. Herein, a novel type of CUR-loaded polymeric micelles with intracellular K+-responsive controlled-release properties is designed and developed. The polymeric micelles are self-assembled by poly (N-isopropylacrylamide-co-acryloylamidobenzo-15-crown-5-co-N, N-dimethylacrylamide)-b-DSPE (PNDB-b-DSPE) block copolymers, and CUR. CUR is successfully loaded into the micelles with a CUR loading content of 6.26 wt%. The proposed CUR-PNDB-DSPE polymeric micelles exhibit a significant CUR release in simulated intracellular fluid due to the formation of 2 : 1 ''sandwich'' host-guest complexes of 15-crown-5 and K+, which lead to the hydrophilic outer shell of micelles to collapse and the drug to rapidly migrate out of the micelles. In vitro, the B16F10 cell experiment indicates that CUR-PNDB-DSPE micelles exhibit a high cellular uptake and excellent intracellular drug release in response to the intracellular K+ concentration. Moreover, CUR-PNDB-DSPE micelles show high cytotoxicity to B16F10 cells compared to free CUR and CUR-PEG-DSPE micelles. The polymeric micelles with intracellular K+-responsive controlled release properties proposed in this study provide a new strategy for designing novel targeted drug delivery systems for CUR delivery for cancer treatment.
    Keywords:  K+ -triggered drug release; anticancer; curcumin; polymer micelles; responsive host–guest system
    DOI:  https://doi.org/10.3389/fbioe.2022.919189
  38. J Biomed Nanotechnol. 2022 Apr 01. 18(4): 957-975
    A New Gold Nanoparticles and Paclitaxel Co-Delivery System for Enhanced Anti-Cancer Effect Through Chemo-Photothermal Combination.
    Honglei Zhan, Wenjing Song, Mingyang Gu, He Zhao, Yujia Liu, Bingnan Liu, Jihui Wang.
      Limited chemotherapeutic efficiency, drug resistance and side effect are primary obstacles for cancer treatment. The development of co-delivery system with synergistic treatment modes should be a promising strategy. Here, we fabricated a multi-functionalized nanocarrier with a combination of chemotherapeutic agent and gold nanoparticles (AuNPs), which could integrate chemo-photothermal therapy and improve entire anti-cancer index. Particularly, Paclitaxel nanocrystals (PTX NC) were first fabricated as a platform, on surface of which AuNPs were decorated and polydopamine (PDA) layer act as capping, stabilizing and hydrophilic agents for PTX NC, providing a bridge connecting AuNPs to PTX. These AuNPs decorated PTX NC exhibited good physico-chemical properties like optimal sizes, stability and photothermal efficiency. Compared to other PTX formulations, they displayed considerably improved biocompatibility, selectivity, intracellular uptake, cytotoxicity, apoptosis induction activity and P-glycoprotein (Pgp) inhibitory capability, owing to a synergistic/ cooperative effect from AuNPs, PTX and NIR treatment, photothermal-triggered drug release and nano-scaled structure. Mitochondria-mediated signaling pathway is underlying mechanism for cytotoxic and apoptotic effect from AuNPs decorated PTX NC, in terms of Mitochondria damage, a loss of Mitochondrial membrane potential, intensified oxidative stress, DNA breakage, Caspase 3 activation, up-regulated expression in pro-apoptotic genes like p53, Caspase 3 and Bax and down-regulated level in anti-apoptotic gene like Bcl-2.
    DOI:  https://doi.org/10.1166/jbn.2022.3309
  39. ACS Omega. 2022 Jul 12. 7(27): 23643-23652
    Simvastatin-Loaded Lipid Emulsion Nanoparticles: Characterizations and Applications.
    Faiz Ullah, Muhammad Farhan Ali Khan, Nazeer Hussain Khan, Muhammad Fayyaz Rehman, Syed Sakhawat Shah, Muhammad Mustaqeem, Sami Ullah, Qidi Zhang, Hongchao Shi.
      Simvastatin (SIM) is a diet drug to treat high lipid levels in the blood. It has the drawback of being metabolized in humans' gastrointestinal tract (GIT) when taken in an oral dosage form. To enhance the role of SIM in treating hyperlipidemias and bypassing its metabolism in GIT, a biodegradable nanocarrier as a SIM-loaded lipid emulsion nanoparticle via the solvent injection method was designed. Cholesterol acts as a lipid core, and Tween 80 was utilized to stabilize the core. The optimized nanoformulation was characterized for its particle diameter, zeta potential, surface morphology, entrapment efficiency, crystallinity, and molecular interaction. Furthermore, the transdermal hydrogel was characterized by physical appearance, rheology, pH, and spreadability. In vitro assays were executed to gauge the potential of LENPs and olive oil for transdermal delivery. The mean particle size and zeta potential of the optimized nanoparticles were 174 nm and -22.5 mV 0.127, respectively. Crystallinity studies and Fourier transform infrared analyses revealed no molecular interactions. Hydrogels showed a sustained release compared to SIM-loaded LENPs that can be proposed as a better delivery system for SIM. We encourage further investigations to explore the effect of reported formulations for transdermal delivery by in vivo experiments.
    DOI:  https://doi.org/10.1021/acsomega.2c02242
  40. Cancer Sci. 2022 Jul 18.
    Effect of Fasting on Cancer: A narrative review of scientific evidence.
    Sagun Tiwari, Namrata Sapkota, Zhenxiang Han.
      Emerging evidence suggests that fasting has a key role in cancer by fostering conditions that limit cancer cells' adaptability, survival, and growth, increasing the effectiveness of cancer treatments and limiting adverse events. Yet, we lack an integrated mechanistic model for how these two complicated systems interact, limiting our ability to understand, prevent, and treat cancer using fasting. Here, we review recent findings at the interface of oncology and fasting metabolism, with an emphasis on human clinical studies of intermittent fasting. We recommend combining prolonged periodic fasting with a standard conventional therapeutic approach to promote cancer-free survival, treatment efficacy, and reduce side effects in cancer patients.
    Keywords:  Cancer; Diet, Review, Intermittent Fasting; Fasting; Oncology
    DOI:  https://doi.org/10.1111/cas.15492
  41. Mater Today Bio. 2022 Dec;16 100338
    A multi-hit therapeutic nanoplatform for hepatocellular carcinoma: Dual stimuli-responsive drug release, dual-modal imaging, and in situ oxygen supply to enhance synergistic therapy.
    Taiying Chen, Ngalei Tam, Yu Mao, Chengjun Sun, Zekang Wang, Yuchen Hou, Wuzheng Xia, Jia Yu, Linwei Wu.
      Nanomedicine has been widely studied for the diagnosis and treatment of hepatocellular carcinoma (HCC). How to synthesize a nanoplatform possessing a high synergistic therapeutic efficacy remains a challenge in this emerging research field. In this study, a convenient all-in-one therapeutic nanoplatform (FTY720@AM/T7-TL) is designed for HCC. This advanced nanoplatform consists of multiple functional elements, including gold-manganese dioxide nanoparticles (AM), tetraphenylethylene (T), fingolimod (FTY720), hybrid-liposome (L), and T7 peptides (T7). The nanoplatform is negatively charged at physiological pH and can transit to a positively charged state once moving to acidic pH environments. The specially designed pH-responsive charge-reversal nanocarrier prolongs the half-life of nanodrugs in blood and improves cellular uptake efficiency. The platform achieves a sustained and controllable drug release through dual stimulus-response, with pH as the endogenous stimulus and near-infrared as the exogenous stimulus. Furthermore, the nanoplatform realizes in situ O2 generation by catalyzing tumor over-expressed H2O2, which alleviates tumor microenvironment hypoxia and improves photodynamic therapy. Both in vitro and in vivo studies show the prepared nanoplatform has good photothermal conversion, cellular uptake efficiency, fluorescence/magnetic resonance imaging capabilities, and synergistic anti-tumor effects. These results suggest that the prepared all-in-one nanoplatform has great potential for dual-modal imaging-guided synergistic therapy of HCC.
    Keywords:  Dual-modal imaging; Hepatocellular carcinoma; In situ oxygen supplement; Stimuli-responsive drug release; Tumor microenvironments
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100338
  42. Front Pharmacol. 2022 ;13 891171
    Research Progress on the Anticancer Activities and Mechanisms of Polysaccharides From Ganoderma.
    Man Wang, Fei Yu.
      Cancer ranks as a primary reason for death worldwide. Conventional anticancer therapies can cause severe side effects, and thus natural products may be promising drug candidates for cancer therapy. Accumulating evidence has verified the prominent anticancer properties of Ganoderma polysaccharides, suggesting that Ganoderma polysaccharides may be effective chemopreventive agents of natural origin. Based on their abilities to prevent cancer development by regulating the DNA damage response, cancer cell proliferation, apoptosis, host immunity, gut microbiota and therapeutic sensitivity, there has been increasing interest in elucidating the clinical implication of Ganoderma polysaccharides in cancer therapy. In this review, we summarize recent findings pertaining to the roles of bioactive polysaccharides from Ganoderma in cancer pathogenesis, discuss the multifarious mechanisms involved and propose future directions for research. A more sophisticated understanding of the anticancer benefits of Ganoderma polysaccharides will be helpful for improving current treatments and developing novel therapeutic interventions for human malignancies.
    Keywords:  Ganoderma; anticancer properties; cancer; chemopreventive agents; polysaccharides; therapeutic intervention
    DOI:  https://doi.org/10.3389/fphar.2022.891171
  43. Front Nutr. 2022 ;9 863619
    Combination of Ashwagandha Water Extract and Intermittent Fasting as a Therapy to Overcome Cisplatin Resistance in Breast Cancer: An in vitro and in vivo Study.
    Sajidah Jawarneh, Wamidh H Talib.
      Breast cancer is considered a universal public health dilemma in women. Due to the high toxicity and low selectivity of conventional anticancer therapies, there is a growing trend of using plant-derived natural products in cancer prevention and therapy. Ashwagandha (Withania somnifera, WS) has been used in the Mediterranean region and Ayurvedic medicine for millennia as a functional food and a medicinal plant with anticancer activity. Besides, intermittent fasting (IF) has been engaged recently in cancer treatment. Hence, the combination of WS and IF provides possible solutions to treat cancer and reduce chemoresistance when combined with chemotherapy. In this study, WS root (WSR), IF, and cisplatin were tested on cisplatin-sensitive (EMT6/P) and cisplatin-resistant (EMT6/CPR) mouse mammary cell lines. The phytochemical content of the WSR extract was analyzed using liquid chromatography-mass spectrometry (LC-MS) analysis. Antiproliferative and apoptotic effects were assessed for WSR extract, cisplatin, and their combination in vitro using [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] (MTT) and caspase-3 assays. An in vivo study was used to assess the effect of WSR extract, IF, cisplatin, and their combinations in mice inculcated with EMT6/P and EMT6/CPR cells. The safety profile was also investigated using liver enzymes and creatinine assays. In vitro, WSR extract and cisplatin had a synergistic effect in both cell lines. The same combination induced an apoptotic effect higher than the single treatment in both cell lines. In vivo, several combinations of WSR extract, IF, or cisplatin caused significant tumor size reduction and improved the cure rate in mice implanted with EMT6/P and EMT6/CPR cell lines. IF-treated groups showed a significant reduction in serum glucose and an elevation in β-hydroxybutyrate (BHB) levels. In the safety profile, WSR extract, IF, and their combinations were safe. Overall, the combination of WSR extract and IF provides a promising solution for breast cancer treatment besides cisplatin by reducing the proliferation of cancer cells through induction of apoptosis. Moreover, they minimize cisplatin toxicity to the liver and kidney.
    Keywords:  Ashwagandha; Warburg effect; apoptosis; breast cancer; cisplatin; intermittent fasting; multidrug resistance; nutritional intervention
    DOI:  https://doi.org/10.3389/fnut.2022.863619
  44. Biomed Chromatogr. 2022 Jul 18. e5451
    Cell Metabolomics Study on Synergistic anti-Hepatocellular Carcinoma Effect of Aidi Injection Combined with Doxorubicin.
    Yanli Wang, Xiaoqing Zhu, Kailiang Wang, Ying Cai, Chunhua Liu, Jie Pan, Jia Sun, Ting Liu, Yong Huang, Yongjun Li, Yuan Lu.
      Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in combined threapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index (CI) was also calculated. A metabolomic strategy based on ultrahigh performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the CI values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 μmol/L DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (L-glutamic acid, L-arginine, and L-tyrosine), organic acids (succinic acid and citric acid), adenosine, and hypoxanthine , etc. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic anti-tumor effect by balancing the metabolism of amino acids and energy-related substances.
    Keywords:  Aidi injection; Cell metabolomics; Doxorubicin; H22 hepatocellular carcinoma; Synergistic effect
    DOI:  https://doi.org/10.1002/bmc.5451
  45. J Nanobiotechnology. 2022 Jul 16. 20(1): 332
    Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy.
    Shaochen Wang, Qiaoqiao Zhou, Shuling Yu, Shuang Zhao, Jiahua Shi, Jintao Yuan.
      The development of chemo/photothermal nanotherapeutic systems with excellent photothermal performance, stable drug loading, tumor targeting and strong membrane penetration still remains a challenge. To address this problem, herein a rod-like nanocomposite system (AuNR@FA-PR/PEG) forming from folic acid (FA) terminated carboxylated cyclodextrin (CD) pseudopolyrotaxane (FA-PR) and polyethylene glycol (PEG) modifying gold nanorods (AuNR) was reported. Cisplatin (CDDP) was loaded in AuNR@FA-PR/PEG via coordination bonds to prepare a rod-like pH-responsive nanosystem (AuNR@FA-PR/PEG/CDDP) with chemotherapy/photothermal therapy. The rod-like morphology of AuNR@FA-PR/PEG was characterized by transmission electron microscope. In vitro drug release experiments showed the pH-responsive of AuNR@FA-PR/PEG/CDDP. In vivo real-time imaging assays proved AuNR@FA-PR/PEG/CDDP could rapidly enrich in the tumor area and stay for a long time because of folate targeting and their rod-like morphology. In vivo photothermal imaging assays showed AuNR@FA-PR/PEG/CDDP excellent photothermal performance, the average temperature of tumor region could reach 63.5 °C after 10 min irradiation. In vitro and in vivo experiments also demonstrated that the combined therapy of chemotherapy and photothermal therapy had an outstandingly synergistic effect and improved the therapeutic efficacy comparing with chemotherapy and photothermal therapy alone. Therefore, the prepared rod-like AuNR@FA-PR/PEG/CDDP will provide a new strategy for the effective treatment of cancer.
    Keywords:  Gold nanorods; Hybrid nanomaterials; Polyrotaxane; Targeted synergistic therapy; pH-Responsive
    DOI:  https://doi.org/10.1186/s12951-022-01527-1
  46. Front Pharmacol. 2022 ;13 906746
    Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer.
    Sze Wan Hung, Yiran Li, Xiaoyan Chen, Kai On Chu, Yiwei Zhao, Yingyu Liu, Xi Guo, Gene Chi-Wai Man, Chi Chiu Wang.
      With a rich abundance of natural polyphenols, green tea has become one of the most popular and healthiest nonalcoholic beverages being consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the predominant catechin found in green tea, which has been shown to promote numerous health benefits, including metabolic regulation, antioxidant, anti-inflammatory, and anticancer. Clinical studies have also shown the inhibitory effects of EGCG on cancers of the male and female reproductive system, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Autophagy is a natural, self-degradation process that serves important functions in both tumor suppression and tumor cell survival. Naturally derived products have the potential to be an effective and safe alternative in balancing autophagy and maintaining homeostasis during tumor development. Although EGCG has been shown to play a critical role in the suppression of multiple cancers, its role as autophagy modulator in cancers of the male and female reproductive system remains to be fully discussed. Herein, we aim to provide an overview of the current knowledge of EGCG in targeting autophagy and its related signaling mechanism in reproductive cancers. Effects of EGCG on regulating autophagy toward reproductive cancers as a single therapy or cotreatment with other chemotherapies will be reviewed and compared. Additionally, the underlying mechanisms and crosstalk of EGCG between autophagy and other cellular processes, such as reactive oxidative stress, ER stress, angiogenesis, and apoptosis, will be summarized. The present review will help to shed light on the significance of green tea as a potential therapeutic treatment for reproductive cancers through regulating autophagy.
    Keywords:  EGCG; anticancer; autophagy; green tea; reproductive cancers
    DOI:  https://doi.org/10.3389/fphar.2022.906746
  47. J Trace Elem Med Biol. 2022 Jul 16. pii: S0946-672X(22)00123-7. [Epub ahead of print]73 127043
    Boric acid exert anti-cancer effect in poorly differentiated hepatocellular carcinoma cells via inhibition of AKT signaling pathway.
    Erkan Kahraman, Erdem Göker.
       BACKGROUND: The possible anti-cancer properties of boron, a trace element for humans, have been demonstrated in various experimental and epidemiological studies, although the effects of boron on liver cancer are unclear. In the present study we evaluate the effects of boric acid on the cell lines of hepatocellular carcinoma (HCC) of the liver, as the leading form of liver cancer, for which a poorly-differentiated HCC cell line (Mahlavu cell line) was used.
    METHODS: The anti-cancer effect of boric acid was investigated with a cell viability assay, apoptosis analysis, cell migration analysis, cell morphology analysis, colony formation assay and 3D cell culture techniques. Also, the effect of boric acid on the AKT signaling pathway was determined through a western blot analysis.
    RESULTS: Boric acid was found to reduce cell viability in a dose- and time-dependent manner, and decreased survival, colony formation ability, migration capability and HCC cell tumor spheroid growth in HCC cell lines, while also inducing apoptosis, autophagy and morphological alteration. Furthermore, boric acid inhibited AKT phosphorylation, and anticancer biological responses in HCC cells were observed only in cells in which AKT phosphorylation was suppressed by boric acid.
    CONCLUSION: Our results suggest that boric acid might be a promising therapeutic candidate in hepatocellular carcinoma via the inhibition of AKT signaling pathway.
    Keywords:  Boric acid; Boron; Cancer drugs; Hepatocellular carcinoma; Liver cancer
    DOI:  https://doi.org/10.1016/j.jtemb.2022.127043
  48. Biomater Res. 2022 Jul 22. 26(1): 35
    Coacervate-mediated novel pancreatic cancer drug Aleuria Aurantia lectin delivery for augmented anticancer therapy.
    Sungjun Kim, Yunyoung Choi, Kyobum Kim.
       BACKGROUND: Pancreatic cancer, one of the cancers with the highest mortality rate, has very limited clinical treatment. Cancer cells express abnormal glycans on the surface, and some lectins with a high affinity for the glycans induce apoptosis in cancer. In this study, the efficacy of Aleuria Aurantia lectin (AAL) for the treatment of pancreatic cancer was evaluated and the efficacy improvement through AAL delivery with mPEGylated coacervate (mPEG-Coa) was investigated.
    METHODS: AAL was treated with pancreatic cancer cells, PANC-1, and the expression level of caspase-3 and subsequent apoptosis was analyzed. In particular, the anticancer efficacy of AAL was compared with that of concanavalin A, one of the representative anticancer lectins. Then, methoxypolyethylene glycol-poly(ethylene arginylaspartate diglyceride), a polycation, was synthesized, and an mPEG-Coa complex was prepared with polyanion heparin. The AAL was incorporated into the mPEG-Coa and the release kinetics of the AAL from the mPEG-Coa and the cargo protection capacity of the mPEG-Coa were evaluated. Finally, improved anticancer ability through Coa-mediated AAL delivery was assessed.
    RESULTS: These results indicated that AAL is a potential effective pancreatic cancer treatment. Moreover, mPEG-Coa rapidly released AAL at pH 6.5, an acidic condition in the cancer microenvironment. The initial rapid release of AAL effectively suppressed pancreatic cancer cells, and the continuous supply of AAL through the Coa transporter effectively inhibited proliferation recurrence of cancer cells.
    CONCLUSION: AAL is a potential novel drug for the treatment of pancreatic cancer therapeutic agent. In addition, a continuous supply of drugs above the therapeutic threshold using mPEG-Coa could improve therapeutic efficacy.
    Keywords:  Aleuria Aurantia lectin; Anticancer therapy; Coacervate; Drug delivery system; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s40824-022-00282-6
  49. J Biomater Sci Polym Ed. 2022 Jul 21. 1-15
    Nanofabrication of PLGA- PEG-Chitosan-Folic acid Systems for Delivery of Colchicine to HT-29 Cancer Cells.
    Farzaneh Sadeghzadeh, Atefeh Sadat Ziaratnia, Masoud Homayouni Tabrizi, Ghazal Hosseini Torshizi, Maitham Alhajamee, Davoud Khademi.
      Aim: This survey was conducted to fabrication of PLGA-based nanosystems modified with PEG, chitosan and folic acid to delivery colchicine to cancer cells and to investigate its antioxidant and pro-apoptotic effects.Materials and Methods: The dual emulsion-evaporation solvent method was used for loading of colchicine on PEGylated PLGA nanoparticles (COL-PP-NPs) and after surface modification with chitosan and folic acid (COL-PPCF-NPs), the nanoparticles were characterized by DLS, SEM and FTIR methods. The HPLC procedure was used to assess the amount of FA binding and Col loading. Antioxidant capacity (ABTS and DPPH free radical scavenging) and toxicity (MTT) of COL-PPCF-NPs were evaluated and then cell inhibition mechanism was assessed by AO/PI staining, flow cytometry and qPCR assay.Results: COL-PPCF-NPs with a size of 250 nm were synthesized in a stable (zeta potential: +34 mV) and mono-dispersed (PDI: 0.32) manner. FA binding and Col loading were reported to be 55% and 89.5%, respectively. Col-PPCF-NPs showed antioxidant effects by inhibiting the free radicals ABTS (108.07µg/ml) and DPPH (361.61µg/ml). The selective toxicity of COL-PPCF-NPs against HT-29 cancer cells (118.5µg/ml) compared to HFF cells was confirmed by MTT data. Increased apoptotic cells (red color) in AO/PI staining, cell arrest in phase SubG1 and G2-M, and altered expression of apoptosis genes confirmed the occurrence of apoptosis in HT-29 treated cells.Conclusion: the use of PPCF-NPs system for delivery of COL can lead to selective toxicity against cancer cells and induction of apoptosis in these cells by folate-mediated binding mechanism at folate receptor positive HT-29 cancer cells.
    Keywords:  Antioxidant; Chitosan; Colchicine; PLGA
    DOI:  https://doi.org/10.1080/09205063.2022.2105103
  50. Drug Deliv. 2022 Dec;29(1): 2386-2402
    Alendronate modified mPEG-PLGA nano-micelle drug delivery system loaded with astragaloside has anti-osteoporotic effect in rats.
    Yanhai Xi, Weiheng Wang, Liang Ma, Ning Xu, Changgui Shi, Guohua Xu, Hailong He, Wenming Pan.
      Astragaloside (AS) has an anti-osteoporotic effect, but its poor water solubility and low bioavailability limit its application. In this study, a novel nano-carrier with bone targeting was prepared by modifying mPEG-PLGA with alendronate (AL) before incorporation into astragaloside nano-micelles (AS-AL-mPEG-PLGA) to enhance the oral bioavailability, bone targeting and anti-osteoporosis effect of AS. The release behavior of AS-AL-mPEG-PLGA in vitro was investigated via dialysis. The pharmacokinetics of AS-AL-mPEG-PLGA was studied in Sprague-Dawley (SD) rats. The cytotoxicity of AS-AL-mPEG-PLGA in vitro (via MTT method), coupled with bone targeting ability in vitro and in vivo were evaluated. The therapeutic effects of free AS and AS-AL-mPEG-PLGA (ELISA, micro-CT, H&E staining) were compared in osteoporotic rats. AS-AL-mPEG-PLGA with smaller particle size (45.3 ± 3.8 nm) and high absolute zeta potential (-23.02 ± 0.51 mV) were successfully prepared, wherein it demonstrated higher entrapment efficiency (96.16 ± 0.18%), a significant sustained-release effect for 96 h and acceptable safety within 10-200 μg/mL. AS-AL-mPEG-PLGA could enhance the hydroxyapatite affinity and bone tissue concentration of AS. The relative bioavailability of AS-AL-mPEG-PLGA was 233.90% compared with free AS. In addition, the effect of AS in reducing serum levels of bone metabolism-related indicators, restoring the bone microarchitecture and improving bone injury could be enhanced by AS-AL-mPEG-PLGA. AS-AL-mPEG-PLGA with small particle size, good stability, remarkable sustained-release effect, safety and bone targeting was successfully constructed in this experiment to potentially improve the oral bioavailability and anti-osteoporosis effect of AS. Thus, AS-AL-mPEG-PLGA may be a promising strategy to prevent and treat osteoporosis.
    Keywords:  Astragaloside; mPEG-PLGA; targeted therapy
    DOI:  https://doi.org/10.1080/10717544.2022.2086942
  51. Galen Med J. 2021 ;10 1-8
    Review On the Effects Curcumin on Tumors of the Reproductive System: Curcumin and Reproductive Tumors.
    Moradi Zahra, Tohidian Mostafa, Hekmatnia Yasaman, Dalili Amin, Sadeghi Mostafa, Neshat Seyed Sina, Jamalnia Sheida, Reihani Elnaz.
      Curcumin, a polyphenolic derivative of Curcuma longa rhizome, has numerous beneficial effects, including antibacterial, anti-inflammatory, antiviral, antioxidant, antifungal, anti-ischemic, anti-cancer, hypoglycemic, nephroprotective, antirheumatic, hepato-protective, and antimutagenic. Curcumin has indicated the capability to exert anti-cancer activity by multifunctional mechanisms, such as induction of apoptosis, inhibition of cancer cell proliferation, cell cycle regulation, chemotherapeutic intestinal absorption, and modification of several cancer cell types signaling pathways. Several studies have shown that curcumin may have protective effects against tumors of the reproductive system. Reproductive system cancers may cause many undesirable physical and, especially, mental disorders. Infertility and its mental consequences, sexual problems, chemotherapy and surgery-related adverse effects, substantial economic burden, and death are the most common complications regarding the cancers of the reproductive system. By modulating several reproductive cancer hallmarks such as signaling pathways, multiple drug resistance, cancer cell growth and proliferation, tumor angiogenesis, and transcription factors, curcumin could be used as a safe, non-toxic, cheap, and easily accessible drug for treating different types of reproductive cancers.
    Keywords:  Breast; Cancer; Curcumin; Ovary; Prostate; Reproduction; Tumor
    DOI:  https://doi.org/10.31661/gmj.v10i0.2178
  52. Cancer Metab. 2022 Jul 18. 10(1): 12
    Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity.
    Daniela D Weber, Sepideh Aminzadeh-Gohari, Maheshwor Thapa, Anna-Sophia Redtenbacher, Luca Catalano, Tânia Capelôa, Thibaut Vazeille, Michael Emberger, Thomas K Felder, René G Feichtinger, Peter Koelblinger, Guido Dallmann, Pierre Sonveaux, Roland Lang, Barbara Kofler.
       BACKGROUND: Growing evidence supports the use of low-carbohydrate/high-fat ketogenic diets as an adjunctive cancer therapy. However, it is unclear which genetic, metabolic, or immunological factors contribute to the beneficial effect of ketogenic diets. Therefore, we investigated the effect of ketogenic diets on the progression and metabolism of genetically and metabolically heterogeneous melanoma xenografts, as well as on the development of melanoma metastases in mice with a functional immune system.
    METHODS: Mice bearing BRAF mutant, NRAS mutant, and wild-type melanoma xenografts as well as mice bearing highly metastatic melanoma allografts were fed with a control diet or ketogenic diets, differing in their triglyceride composition, to evaluate the effect of ketogenic diets on tumor growth and metastasis. We performed an in-depth targeted metabolomics analysis in plasma and xenografts to elucidate potential antitumor mechanisms in vivo.
    RESULTS: We show that ketogenic diets effectively reduced tumor growth in immunocompromised mice bearing genetically and metabolically heterogeneous human melanoma xenografts. Furthermore, the ketogenic diets exerted a metastasis-reducing effect in the immunocompetent syngeneic melanoma mouse model. Targeted analysis of plasma and tumor metabolomes revealed that ketogenic diets induced distinct changes in amino acid metabolism. Interestingly, ketogenic diets reduced the levels of alpha-amino adipic acid, a biomarker of cancer, in circulation to levels observed in tumor-free mice. Additionally, alpha-amino adipic acid was reduced in xenografts by ketogenic diets. Moreover, the ketogenic diets increased sphingomyelin levels in plasma and the hydroxylation of sphingomyelins and acylcarnitines in tumors.
    CONCLUSIONS: Ketogenic diets induced antitumor effects toward melanoma regardless of the tumors´ genetic background, its metabolic signature, and the host immune status. Moreover, ketogenic diets simultaneously affected multiple metabolic pathways to create an unfavorable environment for melanoma cell proliferation, supporting their potential as a complementary nutritional approach to melanoma therapy.
    Keywords:  Cancer metabolism; Ketogenic diet; Melanoma; Metabolomics
    DOI:  https://doi.org/10.1186/s40170-022-00288-7
  53. Proc Natl Acad Sci U S A. 2022 Jul 19. 119(29): e2113180119
    Targeting oncogenic KRAS with molecular brush-conjugated antisense oligonucleotides.
    Dali Wang, Qiwei Wang, Yuyan Wang, Peiru Chen, Xueguang Lu, Fei Jia, Yehui Sun, Tingyu Sun, Lei Zhang, Fangyuan Che, Jialu He, Liming Lian, Gemma Morano, Michael Shen, Mengqi Ren, Sijia S Dong, Jean J Zhao, Ke Zhang.
      The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.
    Keywords:  KRAS; NSCLC; antisense oligonucleotide; gene regulation; molecular brush
    DOI:  https://doi.org/10.1073/pnas.2113180119
  54. Heliyon. 2022 Jul;8(7): e09926
    Formulation and evaluation of a smart drug delivery system of 5-fluorouracil for pH-sensitive chemotherapy.
    Shamla Cheralayikkal, K Manoj, K P Safna Hussan.
      The conventional chemotherapeutic drugs have many side effects due to their non-selective tissue distribution, reduced drug concentration of the drug at the tumor site, and the drug resistance. To overcome these problems the chemotherapeutic agent should selectively accumulate the tumor site and stays there for a prolonged period of time releasing the payloads in a controlled manner. This can be achieved by the administration of a smart drug delivery system (SDDS) loaded with the active drug molecules. In this work, 5-fluorouracil (5-FU) is loaded into amine functionalised hollow mesoporous silica nanoparticles (HMSN-NH2) and then coated with a biocompatible polydopamine (PDA) to formulate SSDS for 5-FU for pH-sensitive drug release. The physiochemical properties were characterised; the structural morphology was observed by using optical microscope, scanning electron microscope and transmission electron microscope, chemical interaction between the drug and excipients were characterised from Fourier transform infrared spectroscopy, the entrapment efficiency of loaded drug and the pH-dependent drug release rate were evaluated using UV-visible spectroscopy. It was observed that, the drug is compatible with excipients by retaining all the characteristics peaks of 5-FU with negligible changes in the position in all physical mixtures. The PDA coated 5-FU loaded HMSN-NH2 also exhibits a nearly spherical and non-aggregated morphology. The release rate was showed to increase with increase in concentration of structure-directing agent (Triton X 100) in the rate of a maximum release at the end of 72 h in pH 4. The prepared novel PDA coated 5-FU HMSN-NH2 was found to be capable of delivering the anti-cancer drug 5-FU specifically at the tumor site in a pH-dependent stimuli-responsive manner. It also showed a controlled release for a period of 72 h. The enhanced cytotoxicity against HeLa cell line were found for the formulated SSD form.
    Keywords:  5-Fluorouracil; FTIR spectroscopy; Hollow mesoporous silica nanoparticles; Optical microscope; Polydopamine; Scanning electron microscope and transmission electron microscope; Smart drug delivery system; UV-visible spectroscopy
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09926
  55. J Cannabis Res. 2022 Jul 22. 4(1): 41
    Anti-cancer properties of cannflavin A and potential synergistic effects with gemcitabine, cisplatin, and cannabinoids in bladder cancer.
    Andrea M Tomko, Erin G Whynot, Denis J Dupré.
       INTRODUCTION: Several studies have shown anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of most compounds present in cannabis in bladder cancer and how these compounds could potentially positively or negatively impact the actions of chemotherapeutic agents. Our study aims to evaluate the effects of a compound found in Cannabis sativa that has not been extensively studied to date, cannflavin A, in bladder cancer cell lines. We aimed to identify whether cannflavin A co-treatment with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, is able to produce synergistic effects. We also evaluated whether co-treatment of cannflavin A with various cannabinoids could produce synergistic effects.
    METHODS: Two transitional cell carcinoma cell lines were used to assess the cytotoxic effects of the flavonoid cannflavin A up to 100 μM. We tested the potential synergistic cytotoxic effects of cannflavin A with gemcitabine (up to 100 nM), cisplatin (up to 100 μM), and cannabinoids (up to 10 μM). We also evaluated the activation of the apoptotic cascade using annexin V and whether cannflavin A has the ability to reduce invasion using a Matrigel assay.
    RESULTS: Cell viability of bladder cancer cell lines was affected in a concentration-dependent fashion in response to cannflavin A, and its combination with gemcitabine or cisplatin induced differential responses-from antagonistic to additive-and synergism was also observed in some instances, depending on the concentrations and drugs used. Cannflavin A also activated apoptosis via caspase 3 cleavage and was able to reduce invasion by 50%. Interestingly, cannflavin A displayed synergistic properties with other cannabinoids like Δ9-tetrahydrocannabinol, cannabidiol, cannabichromene, and cannabivarin in the bladder cancer cell lines.
    DISCUSSION: Our results indicate that compounds from Cannabis sativa other than cannabinoids, like the flavonoid cannflavin A, can be cytotoxic to human bladder transitional carcinoma cells and that this compound can exert synergistic effects when combined with other agents. In vivo studies will be needed to confirm the activity of cannflavin A as a potential agent for bladder cancer treatment.
    Keywords:  Apoptosis; Bladder cancer; Cannabichromene; Cannabidiol; Cannabivarin; Cannflavin A; Cisplatin; Gemcitabine; Invasion; Δ9-Tetrahydrocannabinol
    DOI:  https://doi.org/10.1186/s42238-022-00151-y
  56. Front Biosci (Landmark Ed). 2022 Jul 07. 27(7): 213
    KRAS Mutation: Characterization and Its Impact on Survival Outcome of Patients with Metastatic Colorectal Cancer.
    Datul Damit, Ravi Patnaik, Li Ling Chaw, Shir Kiong Lu, Pemasiri Upali Telisinghe, Zen Huat Lu, Kenneth Kok, Long Chiau Ming, Ya Chee Lim.
       INTRODUCTION: Colorectal cancer (CRC) is one of the most common cancer types, with rising incidence due to imbalanced lifestyle and dietary habit. Association between CRC cases and KRAS mutation has been established recently. Brunei Darussalam, located within the Borneo island, is of diverse ethnicity which could represent the genome of Southeast Asia population. Our study, for the first time, determined the survival outcome of metastatic colorectal cancer (mCRC) and established the link with KRAS mutation by modelling the population in Brunei Darussalam.
    METHODS: We collected data of 76 metastatic CRC (mCRC) patients undergoing treatment at The Brunei Cancer Centre, the national centre for cancer treatment in Brunei. These patients were diagnosed with Stage 4 CRC between 1 January 2013 and 31 December 2017. Age, gender, ethnicity, date of diagnosis, site of primary tumour, metastatic sites and molecular analysis of KRAS mutation status (either KRAS mutated or KRAS wild-type) of tumour were recorded. The survival outcomes of these mCRC patients were analysed.
    RESULTS: The end of this study period recorded 73.1% deceased mutant KRAS mCRC patients and 46.0% deceased wild-type KRAS mCRC patients, contributing to death rates of 45.2% and 54.8%, correspondingly. Chi-squared analysis showed a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients (p-value = 0.024).
    CONCLUSIONS: There is a significant difference between the survival outcomes of wild-type KRAS and mutant KRAS mCRC patients in the Brunei population. In addition, we found that mutations in codon 12 of KRAS gene on mutant KRAS mCRC patients have shorter survival median periods than those with mutations within codon 13 of KRAS gene. This is the first study in Brunei Darussalam to analyse both the survival outcomes of mCRC patients and those of mutant KRAS mCRC patients.
    Keywords:  KRAS; codon; colorectal cancer; median; metastasis; sided; survival; tumour
    DOI:  https://doi.org/10.31083/j.fbl2707213
  57. J Biomater Sci Polym Ed. 2022 Jul 17. 1-44
    Recent advances in multifunctional dendrimer-based nanoprobes for breast cancer theranostics.
    Prashant Kesharwani, Rahul Chadar, Rahul Shukla, Gaurav K Jain, Geeta Aggarwal, Mohammad A S Abourehab, Amirhossein Sahebkar.
      Breast cancer (BC) undoubtedly is one of the most common type of cancers amongst women, which causes about 5 million deaths annually. The treatments and diagnostic therapy choices currently available for Breast Cancer is very much limited . Advancements in novel nanocarrier could be a promising strategy for diagnosis and treatments of this deadly disease. Dendrimer nanoformulation could be functionalized and explored for efficient targeting of overexpressed receptors on Breast Cancer cells to achieve targeted drug delivery, for diagnostics and to overcome the resistance of the cells towards particular chemotherapeutic. Additionally, the dendrimer have shown promising potential in the improvement of therapeutic value for Breast Cancer therapy by achieving synergistic co-delivery of chemotherapeutics and genetic materials for multidirectional treatment. In this review, we have highlighted the application of dendrimer as novel multifunctional nanoplatforms for the treatment and diagnosis of Breast Cancer.
    Keywords:  Breast cancer; Dendrimer; Gene delivery; Nanomedicine; Targeted drug delivery
    DOI:  https://doi.org/10.1080/09205063.2022.2103627
  58. Colloids Surf B Biointerfaces. 2022 Jul 14. pii: S0927-7765(22)00386-1. [Epub ahead of print]217 112703
    Fabrication, GSH-responsive drug release, and anticancer properties of thioctic acid-based intelligent hydrogels.
    Hui Liu, Zhiwei Deng, Tianhao Li, Jiaqi Bu, De Wang, Jiahui Wang, Meng Liu, Jiacheng Li, Yanjing Yang, Shian Zhong.
      Injectable hydrogels are potential local drug delivery systems since they contain plenty of water and soft like biological tissues. Such hydrogels could be injected directly into the tumor site where the drug is released under the tumor microenvironment. However, drug loaded hydrogels for cancer treatment based on lipoic acid (natural small molecule) have not been exploited. Here, a novel poly(lipoic acid)-poly(ethylene glycol) (PEG-PTA) hydrogels were prepared through a two-step reaction. The hydrogels contained disulfide bonds, so they could be degraded via the thiol exchange reaction with the abundant GSH in the tumor microenvironment, and subsequently release the drug. The results in vitro and at cellular level showed that the hydrogels were degraded and released the drugs only in the presence of GSH. Therefore, the injectable GSH-responsive hydrogels are promising to be served as an intelligent drug delivery system for cancer treatment.
    Keywords:  Anticancer; GSH responsive release; Hydrogel; Thioctic acid
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112703
  59. Front Microbiol. 2022 ;13 919424
    Mitochondrial Function and Microbial Metabolites as Central Regulators of Intestinal Immune Responses and Cancer.
    Saskia Weber-Stiehl, Lea Järke, Juan Camilo Castrillón-Betancur, Felix Gilbert, Felix Sommer.
      Energy and anabolic metabolism are essential for normal cellular homeostasis but also play an important role in regulating immune responses and cancer development as active immune and cancer cells show an altered metabolic profile. Mitochondria take a prominent position in these metabolic reactions. First, most key energetic reactions take place within or in conjunction with mitochondria. Second, mitochondria react to internal cues from within the cell but also to external cues originating from the microbiota, a vast diversity of associated microorganisms. The impact of the microbiota on host physiology has been largely investigated in the last decade revealing that the microbiota contributes to the extraction of calories from the diet, energy metabolism, maturation of the immune system and cellular differentiation. Thus, changes in the microbiota termed dysbiosis have been associated with disease development including metabolic diseases, inflammation and cancer. Targeting the microbiota to modulate interactions with the mitochondria and cellular metabolism to delay or inhibit disease development and pathogenesis appears an attractive therapeutic approach. Here, we summarize recent advances in developing the therapeutic potential of microbiota-mitochondria interactions for inflammation and cancer.
    Keywords:  cancer; inflammation; metabolites; microbiota; mitochondria
    DOI:  https://doi.org/10.3389/fmicb.2022.919424
  60. Recent Pat Biotechnol. 2022 Jul 18.
    Plant Extracts and Phytochemicals, a Promising Strategy Against Oral Lichen Planus: a review on Clinical Trials.
    Swati Gupta, Dr Lekshmi R Nath, Dr Sabitha M.
       BACKGROUND: Oral lichen planus (OLP) is an autoimmune disease that distress keratinized cells of the oral epithelium. Topical corticosteroids and other potential therapies like immunosuppressives, hydroxychloroquine, azathioprine, mycophenolate, dapsone, retinoids, biologic agents are used for the management of OLP. However, their effectiveness, best dose, duration of treatment and safety remain mostly unidentified. Moreover, recurrence of disease and dose-related side effects are the other issues.
    OBJECTIVE: The primary objective of the review is to explore the existing clinical trials for the efficacy of phytochemicals in treating OLP in comparison to corticosteroids. A comprehensive information about their mode of action is also discussed.
    METHOD: We have discussed different clinical trials conducted on various phytochemicals and plant extracts/formulations like curcumin, lycopene, quercetin, glycyrrhizin, purslane, raspberry, aloe vera gel and aloe vera mouthwash for the treatment of OLP.
    RESULT: The current therapy for the management of OLP has numerous adverse effects and requires a long-term treatment. Phytochemicals can be a very good alternative in overcoming these side effects and reducing the course of treatment.
    CONCLUSION: Herbal extracts and their formulations can be an effective alternative to the current therapy due to their proven therapeutic effects, reduced side effects, long-term applicability, prevention of recurrence as well as progression into cancer.
    Keywords:  COVID-19; Clinical trials; INF-γ; Oral lichen planus; Phytochemicals; autoimmune.
    DOI:  https://doi.org/10.2174/1872208316666220718145421
  61. Apoptosis. 2022 Jul 18.
    Mechanisms of cancer cell death induction by paclitaxel: an updated review.
    Shuang Zhao, Yufei Tang, Ruohan Wang, Masoud Najafi.
      Chemoresistance of cancer cells is a major problem in treating cancer. Knowledge of how cancer cells may die or resist cancer drugs is critical to providing certain strategies to overcome tumour resistance to treatment. Paclitaxel is known as a chemotherapy drug that can suppress the proliferation of cancer cells by inducing cell cycle arrest and induction of mitotic catastrophe. However, today, it is well known that paclitaxel can induce multiple kinds of cell death in cancers. Besides the induction of mitotic catastrophe that occurs during mitosis, paclitaxel has been shown to induce the expression of several pro-apoptosis mediators. It also can modulate the activity of anti-apoptosis mediators. However, certain cell-killing mechanisms such as senescence and autophagy can increase resistance to paclitaxel. This review focuses on the mechanisms of cell death, including apoptosis, mitotic catastrophe, senescence, autophagic cell death, pyroptosis, etc., following paclitaxel treatment. In addition, mechanisms of resistance to cell death due to exposure to paclitaxel and the use of combinations to overcome drug resistance will be discussed.
    Keywords:  Apoptosis; Autophagic cell death; Cancer; Mitotic catastrophe; Paclitaxel; Senescence
    DOI:  https://doi.org/10.1007/s10495-022-01750-z
  62. Carbohydr Polym. 2022 Oct 15. pii: S0144-8617(22)00631-2. [Epub ahead of print]294 119726
    Recent developments in chitosan hydrogels carrying natural bioactive compounds.
    Nga H N Do, Quyen T Truong, Phung K Le, Anh C Ha.
      Chitosan hydrogel is a smart and highly applicable drug delivery carrier because of its nature, biocompatibility, biodegradability, and ability to encapsulate, carry and release the drug to the desired target flexibly depending on the conditions of the patient. Not only developing delivery systems but natural compounds are also increasingly being studied in supporting the treatment of diseases. However, the physicochemical and pharmacokinetic issues of the phytochemicals are remaining. This review summarizes the remarkable properties of chitosan hydrogel; approaches to loading natural extracts on the hydrogels to overcome the susceptibility of the phytochemicals to degradation; and their applications in biomedical fields. The drug loading efficiency, release profile, in vitro and in vivo results of the chitosan hydrogels carrying natural compounds are discussed to point out the remaining challenges of combining the extracts with chitosan hydrogels and controlling the release of the carried substances.
    Keywords:  Bioactivity; Chitosan hydrogel; Controlled drug delivery; Fabrication; Natural extracts
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119726
  63. Carbohydr Polym. 2022 Oct 15. pii: S0144-8617(22)00713-5. [Epub ahead of print]294 119808
    Polysaccharide-based hydrogels containing herbal extracts for wound healing applications.
    Morteza Abazari, Tayebeh Akbari, Mahdiye Hasani, Elham Sharifikolouei, Mohammad Raoufi, Alireza Foroumadi, Mohammad Sharifzadeh, Loghman Firoozpour, Mehdi Khoobi.
      Development of an ideal wound dressing with effective function for healing various types of wounds is the ultimate desire of the researchers. Natural-based compounds such as polysaccharides and phytochemicals offer useful properties making them perfect candidates for wound management. Polysaccharides-based hydrogels with an interconnected three-dimensional network, and desired properties have great potential as a carrier for delivery of different herbal extracts for oral and topical applications. Herbal extracts are extensively used for wound healing purposes, individually or in combination with other active agents. This study summarizes the current knowledge acquired on the preparation, functionalizing, and application of different kinds of polysaccharide-based hydrogels enriched by herbal extracts for different wound healing applications. The structural, biological, and functional impact of the polysaccharides and herbal extracts on the final hydrogel characteristics, as well as their influence on the different phases of the wound healing process have been discussed.
    Keywords:  Herbal extracts; Polysaccharide-based hydrogel; Wound healing phases
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119808
  64. Drug Resist Updat. 2022 Jul 06. pii: S1368-7646(22)00051-6. [Epub ahead of print]63 100852
    The strategic roles of four enzymes in the interconnection between metabolism and oncogene activation in non-small cell lung cancer: Therapeutic implications.
    Philippe Icard, Luca Simula, Ludovic Fournel, Karen Leroy, Audrey Lupo, Diane Damotte, Marie Christine Charpentier, Catherine Durdux, Mauro Loi, Olivier Schussler, Guillaume Chassagnon, Antoine Coquerel, Hubert Lincet, Vincent De Pauw, Marco Alifano.
      NSCLC is the leading cause of cancer mortality and represents a major challenge in cancer therapy. Intrinsic and acquired anticancer drug resistance are promoted by hypoxia and HIF-1α. Moreover, chemoresistance is sustained by the activation of key signaling pathways (such as RAS and its well-known downstream targets PI3K/AKT and MAPK) and several mutated oncogenes (including KRAS and EGFR among others). In this review, we highlight how these oncogenic factors are interconnected with cell metabolism (aerobic glycolysis, glutaminolysis and lipid synthesis). Also, we stress the key role of four metabolic enzymes (PFK1, dimeric-PKM2, GLS1 and ACLY), which promote the activation of these oncogenic pathways in a positive feedback loop. These four tenors orchestrating the coordination of metabolism and oncogenic pathways could be key druggable targets for specific inhibition. Since PFK1 appears as the first tenor of this orchestra, its inhibition (and/or that of its main activator PFK2/PFKFB3) could be an efficacious strategy against NSCLC. Citrate is a potent physiologic inhibitor of both PFK1 and PFKFB3, and NSCLC cells seem to maintain a low citrate level to sustain aerobic glycolysis and the PFK1/PI3K/EGFR axis. Awaiting the development of specific non-toxic inhibitors of PFK1 and PFK2/PFKFB3, we propose to test strategies increasing citrate levels in NSCLC tumors to disrupt this interconnection. This could be attempted by evaluating inhibitors of the citrate-consuming enzyme ACLY and/or by direct administration of citrate at high doses. In preclinical models, this "citrate strategy" efficiently inhibits PFK1/PFK2, HIF-1α, and IGFR/PI3K/AKT axes. It also blocks tumor growth in RAS-driven lung cancer models, reversing dedifferentiation, promoting T lymphocytes tumor infiltration, and increasing sensitivity to cytotoxic drugs.
    Keywords:  ACLY; EGFR; GLS1; KRAS; NSCLC; PFK1; PI3K; PKM2
    DOI:  https://doi.org/10.1016/j.drup.2022.100852
  65. J Drug Target. 2022 Jul 20. 1-31
    Combinatorial delivery of Ribociclib and Green tea extract mediated nanostructured lipid carrier for oral delivery for the treatment of breast cancer synchronizing in silico, in vitro, and in vivo studies.
    Ali Sartaj, Annu, Meraj Alam, Largee Biswas, Mohammad Shahar Yar, Showkat Rasool Mir, Anita Kamra Verma, Sanjula Baboota, Javed Ali.
      Purpose: The current research investigated the development and evaluation of dual drug-loaded nanostructure lipidic carriers (NLCs) of green tea extract and Ribociclib.Method: In silico study were performed to determine the effectiveness of combinational approach. The prepared NLCs were subjected to in vitro drug release, lipolysis, haemolysis and cell line studies to assess their in vivo prospect.Results: In silico study was done to get docking score of EGCG (-8.98) close to Ribociclib (-10.78) in CDK-4 receptors. The prepared NLCs exhibited particle size (175.80 ± 3.51 nm); PDI (0.571 ± 0.012); and %EE [RBO (80.91 ± 1.66%) and GTE 75.98 ± 2.35%)] respectively. MCF-7 cell lines were used to evaluate the MTT assay, cellular uptake and antioxidant (ROS and SOD) of prepared NLCs. In vitro drug release showed the controlled release up to 72 h. In vitro lipolysis and in vitro haemolysis studies showed the availability of drugs at absorption sites and the greater in vivo prospects of NLCs respectively. Pharmacokinetic study revealed a 3.63-fold and 1.53-fold increment in RBO and GTE bioavailability in female Wistar rats respectively.Conclusion: The prominent potential of green tea extract and RBO-loaded NLCs in enhancing their therapeutic efficacy for better treatment of breast cancer.
    Keywords:  Breast cancer; Epi-gallate-catechin-gallate; Green tea extract; MCF-7 cell lines; Nanostructure lipidic carrier; Ribociclib
    DOI:  https://doi.org/10.1080/1061186X.2022.2104292
  66. J Med Virol. 2022 Jul 22.
    Interplay between Cellular Metabolism and DNA viruses.
    Milad Zandi, Somayeh Shokri, Shahab Mahmoudvand, Ahmad Hosseinzadeh Adli, Ramin Mohammadi, Azita Haddadi.
      Viruses as intracellular pathogens hijack the host metabolism and reprogram to facilitate optimal virus production. DNA viruses can cause alterations in several metabolic pathways, including aerobic glycolysis also known as the Warburg effect, pentose phosphate pathway (PPP) activation, and amino acid catabolism such as glutaminolysis, nucleotide biosynthesis, lipid metabolism, and amino acid biosynthesis. The available energy for productive infection can be increased in infected cells via modification of different carbon source utilization. This review discusses the metabolic alterations of the DNA viruses that will be the basis for future novel therapeutic approaches. This article is protected by copyright. All rights reserved.
    Keywords:  glutaminolysis; glycolysis; host metabolism; lipid metabolism; viruses
    DOI:  https://doi.org/10.1002/jmv.28018
  67. Crit Rev Food Sci Nutr. 2022 Jul 18. 1-12
    Selenium nanoparticles: Enhanced nutrition and beyond.
    Nan Chen, Peng Yao, Wei Zhang, Yutong Zhang, Naicheng Xin, Hongdi Wei, Tiehua Zhang, Changhui Zhao.
      Selenium is a trace nutrient that has both nutritional and nutraceutical functions, whereas narrow nutritional range of selenium intake limits its use. Selenium nanoparticles (SeNPs) are less toxic and more bioavailable than traditional forms of selenium, suggesting that SeNPs have the potential to replace traditional selenium in food industries and/or biomedical fields. From the perspective of how SeNPs can be applied in health area, this review comprehensively discusses SeNPs in terms of its preparation, nutritional aspect, detoxification effect of heavy metals, nutraceutical functions and anti-pathogenic microorganism effects. By physical, chemical, or biological methods, inorganic selenium can be transformed into SeNPs which have increased stability and bioavailability as well as low toxicity. SeNPs are more effective than traditional selenium form in synthesizing selenoproteins like glutathione peroxidases. SeNPs can reshape the digestive system to facilitate digestion and absorption of nutrients. SeNPs have shown excellent potential to adjunctively treat cancer patients, enhance immune system, control diabetes, and prevent rheumatoid arthritis. Additionally, SeNPs have good microbial anti-pathogenic effects and can be used with other antimicrobial agents to fight against pathogenic bacteria, fungi, or viruses. Development of novel SeNPs with enhanced functions can greatly benefit the food-, nutraceutical-, and biomedical industries.
    Keywords:  Nano-selenium; anti-pathogen; heavy metal; nutraceutical; nutrition
    DOI:  https://doi.org/10.1080/10408398.2022.2101093
  68. Int J Pharm. 2022 Jul 15. pii: S0378-5173(22)00582-8. [Epub ahead of print] 122027
    Co-Delivery of Erlotinib and Resveratrol via Nanostructured Lipid Carriers: A Synergistically Promising Approach for Cell Proliferation Prevention and ROS-Mediated Apoptosis Activation.
    Leila Asadollahi, Amin Mahoutforoush, Seyed Sina Dorreyatim, Tannaz Soltanfam, Ana Cláudia Paiva-Santos, Diana Peixoto, Francisco Veiga, Hamed Hamishehkar, Mahdi Zeinali, Soheil Abbaspour-Ravasjani.
      Cancer treatments are always associated with various challenges, and scientists are constantly trying to find new therapies and methods. Erlotinib (ELT) is a well-known medicine against non-small cell lung cancer (NSCLC). However, treatments by ELT disrupt therapy due to drug resistance and pose severe challenges to patients. To achieve high-performance treatment, we gained nanostructured lipid carriers (NLCs) to evaluate synergistic anticancer effects of co-delivery of ELT and resveratrol (RES), a natural herbal derived phenol against NSCLC. NLCs are prepared via the hot homogenization method and characterized. In vitro cytotoxicity of formulations were evaluated on adenocarcinoma human alveolar basal epithelial (A549) cells. Prepared NLCs showed a narrow particle size (97.52 ±17.14 nm), negative zeta potential (-7.67 ± 4.55 mV), and high encapsulation efficiency (EE%) was measured for the prepared co-delivery system (EE% 89.5 ± 5.16 % for ELT and 90.1 ± 6.61 % for RES). In vitro outcomes from cell viability study (12.63 % after 48 h of treatment), apoptosis assay (85.50%.), cell cycle (40.00% arrest in G2-M), and western blotting investigations (decreasing of protein expression levels of survivin, Bcl-2, P-Caspase 3 P-caspase 9, and P-ERK 1/2, and additionally, increasing protein levels of BAX, P53, C-Caspase 3 and 9), DAPI staining, and colony formation assays showed the augment cytotoxic performances for co-delivery of ELT and RES loaded NLCs. Our study introduced the co-delivery of ELT and RES by NLCs as a novel strategy to elevate the efficacy of chemotherapeutics for NSCLC.
    Keywords:  Co-delivery; Erlotinib; Lung cancer; NLCs; Nanostructured lipid carriers; Resveratrol
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122027
  69. Int J Endocrinol. 2022 ;2022 6453882
    Mechanisms Linking Vitamin D Deficiency to Impaired Metabolism: An Overview.
    Nurulmuna Mohd Ghozali, Nelli Giribabu, Naguib Salleh.
      Vitamin D deficiency is a common health problem worldwide. Despite its known skeletal effects, studies have begun to explore its extra-skeletal effects, that is, in preventing metabolic diseases such as obesity, hyperlipidemia, and diabetes mellitus. The mechanisms by which vitamin D deficiency led to these unfavorable metabolic consequences have been explored. Current evidence indicates that the deficiency of vitamin D could impair the pancreatic β-cell functions, thus compromising its insulin secretion. Besides, vitamin D deficiency could also exacerbate inflammation, oxidative stress, and apoptosis in the pancreas and many organs, which leads to insulin resistance. Together, these will contribute to impairment in glucose homeostasis. This review summarizes the reported metabolic effects of vitamin D, in order to identify its potential use to prevent and overcome metabolic diseases.
    DOI:  https://doi.org/10.1155/2022/6453882
  70. Front Pharmacol. 2022 ;13 909821
    Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer.
    Xuan Liu, Yiqian Zhang, Xuyi Wu, Fuyan Xu, Hongbo Ma, Mengling Wu, Yong Xia.
      Ferroptosis is an iron-dependent regulated form of cell death caused by excessive lipid peroxidation. This form of cell death differed from known forms of cell death in morphological and biochemical features such as apoptosis, necrosis, and autophagy. Cancer cells require higher levels of iron to survive, which makes them highly susceptible to ferroptosis. Therefore, it was found to be closely related to the progression, treatment response, and metastasis of various cancer types. Numerous studies have found that the ferroptosis pathway is closely related to drug resistance and metastasis of cancer. Some cancer cells reduce their susceptibility to ferroptosis by downregulating the ferroptosis pathway, resulting in resistance to anticancer therapy. Induction of ferroptosis restores the sensitivity of drug-resistant cancer cells to standard treatments. Cancer cells that are resistant to conventional therapies or have a high propensity to metastasize might be particularly susceptible to ferroptosis. Some biological processes and cellular components, such as epithelial-mesenchymal transition (EMT) and noncoding RNAs, can influence cancer metastasis by regulating ferroptosis. Therefore, targeting ferroptosis may help suppress cancer metastasis. Those progresses revealed the importance of ferroptosis in cancer, In order to provide the detailed molecular mechanisms of ferroptosis in regulating therapy resistance and metastasis and strategies to overcome these barriers are not fully understood, we described the key molecular mechanisms of ferroptosis and its interaction with signaling pathways related to therapy resistance and metastasis. Furthermore, we summarized strategies for reversing resistance to targeted therapy, chemotherapy, radiotherapy, and immunotherapy and inhibiting cancer metastasis by modulating ferroptosis. Understanding the comprehensive regulatory mechanisms and signaling pathways of ferroptosis in cancer can provide new insights to enhance the efficacy of anticancer drugs, overcome drug resistance, and inhibit cancer metastasis.
    Keywords:  cancer; drug resistance; ferroptosis; metastasis; peroxidation
    DOI:  https://doi.org/10.3389/fphar.2022.909821
  71. Carbohydr Polym. 2022 Oct 15. pii: S0144-8617(22)00684-1. [Epub ahead of print]294 119779
    Amphiphilic nano-delivery system based on modified-chitosan and ovalbumin: Delivery and stability in simulated digestion.
    Lihua Li, Xinyu Sun, Hui Zhang, Mengna Dong, Jiao Wang, Shuang Zhao, Minghui Shang, Xin Wang, Hui Zhangsun, Li Wang.
      Nano-delivery systems play an important role in the development of nutritional supplements due to their efficient encapsulation and delivery properties for nutrients. Herein, we prepared protein-polysaccharide nanoparticles as a novel amphiphilic nano-delivery system based on gallic acid modified chitosan (GCS) and ovalbumin (OVA) by pH-driven and calcium ion crosslinking. The nanoparticles loaded with hydrophilic riboflavin (Rib) and hydrophobic quercetin (Que) as nutrient models were abbreviated as GCS-OVA-Rib NPs and GCS-OVA-Que NPs, respectively. Their encapsulation efficiencies for Rib and Que. were 66.36 % and 96.61 %, respectively. In addition, GCS-OVA-Rib NPs and GCS-OVA-Que NPs showed antioxidant activity as well as good stability and delivery capacity for Rib and Que. in simulated digestion with release ratios of 78.38 % and 84.15 %, respectively. More importantly, GCS-OVA-Rib/Que. NPs performed good biocompatibility for further applications. Overall, this work provides some useful insights for the design of novel amphiphilic nano-delivery systems based on polysaccharides and proteins.
    Keywords:  Amphiphilic nano-delivery system; Delivery capacity; Gallic acid modified chitosan; Ovalbumin; Stability
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119779
  72. J Biomed Nanotechnol. 2022 Apr 01. 18(4): 1075-1083
    Targeted Therapy of Lung Adenocarcinoma by the Nanoplatform Based on Milk Exosomes Loaded with Paclitaxel.
    Junge Chen, Fengqiang Cao, Yang Cao, Shujin Wei, Xiurui Zhu, Wanli Xing.
      Lung cancer is the most common cancer throughout the world. Currently, most lung cancer therapies are still limited by serious side effects caused. This paper reports a biocompatible drug delivery system that utilizes milk-derived exosomes to deliver paclitaxel to treat lung adenocarcinoma. First, milk-derived exosomes were modified with integrin αVβ₃, αVβ5-binding peptide iRGD so that they could successfully target lung adenocarcinoma cells. Then, iRGD modified exosomes were loaded with paclitaxel (PAC) via electroporation and used for tumor therapy. These modified exosomes proved effective in killing lung adenocarcinoma cells, and the exosome-based nanoplatform showed no obvious toxicity to normal cells. Further more, the exosome-based nanoplatform could effectively penetrate the interior of the 3D tumor sphere, reaching more tumor cells and demonstrating that it is a promising tool for lung adenocarcinoma therapy.
    DOI:  https://doi.org/10.1166/jbn.2022.3278
  73. J Cosmet Dermatol. 2022 Jul 23.
    Protection of Hair Color With Pomegranate Peel Extract Loaded Liposomal Formulation: Preparation, Characterization and Ex-vivo Activity Studies.
    Sakine Tuncay Tanriverdi, Evren Homan Gokce, Simtac Bengi Filiz, Fadime Aydin Kose, Sedef Kalayci, Ozgen Ozer.
       BACKGROUND: Pomegranate peel extract is known as a powerful antioxidant and due to preventing oxidation, it can reduce color change of dyed hair after washing. Liposomes are vesicular systems that include lipids and can form a film on hair fibers. Delivery system and active agent have a synergistic effect on protecting hair color and reducing dyeing frequency.
    AIMS: This study aims to prepare liposomes suspension as an innovative formulation of pomegranate peel extract to reduce hair color changing.
    METHODS: Pomegranate peel extract loaded liposomes were prepared with lipidic film hydration method. The characterizations of formulations (F1 and F2) were defined by several parameters. The pH, particle size, polydispersity index, zeta potential, microscopical image, loading capacity and encapsulation efficiency of formulations were determined. The antioxidant capacity of formulations and actives were tested. The effect of formulations on hair color change was shown with ex-vivo studies.
    RESULTS: The results showed that cholesterol influenced particle size, zeta potential and antioxidant capacity. The particle sizes of formulations were 217.71±6.74 nm and 577.5±1.41 nm for F1 and F2, respectively. F2 formulation had better results for zeta potential (33.8 mV) while F1 was neutral. Morphologic images confirmed vesicular structure or liposomes. The encapsulation efficiency was found higher for F2 than F1 (F1: 57.14 and F2: 78.69). Antioxidant studies confirmed that active substance and the vesicular system had a synergistic effect on protection from oxidation. Selected formulation reduced hair color change as shown in ex-vivo tests.
    CONCLUSION: Pomegranate peel extract loaded liposomes were designed for hair color protection. It was shown with this study that prepared formulations have a good color protection on hair fibers due to antioxidant properties of pomegranate peel extract and film forming effect of liposomal formulations. According to results, prepared liposomal formulations may serve as a good alternative for reducing dyeing frequency and protecting hair fibers.
    DOI:  https://doi.org/10.1111/jocd.15254
  74. J Control Release. 2022 Jul 13. pii: S0168-3659(22)00425-4. [Epub ahead of print]
    Anti-angiogenic nano-delivery system promotes tumor vascular normalizing and micro-environment reprogramming in solid tumor.
    Ruoyu Shen, Lijun Peng, Wentao Zhou, Ding Wang, Qi Jiang, Jian Ji, Fuqiang Hu, Hong Yuan.
      Aberrant tumor vasculature leads to the malignant tumor microenvironment (TME) for tumor progression. Research has found temporary tumor vascular normalization after treated with low-dose anti-angiogenic agents, however, has paid little attention to prolonging the normalization window and its further influence on tumor tissue. Based on the dose- and time-dependent effect of anti-angiogenic agents, we developed V@LDL NPs, a nano-delivery system sustainedly releasing Vandetanib, an anti-VEGFR2 inhibitor, to control the dose of drug to the normalizing level, and prove its stable tumor vascular normalizing effect in 4 T1 breast cancer model. Furthermore, long-term normalized vasculature could improve tumor perfusion, then provide a circulation to reverse abnormalities in TME, such as hypoxia and heterogeneity, and also inhibit tumor progression. Our findings demonstrate that stable tumor vascular normalization could be a considerable strategy for long-term change to remodel TME and probably result in a therapeutic benefit to anti-cancer treatment, which could be achieved by anti-angiogenic nano-delivery system.
    Keywords:  Angiogenesis; Nano-delivery system; Tumor microenvironment reprogramming; Tumor vascular normalization
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.015
  75. Heliyon. 2022 Jul;8(7): e09931
    Preparation and evaluation of the anti-cancer properties of RGD-modified curcumin-loaded chitosan/perfluorohexane nanocapsules in vitro.
    Liang Wang, Shixia Zhu, Chunpeng Zou, Hongju Kou, Maosheng Xu, Jie Li.
      Curcumin (Cur) encapsulation in nanocapsules (NCs) could improve its availability and therapeutic antitumor efficacy. Cur-loaded chitosan/perfluorohexane (CS/PFH) nanocapsules (CS/PFH-Cur-NCs) were thus synthesized via a nanoemulsion process. To further enhance the selective tumor targeting ability of Cur-loaded NCs, a novel CS/PFH-Cur-NCs with conjugation of Arg-Gly-Asp (RGD) peptide (RGD-CS/PFH-Cur-NCs) were prepared in this study. The properties of these NCs were then explored through in vitro release experiments and confocal laser scanning microscopy-based analyses of the ability of these NCs to target MDA-MB-231 breast cancer cells. In addition, an MTT assay-based approach was used to compare the relative cytotoxic impact of CS/PFH-Cur-NCs and RGD-CS/PFH-Cur-NCs on these breast cancer cells. It was found that both CS/PFH-Cur-NCs and RGD-CS/PFH-Cur-NCs were smooth, relatively uniform, spheroid particles, with the latter being 531.20 ± 68.97 nm in size. These RGD-CS/PFH-Cur-NCs can be ideal for contrast imaging studies, and were better able to target breast cancer cells in comparison to CS/PFH-Cur-NCs. In addition, RGD-CS/PFH-Cur-NCs were observed to induce cytotoxic MDA-MB-231 cell death more swiftly in comparison to CS/PFH-Cur-NCs. These findings suggest that NC encapsulation and RGD surface modification can remarkably improve the anti-tumor efficacy of Cur. These novel NCs may thus manifest a significant potential value in the realm of image-guided cancer therapy, underscoring an important direction for future research.
    Keywords:  Antitumor efficacy; Chitosan; Curcumin; Nanocapsule; Perfluorohexane; RGD
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09931
  76. Front Oncol. 2022 ;12 918416
    Cu-Hemin Nanosheets and Indocyanine Green Co-Loaded Hydrogel for Photothermal Therapy and Amplified Photodynamic Therapy.
    Shu Zhu, Shuntao Wang, Chunping Liu, Meng Lyu, Qinqin Huang.
      Near-infrared (NIR) organic small molecule indocyanine green (ICG) could respond well to 808 nm laser to promote local high temperature and ROS generation for realizing photothermal therapy (PTT)/photodynamic therapy (PDT). However, the high content of GSH in the tumor microenvironment (TME) limited the further therapeutic performance of ICG. Herein, injectable agarose in situ forming NIR-responsive hydrogels (CIH) incorporating Cu-Hemin and ICG were prepared for the first time. When CIH system was located to the tumor tissue through local injection, the ICG in the hydrogel could efficiently convert the light energy emitted by the 808 nm laser into thermal energy, resulting in the heating and softening of the hydrogel matrix, which releases the Cu-Hemin. Then, the over-expressed GSH in the TME could also down-regulated by Cu-Hemin, which amplified ICG-mediated PDT. In vivo experiments validated that ICG-based PDT/PTT and Cu-Hemin-mediated glutathione depletion could eliminate cancer tissues with admirable safety. This hydrogel-based GSH-depletion strategy is instructive to improve the objective response rate of PDT.
    Keywords:  glutathione; hydrogel; indocyanine green; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.3389/fonc.2022.918416
  77. Crit Rev Food Sci Nutr. 2022 Jul 22. 1-26
    New insights into anti-diabetes effects and molecular mechanisms of dietary saponins.
    Yifan Zhou, Baojun Xu.
      Diabetes mellitus (DM) is a long-term metabolic disorder that manifests as chronic hyperglycemia and impaired insulin, bringing a heavy load on the global health care system. Considering the inevitable side effects of conventional anti-diabetic drugs, saponins-rich natural products exert promising therapeutic properties to serve as safer and more cost-effective alternatives for DM management. Herein, this review systematically summarized the research progress on the anti-diabetic properties of dietary saponins and their underlying molecular mechanisms in the past 20 years. Dietary saponins possessed the multidirectional anti-diabetic capabilities by concurrent regulation of various signaling pathways, such as IRS-1/PI3K/Akt, AMPK, Nrf2/ARE, NF-κB-NLRP3, SREBP-1c, and PPARγ, in liver, pancreas, gut, and skeletal muscle. However, the industrialization and commercialization of dietary saponin-based drugs are confronted with a significant challenge due to the low bioavailability and lack of the standardization. Hence, in-depth evaluations in pharmacological profile, function-structure interaction, drug-signal pathway interrelation are essential for developing dietary saponins-based anti-diabetic treatments in the future.
    Keywords:  AMPK; Dietary saponin; PI3K/Akt; anti-diabetes; anti-inflammation; intracellular signaling pathways
    DOI:  https://doi.org/10.1080/10408398.2022.2101425
  78. Heliyon. 2022 Mar;8(3): e09145
    Novel antibacterial hydrogels based on gelatin/polyvinyl-alcohol and graphene oxide/silver nanoconjugates: formulation, characterization, and preliminary biocompatibility evaluation.
    Jorge Luis Patarroyo, Javier Cifuentes, Laura N Muñoz, Juan C Cruz, Luis H Reyes.
      Antibiotic resistance has become a major public health problem generated by their excessive and inappropriate use. This is worrisome because multiple microbial infections that could traditionally be treated without major complications are now considerably challenging to treat. In this regard, research in this field has been focused on searching for new molecules capable of arresting these microbial infections with high effectiveness, including antimicrobial peptides (AMP) and various nanomaterials. Here, we proposed a novel topical hydrogel treatment based on a polymeric network of gelatin-polyvinyl alcohol-hyaluronic acid encapsulating a graphene oxide (GO) nanoconjugate on which silver nanoparticles (Ag NPs) have been grown. This treatment is intended to be stable, biocompatible, non-toxic, pleasant to skin contact, provide bioavailability of the active agent for a prolonged period in the affected skin area where its application is required and inhibit microbial growth effectively. The nanocomposite hydrogels were characterized in terms of microstructure, thermal resistance, rheological behavior, particle size distribution, texture profile and physical stability, as well as a one-month accelerated stability study. The satisfactory results in terms of physical chemistry, stability on storage modulus (G'), TSI values, and microstructure allowed choosing some points of the experimental design to encapsulate the GO-Ag NPs nanoconjugates. The biological evaluation of these nanocomposites showed that the treatments are biocompatible as they have a very low hemolytic effect (less than 5%) and a moderate platelet aggregating capacity (35%-45%). Finally, 100% of bacterial growth was inhibited by the action of the topical nanocomposite hydrogel treatments. These results led to affirm that these treatments can have an excellent performance in this application as well as in wound healing and dressing, bioadhesives, tissue engineering, and other biomedical applications.
    Keywords:  Ag nanoparticles; Antimicrobial activity; Encapsulation; Graphene oxide; Skin infection; Topical treatment
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09145
  79. Iran J Public Health. 2022 Feb;51(2): 278-291
    The Effects of Vitamin D Fortified Products on Bone Biomarkers: A Systematic Review and Meta-Analysis.
    Maryam Emadzadeh, Atieh Mehdizadeh, Payam Sharifan, Mahdieh Khoshakhlagh, Reza Sahebi, Ramin Sadeghi, Gordon A Ferns, Majid Ghayour-Mobarhan.
       Background: Vitamin D plays an essential role in the regulation of bone metabolism. The current meta-analysis aimed to assess the effectiveness of vitamin D fortification on special bone biomarkers.
    Methods: Five main databases (PubMed/Medline, ISI Web of Knowledge, Science Direct, Scopus, Cochrane Library as well as Science Direct, and Scopus) were considered for this systematic review, until Jan 2020. All randomized controlled trials were included to evaluate the probable relationship between consumption of vitamin D fortification products and bone biomarkers profile in this review.
    Results: Among serum bone biomarkers (osteocalcin and telopeptides of type-1 collagen) investigated, only the level of telopeptides of type-1 collagen significantly decreased after fortification of vitamin D in the intervention group. A significant increase in vitamin D was seen in those older than 18 yr old, while the increase in younger children was not statistically significant between intervention and control groups.
    Conclusion: Vitamin D fortification was not associated with a significant improvement in bone mass density (BMD), while it resulted in decreased PTH levels. Vitamin D fortified foods have some benefits on bone health due to increase in the level of vitamin D and IGF-1; and decreasing PTH and CTx levels.
    Keywords:  Bone density; Insulin-like growth factor I; Osteocalcin; Parathyroid hormone; Vitamin D
    DOI:  https://doi.org/10.18502/ijph.v51i2.8681
  80. J Cell Biochem. 2022 Jul 17.
    Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers.
    Iftikhar A Tayubi, Udhaya Kumar S, George Priya Doss C.
      The mutations at the hotspot region of K-Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K-Ras model with anti-cancerous activity from food and drug administration (FDA)-approved drug compounds. We implemented several computational strategies such as pharmacophore-based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K-Ras. We found that the FDA-approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K-Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h-bonds, and potent inhibition against G13D K-Ras. As a result, the current research identifies prospective K-Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K-Ras-driven cancers.
    Keywords:  G13D; K-Ras; anticancer; cancer; inhibitors; metastasis; pharmacophore model
    DOI:  https://doi.org/10.1002/jcb.30305
  81. Int J Pharm. 2022 Jul 14. pii: S0378-5173(22)00577-4. [Epub ahead of print] 122022
    Stability Characterization for Pharmaceutical Liposome Product Development with Focus on Regulatory Considerations: An Update.
    Vaskuri G S Sainaga Jyothi, Raviteja Bulusu, Balaga Venkata Krishna Rao, Mulinti Pranothi, Srikanth Banda, Pradeep Kumar Bolla, Nagavendra Kommineni.
      Liposomes have several advantages, such as the ability to be employed as a carrier/vehicle for a variety of drug molecules and at the same time they are safe and biodegradable. In the recent times, compared to other delivery systems, liposomes have been one of the most well-established and commercializing drug products of new drug delivery methods for majority of therapeutic applications. On the other hand, it has several limitations, particularly in terms of stability, which impedes product development and performance. In this review, we reviewed all the potential instabilities (physical, chemical, and biological) that a formulation development scientist confronts throughout the development of liposomal formulations as along with the ways to overcome these challenges. We have also discussed the effect of microbiological contamination on liposomal formulations with a focus on the use of sterilization methods used to improve the stability. Finally, we have reviewed quality control techniques and regulatory considerations recommended by the agencies (USFDA and MHLW) for liposome drug product development.
    Keywords:  Liposomes; characterization; drug delivery; stability; sterilization
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122022
  82. Acta Pharm Sin B. 2022 Apr;12(4): 2057-2073
    Remodeling "cold" tumor immune microenvironment via epigenetic-based therapy using targeted liposomes with in situ formed albumin corona.
    Yang He, Yuefei Fang, Meng Zhang, Yuge Zhao, Bin Tu, Mingjie Shi, Bahtiyor Muhitdinov, Akmal Asrorov, Qin Xu, Yongzhuo Huang.
      There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8+ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).
    Keywords:  Angiogenesis; Epigenetic therapy; Immune checkpoint; JQ1; Liposome; Panobinostat; Tumor immune microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.apsb.2021.09.022
  83. Saudi J Biol Sci. 2022 May;29(5): 3848-3870
    Laboratory scale medicinal plants mediated green synthesis of biocompatible nanomaterials and their versatile biomedical applications.
    Najlaa S Al-Radadi.
      Nanoparticles and its green synthesis with plants have become an important field of nanoscience due it is great benefits provided to humanity through it and its cost effective, least harm to humans and the environment also, it offering a lot of application in biomedical research, diagnostics, and medicine as well as, drug manufacturing, improvement, or drug discovery. In this work, I focused on green synthesis nanoparticles with antioxidant involve in plants and the method for preparing them also the factors on which the extraction process depends on, spectroscopic techniques like UV-Visible, (TEM), (XRD), (IR), (EDX), (SEM), (HPLC), and zeta potential are use here.
    Keywords:  Applications; Characterization; Green synthesis; Nanoparticles; Nanotechnology
    DOI:  https://doi.org/10.1016/j.sjbs.2022.02.042
  84. J Theor Biol. 2022 Jul 16. pii: S0022-5193(22)00221-1. [Epub ahead of print] 111223
    Nonlinear Multi-Objective Flux Balance Analysis of the Warburg Effect.
    Yi Zhang, Daniel Boley.
      Due to its implication in cancer treatment, the Warburg Effect has received extensive in silico investigation. Flux Balance Analysis (FBA), based on constrained optimization, was successfully applied in the Warburg Effect modelling. Yet, the assumption that cell types have one invariant cellular objective severely limits the applicability of the previous FBA models. Meanwhile, we note that cell types with different objectives show different extents of the Warburg Effect. To extend the applicability of the previous model and model the disparate cellular pathway preferences in different cell types, we built a Nonlinear Multi-Objective FBA (NLMOFBA) model by including three key objective terms (ATP production rate, lactate generation rate and ATP yield) into one objective function through linear scalarization. By constructing a cellular objective map and iteratively varying the objective weights, we showed disparate cellular pathway preferences manifested by different cell types driven by their unique cellular objectives, and we gained insights about the causal relationship between cellular objectives and the Warburg Effect. In addition, we obtained other biologically consistent results by using our NLMOFBA model. For example, augmented with the constraint associated with inefficient mitochondria function, low oxygen availability, or limited substrate, NLMOFBA predicts cellular pathways supported by the biology literature. Collectively, our NLMOFBA model can help build a complete understanding towards the Warburg Effect in different cell types. Finally, we investigated the impact of glutaminolysis, an important pathway related to glycolysis, on the occurrence of the Warburg Effect by using linear programming.
    Keywords:  Flux balance analysis; Multi-objective optimization; Nonconvex optimization; Theoretical biology
    DOI:  https://doi.org/10.1016/j.jtbi.2022.111223
  85. Eur J Pharm Biopharm. 2022 Jul 19. pii: S0939-6411(22)00145-X. [Epub ahead of print]
    Cyclodextrin-based delivery systems in parenteral formulations: a critical update review.
    Laura Ferreira, Joana Campos, Francisco Veiga, Catarina Cardoso, Ana Cláudia Paiva-Santos.
      Parenteral formulations are indispensable in clinical practice and often are the only option to administer drugs that cannot be administrated through other routes, such as proteins and certain anticancer drugs - which are indispensable to treat some of the most prevailing chronic diseases worldwide (like diabetes and cancer). Additionally, parenteral formulations play a relevant role in emergency care since they are the only ones that provide an immediate action of the drug after its administration. However, the development of parenteral formulations is a complex task owing to the specific quality and safety requirements set for these preparations and the intrinsic properties of the drugs. Amongst all the strategies that can be useful in the development of parenteral formulations, the formation of water-soluble host-guest inclusion complexes with cyclodextrins (CDs) has proven to be one of the most advantageous. CDs are multifunctional pharmaceutical excipients able to form water-soluble host-guest inclusion complexes with a wide variety of molecules, particularly drugs, and thus improve their apparent water-solubility, chemical stability, and bioavailability, to make them suitable for parenteral administration. Besides, CDs can be employed as building blocks of more complex injectable drug delivery systems with enhanced characteristics, such as nanoparticles and supramolecular hydrogels, that has been found particularly beneficial for the delivery of anticancer drugs. However, only a few CDs are considered safe when parenterally administered, and some of these types are already approved to be used in parenteral dosage forms. Therefore, the application of CDs in the development of parenteral formulations has been a more common practice in the last few years, due to their significant worldwide acceptance by the health authorities, promoting the development of safer and more efficient injectable drug delivery systems.
    Keywords:  cyclodextrin; cyclodextrin-based nanoparticle; cyclodextrin-based supramolecular hydrogel; parenteral formulation; water-soluble host-guest inclusion complex
    DOI:  https://doi.org/10.1016/j.ejpb.2022.07.007
  86. Front Pharmacol. 2022 ;13 925673
    Editorial: Metabolic Intervention Based on Functional Biomaterial Strategy to Potentiate Cancer Immunotherapy, Volume I.
    Bing Feng.
      
    Keywords:  antitumor immunity; cancer therapy; functional materials; metabolic intervention; targeting delivery
    DOI:  https://doi.org/10.3389/fphar.2022.925673
  87. Front Pharmacol. 2022 ;13 936996
    Curcumin, thymoquinone, and 3, 3'-diindolylmethane combinations attenuate lung and liver cancers progression.
    Amna A Saddiq, Ali H El-Far, Shymaa Abdullah Mohamed Abdullah, Kavitha Godugu, Omar A Almaghrabi, Shaker A Mousa.
      Cancer can develop due to abnormal cell proliferation in any body's cells, so there are over a hundred different types of cancer, each with its distinct behavior and response to treatment. Therefore, many studies have been conducted to slow cancer progression and find effective and safe therapies. Nutraceuticals have great attention for their anticancer potential. Therefore, the current study was conducted to investigate the anticancer effects of curcumin (Cur), thymoquinone (TQ), and 3, 3'-diindolylmethane (DIM) combinations on lung (A549) and liver (HepG2) cancer cell lines' progression. Results showed that triple (Cur + TQ + DIM) and double (Cur + TQ, Cur + DIM, and TQ + DIM) combinations of Cur, TQ, and DIM significantly increased apoptosis with elevation of caspase-3 protein levels. Also, these combinations exhibited significantly decreased cell proliferation, migration, colony formation activities, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT) protein levels with S phase reduction. Triple and double combinations of Cur, TQ, and DIM hindered tumor weight and angiogenesis of A549 and HepG2 implants in the chorioallantoic membrane model. Interestingly, Cur, TQ, and DIM combinations are considered promising for suppressing cancer progression via inhibiting tumor angiogenesis. Further preclinical and clinical investigations are warranted.
    Keywords:  3,3′-diindolylmethane; apoptosis; cell migration; combination; curcumin; thymoquinone; tumor angiogenesis; tumor growth
    DOI:  https://doi.org/10.3389/fphar.2022.936996
  88. Int J Biol Macromol. 2022 Jul 18. pii: S0141-8130(22)01532-X. [Epub ahead of print]
    Extrinsic hyaluronic acid induction differentially modulates intracellular glutamine metabolism in breast cancer stem cells.
    Heena Jariyal, Harsh Thakkar, Adarsh Suresh Kumar, Ravi Shah, Akshay Srivastava.
      The effect of low and high molecular weight hyaluronic acid on glutamine metabolism in luminal and basal breast cancer and cancer stem cells is being investigated. In luminal cell lines (MCF-7), HA enhances the intracellular utilization of gln in redox metabolism and decreases its use in TCA. On the contrary, in MDAMB-231 cells, HA induces the uptake of gln to be utilized in anaplerosis rather than ROS maintenance. However, in MCF-7 CSCs, HA induces up-regulation of xCT, further, it uses gln-derived glutamate for the exchange of cystine, thus maintaining ROS levels through xCT. MDA-MB-231 CSCs reduce the secretion of glutamate in response to HA and decrease the gln flux towards reductive carboxylation. Conclusively, our study demonstrated that although the uptake of gln is enhanced by HA, it is differentially utilized intracellularly in breast cancer cells. This study could significantly influence the therapeutics involving HA and Gln in breast cancer.
    Keywords:  Alanine-serine-cysteine transporter; Breast cancer stem cells; Cystine–glutamate exchanger transporter; Glutamine; Hyaluronic acid; Reductive carboxylation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.099
  89. Oxid Med Cell Longev. 2022 ;2022 7009863
    Selenium Status and Its Antioxidant Role in Metabolic Diseases.
    Jing Huang, Ling Xie, Anni Song, Chun Zhang.
      Selenium (Se), in the form of selenoproteins, is an essential micronutrient that plays an important role in human health and disease. To date, there are at least 25 selenoproteins in humans involved in a wide variety of biological functions, including mammalian development, metabolic progress, inflammation response, chemoprotective properties, and most notably, oxidoreductase functions. In recent years, numerous studies have reported that low Se levels are associated with increased risk, poor outcome, and mortality of metabolic disorders, mainly related to the limited antioxidant defense resulting from Se deficiency. Moreover, the correlation between Se deficiency and Keshan disease has received considerable attention. Therefore, Se supplementation as a therapeutic strategy for preventing the occurrence, delaying the progression, and alleviating the outcomes of some diseases has been widely studied. However, supranutritional levels of serum Se may have adverse effects, including Se poisoning. This review evaluates the correlation between Se status and human health, with particular emphasis on the antioxidant benefits of Se in metabolic disorders, shedding light on clinical treatment.
    DOI:  https://doi.org/10.1155/2022/7009863
  90. Drug Discov Today. 2022 Jul 15. pii: S1359-6446(22)00290-2. [Epub ahead of print]
    Statins and angiogenesis in non-cardiovascular diseases.
    Fatemeh Zahedipour, Alexandra E Butler, Manfredi Rizzo, Amirhossein Sahebkar.
      Statins inhibit HMG-CoA reductase by competitively inhibiting the active site of the enzyme, thus preventing cholesterol synthesis and reducing the risk of developing cardiovascular disease. Many pleiotropic effects of statins have been demonstrated that can be either related or unrelated to their cholesterol-lowering ability. Among these effects are their proangiogenic and antiangiogenic properties that could offer new therapeutic applications. In this regard, pro- and anti-angiogenic properties of statins have been shown to be dose dependent. Statins also appear to have a variety of non-cardiovascular angiogenic effects in many diseases, some examples being ocular disease, brain disease, cancer, preeclampsia, diabetes and bone disease, which are discussed in this review using reports from in vitro and in vivo investigations.
    Keywords:  Statins; angiogenesis; bone disease; brain disease; cancer; cardiovascular; diabetes; ocular disease; preeclampsia; vascularization
    DOI:  https://doi.org/10.1016/j.drudis.2022.07.005
  91. Int J Biol Sci. 2022 ;18(10): 4260-4274
    Emerging Mechanisms and Targeted Therapy of Ferroptosis in Neurological Diseases and Neuro-oncology.
    Yajie Wang, Bufu Tang, Jinyu Zhu, Junchao Yu, Junguo Hui, Shuiwei Xia, Jiansong Ji.
      Ferroptosis is a novel type of cell death characterized by iron-dependent lipid peroxidation that involves a variety of biological processes, such as iron metabolism, lipid metabolism, and oxidative stress. A growing body of research suggests that ferroptosis is associated with cancer and neurodegenerative diseases, such as glioblastoma, Alzheimer's disease, Parkinson's disease, and stroke. Building on these findings, we can selectively induce ferroptosis for the treatment of certain cancers, or we can treat neurodegenerative diseases by inhibiting ferroptosis. This review summarizes the relevant advances in ferroptosis, the regulatory mechanisms of ferroptosis, the participation of ferroptosis in brain tumors and neurodegenerative diseases, and the corresponding drug therapies to provide new potential targets for its treatment.
    Keywords:  GPX4; GSH; ferroptosis; iron metabolism; lipid peroxidation; neurodegenerative diseases
    DOI:  https://doi.org/10.7150/ijbs.72251
  92. Mar Pollut Bull. 2022 Jul 15. pii: S0025-326X(22)00615-4. [Epub ahead of print]181 113933
    Oxidative stress-mediated synergistic deleterious effects of nano- and microplastics in the hypoxia-conditioned marine rotifer Brachionus plicatilis.
    Yoseop Lee, Min-Sub Kim, Jordan Jun Chul Park, Young Hwan Lee, Jae-Seong Lee.
      While pollution due to nano- and micro-sized plastics (NMPs) and hypoxic conditions both occur in coastal areas, the deleterious potential of co-exposure to hypoxia and NMPs (hypoxia and micro-sized plastics, HMPs; hypoxia and nano-sized plastics, HNPs) is largely unclear. Here, we provide evidence for multigenerational effects of HMP and HNP in the marine rotifer Brachionus plicatilis by investigating changes in its life traits, antioxidant system, and hypoxia-inducible factor (HIF) pathway using an orthogonal experimental design, with nanoscale and microscale particles measuring 0.05 μm and 6.0 μm in diameter, respectively, and hypoxic conditions of 0.5 mg/L for six generations. Combined exposure to NMPs and hypoxia caused a significant decrease in fecundity and overproduction of reactive oxygen species (ROS). The HIF pathway and circadian clock genes were also significantly upregulated in response to HMP and HNP exposure. In particular, synergistic deleterious effects of HNP were evident, suggesting that size-dependent toxicity can be a major driver of the effects of hypoxia and NMP co-exposure. After several generations of exposure, ROS levels returned to basal levels and transcriptomic resilience was observed, although rotifer reproduction remained suppressed. These findings help eluciating the underlying molecular mechanisms involved in responses to plastic pollution in hypoxic conditions.
    Keywords:  Antioxidant system; HIF pathway; Hypoxia; Plastics; Rotifer
    DOI:  https://doi.org/10.1016/j.marpolbul.2022.113933
  93. J Biomed Nanotechnol. 2022 Apr 01. 18(4): 1001-1008
    Resveratrol Nanoparticles Suppresses Migration and Invasion of Renal Cell Carcinoma Cells by Inhibiting Matrix Metalloproteinase 2 Expression and Extracellular Signal-Regulated Kinase Pathway.
    Xing-Wang Zhu, Feng-Ming Dong, Jia Liu, Ming-Shan Li.
      The aim of this study was to examine the impact of Resveratrol nanoparticles on migration/invasion capacity of renal cell carcinoma (RCC) cells and its mechanism. Human RCC cells were exposed to dimethyl sulfoxide or gradient concentrations of Resveratrol nanoparticles respectively, and U0126 were also added in some experiments. We examined renal cell viability by MTT assay, and wound healing test and Transwell assays were used detect invasion and migration capability of RCC cells. We used Western blotting assay to analyze the protein levels in extracellular signal-regulated kinase (ERK) signaling. We also detected the enzymatic capacity of matrix metalloproteinase 2 (MMP-2) in cells by gelatin enzymatic profiling. Resveratrol nanoparticles treatment significantly suppressed cell viability to migrate and invade RCC cells in a dose-dependent manner. Also, notably were reduced MMP-2 activity and expression, and elevated TIMP-2 level were observed in RCC cells exposed with Resveratrol nanoparticles. Further, Resveratrol nanoparticles treatment significantly decreased only the expression of p-ERK1/2, but not p-p38 and p-JNK. Moreover, U0126, which is the ERK inhibitor, exerted similar role as Resveratrol nanoparticles did. Of note was that, combined use of U0126 and Resveratrol nanoparticles displayed a more intense suppression of MMP-2 activity and expression, and also the viability to migrate and invade the RCC cells, compared with Resveratrol nanoparticles treatment alone. The Resveratrol nanoparticles inhibited RCC cells migration and invasion by regulating MMP2 expression and ERK pathways.
    DOI:  https://doi.org/10.1166/jbn.2022.3310
  94. Front Cell Dev Biol. 2022 ;10 821855
    Targeting Autophagy in Thyroid Cancer: EMT, Apoptosis, and Cancer Stem Cells.
    Tammy M Holm, Syn Yeo, Kevin M Turner, Jun-Lin Guan.
      Autophagy is a highly conserved recycling process through which cellular homeostasis is achieved and maintained. With respect to cancer biology, autophagy acts as a double-edged sword supporting tumor cells during times of metabolic and therapeutic stress, while also inhibiting tumor development by promoting genomic stability. Accumulating evidence suggests that autophagy plays a role in thyroid cancer, acting to promote tumor cell viability and metastatic disease through maintenance of cancer stem cells (CSCs), supporting epithelial-to-mesenchymal transition (EMT), and preventing tumor cell death. Intriguingly, well-differentiated thyroid cancer is more prevalent in women as compared to men, though the underlying molecular biology driving this disparity has not yet been elucidated. Several studies have demonstrated that autophagy inhibitors may augment the anti-cancer effects of known thyroid cancer therapies. Autophagy modulation has become an attractive target for improving outcomes in thyroid cancer. This review aims to provide a comprehensive picture of the current knowledge regarding the role of autophagy in thyroid cancer, focusing on the potential mechanism(s) through which inhibition of autophagy may enhance cancer therapy and outcomes.
    Keywords:  EMT; apoptosis; autophagy; cancer stem cells; thyroid cancer
    DOI:  https://doi.org/10.3389/fcell.2022.821855
  95. Chem Res Toxicol. 2022 Jul 18. 35(7): 1127-1128
    Natural Products in Redox Toxicology.
      
    DOI:  https://doi.org/10.1021/acs.chemrestox.2c00184
  96. Front Pharmacol. 2022 ;13 865801
    Herb and Spices in Colorectal Cancer Prevention and Treatment: A Narrative Review.
    Md Sanower Hossain, Md Abdul Kader, Khang Wen Goh, Maidul Islam, Md Sharif Khan, Md Harun-Ar Rashid, Der Jiun Ooi, Henrique Douglas Melo Coutinho, Yaser Mohammed Al-Worafi, Said Moshawih, Ya Chee Lim, K M Kaderi Kibria, Long Chiau Ming.
      Colorectal cancer (CRC) is the second most deadly cancer worldwide. CRC management is challenging due to late detection, high recurrence rate, and multi-drug resistance. Herbs and spices used in cooking, practised for generations, have been shown to contain CRC protective effect or even be useful as an anti-CRC adjuvant therapy when used in high doses. Herbs and spices contain many bioactive compounds and possess many beneficial health effects. The chemopreventive properties of these herbs and spices are mainly mediated by the BCL-2, K-ras, and MMP pathways, caspase activation, the extrinsic apoptotic pathway, and the regulation of ER-stress-induced apoptosis. As a safer natural alternative, these herbs and spices could be good candidates for chemopreventive or chemotherapeutic agents for CRC management because of their antiproliferative action on colorectal carcinoma cells and inhibitory activity on angiogenesis. Therefore, in this narrative review, six different spices and herbs: ginger (Zingiber officinale Roscoe), turmeric (Curcuma longa L.), garlic (Allium sativum L.), fenugreek (Trigonella foenum-graecum L.), sesame (Sesamum indicum L.), and flaxseed (Linum usitatissimum L.) used in daily cuisine were selected for this study and analyzed for their chemoprotective or chemotherapeutic roles in CRC management with underlying molecular mechanisms of actions. Initially, this study comprehensively discussed the molecular basis of CRC development, followed by culinary and traditional uses, current scientific research, and publications of selected herbs and spices on cancers. Lead compounds have been discussed comprehensively for each herb and spice, including anti-CRC phytoconstituents, antioxidant activities, anti-inflammatory properties, and finally, anti-CRC effects with treatment mechanisms. Future possible works have been suggested where applicable.
    Keywords:  biomolecules; colon cancer; drug resistance; functional foods; management; nutraceuticals; prevalence
    DOI:  https://doi.org/10.3389/fphar.2022.865801
  97. Oncol Rep. 2022 Sep;pii: 160. [Epub ahead of print]48(3):
    Administration of 4‑hexylresorcinol increases p53‑mediated transcriptional activity in oral cancer cells with the p53 mutation.
    Yei-Jin Kang, Won-Geun Yang, Weon-Sik Chae, Dae-Won Kim, Seong-Gon Kim, Horatiu Rotaru.
      The p53 mutation is inherent in over 50% of human cancers. In head and neck squamous cell carcinoma, the p53 mutation is associated with a poor prognosis. 4‑Hexylresorcinol (4HR) is a pharmacologic chaperone. The present study aimed to investigate the effect of 4HR on p53 transcriptional activity in oral carcinoma cells with p53 mutations. To identify conformational changes induced by 4HR administration, peptides including the DNA‑binding domain from mutant and wild‑type p53 were synthesized, and Fourier transform infrared spectroscopy was performed. To determine the effect of 4HR on p53 mutant carcinoma cells, western blot analysis, p53 transcriptional activity analysis, MTT assay and apoptosis immunocytochemistry were performed. The YD‑15 cell line has a mutation in the DNA binding domain of p53 (Glu258Ala). When p53 Ala‑258 was coupled by 4HR, the p53 Ala‑258 structure lost its original conformation and approached a conformation similar to that of p53 Glu‑258. In the cell experiments, 4HR administration to p53 mutant cells increased p53 transcriptional activity and the expression levels of apoptosis‑associated proteins such as B‑cell lymphoma 2 (BCL2), BCL2‑associated X (BAX) and BCL2‑associated agonist of cell death (BAD). Accordingly, 4HR administration on YD‑15 cells decreased cell viability and increased apoptosis. In conclusion, 4HR is a potential substance for use in the recovery of loss‑of‑function in mutant p53 as a pharmacologic chaperone.
    Keywords:  4‑hexylresorcinol; apoptosis; oral carcinoma; p53; pharmacologic chaperone
    DOI:  https://doi.org/10.3892/or.2022.8375
  98. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2022 Jul 15. 36(7): 908-914
    [Research progress of nanomaterials for intra-articular targeted drug delivery in treatment of osteoarthritis].
    Lujie Zong, Qian Wu, Zhongchen Dong, Lixin Huang, Huilin Yang.
       Objective: To review the research progress of intra-articular targeted delivery of nanomaterials in the treatment of osteoarthritis (OA).
    Methods: The domestic and foreign related literature on intra-articular targeted delivery of nanomaterials for the treatment of OA was extensively reviewed, and their targeting strategies were discussed and summarized.
    Results: Rapid drug clearance from the joint remains a critical limitation in drug efficacy. Nanocarriers can not only significantly improve the residence profiles of drugs in the joint, but also achieve targeted delivery of drugs to specific joint tissues through active or passive targeting strategies.
    Conclusion: With the continuous development of various emerging tissue- or cell-specific drugs, the targeted delivery of drugs with nanomaterials promise to realize the clinical translation of these drugs in the treatment of OA.
    Keywords:  Osteoarthritis; intra-articular injection; nanomaterials; targeted delivery
    DOI:  https://doi.org/10.7507/1002-1892.202203033
  99. J Biomed Nanotechnol. 2022 Apr 01. 18(4): 1215-1226
    Formulation Design, Characterization and In-Vivo Assessment of Cefixime Loaded Binary Solid Lipid Nanoparticles to Enhance Oral Bioavailability.
    Mahwish Kamran, Mir Azam Khan, Muhammad Shafique, Ghallab Alotaibi, Abdulaziz Al Mouslem, Maqsood Rehman, Muhammad Asghar Khan, Sumaira Gul.
      Cefixime; widely employed cephalosporin antibiotic is unfortunately coupled to poor water solubility with resultant low oral bioavailability issues. To solve this problem micro-emulsion technique was used to fabricate binary SLNs using blend of solid and liquid lipids, surfactant as well as co-surfactant. The optimized nano suspension was characterized followed by modification to solidified dosage form. During characterization, optimized nano-suspension (CFX-4) produced particle size 189±2.1 nm with PDI 0.310±0.02 as well as -33.9±2 mV zeta potential. Scanning electron microscopy (SEM) presented nearly identical and spherical shaped particles. Differential scanning calorimetry and X-ray powder diffraction analysis ascertained decrease in drug's crystallinity. In-vitro release of drug pursued zero-order characteristics and demonstrated non-fickian pattern of diffusion. The freeze dried nano suspension (CFX-4) was transformed to capsule dosage form to perform comparison based In-Vivo studies. In-Vivo evaluation corresponded to 2.20-fold and 2.11-fold enhancement in relative bioavailability of CFX nano-formulation (CFX-4) as well as the prepared capsules respectively in contrast to the commercialized product (Cefiget®). In general; the obtained results substantiated superior oral bioavailability along with sustained pattern of drug release for CFX loaded binary nano particles. Thus, binary SLNs could be employed as a resourceful drug carrier for oral CFX delivery.
    DOI:  https://doi.org/10.1166/jbn.2022.3313
  100. Plant Foods Hum Nutr. 2022 Jul 20.
    Bioactive Properties of Bread Formulated with Plant-based Functional Ingredients Before Consumption and Possible Links with Health Outcomes After Consumption- A Review.
    Isaac Amoah, Carolyn Cairncross, Emmanuel Ofori Osei, Jacqueline Afua Yeboah, Jesse Charles Cobbinah, Elaine Rush.
      Bread is a commonly consumed staple and could be a viable medium to deliver plant-based ingredients that demonstrate health effects. This review brings together published evidence on the bioactive properties of bread formulated with plant-based ingredients. Health effects associated with the consumption of bread formulated with plant-based functional ingredients was also reviewed. Bioactive properties demonstrated by the functional ingredients fruits and vegetables, legumes, nuts and tea incorporated into bread include increased phenolic and polyphenolic content, increased antioxidant activity, and extension of bread shelf-life by impairment of lipid and protein oxidation. Acute health effects reported included appetite suppression, reduced diastolic blood pressure, improvements in glycaemia, insulinaemia and satiety effect. These metabolic effects are mainly short lived and not enough for a health claim. Longer term studies or comparison of those who consume and those who do not are needed. The incorporation of plant-based functional ingredients in bread could enhance the health-promoting effects of bread.
    Keywords:  Bioactivity; Functional bread; Health claims; Health effect; Physiological effect; Phytochemicals
    DOI:  https://doi.org/10.1007/s11130-022-00993-0
  101. Folia Med (Plovdiv). 2021 Aug 31. 63(4): 488-495
    Antitumor activity of the combination of artemisinin and epirubicin in human leukemia cells.
    Margarita Y Zhelyazkova, Nadya G Hristova-Avakumova, Georgi Tsv Momekov.
       AIM: We evaluated the tumor-inhibiting effect of artemisinin applied separately and in combination with epirubicin on leukemia HL-60 and HL-60/Dox cell lines, its dose modulation effect and its potency to  influence iron-induced oxidative damage of biologically relevant molecules.
    MATERIALS AND METHODS: MTT assay and the method of Chou-Talalay were used to show the inhibition of tumor cell proliferation and to evaluate the synergistic effect and modulation effect of artemisinin and epirubicin at varying concentrations. We also used spectrophotometric assays to determine the potency of artemisinin to influence iron-induced molecular degradation of lecithin and deoxyribose.
    RESULTS: Artemisinin exhibits tumor-inhibiting effect on both the anthracycline-sensitive and anthracycline-resistant promyelocytic cell lines, reaching 88% and 61% (T/C), respectively, when applied at higher concentrations in a dose-dependent manner. The combination of artemisinin and epirubicin shows synergistic effects in all tested concentrations on doxorubicin-resistant cells (CI<0.7). Artemisinin sensitizes the resistant cells towards epirubicin as shown by the CI (combination index) values and has a dose-modulation effect as shown by DRI (dose reduction index). Artemisinin induces deoxyribose oxidative degradation when applied alone and exerts synergistic deoxyribose degradation effect when applied with iron. However, artemisinin does not influence the studied processes in the lecithin-containing model system and has no potential to induce lipid peroxidation.
    CONCLUSIONS: This study presents a new opportunity to enhance the effectiveness of epirubicin-based treatment regimens with addition of artemisinins for resistant tumors.
    Keywords:  HL-60/Dox; combination chemotherapy; deoxyribose; lecithin; synergism
    DOI:  https://doi.org/10.3897/folmed.63.e55938
  102. Acta Pharm Sin B. 2022 Jul;12(7): 3156-3166
    Biological fate and interaction with cytochromes P450 of the nanocarrier material, d-α-tocopheryl polyethylene glycol 1000 succinate.
    Tianming Ren, Runzhi Li, Liqiang Zhao, J Paul Fawcett, Dong Sun, Jingkai Gu.
      d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS, also known as vitamin E-TPGS) is a biodegradable amphiphilic polymer prepared by esterification of vitamin E with polyethylene glycol (PEG) 1000. It is approved by the US Food and Drug Administration (FDA) and has found wide application in nanocarrier drug delivery systems (NDDS). Fully characterizing the in vivo fate and pharmacokinetic behavior of TPGS is important to promote the further development of TPGS-based NDDS. However, to date, a bioassay for the simultaneous quantitation of TPGS and its metabolite, PEG1000, has not been reported. In the present study, we developed such an innovative bioassay and used it to investigate the pharmacokinetics, tissue distribution and excretion of TPGS and PEG1000 in rat after oral and intravenous dosing. In addition, we evaluated the interaction of TPGS with cytochromes P450 (CYP450s) in human liver microsomes. The results show that TPGS is poorly absorbed after oral administration with very low bioavailability and that, after intravenous administration, TPGS and PEG1000 are mainly distributed to the spleen, liver, lung and kidney before both being slowly eliminated in urine and feces as PEG1000. In vitro studies show the inhibition of human CYP450 enzymes by TPGS is limited to a weak inhibition of CYP3A4. Overall, our results provide a clear picture of the in vivo fate of TPGS which will be useful in evaluating the safety of TPGS-based NDDS in clinical use and in promoting their further development.
    Keywords:  Cytochrome P450; Excretion; LC‒MS/MS; Metabolism; Nanocarrier materials; Pharmacokinetics; TPGS; Tissue distribution
    DOI:  https://doi.org/10.1016/j.apsb.2022.01.014
  103. Int J Biol Sci. 2022 ;18(11): 4289-4300
    High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer.
    Chenyuan Li, Si Sun, Yi Tu, Hanpu Zhang, Feng Yao, Shichong Liao, Shengrong Sun, Zhiyu Li, Zhong Wang.
      Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAGKD)-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAGKD cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAGOE) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes.
    Keywords:  AMPK signaling; EMT; MEDAG; breast cancer; diabetes
    DOI:  https://doi.org/10.7150/ijbs.70002
  104. J Biomed Nanotechnol. 2022 Apr 01. 18(4): 939-956
    Carrier-Free Nanomedicine for Cancer Immunotherapy.
    Yu Fu, Xufei Bian, Pingrong Li, Yulan Huang, Chong Li.
      With the rapid development of nanotechnology, carrier-based nano-drug delivery systems (DDSs) have been widely studied due to their advantages in optimizing pharmacokinetic and distribution profiles. However, despite those merits, some carrier-related limitations, such as low drug-loading capacity, systematic toxicity and unclear metabolism, usually prevent their further clinical transformation. Carrier-free nanomedicines with non-therapeutic excipients, are considered as an excellent paradigm to overcome these obstacles, owing to their superiority in improving both drug delivery efficacy and safety concern. In recent years, carrier-free nanomedicines have opened new horizons for cancer immunotherapy, and have already made outstanding progress. Herein, in this review, we are focusing on making an integrated and exhaustive overview of lately reports about them. Firstly, the major synthetic strategies of carrier-free nanomedicines are introduced, such as nanocrystals, prodrug-, amphiphilic drug-drug conjugates (ADDCs)-, polymer-drug conjugates-, and peptide-drug conjugates (PepDCs)-assembled nanomedicines. Afterwards, the typical applications of carrier-free nanomedicines in cancer immunotherapy are well-discussed, including cancer vaccines, cytokine therapy, enhancing T-cell checkpoint inhibition, as well as modulating tumor microenvironment (TME). After that, both the advantages and the potential challenges, as well as the future prospects of carrier-free nanomedicines in cancer immunotherapy, were discussed. And we believe that it would be of great potential practiced and reference value to the relative fields.
    DOI:  https://doi.org/10.1166/jbn.2022.3315
  105. Front Pharmacol. 2022 ;13 905755
    Review of Shikonin and Derivatives: Isolation, Chemistry, Biosynthesis, Pharmacology and Toxicology.
    Snehlata Yadav, Ajay Sharma, Gulzar Ahmad Nayik, Raymond Cooper, Garima Bhardwaj, Harvinder Singh Sohal, Vishal Mutreja, Ramandeep Kaur, Franklin Ore Areche, Mohannad AlOudat, Ayaz Mukarram Shaikh, Béla Kovács, Abdelhakam Esmaeil Mohamed Ahmed.
      Shikonin and its derivatives, isolated from traditional medicinal plant species of the genus Lithospermum, Alkanna, Arnebia, Anchusa, Onosma, and Echium belonging to the Boraginaceae family, have numerous applications in foods, cosmetics, and textiles. Shikonin, a potent bioactive red pigment, has been used in traditional medicinal systems to cure various ailments and is well known for its diverse pharmacological potential such as anticancer, antithrombotic, neuroprotective, antidiabetic, antiviral, anti-inflammatory, anti-gonadotropic, antioxidants, antimicrobial and insecticidal. Herein, updated research on the natural sources, pharmacology, toxicity studies, and various patents filed worldwide related to shikonin and approaches to shikonin's biogenic and chemical synthesis are reviewed. Furthermore, recent studies to establish reliable production systems to meet market demand, functional identification, and future clinical development of shikonin and its derivatives against various diseases are presented.
    Keywords:  biosynthesis; chemical synthesis; medicinal plant; pharmacology; secondary metabolites; shikonin; toxicology
    DOI:  https://doi.org/10.3389/fphar.2022.905755
  106. Gan To Kagaku Ryoho. 2022 Jul;49(7): 732-736
    [Exercise Therapy for Cancer Cachexia].
    Noriatsu Tatematsu.
      The treatment of cancer cachexia requires not only anti-cancer therapy but also multidisciplinary treatment including nutrition therapy, exercise therapy, and psychosocial intervention. In recent years, exercise therapy is expected to be one of the non-pharmacological treatments for cancer cachexia. However, there is a lack of evidence for exercise therapy for cancer cachexia, and no standard exercise therapy has been established. We have developed a multimodal intervention program (The Nutrition and Exercise Treatment for Advanced Cancer program: NEXTAC program)for older patients with advanced cancer who are at high risk of cachexia, combining nutrition and exercise therapy from the time of initial chemotherapy. In this article, we present an overview of the exercise therapy program in the NEXTAC program and discuss the current best practices for cancer cachexia.
  107. Bioact Mater. 2023 Feb;20 610-626
    A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound.
    Zhengwei Liu, Wanze Tang, Jiayi Liu, Yingying Han, Qinnan Yan, Yuechao Dong, Xiaomei Liu, Dazhi Yang, Guixing Ma, Huiling Cao.
      A novel sprayable adhesive is established (ZnMet-PF127) by the combination of a thermosensitive hydrogel (Pluronic F127, PF127) and a coordination complex of zinc and metformin (ZnMet). Here we demonstrate that ZnMet-PF127 potently promotes the healing of traumatic skin defect and burn skin injury by promoting cell proliferation, angiogenesis, collagen formation. Furthermore, we find that ZnMet could inhibit reactive oxygen species (ROS) production through activation of autophagy, thereby protecting cell from oxidative stress induced damage and promoting healing of skin wound. ZnMet complex exerts better effects on promoting skin wound healing than ZnCl2 or metformin alone. ZnMet complex also displays excellent antibacterial activity against Staphylococcus aureus or Escherichia coli, which could reduce the incidence of skin wound infections. Collectively, we demonstrate that sprayable PF127 could be used as a new drug delivery system for treatment of skin injury. The advantages of this sprayable system are obvious: (1) It is convenient to use; (2) The hydrogel can cover irregular skin defect sites evenly in a liquid state. In combination with this system, we establish a novel sprayable adhesive (ZnMet-PF127) and demonstrate that it is a potential clinical treatment for traumatic skin defect and burn skin injury.
    Keywords:  Autophagy; Reactive oxygen species (ROS); Skin wound; Thermosensitive hydrogel; ZnMet-PF127
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.06.008
  108. Sci Rep. 2022 Jul 22. 12(1): 12551
    A comprehensive analysis of meloxicam particles produced by nanosecond laser ablation as a wet milling technique.
    Eszter Nagy, Zsolt Homik, Tamás Smausz, Judit Kopniczky, Máté Náfrádi, Tünde Alapi, David Kokai, Katalin Burián, Piroska Szabó-Révész, Rita Ambrus, Béla Hopp.
      Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre-few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations.
    DOI:  https://doi.org/10.1038/s41598-022-16728-9
  109. Open Biol. 2022 Jul;12(7): 210371
    A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9.
    Nayibe Tatiana Sanchez-Álvarez, Paula Katherine Bautista-Niño, Juanita Trejos-Suárez, Norma Cecilia Serrano-Díaz.
      Metachromatic leukodystrophy is a neurological lysosomal deposit disease that affects public health despite its low incidence in the population. Currently, few reports are available on pathophysiological events related to enzyme deficiencies and subsequent sulfatide accumulation. This research aims to examine the use of metformin as an alternative treatment to counteract these effects. This was evaluated in human Schwann cells (HSCs) transfected or non-transfected with CRISPR-Cas9, and later treated with sulfatides and metformin. This resulted in transfected HSCs showing a significant increase in cell reactive oxygen species (ROS) production when exposed to 100 µM sulfatides (p = 0.0007), compared to non-transfected HSCs. Sulfatides at concentrations of 10 to 100 µM affected mitochondrial bioenergetics in transfected HSCs. Moreover, these analyses showed that transfected cells showed a decrease in basal and maximal respiration rates after exposure to 100 µM sulfatide. However, maximal and normal mitochondrial respiratory capacity decreased in cells treated with both sulfatide and metformin. This study has provided valuable insights into bioenergetic and mitochondrial effects of sulfatides in HSCs for the first time. Treatment with metformin (500 µM) restored the metabolic activity of these cells and decreased ROS production.
    Keywords:  metabolic activity; metachromatic leukodystrophy (MLD); metformin; neurological lysosomal storage disease; sulfatide therapy
    DOI:  https://doi.org/10.1098/rsob.210371
  110. Nano Lett. 2022 Jul 19.
    An Endogenous H2S-Activated Nanoplatform for Triple Synergistic Therapy of Colorectal Cancer.
    Jufeng Chen, Fengfeng Xue, Wenxian Du, Huizhu Yu, Zebin Yang, Qiujing Du, Hangrong Chen.
      Overproduced hydrogen sulfide (H2S) is a highly potential target for precise colorectal cancer (CRC) therapy; herein, a novel 5-Fu/Cur-P@HMPB nanomedicine is developed by coencapsulation of the natural anticancer drug curcumin (Cur) and the clinical chemotherapeutic drug 5-fluorouracil (5-Fu) into hollow mesoporous Prussian blue (HMPB). HMPB with low Fenton-catalytic activity can react with endogenous H2S and convert into high Fenton-catalytic Prussian white (PW), which can generate in situ a high level of •OH to activate chemodynamic therapy (CDT) and meanwhile trigger autophagy. Importantly, the autophagy can be amplified by Cur to induce autophagic cell death; moreover, Cur also acted as a specific chemosensitizer of the chemotherapy drug 5-Fu, achieving a good synergistic antitumor effect. Such a triple synergistic therapy based on a novel nanomedicine has been verified both in vitro and in vivo to have high efficacy in CRC treatment, showing promising potential in translational medicine.
    Keywords:  5-fluorouracil; Prussian blue; autophagy; chemodynamic therapy; colorectal cancer; curcumin
    DOI:  https://doi.org/10.1021/acs.nanolett.2c01346
  111. Biochem Biophys Res Commun. 2022 Jul 16. pii: S0006-291X(22)01011-7. [Epub ahead of print]623 9-16
    Antitumor effects of pyrrole-imidazole polyamide modified with alkylating agent on prostate cancer cells.
    Daigo Funakoshi, Daisuke Obinata, Kyoko Fujiwara, Shinichiro Yamamoto, Kenichi Takayama, Makoto Hara, Satoru Takahashi, Satoshi Inoue.
      Androgens and androgen receptor (AR) have a central role in prostate cancer progression by regulating its downstream signaling. Although androgen depletion therapy (ADT) is the primary treatment for most prostate cancers, they acquires resistance to ADT and become castration resistant prostate cancers (CRPC). AR complex formation with multiple transcription factors is important for enhancer activity and transcriptional regulation, which can contribute to cancer progression and resistance to ADT. We previously demonstrated that OCT1 collaborates with AR in prostate cancer, and that a pyrrole-imidazole (PI) polyamide (PIP) targeting OCT1 inhibits cell and castration-resistant tumor growth (Obinata D et al. Oncogene 2016). PIP can bind to DNA non-covalently without a drug delivery system unlike most DNA targeted therapeutics. In the present study, we developed a PIP modified with a DNA alkylating agent, chlorambucil (ChB) (OCT1-PIP-ChB). Then its effect on the growth of prostate cancer LNCaP, 22Rv1, and PC3 cells, pancreatic cancer BxPC3 cells, and colon cancer HCT116 cells, as well as non-cancerous MCF-10A epithelial cells, were analyzed. It was shown that the IC50s of OCT1-PIP-ChB for 22Rv1 and LNCaP were markedly lower compared to other cells, including non-cancerous MCF-10A cells. Comprehensive gene expression analysis of CRPC model 22Rv1 cells treated with IC50 concentrations of OCT1-PIP-ChB revealed that the gene group involved in DNA double-strand break repair was the most enriched among gene sets repressed by OCT1-PIP-ChB treatment. Importantly, in vivo study using 22Rv1 xenografts, we showed that OCT1-PIP-ChB significantly reduced tumor growth compared to the control group without showing obvious adverse effects. Thus, the PIP combined with ChB can exert a significant inhibitory effect on prostate cancer cell proliferation and castration-resistant tumor growth, suggesting a potential role as a therapeutic agent.
    Keywords:  Alkylating agent; OCT1; PI polyamide; Prostate cancer
    DOI:  https://doi.org/10.1016/j.bbrc.2022.07.042
  112. ACS Appl Mater Interfaces. 2022 Jul 20.
    Injectable Self-Healing Adhesive Chitosan Hydrogel with Antioxidative, Antibacterial, and Hemostatic Activities for Rapid Hemostasis and Skin Wound Healing.
    Shen Guo, Yikun Ren, Rong Chang, Yuanmeng He, Dan Zhang, Fangxia Guan, Minghao Yao.
      Engineered wound dressing materials with excellent injectability, self-healing ability, tissue-adhesiveness, especially the ones possessing potential therapeutic effects have great practical significance in healthcare. Herein, an injectable quaternary ammonium chitosan (QCS)/tannic acid (TA) hydrogel based on QCS and TA was designed and fabricated by facile mixing of the two ingredients under physiological conditions. In this system, hydrogels were mainly cross-linked by dynamic ionic bonds and hydrogen bonds between QCS and TA, which endows the hydrogel with excellent injectable, self-healing, and adhesive properties. Benefitting from the inherent antioxidative, antibacterial, and hemostatic abilities of TA and QCS, this hydrogel showed superior reactive oxygen species scavenging activity, broad-spectrum antibacterial ability, as well as rapid hemostatic capability. Moreover, the QCS/TA2.5 hydrogel (containing 2.5% TA) exhibited excellent biocompatibility. The in vivo experiments also showed that QCS/TA2.5 hydrogel dressing not only rapidly stopped the bleeding of arterial and deep incompressible wounds in mouse tail amputation, femoral artery hemorrhage, and liver incision models but also significantly accelerated wound healing in a full-thickness skin wound model. For the great potentials listed above, this multifunctional QCS/TA2.5 hydrogel offers a promising network as a dressing material for both rapid hemostasis and skin wound repair.
    Keywords:  antibacterial; antioxidant; hemostasis; injectable; multifunctional wound dressing; self-healing; tissue adhesiveness; wound healing
    DOI:  https://doi.org/10.1021/acsami.2c08870
  113. J Recept Signal Transduct Res. 2022 Jul 21. 1-10
    Target-based in-silico screening of basil polysaccharides against different epigenetic targets responsible for breast cancer.
    Nancy Bhura, Pawan Gupta, Jeena Gupta.
       PURPOSE: Breast cancer (BC) is one of the leading types of cancer found in women. One of the causes reported for BC is improper regulation of epigenetic modifications. Various epigenetic targets such as histone deacetylases (HDAC) and histone acetyltransferases (HAT) regulate many types of cancer, including BC. Basil is known to possess anti-cancer properties; however, the role of its polysaccharides against different epigenetic targets is still not very clear. Therefore, the molecular docking method is used to find out the binding potential of the BPSs against different epigenetic targets responsible for BC.
    METHODS: All the basil polysaccharides (BPSs) were screened against the diverse epigenetic targets reported for BC (HDAC1-2, 4-8, and HAT) using molecular docking studies alongwith swissADME studies to check the drug likeliness of the BPSs.
    RESULTS: It was found that glucosamine ring, glucosamine linear, glucuronic acid linear, rhamnose linear, glucuronic acid ring, galactose ring, mannose, glucose, and xylose were exhibited consistent binding potential against the epigenetic targets (HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HAT,) responsible for BC.
    CONCLUSION: This is the first report where BPSs were reported against these epigenetic targets. These studies can help to understand the underlying mechanism of BPSs used against epigenetic targets for BC. These results can be further validated experimentally to confirm their potential as a promising inhibitor against the epigenetic targets (HDAC1-2, 4-8, and HAT) having a role in BC.
    Keywords:  Basil polysaccharides; breast cancer; epigenetics; molecular docking; target based in-silico screening
    DOI:  https://doi.org/10.1080/10799893.2022.2058016
  114. Artif Cells Nanomed Biotechnol. 2022 Dec;50(1): 208-217
    Anti-inflammatory effect of simvastatin by impeding TNF-α and interleukin-1ß pathways: antiangiogenic activity of simvastatin and simvastatin-loaded silver nanoparticles.
    Manal Buabeid, El-Shaimaa A Arafa, Hafiza Sidra Yaseen, Muhammad Ihtisham Umar, Ghulam Murtaza.
       PURPOSE: The present study was carried out to evaluate anti-inflammatory and antiangiogenic attributes of simvastatin and its nanofilms containing silver nanoparticles.
    METHODS: Silver nanoparticles and simvastatin-loaded nanocomposite (SNSN) films were formulated by using polymeric solution (pectin + sericin) through casting solution method. Different in vitro and in vivo anti-inflammatory assays were performed. In addition, chick chorioallantoic membrane assay (CAM) was also employed for angiogenesis activity.
    RESULTS: FTIR spectra of the film depicted the presence of intact simvastatin. Differential scanning calorimetry exhibited no endothermic expression in F9 film thermogram. The simvastatin release from all films exhibited a burst effect. Cotton-pellet induced granuloma model study showed that high dose of simvastatin and indomethacin produced comparable (p < 0.05) anti-inflammatory effect. Noteworthy, RT-PCR showed dose-dependent, anti-oedematous effect of simvastatin through downregulation of serum TNF-α and interleukin-1ß levels. While results of CAM assay exhibited remarkable anti-angiogenic potential of SNSN films showing dissolved blood vessels network macroscopically.
    CONCLUSION: To reiterate, simvastatin and its SNSN films can add significant contribution to the field of biomedicines due to their promising anti-inflammatory and antiangiogenic properties, however, clinical studies are required to validate their commercial use.
    Keywords:  TNF-alpha; angiogenesis; antihyperlipidemic; inflammation; interleukins
    DOI:  https://doi.org/10.1080/21691401.2022.2098306
  115. Adv Sci (Weinh). 2022 Jul 21. e2105885
    Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.
    Mofei Huang, Donghai Xiong, Jing Pan, Qi Zhang, Shizuko Sei, Robert H Shoemaker, Ronald A Lubet, Luis M Montuenga, Yian Wang, Barbara S Slusher, Ming You.
      Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR-driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single-cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell-mediated immune responses and protects mice against EGFRL858R mutation-driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic- and granulocytic-myeloid-derived suppressor cells, regulatory T cells, and pro-tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory-like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR-driven lung tumorigenesis and promotes an adaptive T cell-mediated tumor-specific immune response that enhances the efficacy of EVax.
    Keywords:  JHU-083; epidermal growth factor receptor vaccines; glutamine metabolism; lung tumorigenesis; tumor immune microenvironment
    DOI:  https://doi.org/10.1002/advs.202105885
  116. J Ultrasound Med. 2022 Jul 23.
    Combination of Focused Ultrasound, Immunotherapy, and Chemotherapy: New Perspectives in Breast Cancer Therapy.
    Myléva Dahan, Marion Cortet, Cyril Lafon, Frédéric Padilla.
      Focused ultrasound is a treatment modality increasingly used for diverse therapeutic applications, and currently approved for several indications, including prostate cancers and uterine fibroids. But what about breast cancer? Breast cancer is the most common and deadliest cancer in women worldwide. While there are different treatment strategies available, there is a need for development of more effective and personalized modalities, with fewer side effects. Therapeutic ultrasound is such an option, and this review summarizes the state of the art in their use for the treatment of breast cancer and evaluate potentials of novel treatment approaches combining therapeutic ultrasound, immuno- and chemo-therapies.
    Keywords:  breast cancer; chemotherapy; high intensity focused ultrasound (HIFU); immunotherapy; targeted therapy; therapeutic ultrasound
    DOI:  https://doi.org/10.1002/jum.16053
  117. Eur J Pharm Sci. 2022 Jul 14. pii: S0928-0987(22)00144-0. [Epub ahead of print]176 106259
    Functionalized FcRn-targeted nanosystems for oral drug delivery: A new approach to colorectal cancer treatment.
    Fatima Hameedat, Nuria A Pizarroso, Natália Teixeira, Soraia Pinto, Bruno Sarmento.
      Colorectal cancer (CRC) is the second type of cancer with the highest lethality rate. The current chemotherapy to treat CRC causes systemic toxicity, unsatisfying response rate, and low tumor-specific selectivity, which is mainly administered by invasive routes. The chronic and aggressive nature of cancers may require long-term regimens. Thus, the oral route is preferred. However, the orally administered drugs still need to surpass the harsh environment of the gastrointestinal tract and the biological barriers. Nanotechnology is a promising strategy to overcome the oral route limitations. Targeted nanoparticle systems decorated with functional groups can enhance the delivery of anticancer agents to tumor sites. It is described in the literature that the neonatal Fc receptor (FcRn) is expressed in cancer tissue and overexpressed in CRC epithelial cells. However, the impact of FcRn-targeted nanosystems in the treatment of CRC has been poorly investigated. This review article discusses the current knowledge on the involvement of the FcRn in CRC, as well as to critically assess its relevance as a target for further localization of oral nanocarriers in CRC tumor cells. Finally, a brief overview of cancer therapeutics, strategies to design the nanoparticles of anticancer drugs and a review of decorated nanoparticles with FcRn moieties are explored.
    Keywords:  Colorectal cancer; FcRn; Nanomedicines; Oral delivery; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejps.2022.106259
  118. Adv Drug Deliv Rev. 2022 Jul 18. pii: S0169-409X(22)00337-4. [Epub ahead of print] 114447
    The role of imaging in targeted delivery of nanomedicine for cancer therapy.
    Puze Li, Dongdong Wang, Jun Hu, Xiangliang Yang.
      Nanomedicines overcome the pharmacokinetic limitations of traditional drug formulations and have promising prospect in cancer treatment. However, nanomedicine delivery in vivo is still facing challenges from the complex physiological environment. For the purpose of effective tumor therapy, they should be designed to guarantee the five features principle, including long blood circulation, efficient tumor accumulation, deep matrix penetration, enhanced cell internalization and accurate drug release. To ensure the excellent performance of the designed nanomedicine, it would be better to monitor the drug delivery process as well as the therapeutic effects by real-time imaging. In this review, we summarize strategies in developing nanomedicines for efficiently meeting the five features of drug delivery, and the role of several imaging modalities (fluorescent imaging (FL), magnetic resonance imaging (MRI), computed tomography (CT), photoacoustic imaging (PAI), positron emission tomography (PET), and electron microscopy) in tracing drug delivery and therapeutic effect in vivo based on five features principle.
    Keywords:  Cancer therapy; Drug delivery; Five features principle; Imaging; Nanomedicine
    DOI:  https://doi.org/10.1016/j.addr.2022.114447
  119. Cell Death Dis. 2022 Jul 21. 13(7): 636
    Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
    Xiaoshu Zhou, Rui Zhou, Xinrui Rao, Jiaxin Hong, Qianwen Li, Xiaohua Jie, Jian Wang, Yingzhuo Xu, Kuikui Zhu, Zhenyu Li, Gang Wu.
      The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
    DOI:  https://doi.org/10.1038/s41419-022-05079-y
  120. J Hematol Oncol. 2022 Jul 18. 15(1): 97
    Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management.
    Ping Jin, Jingwen Jiang, Li Zhou, Zhao Huang, Edouard C Nice, Canhua Huang, Li Fu.
      Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.
    Keywords:  Cancer drug resistance; Drug repurposing; Mitochondrial adaptation; Mitochondrial dynamics; Mitochondrial transplantation; Mitochondrial-targeted drug delivery
    DOI:  https://doi.org/10.1186/s13045-022-01313-4
  121. Int J Dent. 2022 ;2022 9579326
    Effect of Meloxicam on the Proliferation and Apoptosis of the Raji Cell Line: an In Vitro Study.
    Yolanda Kartika Asmarani, Supriatno, Tetiana Haniastuti.
      Meloxicam, a nonsteroidal anti-inflammatory drug, inhibits the production of PGE2 by blocking Cox-2 activity. Specific inhibition of Cox-2 can be useful in cancer therapy by apoptosis stimulation. The objective of the research was to study the effect of meloxicam on the proliferation and apoptosis of Raji cell lines. Burkitt lymphoma (BL) cells (Raji ATCC CCL-86) were treated with various concentrations of meloxicam for 24 hours. The proliferation of the cells was evaluated by using an MTT assay. Cell apoptosis was assessed using flow cytometry, and SEM was performed to observe the morphological changes of the cells. Results showed that meloxicam affected Raji cell proliferation as well as cell apoptosis. The percentage of viable cells was decreased significantly after being treated with meloxicam (p < 0.05). Apoptotic cell percentage was higher in the groups treated with meloxicam compared to the control group (p < 0.05). SEM showed morphological changes in the Raji cells after treatment with meloxicam, showing apoptotic characteristics. These findings suggest that meloxicam has anticancer properties by inhibiting Raji cell proliferation and inducing Raji cell apoptosis in vitro. A combination of meloxicam with chemotherapy agents may improve the outcome of BL treatment.
    DOI:  https://doi.org/10.1155/2022/9579326
  122. Folia Med (Plovdiv). 2021 Dec 31. 63(6): 895-900
    Effects of Vitamin E Supplementation to Metabolic Markers on Diet-Induced Obesity in Mice.
    Eka Roina Megawati, Lokot Donna Lubis, Febi Yanti Harahap.
       INTRODUCTION: Obesity creates health problems by increasing the risks of chronic diseases such as type 2 diabetes and cardiovascular disorders. Obesity leads to insulin resistance, higher blood glucose and cholesterol levels. Adipose tissues synthesize adiponectin which acts as anti-inflammatory, antidiabetic, and anti-atherogenic agent. Meanwhile, vitamin E is an antioxidant that acts as an anti-inflammation.
    AIM: The purpose of this study was to analyze the effects of vitamin E supplementation to metabolic markers on diet-induced obesity in mice.
    MATERIALS AND METHODS: Twenty-four mice (Mus musculus, L) aged four weeks were divided into six groups which were fed different diets and given vitamin E in different dosages or methods. The period of treatment was 18 weeks. The mice body weights were measured every week; blood sugar and cholesterol levels were measured every six weeks, and the adiponectin level measurement was done at week 18.
    RESULTS: A repeated measures ANOVA showed that body weight and cholesterol level within groups were not significantly different [F(15, 54)=1.417, 0.173 and F(10, 36)=1.391, 0.224 respectively]. The glucose levels were found to be significantly different [F(7.646, 27.526)=2.625, 0.030]. There was no significant difference in the adiponectin levels.
    CONCLUSIONS: Vitamin E supplementation could not prevent the increase of body weight, the elevation of blood sugar and cholesterol levels, and also could not increase adiponectin level.
    Keywords:  adiponectin; cholesterol; glucose; obesity; vitamin E
    DOI:  https://doi.org/10.3897/folmed.63.e57877
  123. J Psychopharmacol. 2022 Jul 21. 2698811221112932
    Examining the role of systemic chronic inflammation in diet and sleep relationship.
    Piril Hepsomali, John A Groeger.
       BACKGROUND: It is well known that systemic chronic inflammation (SCI), which can be modulated by diet, is associated with poor sleep outcomes. However, the role of SCI in diet health and sleep quality relationship has not been well established.
    METHODS: Here, by using the UK Biobank data set, we assessed the association between markers of SCI (leukocyte, platelet, lymphocyte, neutrophil, and basophil counts; C-reactive protein levels and neutrophil to lymphocyte ratio (NLR)), habitual intake of food groups, diet health and sleep quality in 449,084 participants. We also formally tested the possibility that SCI might mediate the relationship between diet health and sleep quality.
    RESULTS: Our results revealed (i) negative associations between SCI and food groups that are abundant in healthy diets (fruit, vegetable and oily and non-oily fish) and (ii) positive associations between SCI and food groups that are abundant in unhealthy diets (processed meat). Sleep quality was also negatively associated with platelet counts, CRP levels and NLR. Crucially, however, while platelet and neutrophil counts, CRP levels and NLR fully mediated the association between diet health and sleep quality, leukocyte, lymphocyte and basophil counts partially mediated the associations between diet health and sleep quality.
    CONCLUSION: Reducing SCI via dietary interventions could be an effective primary and/or complementary strategy to increase sleep quality. Further interventional trials are warranted to (i) establish the strength of associations, preferably by using validated diet and sleep measures and (ii) examine longer term effects of anti-inflammatory diets on sleep-, diet- and inflammation-related health outcomes.
    Keywords:  C-reactive protein; Diet; blood cells; inflammation; sleep
    DOI:  https://doi.org/10.1177/02698811221112932
  124. Front Biosci (Landmark Ed). 2022 Jun 28. 27(7): 206
    Therapeutic Efficacy of Polyphenol-Rich Fraction of Boesenbergia rotunda in Diabetic Rats: A Focus on Hypoglycemic, Antihyperlipidemic, Carbohydrate Metabolism, Antioxidant, Anti-Inflammatory and Pancreato-Protective Activities.
    Ting Wang, Chunhong Liu, Shouhong Shu, Qiu Zhang, Opeyemi Joshua Olatunji.
       INTRODUCTION: Boesenbergia rotunda is a famous culinary/medicinal herb native to Southeast Asia region and it is traditionally used in the treatment of several diseases. This study investigated the anti-diabetic properties of Boesenbergia rotunda polyphenol extract (BRE) in high fructose/streptozotocin-induced diabetic rats.
    METHOD: The in vitro antioxidant activity was evaluated using DPPH and ABST colorimetric assays, while the Folin-Ciocalteu method was used for the total phenolic content of BRE. For diabetes induction, a combination of high fructose solution and streptozotocin was administered to the rats and diabetic rats were orally administrated with BRE (100 and 400 mg/kg) for 5 weeks. The fasting blood glucose, body weight gain, food and water consumption were determined during the treatment period.
    RESULTS: BRE showed excellent in vitro DPPH and ABTS scavenging activity with high phenolic content. BRE significantly lowered fasting blood glucose level, HbA1c, lipid profile, hepatorenal biochemical parameters and ameliorated the IPGTT in diabetic rats. Additionally, BRE reversed body weight loss, attenuated food and water intake, serum insulin level, pancreatic β-cell function and pancreatic cell morphology. Furthermore, fructose 1,6 biphosphatase, glucose-6-phosphatase, malondialdehyde (MDA) and proinflammatory cytokines levels were also ameliorated in the BRE-treated diabetic rats, while pancreatic antioxidant enzymes activities (GSH, SOD and CAT) were significantly increased in the treated rats.
    CONCLUSIONS: In conclusion, the results showed that BRE effectively displayed antidiabetic effects and has possible value for antidiabetic oral medication.
    Keywords:  Boesenbergia rotunda; diabetes mellitus; hypoglycemic activity; oxidative stress; polyphenols
    DOI:  https://doi.org/10.31083/j.fbl2707206
  125. J Toxicol Environ Health A. 2022 Jul 17. 1-16
    Protective effects of resveratrol against genotoxicity induced by nano and bulk hydroxyapatite in Drosophila melanogaster.
    Fatma Turna Demir.
      Hydroxyapatite (HAp) is a naturally occurring calcium phosphate mineral predominantly used for its biocompatibility in a number of areas such as bone grafting, prosthesis coating in dentistry, and targeted drug delivery. Since the nano form of HAp (nHAp) has gained popularity attributed to a re-mineralizing effect in dental repair procedures, concerns have been raised over safety and biocompatibility of these nanoparticles (NP). This study, therefore, aimed to (1) investigate mechanisms of potential genotoxicity and enhanced generation of reactive oxygen species (ROS) initiated by bulk and nano forms of HAp and (2) test in vivo whether resveratrol, a type of natural phenol, might mitigate the extent of potential DNA damage. The size of nHAp was determined to be 192.13 ± 9.91 nm after dispersion using transmission electron microscopy (TEM). Drosophila melanogaster was employed as a model organism to determine the genotoxic potential and adverse effects of HAp by use of (comet assay), mutagenic and recombinogenic activity (wing spot test), and ROS-mediated damage. Drosophila wing-spot tests demonstrated that exposure to nontoxic bulk and nHAp concentrations (1, 2.5, 5 or 10 mM) produced no significant recombination effects or mutagenicity. However, bulk and nHAp at certain doses (2.5, 5 or 10 mM) induced genotoxicity in hemocytes and enhanced ROS production. Resveratrol was found to ameliorate the genotoxic effects induced by bulk HAp and nHAp in comet assay. Data demonstrate that treatment with nano and bulk Hap-induced DNA damage and increased ROS generation D. melanogaster which was alleviated by treatment with resveratrol.
    Keywords:  Drosophila melanogaster; Hydroxyapatite nanoparticles; antigenotoxicity; comet assay; resveratrol
    DOI:  https://doi.org/10.1080/15287394.2022.2101568
  126. Rev Infirm. 2022 May;pii: S1293-8505(22)00115-4. [Epub ahead of print]71(281): 20-21
    [Professional activity and cancer].
    Dominique Thirry.
      A cancer diagnosis and the ensuing treatment process are a very sensitive period in a person's life. Beyond the disease and the treatments that can be spread out over time, the repercussions on the professional life and the financial balance of the household often worry patients. They are looking for simple and reliable advice to help them better understand their social and professional rights, as well as their duties.
    Keywords:  arrêt de travail; cancer; compensation; droit du travail; employment law; indemnisation; work interruption
    DOI:  https://doi.org/10.1016/j.revinf.2022.03.007
  127. Neurosurgery. 2022 Jul 25.
    Neuropharmacological Study of Posaconazole for Glioblastoma: A Phase 0 Clinical Trial Protocol.
    Debarati Bhanja, Jeffrey Neighbors, James Connor, Gelareh Zadeh, Alireza Mansouri.
       BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor with a universally poor prognosis. GBMs express elevated levels of hexokinase 2 (HK2), catalyzing the critical step in glycolysis and influencing several oncogenic pathways. Previous preclinical work has suggested a role for repurposed posaconazole (PCZ) in downregulating HK2 activity, reducing lactate and pyruvate production, interfering with tumor cell metabolism, and increasing mouse survival.
    OBJECTIVE: To establish brain tumor penetrance, neuropharmacokinetic profile, and mechanistic effect on tumor cell metabolism of PCZ in adults with GBM.
    METHODS: This is an open label, nonrandomized, parallel arm trial involving patients with GBM. Cohorts will receive PCZ (intervention, n = 5) or will not receive PCZ (control, n = 5), followed by tumor resection and microdialysis catheter placement. Dialysate, plasma, and tumor samples will be analyzed for lactate and pyruvate concentrations. Tumor samples will also be assessed for PCZ concentration, HK2 expression, angiogenesis, and apoptosis. PCZ's neuropharmacokinetics will be determined based on the concentration vs time profile and area under the curve 0 to 24 hours of PCZ concentration in the brain interstitium.
    EXPECTED OUTCOMES: (1) Increased PCZ concentration in contrast-enhancing brain regions compared with nonenhancing regions; (2) inverse correlation between lactate/pyruvate and PCZ concentrations in dialysate samples from treated patients, over time; and (3) decreased HK2 activity in PCZ-treated tumor samples.
    DISCUSSION: A successful trial will support the decision to proceed to advanced phase trials. Any tumor penetration by PCZ, with concomitant effect on glycolysis, warrants further in-depth analysis, as therapeutic options for these deadly tumors are currently limited.
    DOI:  https://doi.org/10.1227/neu.0000000000002071
  128. Trends Cancer. 2022 Jul 13. pii: S2405-8033(22)00137-6. [Epub ahead of print]
    Drug independence and the curability of cancer by combination chemotherapy.
    Amy E Pomeroy, Emmett V Schmidt, Peter K Sorger, Adam C Palmer.
      Combination chemotherapy can cure certain leukemias and lymphomas, but most solid cancers are only curable at early stages. We review quantitative principles that explain the benefits of combining independently active cancer therapies in both settings. Understanding the mechanistic principles underlying curative treatments, including those developed many decades ago, is valuable for improving future combination therapies. We discuss contemporary evidence for long-established but currently neglected ideas of how combination therapy overcomes tumor heterogeneity. We show that a unified model of interpatient and intratumor heterogeneity describes historical progress in the treatment of pediatric acute lymphocytic leukemia (ALL), in which increasingly intensive combination regimens ultimately achieved high cure rates. We also describe three distinct aspects of drug independence that apply at different biological scales. The ability of these principles to quantitatively explain curative regimens suggests that supra-additive (synergistic) drug interactions are not required for successful combination therapy.
    Keywords:  combination therapy; drug independence; tumor heterogeneity
    DOI:  https://doi.org/10.1016/j.trecan.2022.06.009
  129. Rev Neurol (Paris). 2022 Jul 16. pii: S0035-3787(22)00641-5. [Epub ahead of print]
    Therapeutic ultrasound: The future of epilepsy surgery?
    A Bex, V Bex, A Carpentier, B Mathon.
      Epilepsy is one of the leading neurological diseases in both adults and children and in spite of advancement in medical treatment, 20 to 30% of patients remain refractory to current medical treatment. Medically intractable epilepsy has a real impact on a patient's quality of life, neurologic morbidity and even mortality. Actual therapy options are an increase in drug dosage, radiosurgery, resective surgery and non-resective neuromodulatory treatments (deep brain stimulation, vagus nerve stimulation). Resective, thermoablative or neuromodulatory surgery in the treatment of epilepsy are invasive procedures, sometimes requiring long stay-in for the patients, risks of permanent neurological deficit, general anesthesia and other potential surgery-related complications such as a hemorrhage or an infection. Radiosurgical approaches can trigger radiation necrosis, brain oedema and transient worsening of epilepsy. With technology-driven developments and pursuit of minimally invasive neurosurgery, transcranial MR-guided focused ultrasound has become a valuable treatment for neurological diseases. In this critical review, we aim to give the reader a better understanding of current advancement for ultrasound in the treatment of epilepsy. By outlining the current understanding gained from both preclinical and clinical studies, this article explores the different mechanisms and potential applications (thermoablation, blood brain barrier disruption for drug delivery, neuromodulation and cortical stimulation) of high and low intensity ultrasound and compares the various possibilities available to patients with intractable epilepsy. Technical limitations of therapeutic ultrasound for epilepsy surgery are also detailed and discussed.
    Keywords:  Blood-brain barrier opening; Drug-resistant epilepsy; HIFU; Innovative technologies; Neuromodulation; Noninvasive approach; Thermoablation
    DOI:  https://doi.org/10.1016/j.neurol.2022.03.015
  130. Aging Dis. 2022 Jul 11. 13(4): 1146-1165
    Effects of Ketogenic Diet on Neuroinflammation in Neurodegenerative Diseases.
    Ziying Jiang, Xi Yin, Miao Wang, Tong Chen, Yuanyuan Wang, Zhongbao Gao, Zhenfu Wang.
      The ketogenic diet (KD) is a low-carbohydrate, high-fat and adequate-protein diet. As a diet mimicking fasting, it triggers the production of ketone bodies (KBs) and brings the body into a state of ketosis. Recent and accumulating studies on humans and animal models have shown that KD is beneficial to neurodegenerative diseases through modulating central and peripheral metabolism, mitochondrial function, inflammation, oxidative stress, autophagy, and the gut microbiome. Complicated interplay of metabolism, gut microbiome, and other mechanisms can regulate neuroinflammation in neurodegenerative diseases by activating multiple molecular and cellular pathways. In this review, we detail the physiological basis of the KD, its functions in regulating neuroinflammation, and its protective role in normal brain aging and neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We aimed to elucidate the underlying neuroinflammatory mechanisms of KD therapies in neurodegenerative diseases and provide novel insights into their application for neurodegenerative disease prevention and treatment.
    Keywords:  experimental and clinical evidence; ketogenic diet; ketone bodies; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.14336/AD.2021.1217
  131. Front Bioeng Biotechnol. 2022 ;10 951513
    Advanced Hydrogels With Nanoparticle Inclusion for Cartilage Tissue Engineering.
    Yunong Ao, En Zhang, Yangxi Liu, Liu Yang, Jun Li, Fuyou Wang.
      Cartilage dysfunctions caused by congenital disease, trauma and osteoarthritis are still a serious threat to joint activity and quality of life, potentially leading to disability. The relatively well-established tissue engineering technology based on hydrogel is a promising strategy for cartilage defect repairing. However, several unmet challenges remain to be resolved before its wide application and clinical translation, such as weak mechanical property and compromised bioactivity. The development of nanomedicine has brought a new dawn to cartilage tissue engineering, and composite hydrogel containing nanoparticles can substantially mimic natural cartilage components with good histocompatibility, demonstrating unique biological effects. In this review, we summarize the different advanced nanoparticle hydrogels currently adopted in cartilage tissue engineering. In addition, we also discuss the various application scenarios including injection and fabrication strategies of nanocomposite hydrogel in the field of cartilage repair. Finally, the future application prospects and challenges of nanocomposite hydrogel are also highlighted.
    Keywords:  cartilage; composite hydrogels; nanoparticles; repairing; tissue engineering
    DOI:  https://doi.org/10.3389/fbioe.2022.951513
  132. Bioact Mater. 2023 Feb;20 539-547
    Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy.
    Yinglan Yu, Shujie Li, Yuan Yao, Xinran Shen, Lian Li, Yuan Huang.
      Inhaled nanoparticles (NPs) need to penetrate the bronchial mucosa to deliver drug payloads deeply in the lung for amplified local therapy. However, the bronchial mucociliary barrier eliminates NPs rapidly, which considerably limits their mucosal penetration. In this study, we find that surface ligand modification and stiffness adjustment of NPs contribute to the significantly enhanced bronchial mucosal absorption and pulmonary retention of inhaled drugs. We utilize neonatal Fc receptor ligand (FcBP) to modify the rationally designed low stiffness NPs (Soft-NP) and high stiffness NPs (Stiff-NP) to target bronchial mucosa. In an acute lung inflammation rat model, after intranasal administration with dexamethasone-loaded NPs, Stiff-NP endowed with FcBP displays superior therapeutic effects. The in vitro data demonstrate that the promotion effect of FcBP to bronchial mucosal absorption of Stiff-NP dominates over Soft-NP. This could be attributed to the higher affinity between ligand-receptor when incorporating FcBP on the Stiff-NP surface. Meanwhile, high stiffness modulates more actin filaments aggregation to mediate endocytosis, along with strengthened Ca2+ signal to enhance exocytosis. Conclusively, we highlight that FcBP-modified NPs with higher stiffness would be a potential pulmonary drug delivery system.
    Keywords:  Acute lung inflammation; Epithelial barrier; Ligand modification; Mucus barrier; Pulmonary drug delivery; Stiffness
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.06.016
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