bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–09–18
166 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Hyaluronic acid-based nano drug delivery systems for breast cancer treatment: Recent advances.
  2. Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review.
  3. Application of nanosonosensitizer materials in cancer sono-dynamic therapy.
  4. Drosophila as a toolkit to tackle cancer and its metabolism.
  5. Synergistic chemo-photothermal and ferroptosis therapy of polydopamine nanoparticles for esophageal cancer.
  6. Tumor acidity: From hallmark of cancer to target of treatment.
  7. Challenging the fundamental conjectures in nanoparticle drug delivery for chemotherapy treatment of solid cancers.
  8. Role of lignin-based nanoparticles in anticancer drug delivery and bioimaging: An up-to-date review.
  9. Hemin-incorporating DNA nanozyme enabling catalytic oxygenation and GSH depletion for enhanced photodynamic therapy and synergistic tumor ferroptosis.
  10. Current Advances in Chitosan Nanoparticles Based Oral Drug Delivery for Colorectal Cancer Treatment.
  11. Polydopamine-doped supramolecular chiral hydrogels for postoperative tumor recurrence inhibition and simultaneously enhanced wound repair.
  12. Targeting therapy and tumor microenvironment remodeling of triple-negative breast cancer by ginsenoside Rg3 based liposomes.
  13. Nucleobase-crosslinked poly(2-oxazoline) nanoparticles as paclitaxel carriers with enhanced stability and ultra-high drug loading capacity for breast cancer therapy.
  14. Research progress on tumor hypoxia-associative nanomedicine.
  15. Photodynamic therapy of lung cancer, where are we?
  16. Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets.
  17. 100 years of the Warburg effect: a historical perspective.
  18. Liposomal oxaliplatin prodrugs loaded with metformin potentiate immunotherapy for colorectal cancer.
  19. Cellulose nanocrystals based delivery vehicles for anticancer agent curcumin.
  20. The molecular mechanisms of ferroptosis and its role in glioma progression and treatment.
  21. Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers.
  22. Lipid metabolism in pancreatic cancer: emerging roles and potential targets.
  23. The effectiveness of whey proteins in prevention and treatment of cancer: a review.
  24. Platycodon grandiflorum (Jacq.) A. DC.: A review of phytochemistry, pharmacology, toxicology and traditional use.
  25. Functionalized-DNA nanostructures as potential targeted drug delivery systems for cancer therapy.
  26. A comprehensive review on methotrexate containing nanoparticles; an appropriate tool for cancer treatment.
  27. Apigenin in cancer therapy; prevention of genomic instability and anti-cancer mechanisms.
  28. Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death autophagy/mitophagy.
  29. Hypoxia-Activated PEGylated Paclitaxel Prodrug Nanoparticles for Potentiated Chemotherapy.
  30. Application of MXene in the diagnosis and treatment of breast cancer: A critical overview.
  31. Advances in polysaccharides of natural source of the anti-Alzheimer's disease effect and mechanism.
  32. A review on the traditional uses, phytochemistry, and pharmacology of the genus veronicastrum (Plantaginaceae).
  33. Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer.
  34. Membrane-Wrapped Nanoparticles for Enhanced Chemotherapy of Acute Myeloid Leukemia.
  35. "Carrier-drug" layer-by-layer hybrid assembly of biocompatible polydopamine nanoparticles to amplify photo-chemotherapy.
  36. Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments.
  37. Combined Chemo-Immuno-Photothermal Therapy for Effective Cancer Treatment via an All-in-One and One-for-All Nanoplatform.
  38. Comparative Study of Nano-liposome and Nano-niosome for Delivery of Achillea Millefolium Essential Oils: Development, Optimization, Characterization and Their Cytotoxicity Effects on Cancer Cell Line and Antibacterial Activity.
  39. Salinomycin-Loaded High-Density Lipoprotein Exerts Promising Anti-Ovarian Cancer Effects by Inhibiting Epithelial-Mesenchymal Transition.
  40. A Nanozyme-immobilized Hydrogel with Endogenous ROS-scavenging and Oxygen Generation Abilities for Significantly Promoting Oxidative Diabetic Wound Healing.
  41. Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers.
  42. Anxiolytic and antidepressive potentials of rosmarinic acid: A review with a focus on antioxidant and anti-inflammatory effects.
  43. Lipopeptide liposomes-loaded hydrogel for multistage transdermal chemotherapy of melanoma.
  44. Micro-Nanocarriers Based Drug Delivery Technology for Blood-Brain Barrier Crossing and Brain Tumor Targeting Therapy.
  45. Advances in anti-cancer effects and underlying mechanisms of marine algae polysaccharides.
  46. Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy.
  47. Combination Treatment Using Pyruvate Kinase M2 Inhibitors for the Sensitization of High Density Triple-negative Breast Cancer Cells.
  48. Metabolic reprogramming: A novel metabolic model for pulmonary hypertension.
  49. A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
  50. Recent nanotechnology advancements to treat multidrug-resistance pancreatic cancer: Pre-clinical and clinical overview.
  51. Advances in Engineered Biomaterials Targeting Angiogenesis and Cell Proliferation for Cancer Therapy.
  52. Octenyl-succinylated inulins for the delivery of hydrophobic drug.
  53. Nanozyme-laden intelligent macrophage EXPRESS amplifying cancer photothermal-starvation therapy by responsive stimulation.
  54. Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines.
  55. Activity-Based Photosensitizer to Reverse Hypoxia and Oxidative Resistance for Tumor Photodynamic Eradication.
  56. Functional gelatin hydrogel scaffold with degraded-release of glutamine to enhance cellular energy metabolism for cartilage repair.
  57. Comparison of the effect of vitamin C and selenium nanoparticles on gentamicin-induced renal impairment in male rats: A biochemical, molecular and histological study.
  58. Kaempferol and atherosclerosis: From mechanism to medicine.
  59. Loss of MLL induces epigenetic dysregulation of Rasgrf1 to attenuate Kras-driven lung tumorigenesis.
  60. Curcumin encapsulated polylactic acid nanoparticles embedded in alginate/gelatin bioinks for in situ immunoregulation: Characterization and biological assessment.
  61. Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo.
  62. Basil seed gum promotes the electrospinnability of WPI for co-encapsulation of ZnO nanoparticles and curcumin.
  63. The combination of in situ photodynamic promotion and ion-interference to improve the efficacy of cancer therapy.
  64. Diet and the microbiota-gut-brain-axis: a primer for clinical nutrition.
  65. Chitosan-based scaffolds as drug delivery systems in bone tissue engineering.
  66. A Comprehensive Insight on Recent Advancements in Self Emulsifying Drug Delivery Systems.
  67. Bovine Lactoferrin Induces Cell Death in Human Prostate Cancer Cells.
  68. Naringenin: A prospective therapeutic agent for Alzheimer's and Parkinson's disease.
  69. System Xc -/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy.
  70. Effects of curcumin on low-density lipoprotein oxidation: From experimental studies to clinical practice.
  71. Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy.
  72. Tumor-treating fields in combination with sorafenib curtails the growth of colorectal carcinoma by inactivating AKT/STAT3 signaling.
  73. Exploration of metabolic responses towards hypoxia mimetic DMOG in cancer cells by using untargeted metabolomics.
  74. Capsicum fruits as functional ingredients with antimicrobial activity: an emphasis on mechanisms of action.
  75. An Insight into Diverse Activities and Targets of Flavonoids.
  76. Recent advances and limitations of mTOR inhibitors in the treatment of cancer.
  77. Bufalin for an innovative therapeutic approach against cancer.
  78. Subtype and site specific-induced metabolic vulnerabilities in prostate cancer.
  79. A simulation of parental and glycolytic tumor phenotype competition predicts observed responses to pH changes and increased glycolysis after anti-VEGF therapy.
  80. Darwinian Repurposing of Molecular Motifs in an Evolving Redox Environment and Its Biomedical Implications.
  81. Nanocarriers Based Ocular Therapeutics: Updates, Challenges and Future Prospectives.
  82. Discovery and Activity Evaluation of the Inhibitory Effect of Four Kinds Traditional Chinese Medicine Extracts on the CYP3A4 Enzyme.
  83. Recent advances in engineered polymeric materials for efficient photodynamic inactivation of bacterial pathogens.
  84. Single-layer and double-layer zein-gum arabic nanoencapsulations: Preparation, structural characterization, thermal properties, and controlled release in the gastrointestinal tract.
  85. Peptide-based assembled nanostructures that can direct cellular responses.
  86. Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis.
  87. Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets.
  88. Fusion of Tumor-Derived Exosomes with Long-Circulating and pH-Sensitive Liposomes Loaded with Doxorubicin for the Treatment of Breast Cancer.
  89. Hepatocyte-targeting and tumor microenvironment-responsive liposomes for enhanced anti-hepatocarcinoma efficacy.
  90. Regulation of dietary polyphenols on cancer cell pyroptosis and the tumor immune microenvironment.
  91. Gankyrin and TIGAR cooperatively accelerate glucose metabolism toward PPP and TCA cycle in hepatocellular carcinoma.
  92. Review of phytomedicine, phytochemistry, ethnopharmacology, toxicology, and pharmacological activities of Cymbopogon genus.
  93. Nanophytosomes of Hesperidin and of Hesperetin: Preparation, characterization and in vivo evaluation.
  94. Cancer cell membrane-wrapped nanoparticles for cancer immunotherapy: A review of current developments.
  95. Chemosensitizing Effect and Efficacy of Wilforlide A in Combination With Docetaxel in Drug-resistant Prostate Cancer.
  96. Levistilide a Induces Ferroptosis by Activating the Nrf2/HO-1 Signaling Pathway in Breast Cancer Cells.
  97. Is Vitamin D Important in Anxiety or Depression? What Is the Truth?
  98. Pharmacological features, health benefits and clinical implications of honokiol.
  99. The potential of oxygen and nitrogen species-regulating drug delivery systems in medicine.
  100. Editorial: Chemosensitizing effect of natural products against cancers: Applications in enhancing chemotherapy and immunotherapy.
  101. Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine.
  102. pH-responsive glycodendrimer as a new active targeting agent for doxorubicin delivery.
  103. Cactaceae plants as sources of active bioavailable phytochemicals.
  104. Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies.
  105. Waxy maize starch nanoparticles incorporated tea polyphenols to stabilize Pickering emulsion and inhibit oil oxidation.
  106. Exosomes: A novel insight into traditional Chinese medicine.
  107. The evolving view of thermogenic fat and its implications in cancer and metabolic diseases.
  108. Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer.
  109. Combination of Peglated-H1/HGFK1 Nanoparticles and TAE in the Treatment of Hepatocellular Carcinoma.
  110. Medicinal prospects of targeting tyrosinase: A feature review.
  111. Computer-Aided Design of Lasso-like Self-Assembling Anticancer Peptides with Multiple Functions for Targeted Self-Delivery and Cancer Treatments.
  112. Potential role of tea drinking in preventing hyperuricaemia in rats: biochemical and molecular evidence.
  113. Self-assembly hydrogels of therapeutic agents for local drug delivery.
  114. Deciphering the therapeutical potentials of rosmarinic acid.
  115. Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms.
  116. In situ forming oxygen/ROS-responsive niche-like hydrogel enabling gelation-triggered chemotherapy and inhibition of metastasis.
  117. Bimetallic silver-platinum (AgPt) nanoparticles and chitosan fabricated cotton gauze for enhanced antimicrobial and wound healing applications.
  118. The genus Ageratina (Asteraceae) in America: An insight into its chemistry, and pharmacological potential.
  119. Spicy Food and Chili Peppers and Multiple Health Outcomes: Umbrella Review.
  120. Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche.
  121. Enhancing Metformin Effects by Adding Gut Microbiota Modulators to Ameliorate the Metabolic Status of Obese, Insulin-Resistant Hosts.
  122. Recent advances of IDH1 mutant inhibitor in cancer therapy.
  123. Berberine for Gastric Cancer Prevention and Treatment: Multi-step Actions on the Correa's Cascade Underlie its Therapeutic Effects.
  124. Emerging ROS-Modulating Technologies for Augmentation of the Wound Healing Process.
  125. Carvacrol encapsulation into nanoparticles produced from chia and flaxseed mucilage: Characterization, stability and antimicrobial activity against Salmonella and Listeria monocytogenes.
  126. Targeted delivery of Chinese herb pair-based berberine/tannin acid self-assemblies for the treatment of ulcerative colitis.
  127. Vitamin D and Gut Health.
  128. Curcumin nanoparticles: the topical antimycotic suspension treating oral candidiasis.
  129. Nanodelivery of cGAS-STING activators for tumor immunotherapy.
  130. Exploring potential antidiabetic and anti-inflammatory flavonoids from Euphorbia humifusa with an integrated strategy.
  131. Natural polyphenol self-assembled pH-responsive nanoparticles loaded into reversible hydrogel to inhibit oral bacterial activity.
  132. Flavonols and Flavones as Potential anti-Inflammatory, Antioxidant, and Antibacterial Compounds.
  133. Drug affinity-responsive target stability unveils filamins as biological targets for artemetin, an anti-cancer flavonoid.
  134. Photodynamic therapy for treating infected skin wounds: A systematic review and meta-analysis from randomized clinical trials.
  135. Research progress on the pharmacological effects of matrine.
  136. Diosgenin: An ingress towards solving puzzle for diabetes treatment.
  137. Stealth nanoparticles in oncology: Facing the PEG dilemma.
  138. Dietary Phytochemical Index and the Risk of Breast Cancer: A Case-Control Study.
  139. Insulin fibrillation: Strategies for inhibition.
  140. Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies.
  141. Targeting cancer cachexia: Molecular mechanisms and clinical study.
  142. Overcoming the blood-brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches.
  143. Combination treatment with cyclosporin A and arsenic trioxide induce synergistic cell death via non-apoptotic pathway in uterine cervical cancer cells.
  144. Metabolic profiling of induced acute pancreatitis and pancreatic cancer progression in a mutant Kras mouse model.
  145. A self-healing hydrogel based on oxidized microcrystalline cellulose and carboxymethyl chitosan as wound dressing material.
  146. Chrysin inhibits the cell viability, induces apoptosis and modulates expression of genes related to epigenetic events in bladder cancer cells.
  147. Liposomal formulations for treating lysosomal storage disorders.
  148. Dual-functional polyetheretherketone surface with programmed sequential drug release coating.
  149. Diet fuelling inflammatory bowel diseases: preclinical and clinical concepts.
  150. Asian herbal medicine and chronic urticaria: which are the therapeutic perspectives?
  151. Onion (Allium cepa L.) peel: A review on the extraction of bioactive compounds, its antioxidant potential, and its application as a functional food ingredient.
  152. [Time-restricted eating as a novel strategy for treatment of obesity and it's comorbid conditions].
  153. Dietary phytochemicals alter hypopharyngeal gland size in honey bee (Apis mellifera L.) workers.
  154. Metabolic reprogramming in the OPA1-deficient cells.
  155. Bioactive-loaded nanodelivery systems for the feed and drugs of livestock; purposes, techniques and applications.
  156. Disulfiram in glioma: Literature review of drug repurposing.
  157. Ancient Wheats as Promising Nutraceuticals for the Prevention of Chronic and Degenerative Diseases.
  158. Exosomes to control glioblastoma multiforme: Investigating the effects of mesenchymal stem cell-derived exosomes on C6 cells in vitro.
  159. Metabolic reprogramming and alteration of the redox state in hyper-productive MDCK cells for influenza a virus production.
  160. Current progress of ferroptosis study in ovarian cancer.
  161. Adipocyte mesenchymal transition contributes to mammary tumor progression.
  162. How zoledronic acid improves osteoporosis by acting on osteoclasts.
  163. Natural Alternatives and the Common Cold and Influenza.
  164. ROS generation strategy based on biomimetic nanosheets by self-assembly of nanozymes.
  165. Is Ramadan fasting associated with low scores of Healthy Eating Index?
  166. Natural Food for Sarcopenia: A Narrative Review.
  1. Front Bioeng Biotechnol. 2022 ;10 990145
    Hyaluronic acid-based nano drug delivery systems for breast cancer treatment: Recent advances.
    Yufeng Jia, Siwen Chen, Chenyu Wang, Tao Sun, Liqun Yang.
      Breast cancer (BC) is the most common malignancy among females worldwide, and high resistance to drugs and metastasis rates are the leading causes of death in BC patients. Releasing anti-cancer drugs precisely to the tumor site can improve the efficacy and reduce the side effects on the body. Natural polymers are attracting extensive interest as drug carriers in treating breast cancer. Hyaluronic acid (HA) is a natural polysaccharide with excellent biocompatibility, biodegradability, and non-immunogenicity and is a significant component of the extracellular matrix. The CD44 receptor of HA is overexpressed in breast cancer cells and can be targeted to breast tumors. Therefore, many researchers have developed nano drug delivery systems (NDDS) based on the CD44 receptor tumor-targeting properties of HA. This review examines the application of HA in NDDSs for breast cancer in recent years. Based on the structural composition of NDDSs, they are divided into HA NDDSs, Modified HA NDDSs, and HA hybrid NDDSs.
    Keywords:  anticancer drugs; breast cancer; drug delivery system (DDS); hyaluronic acid; nanoparticles
    DOI:  https://doi.org/10.3389/fbioe.2022.990145
  2. Asian J Pharm Sci. 2022 Jul;17(4): 475-490
    Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review.
    Ka Hong Wong, Donglin Yang, Shanshan Chen, Chengwei He, Meiwan Chen.
      Dihydroartemisinin (DHA), a first-line antimalarial drug, has demonstrated great anticancer effects in many types of tumors, including liver cancer, glioblastoma, and pancreatic cancer. Due to its abilities to induce programmed cell death (PCD; apoptosis, autophagy and ferroptosis), inhibit tumor metastasis and angiogenesis, and modulate the tumor microenvironment, DHA could become an antineoplastic agent in the foreseeable future. However, the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages, including poor stability, low aqueous solubility, and short plasma half-life. To overcome these drawbacks, nanoscale drug delivery systems (NDDSs), such as polymeric nanoparticles (NPs), liposomes, and metal-organic frameworks (MOFs), have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy. Based on the beneficial properties of NDDSs, including enhanced stability and solubility of the drug, prolonged circulation time and selective accumulation in tumors, the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA. This review first summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines, aiming to provide inspiration for further application of DHA as an anticancer drug.
    Keywords:  Chemodynamic therapy; Dihydroartemisinin; Ferroptosis; Nano-drug delivery; Photodynamic therapy; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.ajps.2022.04.005
  3. RSC Adv. 2022 Aug 10. 12(35): 22722-22747
    Application of nanosonosensitizer materials in cancer sono-dynamic therapy.
    Chaotao Hu, Biao Hou, Songlin Xie.
      Sonodynamic therapy (SDT) is a novel non-invasive treatment for cancer combining low-intensity ultrasound and sonosensitizers. SDT activates sonosensitizers through ultrasound, releasing energy and generating reactive oxygen species to kill tumor cells. Compared with traditional photodynamic therapy (PDT), SDT is a promising anti-cancer therapy with the advantages of better targeting, deeper tissue penetration, and higher focusing ability. With the development and broad application of nanomaterials, novel sonosensitizers with tumor-targeting specificity can deliver to deep tumors and enhance the tumor microenvironment. In this review, we first review the mechanisms of sonodynamic therapy. In addition, we also focus on the current types of sonosensitizers and the latest design strategies of nanomaterials in sonosensitizers. Finally, we summarize the combined strategy of sonodynamic therapy.
    DOI:  https://doi.org/10.1039/d2ra03786f
  4. Front Oncol. 2022 ;12 982751
    Drosophila as a toolkit to tackle cancer and its metabolism.
    Hui Jiang, Taku Kimura, Han Hai, Ryodai Yamamura, Masahiro Sonoshita.
      Cancer is one of the most severe health problems worldwide accounting for the second leading cause of death. Studies have indicated that cancers utilize different metabolic systems as compared with normal cells to produce extra energy and substances required for their survival, which contributes to tumor formation and progression. Recently, the fruit fly Drosophila has been attracting significant attention as a whole-body model for elucidating the cancer mechanisms including metabolism. This tiny organism offers a valuable toolkit with various advantages such as high genetic conservation and similar drug response to mammals. In this review, we introduce flies modeling for cancer patient genotypes which have pinpointed novel therapeutic targets and drug candidates in the salivary gland, thyroid, colon, lung, and brain. Furthermore, we introduce fly models for metabolic diseases such as diabetes mellitus, obesity, and cachexia. Diabetes mellitus and obesity are widely acknowledged risk factors for cancer, while cachexia is a cancer-related metabolic condition. In addition, we specifically focus on two cancer metabolic alterations: the Warburg effect and redox metabolism. Indeed, flies proved useful to reveal the relationship between these metabolic changes and cancer. Such accumulating achievements indicate that Drosophila offers an efficient platform to clarify the mechanisms of cancer as a systemic disease.
    Keywords:  Drosophila; cancer; drug discovery; genetics; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fonc.2022.982751
  5. Nanomedicine (Lond). 2022 Sep 12. 0
    Synergistic chemo-photothermal and ferroptosis therapy of polydopamine nanoparticles for esophageal cancer.
    Yukun Chen, Mingliang Su, Lijun Jia, Zhanxia Zhang.
      Aim: To develop synergistic chemo-photothermal and ferroptosis therapy nanoparticles to improve the efficacy of treatment for esophageal cancer. Materials & methods: Fe3O4@PDA-HCPT nanoparticles (NPs) were constructed and characterized. Their synergistic antitumor effects were evaluated in EC1 and EC109 esophageal cancer cells as well as in esophageal cancer-bearing mice. Results: In vitro and in vivo experiments showed that Fe3O4@PDA-HCPT NPs exhibited significant tumor inhibition and excellent diagnostic properties. The killing ability of tumor cells was significantly enhanced after irradiation. Conclusion: Synergistic application of the three therapies effectively inhibited tumor growth and exhibited potent antitumor effects, providing strong support for developing nanoparticles with synergistic antitumor effects of multiple therapies.
    Keywords:  10-hydroxycamptothecin; Fe3O4; chemo-photothermal therapy; ferroptosis; polydopamine
    DOI:  https://doi.org/10.2217/nnm-2022-0064
  6. Front Oncol. 2022 ;12 979154
    Tumor acidity: From hallmark of cancer to target of treatment.
    Alexey Bogdanov, Andrey Bogdanov, Viacheslav Chubenko, Nikita Volkov, Fedor Moiseenko, Vladimir Moiseyenko.
      Tumor acidity is one of the cancer hallmarks and is associated with metabolic reprogramming and the use of glycolysis, which results in a high intracellular lactic acid concentration. Cancer cells avoid acid stress major by the activation and expression of proton and lactate transporters and exchangers and have an inverted pH gradient (extracellular and intracellular pHs are acid and alkaline, respectively). The shift in the tumor acid-base balance promotes proliferation, apoptosis avoidance, invasiveness, metastatic potential, aggressiveness, immune evasion, and treatment resistance. For example, weak-base chemotherapeutic agents may have a substantially reduced cellular uptake capacity due to "ion trapping". Lactic acid negatively affects the functions of activated effector T cells, stimulates regulatory T cells, and promotes them to express programmed cell death receptor 1. On the other hand, the inversion of pH gradient could be a cancer weakness that will allow the development of new promising therapies, such as tumor-targeted pH-sensitive antibodies and pH-responsible nanoparticle conjugates with anticancer drugs. The regulation of tumor pH levels by pharmacological inhibition of pH-responsible proteins (monocarboxylate transporters, H+-ATPase, etc.) and lactate dehydrogenase A is also a promising anticancer strategy. Another idea is the oral or parenteral use of buffer systems, such as sodium bicarbonate, to neutralize tumor acidity. Buffering therapy does not counteract standard treatment methods and can be used in combination to increase effectiveness. However, the mechanisms of the anticancer effect of buffering therapy are still unclear, and more research is needed. We have attempted to summarize the basic knowledge about tumor acidity.
    Keywords:  acidity; cancer; hallmark; metabolism; treatment target
    DOI:  https://doi.org/10.3389/fonc.2022.979154
  7. Adv Drug Deliv Rev. 2022 Sep 10. pii: S0169-409X(22)00415-X. [Epub ahead of print] 114525
    Challenging the fundamental conjectures in nanoparticle drug delivery for chemotherapy treatment of solid cancers.
    Juanjuan Yang, Xiaojin Wang, Bingshun Wang, Kinam Park, Karen Wooley, Shiyi Zhang.
      Nanomedicines for cancer treatment have been studied extensively over the last few decades. Yet, only five anticancer nanomedicines have received approvals from the United States Food and Drug Administration (FDA) for treating solid tumors. This drastic mismatch between effort and return calls into question the basic understanding of this field. Various viewpoints on nanomedicines have been presented regarding their potentials and inefficiencies. However, the underlying logics of nanomedicine research and its inadequate translation to the successful use in the clinic have not been thoroughly examined. Tumor-targeted drug delivery was used to understand the shortfalls of the nanomedicine field in general. The concept of tumor-targeted drug delivery by nanomedicine has been based on two conjectures: (i) increased drug delivery to tumors provides better efficacy, and (ii) decreased drug delivery to healthy organs results in fewer side effects. The clinical evidence gathered from the literature indicates that nanomedicines bearing classic chemotherapeutic drugs, such as Dox, cis-Pt, CPT and PTX, have already reached the maximum drug delivery limit to solid tumors in humans. Still, the anticancer efficacy and safety remain unchanged despite the increased tumor accumulation. Thus, it is understandable to see few nanomedicine-based formulations approved by the FDA. The examination of FDA-approved nanomedicine formulations indicates that their approvals were not based on the improved delivery to tumors but mostly on changes in dose-limiting toxicity unique to each drug. This comprehensive analysis of the fundamentals of anticancer nanomedicines is designed to provide an accurate picture of the field's underlying false conjectures, hopefully, thereby accelerating the future clinical translations of many formulations under research.
    Keywords:  Conjectures used in nanomedicine; FDA approval; clinical products; efficacy; toxicity; translation
    DOI:  https://doi.org/10.1016/j.addr.2022.114525
  8. Int J Biol Macromol. 2022 Sep 08. pii: S0141-8130(22)01928-6. [Epub ahead of print]
    Role of lignin-based nanoparticles in anticancer drug delivery and bioimaging: An up-to-date review.
    Dana A Ali, Mohammed M Mehanna.
      Lignin, an aromatic biopolymer, is the second most abundant naturally occurring one after cellulose that has drawn a great deal of interest over the years for their potential uses owing to the presence of high content of phenolic compounds, ecofriendly feature and cost-efficiency in comparison to the synthetic polymers. Nevertheless, with the intention of advancing their development, several efforts have been performed in the direction of utilizing lignin on the nanoscale due to its inimitable properties. The notable absorption capacity, fluorescence emission, biodegradability and non-toxicity of lignin nanoparticles permit its appropriateness as a vehicle for drugs and as a bioimaging material. Moreover, lignin nanoparticles have shown plausible therapeutic effects, such as anticancer, antimicrobial, and antioxidant. The current review sheds light on the recent development in the formulation and anticancer applications of lignin nanoparticles as a drug carrier and diagnostic tool. The surface properties of the nanomaterial affect the end product characteristics, hence, factors namely; lignin source, isolation technique, purification and quantitation methods, are discussed in this review. This study represents original work that has not been published elsewhere and that has not been submitted simultaneously for publication elsewhere. The manuscript has been read, revised, and approved by the authors.
    Keywords:  Anticancer; Antioxidant; Bioimaging; Drug delivery; Lignin; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.007
  9. J Nanobiotechnology. 2022 Sep 15. 20(1): 410
    Hemin-incorporating DNA nanozyme enabling catalytic oxygenation and GSH depletion for enhanced photodynamic therapy and synergistic tumor ferroptosis.
    Xiaoxiong Xiao, Min Chen, Yuchen Zhang, Liang Li, Ying Peng, Wenhu Zhou, Junyu Li.
      Photodynamic therapy (PDT) has emerged as a promising tumor treatment method via light-triggered generation of reactive oxygen species (ROS) to kill tumor cells. However, the efficacy of PDT is usually restricted by several biological limitations, including hypoxia, excess glutathione (GSH) neutralization, as well as tumor resistance. To tackle these issues, herein we developed a new kind of DNA nanozyme to realize enhanced PDT and synergistic tumor ferroptosis. The DNA nanozyme was constructed via rolling circle amplification, which contained repeat AS1411 G quadruplex (G4) units to form multiple G4/hemin DNAzymes with catalase-mimic activity. Both hemin, an iron-containing porphyrin cofactor, and chlorine e6 (Ce6), a photosensitizer, were facilely inserted into G4 structure with high efficiency, achieving in-situ catalytic oxygenation and photodynamic ROS production. Compared to other self-oxygen-supplying tools, such DNA nanozyme is advantageous for high biological stability and compatibility. Moreover, the nanostructure could achieve tumor cells targeting internalization and intranuclear transport of Ce6 by virtue of specific nucleolin binding of AS1411. The nanozyme could catalyze the decomposition of intracellular H2O2 into oxygen for hypoxia relief as evidenced by the suppression of hypoxia-inducible factor-1α (HIF-1α), and moreover, GSH depletion and cell ferroptosis were also achieved for synergistic tumor therapy. Upon intravenous injection, the nanostructure could effectively accumulate into tumor, and impose multi-modal tumor therapy with excellent biocompatibility. Therefore, by integrating the capabilities of O2 generation and GSH depletion, such DNA nanozyme is a promising nanoplatform for tumor PDT/ferroptosis combination therapy.
    Keywords:  Aptamer; Catalysis; DNAzyme; Nanomedicine; Phototherapy; Targeting; Tumor hypoxia
    DOI:  https://doi.org/10.1186/s12951-022-01617-0
  10. Int J Nanomedicine. 2022 ;17 3933-3966
    Current Advances in Chitosan Nanoparticles Based Oral Drug Delivery for Colorectal Cancer Treatment.
    Hazem Choukaife, Salma Seyam, Batoul Alallam, Abd Almonem Doolaanea, Mulham Alfatama.
      As per the WHO, colorectal cancer (CRC) caused around 935,173 deaths worldwide in 2020 in both sexes and at all ages. The available anticancer therapies including chemotherapy, radiotherapy and anticancer drugs are all associated with limited therapeutic efficacy, adverse effects and low chances. This has urged to emerge several novel therapeutic agents as potential therapies for CRC including synthetic and natural materials. Orally administrable and targeted drug delivery systems are attractive strategies for CRC therapy as they minimize the side effects, enhance the efficacy of anticancer drugs. Nevertheless, oral drug delivery till today faces several challenges like poor drug solubility, stability, and permeability. Various oral nano-based approaches and targeted drug delivery systems have been developed recently, as a result of the ability of nanoparticles to control the release of the encapsulant, drug targeting and reduce the number of dosages administered. The unique physicochemical properties of chitosan polymer assist to overcome oral drug delivery barriers and target the colon tumour cells. Chitosan-based nanocarriers offered additional improvements by enhancing the stability, targeting and bioavailability of several anti-colorectal cancer agents. Modified chitosan derivatives also facilitated CRC targeting through strengthening the protection of encapsulant against acidic and enzyme degradation of gastrointestinal track (GIT). This review aims to provide an overview of CRC pathology, therapy and the barriers against oral drug delivery. It also emphasizes the role of nanotechnology in oral drug targeted delivery system and the growing interest towards chitosan and its derivatives. The present review summarizes the relevant works to date that have studied the potential applications of chitosan-based nanocarrier towards CRC treatment.
    Keywords:  chitosan; colorectal cancer; drug targeting; nanocarriers; nanotechnology; oral delivery
    DOI:  https://doi.org/10.2147/IJN.S375229
  11. Acta Biomater. 2022 Sep 12. pii: S1742-7061(22)00574-8. [Epub ahead of print]
    Polydopamine-doped supramolecular chiral hydrogels for postoperative tumor recurrence inhibition and simultaneously enhanced wound repair.
    Xueqian Wang, Beibei Wu, Yaqian Zhang, Xiaoqiu Dou, Changli Zhao, Chuanliang Feng.
      Cancer recurrence remains a major challenge after primary tumor excision, and the inflammation of tumor-caused wounds can hinder wound healing and potentially promote tumor growth. Herein, a chiral L-phenylalanine-based (LPFEG) supramolecular hydrogel system encapsulated with polydopamine nanoparticles (PDA-NPs) has been developed in order to prevent tumor relapse after surgery and promote wound repair. PDA-NPs allow for near-infrared (NIR) light-triggered photothermal therapy, especially, it can scavenge free radicals in the surgical wound. LPFEG can mimic native extracellular matrix (ECM) structure to create a chiral microenvironment that enhances fibroblast adhesion, proliferation, and new tissue regeneration. With anticancer drug doxorubicin (DOX) loaded into the composite hydrogel, the antitumor effect is significantly enhanced by the integration of chemo-photothermal therapy both in vitro and in vivo. The PDA-based chiral supramolecular composite hydrogel as an effective postoperative adjuvant possesses promising applicable prospects in inhibiting tumor recurrence and accelerating wound healing after operation. STATEMENT OF SIGNIFICANCE: After primary tumor excision, cancer recurrence remains a severe concern, and the inflammation induced by tumor-related wounds can delay wound healing. Herein, we designed a chiral L-phenylalanine-based (LPFEG) supramolecular hydrogel platform that was co-assembled with polydopamine nanoparticles (PDA-NPs). Among them, PDA-NPs can offer photothermal therapy and scavenge free radicals in surgical wounds. LPFEG can create a chiral microenvironment that promotes fibroblast adhesion, proliferation, and new tissue regeneration. Furthermore, with anticancer drug doxorubicin (DOX) loaded into the composite hydrogel, the antitumor effect is considerably boosted. Therefore, the PDA-based chiral supramolecular hydrogel shows high application potential as a postoperative adjuvant in preventing tumor relapse as well as accelerating wound healing after surgery.
    Keywords:  Chirality; Hydrogel; Tumor recurrence; Wound repair
    DOI:  https://doi.org/10.1016/j.actbio.2022.09.012
  12. J Nanobiotechnology. 2022 Sep 15. 20(1): 414
    Targeting therapy and tumor microenvironment remodeling of triple-negative breast cancer by ginsenoside Rg3 based liposomes.
    Jiaxuan Xia, Shuya Zhang, Ru Zhang, Anni Wang, Ying Zhu, Meichen Dong, Shaojie Ma, Chao Hong, Shengyao Liu, Dan Wang, Jianxin Wang.
      The chemotherapy effect of docetaxel (DTX) against triple-negative breast cancer (TNBC) remains mediocre and limited when encapsulated in conventional cholesterol liposomes, mainly ascribed to poor penetration and immunosuppressive tumor microenvironment (TME) caused by tumor stroma cells, especially cancer-associated fibroblasts (CAFs). Many studies have attempted to address these problems but trapped into the common dilemma of excessively complicated formulation strategies at the expense of druggability as well as clinical translational feasibility. To better address the discrepancy, ginsenoside Rg3 was utilized to substitute cholesterol to develop a multifunctional DTX-loaded Rg3 liposome (Rg3-Lp/DTX). The obtained Rg3-Lp/DTX was proved to be preferentially uptake by 4T1 cells and accumulate more at tumor site via the interaction between the glycosyl moiety of Rg3 exposed on liposome surface and glucose transporter1 (Glut1) overexpressed on tumor cells. After reaching tumor site, Rg3 was shown to reverse the activated CAFs to the resting stage and attenuate the dense stroma barrier by suppressing secretion of TGF-β from tumor cells and regulating TGF-β/Smad signaling. Therefore, reduced levels of CAFs and collagens were found in TME after incorporation of Rg3, inducing enhanced penetration of Rg3-Lp/DTX in the tumor and reversed immune system which can detect and neutralize tumor cells. Compared with wooden cholesterol liposomes, the smart and versatile Rg3-Lp/DTX could significantly improve the anti-tumor effect of DTX, providing a promising approach for TNBC therapy with excellent therapeutic efficacy and simple preparation process.
    Keywords:  Cancer-associated fibroblasts; Docetaxel; Ginsenoside Rg3; Liposomes; Stroma cells; Triple-negative breast cancer; Tumor active targeting; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12951-022-01623-2
  13. Asian J Pharm Sci. 2022 Jul;17(4): 571-582
    Nucleobase-crosslinked poly(2-oxazoline) nanoparticles as paclitaxel carriers with enhanced stability and ultra-high drug loading capacity for breast cancer therapy.
    Si Dong, Sheng Ma, Hongyu Chen, Zhaohui Tang, Wantong Song, Mingxiao Deng.
      Poly(2-oxazoline) (POx) has been regarded as a potential candidate for drug delivery carrier to meet the challenges of nanomedicine clinical translation, due to its excellent biocompatibility and self-assembly properties. The drug loading capacity and stability of amphiphilic POxs as drug nanocarriers, however, tend to be insufficient. Herein, we report a strategy to prepare nucleobase-crosslinked POx nanoparticles (NPs) with enhanced stability and ultra-high paclitaxel (PTX) loading capacity for breast cancer therapy. An amphiphilic amine-functionalized POx (PMBEOx-NH2) was firstly prepared through a click reaction between cysteamines and vinyl groups in poly(2-methyl-2-oxazoline)-block-poly (2‑butyl‑2-oxazoline-co-2-butenyl-2-oxazoline) (PMBEOx). Complementary nucleobase-pairs adenine (A) and uracil (U) were subsequently conjugated to PMBEOx-NH2 to give functional POxs (POxA and POxU), respectively. Due to the nucleobase interactions formed between A and U, NPs formed by POxA and POxU at a molar ratio of 1:1 displayed ultrahigh PTX loading capacity (38.2%, PTX/POxA@U), excellent stability, and reduced particle size compared to the uncross-linked PTX-loaded NPs (PTX/PMBEOx). Besides the prolonged blood circulation and enhanced tumor accumulation, the smaller PTX/POxA@U NPs also have better tumor penetration ability compared with PTX/PMBEOx, thus leading to a higher tumor suppression rate in two murine breast cancer models (E0711 and 4T1). These results proved that the therapeutic effect of chemotherapeutic drugs could be improved remarkably through a reasonable optimization of nanocarriers.
    Keywords:  Murine breast cancer; Nanoparticles; Nucleobase-crosslinked; Paclitaxel; Poly(2-oxaozoline)
    DOI:  https://doi.org/10.1016/j.ajps.2022.04.006
  14. J Control Release. 2022 Sep 13. pii: S0168-3659(22)00587-9. [Epub ahead of print]350 829-840
    Research progress on tumor hypoxia-associative nanomedicine.
    Xiao-Xue Xu, Si-Yi Chen, Ning-Bo Yi, Xin Li, Si-Lin Chen, Zhixin Lei, Dong-Bing Cheng, Taolei Sun.
      Hypoxia at the solid tumor site is generally related to the unrestricted proliferation and metabolism of cancerous cells, which can cause tumor metastasis and aggravate tumor progression. Besides, hypoxia plays a substantial role in tumor treatment, and it is one of the main reasons that malignant tumors are difficult to cure and have a poor prognosis. On account of the tumor specific hypoxic environment, many hypoxia-associative nanomedicine have been proposed for tumor treatment. Considering the enhanced targeting effect, designing hypoxia-associative nanomedicine can not only minimize the adverse effects of drugs on normal tissues, but also achieve targeted therapy at the lesion site. Mostly, there can be three strategies for the treatment of hypoxic tumor, including improvement of hypoxic environment, hypoxia responsive drug release and hypoxia activated prodrug. The review describes the design principle and applications of tumor hypoxia-associative nanomedicine in recent years, and also explores its development trends in solid tumor treatment. Moreover, this review presents the current limitations of tumor hypoxia-associative nanomedicine in chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy and immunotherapy, which may provide a reference for clinic translation of tumor hypoxia-associative nanomedicine.
    Keywords:  Hypoxia modulation; Hypoxia responsiveness; Nanomedicine; Tumor hypoxia
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.003
  15. Front Pharmacol. 2022 ;13 932098
    Photodynamic therapy of lung cancer, where are we?
    Anine Crous, Heidi Abrahamse.
      Lung cancer remains the leading threat of death globally, killing more people than colon, breast, and prostate cancers combined. Novel lung cancer treatments are being researched because of the ineffectiveness of conventional cancer treatments and the failure of remission. Photodynamic therapy (PDT), a cancer treatment method that is still underutilized, is a sophisticated cancer treatment that shows selective destruction of malignant cells via reactive oxygen species production. PDT has been extensively studied in vitro and clinically. Various PDT strategies have been shown to be effective in the treatment of lung cancer. PDT has been shown in clinical trials to considerably enhance the quality of life and survival in individuals with incurable malignancies. Furthermore, PDT, in conjunction with the use of nanoparticles, is currently being researched for use as an effective cancer treatment, with promising results. PDT and the new avenue of nanoPDT, which are novel treatment options for lung cancer with such promising results, should be tested in clinical trials to determine their efficacy and side effects. In this review, we examine the status and future potentials of nanoPDT in lung cancer treatment.
    Keywords:  lung cancer; nanoPDT; nanomaterials; nanomedicine; nanotechnology; photodynamic therapy; photosensitizer
    DOI:  https://doi.org/10.3389/fphar.2022.932098
  16. Transl Oncol. 2022 Sep 13. pii: S1936-5233(22)00193-0. [Epub ahead of print]26 101534
    Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets.
    Xuewei Zheng, Haodi Ma, Jingjing Wang, Mengjiao Huang, Dongliao Fu, Ling Qin, Qinan Yin.
      Breast cancer (BC) is a malignant tumor that seriously endangers health in women. BC, like other cancers, is accompanied by metabolic reprogramming. Among energy metabolism-related pathways, BC exhibits enhanced glycolysis, tricarboxylic acid (TCA) cycle, pentose phosphate pathway (PPP), glutamate metabolism, and fatty acid metabolism activities. These pathways facilitate the proliferation, growth and migration of BC cells. The progression of BC is closely related to the alterations in the activity or expression level of several metabolic enzymes, which are regulated by the intrinsic factors such as the key signaling and transcription factors. The metabolic reprogramming in the progression of BC is attributed to the aberrant expression of the signaling and transcription factors associated with the energy metabolism pathways. Understanding the metabolic mechanisms underlying the development of BC will provide a druggable potential for BC treatment and drug discovery.
    Keywords:  Breast cancer (BC); Glutamine metabolism; Glycolysis; Metabolic reprogramming; Transcription factors
    DOI:  https://doi.org/10.1016/j.tranon.2022.101534
  17. Endocr Relat Cancer. 2022 Sep 01. pii: ERC-22-0173. [Epub ahead of print]
    100 years of the Warburg effect: a historical perspective.
    David Grahame Hardie.
      Otto Warburg published the first papers describing what became known as the Warburg effect in 1923. All that was known about glucose metabolism at that time was that it occurred in two stages: (i) fermentation or glycolysis, in which glucose was converted to lactate, which did not require oxygen, and (ii) oxidative metabolism, in which the carbon atoms derived from glycolysis were fully oxidized to carbon dioxide, which did require oxygen. Warburg discovered that most tumour tissues produced a large amount of lactate that was reduced but not eliminated in the presence of oxygen, while most normal tissues produced a much smaller amount of lactate that was eliminated by provision of oxygen. These findings were clearly well ahead of their time because it was another 80 years before they were to have any major impact, and even today the mechanisms underlying the Warburg effect are not completely understood.
    DOI:  https://doi.org/10.1530/ERC-22-0173
  18. J Control Release. 2022 Sep 12. pii: S0168-3659(22)00597-1. [Epub ahead of print]
    Liposomal oxaliplatin prodrugs loaded with metformin potentiate immunotherapy for colorectal cancer.
    Li Song, Yu Hao, Chunjie Wang, Yikai Han, Yujie Zhu, Liangzhu Feng, Liyan Miao, Zhuang Liu.
      Tumor hypoxia is confirmed to be associated with the formation of tumor immunosuppression, a general feature of solid tumors, and thus attenuates the effectiveness of various cancer therapies in clinic. We herein develop a tumor microenvironment (TME) modulating liposomal nanomedicine by encapsulating metformin with amphiphilic oxaliplatin prodrug constructed liposomes to potentiate cancer immunotherapy. While metformin could regulate metabolisms of tumor cells to reduce their oxygen consumption and relieve tumor hypoxia, oxaliplatin is a chemotherapy drug that induces immunogenic cell death (ICD). The obtained met-oxa(IV)-liposome upon intravenous injection effectively attenuates tumor hypoxia and induce ICD of cancer cells, thereby collectively suppresses the growth of murine colorectal tumors by eliciting potent antitumor immunity and reversing the immunosuppressive TME. As the result, the treatment with met-oxa(IV)-liposome effectively potentiates the immune checkpoint blockade (ICB) therapy against murine colorectal tumors. This liposomal nanomedicine is highlighted to be a TME modulating liposomal nanomedicine with high potency in suppressing tumor growth, particularly promising in synergizing with ICB therapy by boosting antitumor immune responses.
    Keywords:  Colorectal cancer; Immune checkpoint blockade therapy; Metformin; Oxaliplatin prodrugs
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.013
  19. Int J Biol Macromol. 2022 Sep 11. pii: S0141-8130(22)02008-6. [Epub ahead of print]221 842-864
    Cellulose nanocrystals based delivery vehicles for anticancer agent curcumin.
    Rajesh Kumar, Sandeep Chauhan.
      Cancer is a complex disease that starts with genetic alterations and mutations in healthy cells. The past decade has witnessed a huge demand for new biocompatibility and high-performance intelligent drug delivery systems. Curcumin (CUR) is a bioactive stimulant with numerous medical benefits. However, because of its hydrophobic nature, it has low bioavailability. The utilization of many biobased materials has been found to improve the loading of hydrophobic drugs. Cellulose nanocrystals (CNCs) with exceptional qualities and a wide range of applications, feature strong hydrophilicity and lipophilicity, great emulsification stability, high crystallinity and outstanding mechanical attributes. In this review, numerous CNCs-based composites have been evaluated for involvement in the controlled release of CUR. The first part of the review deals with recent advancements in the extraction of CNCs from lignocellulose biomass. The second elaborates some recent developments in the post-processing of CNCs in conjunction with other materials like natural polymers, synthetic polymers, β-CD, and surfactants for CUR loading/encapsulation and controlled release. Furthermore, numerous CUR drug delivery systems, challenges, and techniques for effective loading/encapsulation of CUR on CNCs-based composites have been presented. Finally, conclusions and future outlooks are also explored.
    Keywords:  CNC-composites; Cellulose nanocrystals; Curcumin; Drug delivery; Extraction of CNCs
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.077
  20. Front Oncol. 2022 ;12 917537
    The molecular mechanisms of ferroptosis and its role in glioma progression and treatment.
    Mengyang Lu, Yuanshuai Zhou, Linjuan Sun, Shaheryar Shafi, Nafees Ahmad, Minxuan Sun, Jun Dong.
      Ferroptosis is one of the programmed modes of cell death that has attracted widespread attention recently and is capable of influencing the developmental course and prognosis of many tumors. Glioma is one of the most common primary tumors of the central nervous system, but effective treatment options are very limited. Ferroptosis plays a critical role in the glioma progression, affecting tumor cell proliferation, angiogenesis, tumor necrosis, and shaping the immune-resistant tumor microenvironment. Inducing ferroptosis has emerged as an attractive strategy for glioma. In this paper, we review ferroptosis-related researches on glioma progression and treatment.
    Keywords:  combination therapy; ferroptosis; glioma progression; molecular mechanism; role
    DOI:  https://doi.org/10.3389/fonc.2022.917537
  21. Asian J Pharm Sci. 2022 Jul;17(4): 523-543
    Overcoming the cellular barriers and beyond: Recent progress on cell penetrating peptide modified nanomedicine in combating physiological and pathological barriers.
    Yingke Liu, Zhihe Zhao, Man Li.
      The complex physiological and pathological conditions form barriers against efficient drug delivery. Cell penetrating peptides (CPPs), a class of short peptides which translocate drugs across cell membranes with various mechanisms, provide feasible solutions for efficient delivery of biologically active agents to circumvent biological barriers. After years of development, the function of CPPs is beyond cell penetrating. Multifunctional CPPs with bioactivity or active targeting capacity have been designed and successfully utilized in delivery of various cargoes against tumor, myocardial ischemia, ocular posterior segment disorders, etc. In this review, we summarize recent progress in CPP-functionalized nano-drug delivery systems to overcome the physiological and pathological barriers for the applications in cardiology, ophtalmology, mucus, neurology and cancer, etc. We also highlight the prospect of clinical translation of CPP-functionalized drug delivery systems in these areas.
    Keywords:  Cell penetrating peptide; Drug delivery system; Nanomedicine; Physiological barriers
    DOI:  https://doi.org/10.1016/j.ajps.2022.05.002
  22. Cancer Commun (Lond). 2022 Sep 15.
    Lipid metabolism in pancreatic cancer: emerging roles and potential targets.
    Xinpeng Yin, Ruiyuan Xu, Jianlu Song, Rexiati Ruze, Yuan Chen, Chengcheng Wang, Qiang Xu.
      Pancreatic cancer is one of the most serious health issues in developed and developing countries, with a 5-year overall survival rate currently <9%. Patients typically present with advanced disease due to vague symptoms or lack of screening for early cancer detection. Surgical resection represents the only chance for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Although adjuvant chemotherapy has improved long-term outcomes in advanced cancer patients, its response rate is low. So, exploring other new treatments is urgent. In recent years, increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage, and catabolism. Therefore, a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis, prognosis estimation, and targeted therapy for pancreatic cancer patients. In this review, we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer. In addition, we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer. Finally, we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.
    Keywords:  clinical trials; lipid metabolism; pancreatic cancer; targeting therapy
    DOI:  https://doi.org/10.1002/cac2.12360
  23. Crit Rev Food Sci Nutr. 2022 Sep 15. 1-17
    The effectiveness of whey proteins in prevention and treatment of cancer: a review.
    Anjana Thampy, Meena Kumari Palani Kumar, Muthukumar Serva Peddha, Madhavi Reddy.
      Cancer prevalence is rising rapidly around the globe, contributing immensely to the burden on health systems, hence the search for more effective and selective treatments still remains enticing. Whey, as a natural source, has received extensive focus in recent years because of its intriguing applications to health benefits. Growing consumer appreciation of the nutraceutical effects of whey components makes them an attractive field within cancer research. Whey is a valuable source of superior-quality proteins, lactose, vitamins, and minerals that contribute to proper nutrition as well as help hamper illness and even complement certain disease-related therapy prognosis. As a result, industry leaders and dairy producers are devising new ways to valorize it. Great emphasis on cancer prevention and treatment has been given to whey protein (WP) by the scientific community. WP intake has been proven to induce anti-cancer effects in various in vitro and in vivo studies. Nutritionists and dietitians are now enormously endorsing the role of WP in the therapeutic field, notably for cancer cachexia management. However, human intervention studies with WP are in their infancy and remain to be established with different tumor entities to provide valid proof of its ability to act as a coadjuvant in cancer treatment.
    Keywords:  Dairy; cachexia; muscle protein; nutraceuticals; supplements; therapeutics
    DOI:  https://doi.org/10.1080/10408398.2022.2121256
  24. Phytomedicine. 2022 Aug 28. pii: S0944-7113(22)00511-6. [Epub ahead of print]106 154422
    Platycodon grandiflorum (Jacq.) A. DC.: A review of phytochemistry, pharmacology, toxicology and traditional use.
    Shengnan Zhang, Xiaoyun Chai, Guige Hou, Fenglan Zhao, Qingguo Meng.
       BACKGROUND: The traditional Chinese medicine Platycodon grandiflorum (Jacq.) A. DC. (PG, balloon flower) has medicinal and culinary value. It consists of a variety of chemical components including triterpenoid saponins, polysaccharides, flavonoids, polyphenols, polyethylene glycols, volatile oils and mineral components, which have medicinal and edible value.
    PURPOSE: The ultimate goal of this review is to summarize the phytochemistry, pharmacological activities, safety and uses of PG in local and traditional medicine.
    METHODS: A comprehensive search of published literature up to March 2022 was conducted using the PubMed, China Knowledge Network and Web of Science databases to identify original research related to PG, its active ingredients and pharmacological activities.
    RESULTS: Triterpene saponins are the primary bioactive compounds of PG. To date, 76 triterpene saponin compounds have been isolated and identified from PG. In addition, there are other biological components, such as flavonoids, polyacetylene and phenolic acids. These extracts possess antitussive, immunostimulatory, anti-inflammatory, antioxidant, antitumor, antiobesity, antidepressant, and cardiovascular system activities. The mechanisms of expression of these pharmacological effects include inhibition of the expression of proteins such as MDM and p53, inhibition of the activation of enzymes, such as AKT, the secretion of inflammatory factors, such as IFN-γ, TNF-α, IL-2 and IL-1β, and activation of the AMPK pathway.
    CONCLUSION: This review summarizes the chemical composition, pharmacological activities, molecular mechanism, toxicity and uses of PG in local and traditional medicine over the last 12 years. PG contains a wide range of chemical components, among which triterpene saponins, especially platycoside D (PD), play a strong role in pharmacological activity, representing a natural phytomedicine with low toxicity that has applications in food, animal feed and cosmetics. Therefore, PG has value for exploitation and is an excellent choice for treating various diseases.
    Keywords:  Antitussive activities; Pharmacology; Phytochemistry; Platycodon grandiflorum; Toxicology; Triterpenoid saponin
    DOI:  https://doi.org/10.1016/j.phymed.2022.154422
  25. Semin Cancer Biol. 2022 Sep 07. pii: S1044-579X(22)00200-0. [Epub ahead of print]86(Pt 2): 54-68
    Functionalized-DNA nanostructures as potential targeted drug delivery systems for cancer therapy.
    Ajay Kumar, Anas Ahmad, Md Meraj Ansari, Vemana Gowd, Summya Rashid, Anis Ahmad Chaudhary, Hassan Ahmed Rudayni, Sulaiman A Alsalamah, Rehan Khan.
      Seeman's pioneer idea has led to the foundation of DNA nanostructures, resulting in a remarkable advancement in DNA nanotechnology. Over the last few decades, remarkable advances in drug delivery techniques have resulted in the self-assembly of DNA for encapsulating candidate drug molecules. The nuclear targeting capability of DNA nanostructures is lies within their high spatial addressability and tremendous potential for active targeting. However, effective programming and assembling those DNA molecules remains a challenge, making the path to DNA nanostructures for real-world applications difficult. Because of their small size, most nanostructures are self-capable of infiltrating into the tumor cellular environment. Furthermore, to enable controlled and site-specific delivery of encapsulated drug molecules, DNA nanostructures are functionalized with special moieties that allow them to bind specific targets and release cargo only at targeted sites rather than non-specific sites, resulting in the prevention/limitation of cellular toxicity. In light of this, the current review seeks to shed light on the versatility of the DNA molecule as a targeting and encapsulating moiety for active drugs in order to achieve controlled and specific drug release with spatial and temporal precision. Furthermore, this review focused on the challenges associated with the construction of DNA nanostructures as well as the most recent advances in the functionalization of DNA nanostructures using various materials for controlled and targeted delivery of medications for cancer therapy.
    Keywords:  Cancer treatment; DNA nanotechnology; Functionalized DNA nanostructures; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.semcancer.2022.09.003
  26. Mol Biol Rep. 2022 Sep 12.
    A comprehensive review on methotrexate containing nanoparticles; an appropriate tool for cancer treatment.
    Hanifeh Shariatifar, Fateme Ranjbarian, Fahimeh Hajiahmadi, Alireza Farasat.
      For more than seven decades, methotrexate has been used all over the world for treatment of different diseases such as: cancer, autoimmune diseases, and rheumatoid arthritis. Several studies have addressed its formula, efficacy, and delivery methods in recent years. These studies have been focused on the effectiveness of different nanoparticles on drug delivery, delivery of the drug to the target cells, and attenuation of harm to the host cell. Whereas, the main usages of methotrexate are in cancer treatment field, this review provided a brief perspective into using different nanoparticles and their role in the treatment of different cancers.
    Keywords:  Cancer; Methotrexate (MTX); Nanoparticles
    DOI:  https://doi.org/10.1007/s11033-022-07782-7
  27. Clin Exp Pharmacol Physiol. 2022 Sep 16.
    Apigenin in cancer therapy; prevention of genomic instability and anti-cancer mechanisms.
    Masoud Moslehi, Sepideh Rezaei, Pourya Talebzadeh, Mohammad Javed Ansari, Mohammed Abed Jawad, Abduladheem Turki Jalil, Nima Rastegar-Pouyani, Emad Jafarzadeh, Shahram Taeb, Masoud Najafi.
      The incidence of cancer has been growing worldwild. Better survival rates following the administration of novel drugs and new combination therapies may concomitantly cause concern regarding the long-term adverse effects of cancer therapy e.g., second primary malignancies. Besides, overcoming tumour resistance to anticancer agents has been long considered as a critical challenge in cancer research. Some low toxic adjuvants such as herb-derived molecules may be of interest for chemoprevention and overcoming the resistance of malignancies to cancer therapy. Apigenin is a plant-derived molecule with attractive properties for chemoprevention, for instance promising anti-tumour effects, which may make it a desirable adjuvant to reduce genomic instability and the risks of second malignancies among normal tissues. Moreover, it may improve the efficiency of anti-cancer modalities. This paper aims to review various effects of apigenin in both normal tissues and malignancies. In addition, we explain how apigenin may have the ability to protect usual cells against the genotoxic repercussions following radiotherapy and chemotherapy. Furthermore, the inhibitory effects of apigenin on tumours will be discussed. This article is protected by copyright. All rights reserved.
    Keywords:  Apigenin; Cancer; Chemoprevention; Drug Resistance; Metastasis
    DOI:  https://doi.org/10.1111/1440-1681.13725
  28. Biomaterials. 2022 Sep 08. pii: S0142-9612(22)00436-7. [Epub ahead of print]289 121796
    Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death autophagy/mitophagy.
    Quanwei Sun, Jinming Yang, Wei Shen, Huiyu Lu, Xiaohui Hou, Yang Liu, Yujing Xu, Qinghua Wu, Zihua Xuan, Ye Yang, Dengke Yin.
      Generally, autophagy/mitophagy, as a highly conserved lysosomal-based catabolic pathway, compromises the photodynamic therapy (PDT) efficiency by increasing the adaptation of tumor cells toward reactive oxygen species (ROS)-triggered protein damages and mitochondrial destruction. On the other hand, excessively activated autophagy/mitophagy cascades can provoke autophagic cell death and promote the endogenous antigens release of dying cells, thus playing a vital role in initiating the antitumor immune responses. To harness the exquisite immunomodulating effect of pro-death autophagy/mitophagy, we rationally constructed a MnO2 shell-coated multifunctional porphyrinic metal-organic framework (MOF) to load carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The wrapped MnO2 shell could not only prevent premature release of CCCP during blood circulation but also conquer tumor hypoxia by catalyzing the decomposition of intratumoral H2O2. After entering tumor cells, the MnO2 shell could scavenge over-expressed glutathione (GSH), resulting in burst CCCP release and GSH-depletion/O2-generation enhanced PDT. More importantly, the released CCCP acts as a mitochondrial uncoupler can elicit mitochondrial depolarization and mitophagy, which could significantly boost the autophagy/mitophagy levels generated during PDT and consequently convert the pro-survival autophagy/mitophagy to pro-death, leading tumor cells to autophagic and immunogenic cell death. In vivo results reveal that the CCCP synergistic PDT could induce excessive immunostimulatory autophagy/mitophagy associated with T-cell responses and immunological memory, leading to complete ablation of primary tumors and prevention of tumor recurrence and lung metastasis. The effectiveness of this strategy may highlight the pro-death role and immunomodulating effect of autophagy/mitophagy in cancer therapy, providing a novel yet versatile avenue to enhance the efficacy of cancer treatments.
    Keywords:  Autophagic cell death; Immunogenic cell death; Metal-organic framework; Mitochondrial uncoupler; Mitophagy; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121796
  29. ACS Nano. 2022 Sep 16.
    Hypoxia-Activated PEGylated Paclitaxel Prodrug Nanoparticles for Potentiated Chemotherapy.
    Dengyuan Hao, Qian Meng, Bowen Jiang, Shaojin Lu, Xiujuan Xiang, Qing Pei, Haijun Yu, Xiabin Jing, Zhigang Xie.
      Developing controlled drug-release systems is imperative and valuable for increasing the therapeutic index. Herein, we synthesized hypoxia-responsive PEGylated (PEG = poly(ethylene glycol)) paclitaxel prodrugs by utilizing azobenzene (Azo) as a cleavable linker. The as-fabricated prodrugs could self-assemble into stable nanoparticles (PAP NPs) with high drug content ranging from 26 to 44 wt %. The Azo group in PAP NPs could be cleaved at the tumorous hypoxia microenvironment and promoted the release of paclitaxel for exerting cytotoxicity toward cancer cells. In addition, comparative researches revealed that the PAP NPs with the shorter methoxy-PEG chain (molecular weight = 750) possessed enhanced tumor suppression efficacy and alleviated off-target toxicity. Our work demonstrates a promising tactic to develop smart and simple nanomaterials for disease treatment.
    Keywords:  PEGylation; hypoxia-responsive; paclitaxel; prodrugs; self-assembly
    DOI:  https://doi.org/10.1021/acsnano.2c05341
  30. Front Bioeng Biotechnol. 2022 ;10 984336
    Application of MXene in the diagnosis and treatment of breast cancer: A critical overview.
    Sara Ranjbari, Mahdieh Darroudi, Behnaz Hatamluyi, Reza Arefinia, Seyed Hamid Aghaee-Bakhtiari, Majid Rezayi, Majid Khazaei.
      Breast cancer is the second most common cancer worldwide. Prognosis and timely treatment can reduce the illness or improve it. The use of nanomaterials leads to timely diagnosis and effective treatment. MXenes are a 2D material with a unique composition of attributes, containing significant electrical conductance, high optical characteristics, mechanical consistency, and excellent optical properties. Current advances and insights show that MXene is far more promising in biotechnology applications than current nanobiotechnology systems. MXenes have various applications in biotechnology and biomedicine, such as drug delivery/loading, biosensor, cancer treatment, and bioimaging programs due to their high surface area, excellent biocompatibility, and physicochemical properties. Surface modifications MXenes are not only biocompatible but also have multifunctional properties, such as aiming ligands for preferential agglomeration at the tumor sites for photothermal treatment. Studies have shown that these nanostructures, detection, and breast cancer therapy are more acceptable than present nanosystems in in vivo and in vitro. This review article aims to investigate the structure of MXene, its various synthesis methods, its application to cancer diagnosis, cytotoxicity, biodegradability, and cancer treatment by the photothermal process (in-vivo and in-vitro).
    Keywords:  MXene; advanced nanomaterials; biomedical analysis; biomedicine; biosensor; breast cancer; cancer treatment
    DOI:  https://doi.org/10.3389/fbioe.2022.984336
  31. Carbohydr Polym. 2022 Nov 15. pii: S0144-8617(22)00866-9. [Epub ahead of print]296 119961
    Advances in polysaccharides of natural source of the anti-Alzheimer's disease effect and mechanism.
    Zhiyuan Zhang, Shuai Wang, Haining Tan, Pei Yang, Yuanyuan Li, Lingchuan Xu, Baoguo Duan, Yuhong Liu.
      Alzheimer's disease (AD) is a complex neurodegenerative disorder. The pathology is characterized by the generation of amyloid plaques and neuronal fiber tangles in the brain. Although decades of research have been conducted, there is still a lack of effective treatments and countermeasures. Polysaccharide components of natural origin obtained by extraction and isolation possess a variety of pharmacological activities and medicinal values, and they are receiving increasing attention. Polysaccharides have shown good promise in the field of AD prevention and treatment, and polysaccharides ameliorate AD in multiple ways by targeting different mechanisms with almost no toxic side effects. In this paper, we review the research on polysaccharides of natural sources regulation in AD in recent years and list systematically the possible intervention pathways of polysaccharides targeting different mechanisms.
    Keywords:  Alzheimer's disease; Apoptosis; Neuroinflammation; Oxidative stress; Polysaccharide; β-Amyloid
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119961
  32. J Ethnopharmacol. 2022 Sep 12. pii: S0378-8741(22)00734-6. [Epub ahead of print] 115695
    A review on the traditional uses, phytochemistry, and pharmacology of the genus veronicastrum (Plantaginaceae).
    Elizabeth Syowai Mutinda, Elijah Mbandi Mkala, Jing Ren, Festus Kimutai, Emmanuel Nyongesa Waswa, Wyclif Ochieng Odago, Consolata Nanjala, Moses Kirega Gichua, Moses Muguci Njire, Guang-Wan Hu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Veronicastrum Heist. ex Fabr. (Plantaginaceae) is a multifunctional plant in China and other parts of the continent. It has traditionally been used in the treatment of ascites, edema, blood stasis, pain relief, chronic nephritis injury, fever, cough, headache, arthritis, dysentery, rheumatism, pleural effusion, liver damage, and other disorders. Although research has confirmed that the genus Veronicastrum contain many active compounds, no review of its traditional uses, phytochemistry or pharmacology has been conducted to date.
    AIM: This review aims to systematically evaluate the traditional uses, phytochemistry, and pharmacology of the genus Veronicastrum, discuss its medicinal potential, modern scientific research, and the relationship between them, and put forward some suggestions to promote further development and utilization of Veronicastrum.
    MATERIALS AND METHODS: The traditional uses, phytochemical and pharmacological data related to the genus Veronicastrum from 1955 to date was compiled by surveying the ethnomedicinal books and published papers, and searching the online databases including Google Scholar, China National Knowledge Infrastructure (CNKI), Science Direct, Web of Science and World Flora Online.
    RESULTS: Species of the genus Veronicastrum are widely used in folkloric medicine and some of their uses have been confirmed in modern pharmacological activities. A total of 89 chemical constituents have been isolated from the genus Veronicastrum, including flavonoids, carbohydrates, iridoids, terpenoids, phytosterols, phenolic acids, and other constituents. Among the compounds isolated, iridoids, flavonoids, and terpenoids are responsible for the biological activities of this genus with significant pharmacological activities both in vitro and in vivo. The extracts and compounds isolated from this genus have been reported to contain a wide range of pharmacological activities such as immunosuppressive, antioxidant, anti-cancer, anti-inflammatory, gastro protective, and antimicrobial activity.
    CONCLUSION: The genus Veronicastrum is not only a great herbal remedy, but also has numerous bioactive chemicals with potential for new drug discovery. In the literature, phytochemical investigations have been undertaken on five species. Detailed scientific research is still needed to fully understand this genus. Furthermore, its bioactive chemicals' structure-activity connection, in vivo activity, and mechanism of action ought to be investigated further.
    Keywords:  Pharmacology; Phytochemistry; Traditional Chinese medicine; Veronicastrum
    DOI:  https://doi.org/10.1016/j.jep.2022.115695
  33. Mater Today Bio. 2022 Dec;16 100416
    Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer.
    Junjian Shen, Minghui Lin, Mengbin Ding, Ningyue Yu, Chun Yang, Deping Kong, Haitao Sun, Zongyu Xie.
      Immunotherapy has recently been seen as a hopeful therapeutic device to inhibit tumor growth and metastasis, while the curative efficacy is limited by intrinsic immunosuppressive tumor microenvironment. Herein, we reported a tumor immunosuppressive microenvironment modulating hydrogel (TIMmH) platform to achieve second near-infrared (NIR-II) photothermal therapy (PTT) combined immunotherapy for durable inhibition of breast cancer. This TIMmH platform was synthesized through co-loading of NIR-II photothermal nanoagent and an immunoadjuvant cytosine-phosphateguanosine oligodeoxynucleotides (CpG ODNs) into the alginate hydrogel (ALG). Upon the administration of ALG into the tumor, the TIMmH was in situ formed via the coordination effect with Ca2+, locally encapsulating the semiconducting polymer nanoparticles (SPIIN) and CpG in the colloid, achieving to prolong the accumulation time and prevent the premature damage and release of immunotherapeutic agents. Upon 1064-nm photoirradiation, the TIMmHSD was able to elevate the intratumoral temperature for the ablation of tumors, which could induce the apoptosis of tumor cells and achieve thermal immune activation by regulating of an immunosuppressive microenvironment. The TIMmH-mediated combined treatment effectively suppressed the growths of breast cancers, and even acquired a sustained inhibition of the lung metastasis. This study provides a novel tumor immunosuppressive microenvironment modulating hydrogel platform with NIR-II photoexcited capacity for the safe, effective and durable lung metastasis-inhibiting breast cancer treatment.
    Keywords:  Breast cancer; Hydrogels; Immunotherapy; Metastasis; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100416
  34. ACS Biomater Sci Eng. 2022 Sep 14.
    Membrane-Wrapped Nanoparticles for Enhanced Chemotherapy of Acute Myeloid Leukemia.
    Jenna C Harris, Eric H Sterin, Emily S Day.
      This work reports the development of a biomimetic membrane-wrapped nanoparticle (MWNP) platform for targeted chemotherapy of acute myeloid leukemia (AML). Doxorubicin (DOX), a chemotherapeutic used to treat leukemias, lymphomas, and other cancers, was encapsulated in polymeric NPs that were coated with cytoplasmic membranes derived from human AML cells. The release rate of DOX from the MWNPs was characterized under both storage and physiological conditions, with faster release observed at pH 5.5 than pH 7.4. The system was then introduced to AML cell cultures to test the functionality of the released DOX cargo as compared to DOX delivered freely or via NPs coated with poly(ethylene glycol) (PEG). The MWNPs delivered DOX in an efficient and targeted manner, inducing up to 80% apoptosis in treated cells at a dose of 5 μM, compared to 15% for free DOX and 17% for DOX-loaded PEG-coated NPs at the same drug concentration. The mechanism of cell death was confirmed as DNA double-strand breaks through a γH2A.X assay, indicating that the released DOX retained its expected mechanism of action. These findings designate MWNPs as a robust drug delivery system with great potential for future development in treatments of AML and other blood cancers.
    Keywords:  biomimetic; biomimicry; cancer; doxorubicin; drug release; membrane-coated
    DOI:  https://doi.org/10.1021/acsbiomaterials.2c00832
  35. Nanoscale. 2022 Sep 13.
    "Carrier-drug" layer-by-layer hybrid assembly of biocompatible polydopamine nanoparticles to amplify photo-chemotherapy.
    Lingyu Lv, Hao Cheng, Zhen Wang, Zhangyi Miao, Feng Zhang, Jie Chen, Gang Wang, Ling Tao, Jianping Zhou, Huaqing Zhang, Yang Ding.
      Polydopamine (PDA) is capable of wide drug delivery for biomedical applications by virtue of an adjustable polymerization process, including surface coating and conjugation. Inspired by the polymerization of dopamine, we introduce a layer-by-layer hybrid co-assembly strategy for the incorporation of doxorubicin (DOX) and dopamine to form PDA "carrier-drug" hybrid assembly. The "carrier-drug" hybrid assembly relies on the π-π stacking interaction between the drug (DOX) and carrier (PDA), and such the stacked-layer structure enables PDA nanoparticles with a superior drug loading of 58%, which is about 1.7-fold higher than that of the DOX surface coating (∼35%). To further improve blood circulation stability and enhance tumor penetration, we herein propose the conjugation of native apolipoprotein A-I (apoA-I) with tumor-homing cyclic peptide iRGD for PDA surface modification. The "carrier-drug" hybrid assembly can respond to triple stimuli of the acidic pH, concentrated reactive oxygen species (ROS), and near-infrared (NIR) light irradiation for realizing site-specific and on-demand drug release. In chemo-photothermal synergy therapy, the "carrier-drug" hybrid assembly performs efficient tumor penetration and accumulation, dramatically suppressing tumor growth and metastasis in a 4T1 orthotopic tumor-bearing mice model at a safe level. Collectively, our findings share new insights into the design of "carrier-drug" hybrid assembly for enhanced chemo-photothermal oncotherapy.
    DOI:  https://doi.org/10.1039/d2nr03200g
  36. PPAR Res. 2022 ;2022 4714914
    Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments.
    Ayesheh Enayati, Mobina Ghojoghnejad, Basil D Roufogalis, Seyed Adel Maollem, Amirhossein Sahebkar.
      Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.
    DOI:  https://doi.org/10.1155/2022/4714914
  37. ACS Appl Mater Interfaces. 2022 Sep 15.
    Combined Chemo-Immuno-Photothermal Therapy for Effective Cancer Treatment via an All-in-One and One-for-All Nanoplatform.
    Xianglong Yu, Ning Han, Ziyi Dong, Yunni Dang, Qing Zhang, Wenjun Hu, Changhai Wang, Shouying Du, Yang Lu.
      Tumor metastasis and recurrence are recognized to be the main causes of failure in cancer treatment. To address these issues, an "all in one" and "one for all" nanoplatform was established for combined "chemo-immuno-photothermal" therapy with the expectation to improve the antitumor efficacy. Herein, Docetaxel (DTX, a chemo-agent) and cynomorium songaricum polysaccharide (CSP, an immunomodulator) were loaded into zein nanoparticles coated by a green tea polyphenols/iron coordination complex (GTP/FeIII, a photothermal agent). From the result, the obtained nanoplatform denoted as DTX-loaded Zein/CSP-GTP/FeIII NPs was spherical in morphology with an average particle size of 274 nm, and achieved pH-responsive drug release. Moreover, the nanoplatform exhibited excellent photothermal effect both in vitro and in vivo. It was also observed that the nanoparticles could be effectively up take by tumor cells and inhibited their migration. From the results of the in vivo experiment, this nanoplatform could completely eliminate the primary tumors, prevent tumor relapses on LLC (Lewis lung cancer) tumor models, and significantly inhibit metastasis on 4T1 (murine breast cancer) tumor models. The underlying mechanism was also explored. It was discovered that this nanoplatform could induce a strong ICD effect and promote the release of damage-associated molecular patterns (DAMPs) including CRT, ATP, and HMGB1 by the dying tumor cells. And the CSP could assist the DAMPs in inducing the maturation of dendritic cells (DCs) and facilitate the intratumoral infiltration of T lymphocytes to clear up the residual or disseminated tumor cells. In summary, this study demonstrated that the DTX-loaded Zein/CSP-GTP/FeIII is a promising nanoplatform to completely inhibit tumor metastasis and recurrence.
    Keywords:  all-in-one and one-for-all nanoplatform; cancer immunotherapy; chemo−immuno−photothermal; immunogenic cell death; polysaccharide
    DOI:  https://doi.org/10.1021/acsami.2c12969
  38. Chem Biodivers. 2022 Sep 12.
    Comparative Study of Nano-liposome and Nano-niosome for Delivery of Achillea Millefolium Essential Oils: Development, Optimization, Characterization and Their Cytotoxicity Effects on Cancer Cell Line and Antibacterial Activity.
    Hamideh Emtiazi, Ali Salari Sharif, Mahdie Hemati, BiBi Fatemeh Haghiralsadat, Abbas Pardakhti.
      Nanoencapsulation of essential oils (EOs) in drug delivery systems leads to their capability of improving their solubility, stability, and bioavailability of them. The aim of this study was preparation, optimization, and characterization of nano-liposomes/nano-niosomes containing Achillea millefolium essential oils ( A. millefolium EOs) and comparison of their properties. In the experimental study, characteristics of nanoparticles including size, zeta potential, Fourier Transform Infrared Spectroscopy (FTIR), %encapsulation efficiency (EE %) and, the release amount of essential oils from nano-liposome or niosome were assessed using different techniques. Then to determine cell viability at different concentrations, the MTT assay was used. Also, the dilution method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of antimicrobial agents. The optimized formulations provided potential advantages, including an appropriate nano-size scale, and a negative charge, and also showed a continuous drug release behavior, which successfully encapsulated essential oil with high entrapment efficiency. In terms of size and release amount, nano-niosome had superiority to nano-liposome with smaller size and also slower release but nano-liposome could encapsulate essential oils in a higher percentage compared to nano-niosome. Also, there was a significant difference between the toxicity of encapsulated EOs and free EOs in terms of viability (P<0.05). In addition, the antimicrobial effect of liposomal and niosomal EO was greater than free EO. In conclusion, the designed nano-based systems were determined as promising lipid-based nano-carriers for essential oil delivery that proffered a novel, high potential therapy for breast cancer and favorable antimicrobial effects.
    Keywords:  Achillea millefolium essential oil * Anticancer * Antimicrobial * Nano-liposome * Nano-niosome
    DOI:  https://doi.org/10.1002/cbdv.202200397
  39. Int J Nanomedicine. 2022 ;17 4059-4071
    Salinomycin-Loaded High-Density Lipoprotein Exerts Promising Anti-Ovarian Cancer Effects by Inhibiting Epithelial-Mesenchymal Transition.
    Miao Zou, Xirui Yin, Xuan Zhou, Xinhui Niu, Yi Wang, Manman Su.
       Background: Effective treatments for ovarian cancer remain elusive, and survival rates have long been considered grim. Ovarian cancer stem cells (OCSCs) and epithelial-mesenchymal transition (EMT) are associated with cancer progression and metastasis, as well as drug resistance and eventual treatment failure. Salinomycin (Sal) has an extensive effect on a variety of cancer stem cells (CSCs); however, its poor water solubility and toxicity to healthy tissues at high doses limit further research into its potential as an anti-cancer drug. We proposed a therapeutic strategy by constructing a tumor-targeting carrier that mimics high-density lipoprotein (HDL) to synthesize salinomycin-loaded high-density lipoprotein (S-HDL). This strategy helps reduce the side effects of salinomycin, thereby improving its clinical benefits.
    Methods: OCSCs were isolated from ovarian cancer cells (OCCs) and the uptake of HDL nanoparticles was observed using laser confocal microscopes. After the cell viability analysis revealed the inhibitory effect of S-HDL on OCCs and OCSCs, the main biological processes influenced by S-HDL were predicted with a transcriptome sequencing analysis and verified in vitro and in vivo.
    Results: Cellular uptake analysis showed that the HDL delivery system was able to significantly enhance the uptake of Sal by OCCs, tentatively validating the targeting role of recombinant HDL, so that S-HDL could reduce the toxicity of Sal and increase its anti-ovarian cancer effects. Conversely, S-HDL could exert anti-ovarian cancer effects by inhibiting the proliferation of OCCs and OCSCs, promoting apoptosis, blocking EMT, and suppressing stemness and angiogenesis-related protein expression in vitro and in vivo.
    Conclusion: S-HDL had stronger anti-ovarian cancer effects than unencapsulated Sal. Thus, it may be a potential agent for ovarian cancer treatment in the future.
    Keywords:  epithelial–mesenchymal transition; high-density lipoprotein; ovarian cancer; ovarian cancer stem cells; salinomycin
    DOI:  https://doi.org/10.2147/IJN.S380598
  40. Adv Healthc Mater. 2022 Sep 13. e2201524
    A Nanozyme-immobilized Hydrogel with Endogenous ROS-scavenging and Oxygen Generation Abilities for Significantly Promoting Oxidative Diabetic Wound Healing.
    Zuhao Li, Yue Zhao, Hanwei Huang, Changru Zhang, He Liu, Zhonghan Wang, Mingjie Yi, Neng Xie, Yuling Shen, Xiangzhong Ren, Jincheng Wang, Jinwu Wang.
      Non-healing wound is a common complication of diabetic patients associated with high morbidity and mortality. Engineered therapeutic hydrogels have enviable advantages in tissue regeneration, however, they are suboptimal for the healing of diabetic wounds characterized by reactive oxygen species (ROS) accumulation and chronic hypoxia. Here, we present a unique biological metabolism-inspired hydrogel for ameliorating this hostile diabetic microenvironment. Consisting of natural polymers (hydrazide modified hyaluronic acid and aldehyde modified hyaluronic acid) and a metal-organic frameworks derived catalase-mimic nanozyme (ε-polylysine coated mesoporous manganese cobalt oxide), the engineered nanozyme-reinforced hydrogels can not only capture the endogenous elevated ROS in diabetic wounds, but also synergistically produce oxygen through the ROS-driven oxygen production ability. These fascinating properties of hydrogels protected skin cells (e.g., keratinocytes, fibroblasts, and vascular endothelial cells) from ROS and hypoxia-mediated death and proliferation inhibition. Diabetic wounds treated with the nanozyme-reinforced hydrogels highlighted the potential of inducing the macrophages polarization from pro-inflammatory phenotype (M1) to anti-inflammatory subtype (M2). The hydrogel dressings demonstrated a prominently accelerated healing rate as featured by alleviating the excessive inflammatory, inducing efficiently proliferation, re-epithelialization, collagen deposition, and neovascularization. This work provides an effective strategy based on nanozyme-reinforced hydrogel as a ROS-driven oxygenerator for enhancing diabetic wound healing. This article is protected by copyright. All rights reserved.
    Keywords:  anti-inflammatory; diabetic wound healing; nanocomposite hydrogel; nanozyme
    DOI:  https://doi.org/10.1002/adhm.202201524
  41. Semin Cancer Biol. 2022 Sep 09. pii: S1044-579X(22)00198-5. [Epub ahead of print]
    Lactate Dehydrogenase and its clinical significance in pancreatic and thoracic cancers.
    Annalisa Comandatore, Marika Franczak, Ryszard T Smolenski, Luca Morelli, Godefridus J Peters, Elisa Giovannetti.
      The energy metabolism of tumor cells is considered one of the hallmarks of cancer because it is different from normal cells and mainly consists of aerobic glycolysis, fatty acid oxidation, and glutaminolysis. It is about one hundred years ago since Warburg observed that cancer cells prefer aerobic glycolysis even in normoxic conditions, favoring their high proliferation rate. A pivotal enzyme driving this phenomenon is lactate dehydrogenase (LDH), and this review describes prognostic and therapeutic opportunities associated with this enzyme, focussing on tumors with limited therapeutic strategies and life expectancy (i.e., pancreatic and thoracic cancers). Expression levels of LDH-A in pancreatic cancer tissues correlate with clinicopathological features: LDH-A is overexpressed during pancreatic carcinogenesis and showed significantly higher expression in more aggressive tumors. Similarly, LDH levels are a marker of negative prognosis in patients with both adenocarcinoma or squamous cell lung carcinoma, as well as in malignant pleural mesothelioma. Additionally, serum LDH levels may play a key role in the clinical management of these diseases because they are associated with tissue damage induced by tumor burden. Lastly, we discuss the promising results of strategies targeting LDH as a treatment strategy, reporting recent preclinical and translational studies supporting the use of LDH-inhibitors in combinations with current/novel chemotherapeutics that can synergistically target the oxygenated cells present in the tumor.
    Keywords:  Pancreatic cancer Lung cancer; Tumor metabolism; glycolysis; lactate dehydrogenase
    DOI:  https://doi.org/10.1016/j.semcancer.2022.09.001
  42. Pharmacol Res. 2022 Sep 09. pii: S1043-6618(22)00366-8. [Epub ahead of print]184 106421
    Anxiolytic and antidepressive potentials of rosmarinic acid: A review with a focus on antioxidant and anti-inflammatory effects.
    Abdelkader Dahchour.
      Depression and anxiety are the most prevalent neuropsychiatric disorders that have emerged as global health concerns. Anxiolytic and antidepressant drugs, such as benzodiazepines, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclics, are the first line used in treating anxiety and depression. Although these drugs lack efficacy and have a delayed response time and numerous side effects, their widespread abuse and market continue to grow. Over time, traditional practices using natural and phytochemicals as alternative therapies to chemical drugs have emerged to treat many pathological conditions, including anxiety and depression. Recent preclinical studies have demonstrated that the phenolic compound, rosmarinic acid, is effective against several neuropsychiatric disorders, including anxiety and depression. In addition, rosmarinic acid showed various pharmacological effects, such as cardioprotective, hepatoprotective, lung protective, antioxidant, anti-inflammatory, and neuroprotective effects. However, the potentialities of the use of rosmarinic acid in the treatment of nervous system-related disorders, such as anxiety and depression, are less or not yet reviewed. Therefore, the purpose of this review was to present several preclinical and clinical studies, when available, from different databases investigating the effects of rosmarinic acid on anxiety and depression. These studies showed that rosmarinic acid produces advantageous effects on anxiety and depression through its powerful antioxidant and anti-inflammatory properties. This review will examine and discuss the possibility that the anxiolytic and anti-depressive effects of rosmarinic acid could be associated with its potent antioxidant and anti-inflammatory activities.
    Keywords:  Anti-depressive; Anti-inflammation; Anti-oxidant; Anxiolytic; Rosmarinic acid
    DOI:  https://doi.org/10.1016/j.phrs.2022.106421
  43. J Control Release. 2022 Sep 12. pii: S0168-3659(22)00598-3. [Epub ahead of print]
    Lipopeptide liposomes-loaded hydrogel for multistage transdermal chemotherapy of melanoma.
    Yifei Ni, Wanzhu Zhao, Wenjing Cheng, Chengyu Deng, Zhuoyang Ying, Lei Li, Xulei Wang, Chunmeng Sun, Jiasheng Tu, Lei Jiang.
      Transdermal administration of chemotherapeutics into tumor tissues may be an effective treatment to reduce toxic side effects and improve patient compliance for melanoma. Herein, we report a multistage transdermal drug delivery system for chemotherapy of melanoma. In this system, dendritic lipopeptide (DLP) modified multistage targeted liposomes (Mtlip) were incorporated into the hydrogel matrix to achieve localized and sustained drug release; Ultra-deformability of Mtlip can pass through dense stratum corneum to the epidermis where melanoma is located; Virus-mimicking Mtlip enhances the payload in tumor tissues by high permeability; The positive charged Mtlip can improve cell uptake efficiency and selectively accumulate into mitochondria to increases toxic. The efficacy of this type of multistage targeted liposomes loaded hydrogel in treating melanoma was systematically evaluated both in vitro and in vivo.
    Keywords:  Dendritic lipopeptide; Melanoma therapy; Mitochondria targeting; Transdermal drug delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.014
  44. Small. 2022 Sep 14. e2203678
    Micro-Nanocarriers Based Drug Delivery Technology for Blood-Brain Barrier Crossing and Brain Tumor Targeting Therapy.
    Luyao Wang, Youyuan Shi, Jingzhen Jiang, Chan Li, Hengrui Zhang, Xinhui Zhang, Tao Jiang, Liang Wang, Yinyan Wang, Lin Feng.
      The greatest obstacle to using drugs to treat brain tumors is the blood-brain barrier (BBB), making it difficult for conventional drug molecules to enter the brain. Therefore, how to safely and effectively penetrate the BBB to achieve targeted drug delivery to brain tumors has been a challenging research problem. With the intensive research in micro- and nanotechnology in recent years, nano drug-targeted delivery technologies have shown great potential to overcome this challenge, such as inorganic nanocarriers, organic polymer-carriers, liposomes, and biobased carriers, which can be designed in different sizes, shapes, and surface functional groups to enhance their ability to penetrate the BBB and targeted drug delivery for brain tumors. In this review, the composition and overcoming patterns of the BBB are detailed, and then the hot research topics of drug delivery carriers for brain tumors in recent years are summarized, and their mechanisms of action on the BBB and the factors affecting drug delivery are described in detail, and the effectiveness of targeted therapy for brain tumors is evaluated. Finally, the challenges and dilemmas in developing brain tumor drug delivery systems are discussed, which will be promising in the future for targeted drug delivery to brain tumors based on micro-nanocarriers technology.
    Keywords:  blood-brain barrier; brain tumors; micro-nanocarriers; targeted drug delivery
    DOI:  https://doi.org/10.1002/smll.202203678
  45. Int J Biol Macromol. 2022 Sep 09. pii: S0141-8130(22)01977-8. [Epub ahead of print]221 472-485
    Advances in anti-cancer effects and underlying mechanisms of marine algae polysaccharides.
    Wanzi Yao, Hua-Mai Qiu, Kit-Leong Cheong, Saiyi Zhong.
      Cancer is a leading cause of death in both developing and developed countries. With the increase in the average global life expectancy, it has become a major health problem and burden for most public healthcare systems worldwide. Due to the fewer side effects of natural compounds than of chemotherapeutic drugs, increasing scientific attention is being focused on the development of anti-cancer drugs derived from natural sources. Marine algae are an interesting source of functional compounds with diverse health-promoting activities. Among these compounds, polysaccharides have attracted considerable interest for many years because of their excellent anti-cancer abilities. They improve the efficacy of conventional chemotherapeutic drugs with relatively low toxicity to normal human cells. However, there are few reviews summarising the unique anti-cancer effects and underlying mechanisms of marine algae polysaccharides (MAPs). Thus, the current review focuses on updating the advances in the discovery and evaluation of MAPs with anti-cancer properties and the elucidation of their mechanisms of action, including the signalling pathways involved. This review aims to provide a deeper understanding of the anti-cancer functions of the natural compounds derived from medicinal marine algae and thereby offer a new perspective on cancer prevention and therapy with high effectiveness and safety.
    Keywords:  Anti-cancer; Marine algae; Mechanisms; Polysaccharides; Signalling pathways
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.055
  46. J Exp Clin Cancer Res. 2022 Sep 12. 41(1): 271
    Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy.
    Peijie Zheng, Chuntao Zhou, Liuyi Lu, Bin Liu, Yuemin Ding.
      Elesclomol is an anticancer drug that targets mitochondrial metabolism. In the past, elesclomol was recognized as an inducer of oxidative stress, but now it has also been found to suppress cancer by inducing cuproptosis. Elesclomol's anticancer activity is determined by the dependence of cancer on mitochondrial metabolism. The mitochondrial metabolism of cancer stem cells, cancer cells resistant to platinum drugs, proteasome inhibitors, molecularly targeted drugs, and cancer cells with inhibited glycolysis was significantly enhanced. Elesclomol exhibited tremendous toxicity to all three kinds of cells. Elesclomol's toxicity to cells is highly dependent on its transport of extracellular copper ions, a process involved in cuproptosis. The discovery of cuproptosis has perfected the specific cancer suppressor mechanism of elesclomol. For some time, elesclomol failed to yield favorable results in oncology clinical trials, but its safety in clinical application was confirmed. Research progress on the relationship between elesclomol, mitochondrial metabolism and cuproptosis provides a possibility to explore the reapplication of elesclomol in the clinic. New clinical trials should selectively target cancer types with high mitochondrial metabolism and attempt to combine elesclomol with platinum, proteasome inhibitors, molecularly targeted drugs, or glycolysis inhibitors. Herein, the particular anticancer mechanism of elesclomol and its relationship with mitochondrial metabolism and cuproptosis will be presented, which may shed light on the better application of elesclomol in clinical tumor treatment.
    Keywords:  Anticancer drugs; Cancer; Cancer stem cells; Clinical trials; Cuproptosis; Drug safety; Elesclomol; Mitochondrial metabolism
    DOI:  https://doi.org/10.1186/s13046-022-02485-0
  47. In Vivo. 2022 Sep-Oct;36(5):36(5): 2105-2115
    Combination Treatment Using Pyruvate Kinase M2 Inhibitors for the Sensitization of High Density Triple-negative Breast Cancer Cells.
    Ji Sun Lee, Yunmoon Oh, Jin-Sol Lee, Jae Hyeon Park, Joo-Kyung Shin, Joo-Hee Han, Hyung Sik Kim, Sungpil Yoon.
       BACKGROUND/AIM: Few studies have examined the correlation between pyruvate kinase M2 (PKM2) overexpression and triple-negative breast cancer (TNBC). TNBC is considered incurable with the currently available treatments, highlighting the need for alternative therapeutic targets.
    MATERIALS AND METHODS: PKM2 expression was examined immunohistochemically in human breast tumor samples. Furthermore, we studied the effect of three PKM2 inhibitors (gliotoxin, shikonin, and compound 3K) in the MDA-MB-231 TNBC cell line.
    RESULTS: PKM2 overexpression correlates with TNBC. Interestingly, most TNBC tissues showed increased levels of PKM2 compared to those of receptor-positive breast cancer tissues. This suggests that PKM2 overexpression is an important factor in the development of TNBC. MDA-MB-231 TNBC cells are resistant to anticancer drugs, such as vincristine (VIC) compared to other cancer cells. We found that the recently developed PKM2 inhibitor gliotoxin sensitized MDA-MB-231 cells at a relatively low dose to the same extent as the known PKM2 inhibitor shikonin, suggesting that PKM2 inhibitors could be an effective treatment for TNBC. Detailed sensitization mechanisms were also analyzed. Both gliotoxin and shikonin highly increased late apoptosis in MDA-MB-231 cells, as revealed by annexin V staining. However, MDA-MB-231 cells with high cellular density inhibited the sensitizing effect of PKM2 inhibitors; therefore, we investigated ways to overcome this inhibitory effect. We found that gliotoxin+shikonin co-treatment highly increased toxicity in MDA-MB-231 cells with high density, whereas either VIC+gliotoxin or VIC+shikonin were not effective. Thus, combination therapy with various PKM2 inhibitors may be more effective than combination therapy with anticancer drugs. Gliotoxin+shikonin co-treatment did not increase S or G2 arrest in cells, suggesting that the co-treatment showed a high increase in apoptosis without S or G2 arrest. We confirmed that another recently developed PKM2 inhibitor compound 3K had similar mechanisms of sensitizing MDA-MB-231 cells, suggesting that PKM2 inhibitors have similar sensitization mechanisms in TNBC.
    CONCLUSION: PKM2 is a regulator of the oncogenic function of TNBC, and combination therapy with various PKM2 inhibitors may be effective for high-density TNBC. Targeting PKM2 in TNBC lays the foundation for the development of PKM2 inhibitors as promising anti-TNBC agents.
    Keywords:  PKM2; compound 3K; gliotoxin; shikonin; triple-negative breast cancer
    DOI:  https://doi.org/10.21873/invivo.12936
  48. Front Cardiovasc Med. 2022 ;9 957524
    Metabolic reprogramming: A novel metabolic model for pulmonary hypertension.
    Xuhan Liu, Liping Zhang, Weihua Zhang.
      Pulmonary arterial hypertension, or PAH, is a condition that is characterized by pulmonary artery pressures above 20 mmHg (at rest). In the treatment of PAH, the pulmonary vascular system is regulated to ensure a diastolic and contraction balance; nevertheless, this treatment does not prevent or reverse pulmonary vascular remodeling and still causes pulmonary hypertension to progress. According to Warburg, the link between metabolism and proliferation in PAH is similar to that of cancer, with a common aerobic glycolytic phenotype. By activating HIF, aerobic glycolysis is enhanced and cell proliferation is triggered. Aside from glutamine metabolism, the Randle cycle is also present in PAH. Enhanced glutamine metabolism replenishes carbon intermediates used by glycolysis and provides energy to over-proliferating and anti-apoptotic pulmonary vascular cells. By activating the Randle cycle, aerobic oxidation is enhanced, ATP is increased, and myocardial injury is reduced. PAH is predisposed by epigenetic dysregulation of DNA methylation, histone acetylation, and microRNA. This article discusses the abnormal metabolism of PAH and how metabolic therapy can be used to combat remodeling.
    Keywords:  FAO; PAH; glutamine; metabolism; mitochondria; randle cycle
    DOI:  https://doi.org/10.3389/fcvm.2022.957524
  49. Front Oncol. 2022 ;12 962928
    A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
    Eric A Hanse, Mei Kong.
      A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.
    Keywords:  alpha ketoglutarate; epigenetics; glutamine; glutaminolysis-inhibition; metabolism; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.962928
  50. Front Pharmacol. 2022 ;13 933457
    Recent nanotechnology advancements to treat multidrug-resistance pancreatic cancer: Pre-clinical and clinical overview.
    Abdullah K Alshememry, Nasser B Alsaleh, Nora Alkhudair, Rami Alzhrani, Aws Alshamsan.
      Pancreatic cancer (PC) remains one of the most lethal and incurable forms of cancer and has a poor prognosis. One of the significant therapeutic challenges in PC is multidrug resistance (MDR), a phenomenon in which cancer cells develop resistance toward administered therapy. Development of novel therapeutic platforms that could overcome MDR in PC is crucial for improving therapeutic outcomes. Nanotechnology is emerging as a promising tool to enhance drug efficacy and minimize off-target responses via passive and/or active targeting mechanisms. Over the past decade, tremendous efforts have been made to utilize nanocarriers capable of targeting PC cells while minimizing off-target effects. In this review article, we first give an overview of PC and the major molecular mechanisms of MDR, and then we discuss recent advancements in the development of nanocarriers used to overcome PC drug resistance. In doing so, we explore the developmental stages of this research in both pre-clinical and clinical settings. Lastly, we discuss current challenges and gaps in the literature as well as potential future directions in the field.
    Keywords:  clinical studies; drug delivery; multidrug resistance; non-clinical studies; paclitaxel; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2022.933457
  51. Chem Rec. 2022 Sep 14. e202200152
    Advances in Engineered Biomaterials Targeting Angiogenesis and Cell Proliferation for Cancer Therapy.
    Poonam Yadav, Chhavi Dua, Avinash Bajaj.
      Antiangiogenic therapy in combination with chemotherapeutic agents is an effective strategy for cancer treatment. However, this combination therapy is associated with several challenges including non-specific biodistribution leading to systemic toxicity. Biomaterial-mediated codelivery of chemotherapeutic and anti-angiogenic agents can exploit their passive and active targeting abilities, leading to improved drug accumulation at the tumor site and therapeutic outcomes. In this review, we present the progress made in the field of engineered biomaterials for codelivery of chemotherapeutic and antiangiogenic agents. We present advances in engineering of liposome/hydrogel/micelle-based biomaterials for delivery of combination of anticancer and anti-angiogenesis drugs, or combination of anticancer and siRNA targeting angiogenesis, and targeted nanoparticles. We then present our perspective on developing strategies for targeting angiogenesis and cell proliferation for cancer therapy.
    Keywords:  Angiogenesis; Anticancer Drugs; Cancer; Hydrogels; Nanomicelles; Nanoparticles
    DOI:  https://doi.org/10.1002/tcr.202200152
  52. Int J Biol Macromol. 2022 Sep 10. pii: S0141-8130(22)02000-1. [Epub ahead of print]
    Octenyl-succinylated inulins for the delivery of hydrophobic drug.
    Lingyu Han, Jiao Sun, Peter A Williams, Jixin Yang, Shubiao Zhang.
      The efficacy of hydrophobic anticancer drugs is limited by their poor solubility in water, inefficient target delivery, and toxic side effects. In this work, doxorubicin (DOX) was solubilized using OSA-inulins which created micellar aggregates in aqueous solution above a critical concentration. In vitro delivery of OSA-inulin-DOX micelles resulted in strong inhibition of the growth of MCF-7 breast cancer cells as compared to free DOX. They also displayed a faster cellular uptake rate, indicating that the micelles were promptly internalized into the cells through CD44 receptor-mediated endocytosis. During in vivo tumor suppression experiments in tumor-bearing mice, the OSA-inulin-DOX micelles strongly hindered tumor growth and showed substantially lower systemic toxicity compared with free DOX. Our achievements demonstrate that OSA-inulin has great potential for the encapsulating, dissolving, and targeted delivery of hydrophobic drugs, especially antitumor drugs, for nutraceutical, medical, and pharmaceutical applications.
    Keywords:  Encapsulation; Octenyl-succinylated inulin; Release
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.068
  53. Mater Today Bio. 2022 Dec;16 100421
    Nanozyme-laden intelligent macrophage EXPRESS amplifying cancer photothermal-starvation therapy by responsive stimulation.
    Yan Zhang, Kunpeng Wang, Guozheng Xing, Xia Dong, Dunwan Zhu, Wenzhi Yang, Lin Mei, Feng Lv.
      Precise delivery and responsive activation of therapeutic agents are critical for tumor precise therapy. Herein, inspired by intelligent express, a nanozyme-laden intelligent macrophage express was fabricated based on IR 820-macrophage loaded with GOx nanozymes for tumor-targeted photothermal-amplified starvation therapy with fluorescence imaging guidance. The nanozyme-laden intelligent macrophage express exerted precise delivery through cargo loading, conveying and unloading. For efficient cargo loading, H2O2-sensitive GOx nanozymes with blocked enzymatic activity were packaged on macrophage expresses with excellent phagocytic ability. Due to the inherent tumor tropism, the therapeutic agents-laden macrophage expresses naturally accumulated at tumor site with fluorescence navigation to track the conveying process. The spatiotemporal unpacking of the laden therapeutic agents at tumor site was triggered by the external laser for the macrophage express photothermal property. The released special tumor-microenvironment responsive GOx nanozymes were activated by H2O2 in tumor to start starvation therapy. Photothermal therapy generated mild hyperthermia and starvation therapy produced H2O2 further increased the nanozymes enzymatic activity, enhancing GOx-mediated starvation therapy. The nanozyme-laden intelligent macrophage express integrated laser-induce drug release and activation, tumor microenvironment-responsiveness, and circular amplification property, achieving the synergistic effects of PTT and starvation therapy in vitro and in vivo.
    Keywords:  Cancer photothermal-starvation therapy; Environment-responsiveness; Macrophages express; Nanozyme; Precise delivery
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100421
  54. Acta Pharmacol Sin. 2022 Sep 16.
    Multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines.
    Chuan Li, Wei-Wei Jia, Jun-Ling Yang, Chen Cheng, Olajide E Olaleye.
      Traditional medicine has provided a basis for health care and disease treatment to Chinese people for millennia, and herbal medicines are regulated as drug products in China. Chinese herbal medicines have two features. They normally possess very complex chemical composition. This makes the identification of the constituents that are together responsible for the therapeutic action of an herbal medicine challenging, because how to select compounds from an herbal medicine for pharmacodynamic study has been a big hurdle in such identification efforts. To this end, a multi-compound pharmacokinetic approach was established to identify potentially important compounds (bioavailable at the action loci with significant exposure levels after dosing an herbal medicine) and to characterize their pharmacokinetics and disposition. Another feature of Chinese herbal medicines is their typical use as or in combination therapies. Coadministration of complex natural products and conventional synthetic drugs is prevalent worldwide, even though it remains very controversial. Natural product-drug interactions have raised wide concerns about reduced drug efficacy or safety. However, growing evidence shows that incorporating Chinese herbal medicines into synthetic drug-based therapies delivers benefits in the treatment of many multifactorial diseases. To address this issue, a drug-combination pharmacokinetic approach was established to assess drug-drug interaction potential of herbal medicines and degree of pharmacokinetic compatibility for multi-herb combination and herbal medicine-synthetic drug combination therapies. In this review we describe the methodology, techniques, requirements, and applications of multi-compound and drug-combination pharmacokinetic research on Chinese herbal medicines and to discuss further development for these two types of pharmacokinetic research.
    Keywords:  Chinese herbal medicine; drug-combination pharmacokinetic research; multi-compound pharmacokinetic research; pharmacokinetic compatibility; pharmacokinetics
    DOI:  https://doi.org/10.1038/s41401-022-00983-7
  55. Adv Mater. 2022 Sep 15. e2206659
    Activity-Based Photosensitizer to Reverse Hypoxia and Oxidative Resistance for Tumor Photodynamic Eradication.
    Leilei Shi, Peng Zhang, Xiaoxiao Liu, Yuzhen Li, Wenbo Wu, Xihui Gao, Bin Liu.
      Photodynamic therapy (PDT) has been a well-accepted clinical treatment for malignant tumors owing to its non-invasiveness and high spatiotemporal selectivity. However, the treatment outcome of current PDT applications is hindered by hypoxia and intracellular oxidative resistance of solid tumors. Recent studies showed that inhibiting histone deacetylases (HDACs) could induce cell ferroptosis, reverse hypoxia and elevate oxidative status. Theoretically, the design and synthesis of activity-based photosensitizers that target HDACs could address the bottlenecks of PDT. Herein, we present a concept of activity-based photosensitizer for targeting HDACs, which was designed based on a quinoxalinone scaffold through a pharmacophore migration strategy. The developed activity-based photosensitizer could inhibit HDACs, and overcome hypoxia and intracellular oxidative resistance, realizing the full potential of photosensitizers for malignant tumor treatment. The molecular design strategy proposed in this project should provide theoretical guidance for the development of ideal photosensitizers for practical applications. This article is protected by copyright. All rights reserved.
    Keywords:  (activity-based photosensitizer; histone deacetylases; hypoxia; oxidative resistance; photodynamic eradication)
    DOI:  https://doi.org/10.1002/adma.202206659
  56. Int J Biol Macromol. 2022 Sep 08. pii: S0141-8130(22)01961-4. [Epub ahead of print]
    Functional gelatin hydrogel scaffold with degraded-release of glutamine to enhance cellular energy metabolism for cartilage repair.
    Ran Yang, Xu Zhang, Jiahui Liu, Xiaoyuan Li, Dongfang Zhou, Shifang Luan.
      Cartilage defect is one of the most common pathogenesis of osteoarthritis (OA), a degenerative joint disease that affects millions of people globally. Due to lack of nutrition and local metabolic inertia, the repair of cartilage has always been a difficult problem to be urgently solved. Herein, a functional gelatin hydrogel scaffold (GelMA-AG) chemically modified with alanyl-glutamine (AG) is proposed and prepared. The GelMA-AG can release glutamine through in vivo degradation that can activate the energy metabolism process of chondrocytes, thus effectively promoting damaged cartilage repair. The results demonstrate that compared with the AG-free gelatin hydrogel (GelMA), GelMA-AG exhibits an increase in both the mitochondrial membrane potential level and the production of intracellular adenosine triphosphate (ATP), while the intracellular reactive oxygen species (ROS) of chondrocytes is decreased, thus contributing to the higher level of cellular metabolism and the lower inflammation in cartilage tissue. In contrast to GelMA (Reduced Modulus (Er): 24.33 MPa), the Er value of the remodeled rabbit knee articular cartilage is up to 70.14 MPa, which is more comparable to natural cartilage. In particular, this strategy does not involve exogenous cells and growth factors, and the therapeutic strategy of actively regulating the metabolic microenvironment through a functional gelatin hydrogel scaffold represents a new and prospective idea for the design of tissue engineering biomaterials in cartilage repair with simplification and effectiveness.
    Keywords:  Cartilage repair; Energy metabolism; Gelatin hydrogel; Glutamine
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.039
  57. Toxicol Mech Methods. 2022 Sep 11. 1-27
    Comparison of the effect of vitamin C and selenium nanoparticles on gentamicin-induced renal impairment in male rats: A biochemical, molecular and histological study.
    Su Zheng, Afrah Hameed Sultan, Prshng Tofiq Kurtas, Layla Abdulsattar Kareem, Abolfazl Akbari.
      Renal failure caused by gentamicin is mainly mediated through oxidative damage, inflammation, and apoptosis. Hence, vitamin C and selenium, which have antioxidant, anti-inflammatory, and anti-apoptotic properties, and their nanoparticle forms, which have recently received attention, may reduce gentamicin-induced side effects. Therefore, the aim of this study was to investigate the therapeutic effects of vitamin C and selenium, and their nanoparticles on gentamicin-induced renal damage in male rats. 128 adult male Wistar rats were randomly divided into equal sixteen controlled and treated groups. Serum levels of uric acid, blood urea nitrogen, urea, and creatinine were measured. Renal levels of oxidative parameters such as MDA, SOD, and CAT and inflammatory parameters including IL-1β, and TNF-α were measured. Renal expression of Nrf2, NF-κB, Bcl2, caspase-3, BAX and mTORc1 was also evaluated. The results showed that gentamicin causes oxidative damage, inflammation, apoptosis and disruption of autophagy in kidney tissue in a dose-dependent manner. However, treatment with vitamin C, selenium and their nanoparticles could significantly improve these effects. Also, the results showed that the inflammatory and oxidative parameters and the expression of genes involved in them and apoptosis in the gentamicin groups treated with vitamin C nanoparticles and selenium nanoparticles reduced significantly compared to those treated with vitamin C and selenium. It can be concluded that vitamin C, selenium and their nanoparticles can improve gentamicin-induced kidney damage by inhibiting oxidative damage, inflammation and apoptosis-induced by autophagy, and can be a good option for kidney damage caused by gentamicin or as an adjunctive treatment to reduce its side effects.
    Keywords:  Gentamicin; Nephrotoxicity; Selenium Nanoparticle; Vitamin C Nanoparticle
    DOI:  https://doi.org/10.1080/15376516.2022.2124136
  58. Crit Rev Food Sci Nutr. 2022 Sep 13. 1-19
    Kaempferol and atherosclerosis: From mechanism to medicine.
    Meijie Chen, Jianbo Xiao, Hesham R El-Seedi, Krystyna Skalicka Woźniak, Maria Daglia, Peter J Little, Jianping Weng, Suowen Xu.
      Natural products possess pleiotropic cardiovascular protective effects owing to their anti-oxidation, anti-inflammation and anti-thrombotic properties. Kaempferol, (3,5,7-trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), is a kind of naturally occurring flavonoid existing in many common fruits and vegetables (e.g., onions, broccoli, strawberries and grapes) and particularly in traditional Chinese medicine as exemplified by Ginkgo biloba. Epidemiological, preclinical and clinical studies have revealed an inverse association between the consumption of kaempferol-containing foods and medicines and the risk of developing cardiovascular diseases. Numerous translational studies in experimental animal models and cultured cells have demonstrated a wide range of pharmacological activities of kaempferol. In this article, we reviewed the antioxidant, anti-inflammatory and cardio-protective activities of kaempferol and elucidated the potential molecular basis of the therapeutic capacity of kaempferol by focusing on its anti-atherosclerotic effects. Overall, the review presents the health benefits of kaempferol-containing plants and medicines and reflects on the potential of kaempferol as a possible drug candidate to prevent and treat atherosclerosis, the underlying pathology of most cardiovascular diseases.
    Keywords:  Kaempferol; anti-inflammatory effects; antioxidant; cardiovascular diseases; medicinal plants
    DOI:  https://doi.org/10.1080/10408398.2022.2121261
  59. Cancer Res. 2022 Sep 13. pii: CAN-22-1475. [Epub ahead of print]
    Loss of MLL induces epigenetic dysregulation of Rasgrf1 to attenuate Kras-driven lung tumorigenesis.
    Ling-Yu Zhu, Jun-Bo Yuan, Li Zhang, Chun-Xiao He, Xiao Lin, Bin Xu, Guang-Hui Jin.
      Menin is necessary for the formation of the menin/MLL complex and is recruited directly to chromatin. Menin is an important tumor suppressor in several cancer types, including lung cancer. Here, we investigated the role of MLL in menin-regulated lung tumorigenesis. Ablation of MLL suppressed KrasG12D-induced lung tumorigenesis in a genetically-engineered mouse model. MLL deficiency decreased histone H3 lysine 4 trimethylation (H3K4me3) and subsequently suppressed expression of the Ras protein-specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene. Rasgrf1 was essential for the GTP-bound active state of Kras and the activation of Kras downstream pathways as well as their cancer-promoting activities. MI-3, a small molecule inhibitor targeting MLL, specifically inhibited the growth of Kras-mutated lung cancer cells in vitro and in vivo with minimal effect on wild-type Kras lung cancer growth. Together, these results demonstrate a novel tumor promoter function of MLL in mutant Kras-induced lung tumorigenesis and further indicate that specific blockade of the MLL-Rasgrf1 pathway may be a potential therapeutic strategy for the treatment of tumors containing Kras mutations.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1475
  60. Int J Biol Macromol. 2022 Sep 07. pii: S0141-8130(22)01936-5. [Epub ahead of print]
    Curcumin encapsulated polylactic acid nanoparticles embedded in alginate/gelatin bioinks for in situ immunoregulation: Characterization and biological assessment.
    Fernanda Zamboni, Guang Ren, Mario Culebras, John O'Driscoll, Jack O'Dwyer, Elizabeth J Ryan, Maurice N Collins.
      Curcumin is a known naturally occurring anti-inflammatory agent derived from turmeric, and it is commonly used as a herbal food supplement. Here, in order to overcome the inherent hydrophobicity of curcumin (Cur), polylactic acid (PLA) nanoparticles (NPs) were synthesised using a solvent evaporation, and an oil-in-water emulsion method used to encapsulate curcumin. Polymeric NPs also offer the ability to control rate of drug release. The newly synthesised NPs were analysed using a scanning electron microscope (SEM), where results show the NPs range from 50 to 250 nm. NPs containing graded amounts of curcumin (0 %, 0.5 %, and 2 %) were added to cultures of NIH3T3 fibroblast cells for cytotoxicity evaluation using the Alamar Blue assay. Then, the curcumin NPs were incorporated into an alginate/gelatin solution, prior to crosslinking using a calcium chloride solution (200 nM). These hydrogels were then characterised with respect to their chemical, mechanical and rheological properties. Following hydrogel optimization, hydrogels loaded with NP containing 2 % curcumin were selected as a candidate as a bioink for three-dimensional (3D) printing. The biological assessment for these bioinks/hydrogels were conducted using THP-1 cells, a human monocytic cell line. Cell viability and immunomodulation were evaluated using lactate dehydrogenase (LHD) and a tumour necrosis factor alpha (TNF-α) enzyme-linked immunosorbent (ELISA) assay, respectively. Results show that the hydrogels were cytocompatible and supressed the production of TNF-α. These bioactive hydrogels are printable, supress immune cell activation and inflammation showing immense potential for the fabrication of tissue engineering constructs.
    Keywords:  Alginate; Bioink; Curcumin; Hydrogel; Immunomodulation; Intervertebral disc degeneration; Nanoparticles
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.014
  61. Cell Commun Signal. 2022 Sep 14. 20(1): 142
    Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo.
    Yuchen Zhang, Cheukfai Li, Chenglai Xia, Keneth Kin Wah To, Zhixing Guo, Chongyang Ren, Lingzhu Wen, Fang Wang, Liwu Fu, Ning Liao.
       BACKGROUND: Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849.
    METHODS: The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses.
    RESULTS: MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations.
    CONCLUSIONS: In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR. Video Abstract.
    Keywords:  ABC transporters; Adagrasib (MRTX849); Cancer chemotherapy; KRAS mutation; Multidrug resistance
    DOI:  https://doi.org/10.1186/s12964-022-00955-8
  62. Carbohydr Polym. 2022 Nov 15. pii: S0144-8617(22)00871-2. [Epub ahead of print]296 119966
    Basil seed gum promotes the electrospinnability of WPI for co-encapsulation of ZnO nanoparticles and curcumin.
    Marjan Larki, M H Enayati, Hadis Rostamabadi.
      The incorporation of carbohydrate polymers is one of the most efficient strategies to reinforce protein matrices for electrospinning application. In the present work, a basil seed gum (BSG)-reinforced whey protein isolate (WPI) was developed via electrospinning for the co-encapsulation of zinc oxide nanoparticles (ZnONPs) and curcumin (CU). The physicochemical attributes of the nanofiber samples could be controlled by varying the BSG mixing ratio. The Field emission scanning electron microscopy images showed bead-free morphology of WPI/BSG/ZnONPs/CU nanofibers with average fiber diameter of around 362 ± 41 nm. The formation of new H2 bonds after introduction of BSG and active components was corroborated by Fourier-transform infrared spectroscopy. The nanofibers loaded with ZnONPs/CU displayed improved surface hydrophobicity and high potential for hampering colon cancer cells in vitro. The results proved that the proposed electrospun structures were thermally stable and composed by homogenous nanofibers of high bactericide properties, thus representing promising structures suitable for various biomedical applications.
    Keywords:  Basil seed gum; Curcumin; Curcumin (PubChem CID: 969516); Dimethyl sulfoxide (PubChem CID: 679); Electrospinning; Hexane (PubChem CID: 8058); Hydrochloric acid (PubChem CID: 313); Methanol (PubChem CID: 887); Nanofibers; Sodium hydroxide (PubChem CID: 14798); Whey protein isolate; ZnO NPs (PubChem CID: 14806); ZnO nanoparticles
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119966
  63. J Colloid Interface Sci. 2022 Aug 22. pii: S0021-9797(22)01497-7. [Epub ahead of print]629(Pt A): 522-533
    The combination of in situ photodynamic promotion and ion-interference to improve the efficacy of cancer therapy.
    Pengfei Yang, Yi Chang, Jie Zhang, Fangli Gao, Xinhe Liu, Qingcong Wei, Xiaoming Ma, Yuming Guo.
      Photodynamic therapy (PDT) is proved to be a promising modality for clinical cancer treatment. However, it also suffers from a key obstacle in association with its oxygen-dependent nature which greatly limits its effective application against hypoxic tumors. Herein, on the basis of the unique property of calcium peroxide (CaO2), we propose an O2-self-supply strategy for the promotion of PDT by combining the in situ O2-generation characteristic of calcium peroxide with the photosensitive nature of porphyrin. A shell of ZIF-8 was synthesized surround the CaO2 core to prevent the CaO2 from premature decomposition and increased the loading of THPP efficiently. Depending on the in situ self-supply of O2, the photosensitizer was able to exhibit an enhanced PDT effect that significantly inhibit the growth of tumor. Moreover, the enrichment of free calcium ions derived from the decomposition of CaO2 under acidic tumor microenvironment also shows the unique ion-interference effect and contributes to the obvious inhibition against tumor growth. This work presents a synergistic strategy for the construction of a photodynamic promotion/ion-interference combined nano-platform which can also serve as an inspiration for the future design of effective nanocomposites in tumor treatment.
    Keywords:  Calcium peroxide; In situ O(2)-generation; Ion-interference; Photodynamic therapy; Synergistic effect
    DOI:  https://doi.org/10.1016/j.jcis.2022.08.125
  64. Curr Opin Clin Nutr Metab Care. 2022 Sep 15.
    Diet and the microbiota-gut-brain-axis: a primer for clinical nutrition.
    Gabriela Ribeiro, Aimone Ferri, Gerard Clarke, John F Cryan.
       PURPOSE OF REVIEW: Diet is an essential modulator of the microbiota-gut-brain communication in health and disease. Consequently, diet-induced microbiome states can impact brain health and behaviour. The integration of microbiome into clinical nutrition perspectives of brain health is sparse. This review will thus focus on emerging evidence of microbiome-targeted dietary approaches with the potential to improve brain disorders.
    RECENT FINDINGS: Research in this field is evolving toward randomized controlled trials using dietary interventions with the potential to modulate pathways of the microbiota-gut-brain-axis. Although most studies included small cohorts, the beneficial effects of Mediterranean-like diets on symptoms of depression or fermented foods on the immune function of healthy individuals shed light on how this research line can grow. With a clinical nutrition lens, we highlight several methodological limitations and knowledge gaps, including the quality of dietary intake information, the design of dietary interventions, and missing behavioural outcomes.
    SUMMARY: Findings in diet-microbiome-brain studies can have groundbreaking implications in clinical nutrition practice and research. Modulating brain processes through diet via the gut microbiota raises numerous possibilities. Novel dietary interventions targeting the microbiota-gut-brain-axis can offer various options to prevent and treat health problems such as mental disorders. Furthermore, knowledge in this field will improve current nutritional guidelines for disease prevention.
    DOI:  https://doi.org/10.1097/MCO.0000000000000874
  65. Int J Biol Macromol. 2022 Sep 12. pii: S0141-8130(22)01986-9. [Epub ahead of print]
    Chitosan-based scaffolds as drug delivery systems in bone tissue engineering.
    R Bharathi, S Shree Ganesh, G Harini, Kumari Vatsala, R Anushikaa, S Aravind, S Abinaya, N Selvamurugan.
      The bone tissue engineering approach for treating large bone defects becomes necessary when the tissue damage surpasses the threshold of the inherent regenerative ability of the human body. A myriad of natural biodegradable polymers and scaffold fabrication techniques have emerged in the last decade. Chitosan (CS) is especially attractive as a bone scaffold material to support cell attachment and proliferation and mineralization of the bone matrix. The primary amino groups in CS are responsible for properties such as controlled drug release, mucoadhesion, in situ gelation, and transfection. CS-based smart drug delivery scaffolds that respond to environmental stimuli have been reported to have a localized sustained delivery of drugs in the large bone defect area. This review outlines the recent advances in the fabrication of CS-based scaffolds as a pharmaceutical carrier to deliver drugs such as antibiotics, growth factors, nucleic acids, and phenolic compounds for bone tissue regeneration.
    Keywords:  Bone tissue engineering; Chitosan; Drug delivery; Osteomimetic; Scaffolds
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.058
  66. Curr Drug Deliv. 2022 Sep 14.
    A Comprehensive Insight on Recent Advancements in Self Emulsifying Drug Delivery Systems.
    Renu Kadian, Arun Nanda.
      A large proportion of new chemical moieties are poorly water-soluble. As a result, the biggest challenge for researchers is to enhance the solubility and oral bioavailability of lipophilic drugs. Self-emulsifying systems offer immense potential for improving lipophilic drugs' oral bioavailability and solubility through various mechanisms such as: inhibiting efflux transporters, absorption of the lipophilic drug through the lymphatic system, and bypassing hepatic first-pass metabolism. These systems dissolve hydrophobic drugs, allowing them to be delivered as a unit dose form for oral administration. Despite much potential, issues like stability, low drug loading, packaging, etc., are associated with the self-emulsifying technique. This review discusses conventional Self-Emulsifying Drug Delivery Systems (SEDDS), which are used to deliver poorly water-soluble drugs. Recent advancements in self-emulsifying systems to solve the issues associated with conventional SEDDS are described exhaustively, including their methodologies and excipients utilized for preparation. The current article also furnishes the literature review on recent advancements in self-emulsifying systems. Recent advances in SEDDS can be seen as a great option for overcoming oral bioavailability, stability, and solubility issues of lipophilic drugs. Solid-self emulsifying system can be used to improve the stability of the formulation, hydrophobic ion-pairing for improving mucus permeation properties, while supersaturatable-self emulsifying systems with a low concentration of surfactant to overcome issues such as precipitation of drug after dilution and gastrointestinal related side effects. The day will come when medicine companies will see the value of self-emulsifying system developments and will adopt this technology for next-generation product releases.
    Keywords:  Eutectic; hydrophobic ion pairing; lipophilic drugs; osmotic; phospholipid complex; self double emulsifying drug delivery systems; self emulsifying drug delivery systems
    DOI:  https://doi.org/10.2174/1567201819666220914113324
  67. Oxid Med Cell Longev. 2022 ;2022 2187696
    Bovine Lactoferrin Induces Cell Death in Human Prostate Cancer Cells.
    Vanessa P Rocha, Samir P C Campos, Caroline A Barros, Pablo Trindade, Leticia R Q Souza, Triciana G Silva, Etel R P Gimba, Anderson J Teodoro, Rafael B Gonçalves.
      Bovine lactoferrin (bLf) is a multifunctional protein widely associated with anticancer activity. Prostate cancer is the second most frequent type of cancer worldwide. This study was aimed at evaluating the influence of bLf on cell viability, cell cycle progression, reactive oxygen species (ROS) production, and rate of apoptosis in the human prostate cancer cell line (DU-145). MTT assay and trypan blue exclusion were used to analyze cell viability. Morphological changes were analyzed through optical microscopy after 24 h and 48 h of bLf treatment. FITC-bLf internalization and cellular damage were observed within 24 h by confocal fluorescence microscopy. Cell cycle analyses were performed by flow cytometry and propidium iodide. For caspases 3/7 activation and reactive oxygen species production evaluation, cells were live-imaged using the high-throughput system Operetta. The cell viability assays demonstrated that bLf induces cell death and morphological changes after 24 h and 48 h of treatment compared to control on DU-145 cells. The bLf internalization was detected in DU-145 cells, G1-phase arrest of the cell cycle, caspase 3/7 activation, and increased oxidative stress on bLf-treated cells. Our data support that bLf has an important anticancer activity, thus offering new perspectives in preventing and treating prostate cancer.
    DOI:  https://doi.org/10.1155/2022/2187696
  68. J Food Biochem. 2022 Sep 15. e14415
    Naringenin: A prospective therapeutic agent for Alzheimer's and Parkinson's disease.
    Ahsas Goyal, Aanchal Verma, Nandini Dubey, Jyoti Raghav, Anant Agrawal.
      Neurodegenerative disorders (NDs) are a cluster of progressive, severe, and disabling disorders that affect millions of people worldwide and are on the surge. These disorders are characterized by the gradual loss of a selectively vulnerable group of neurons. Due to the complex pathophysiological mechanisms behind neurodegeneration and despite enormous efforts and understanding of the occurrence and progression of NDs, there is still a lack of an effective treatment for such diseases. Therefore, the development of a new therapeutic strategy for NDs is an unmet clinical need. Various natural compounds extracted from medicinal plants or fruits have shown promising activities in treating different types of NDs by targeting multiple signaling pathways. Among natural entities, flavonoids have incited a rise in public and scientific interest in recent years because of their purported health-promoting effects. Dietary supplementation of flavonoids has been shown to mitigate the severity of NDs such as Parkinson's disease (PD), Alzheimer's disease (AD), and dementia by their antioxidant effects. Naringenin is a citrus flavonoid that is known to possess numerous biological activities like antioxidant, anti-proliferative, and anti-inflammatory activities. Therefore, naringenin has emerged as a potential therapeutic agent that exerts preventive and curative effects on several neurological disorders. Increasing evidence has attained special attention on the variety of therapeutic targets along with complex signaling pathways of naringenin, which suggest its possible therapeutic applications in several NDs. Derived from the results of several pre-clinical research and considering the therapeutic effects of this compound, this review focuses on the potential role of naringenin as a pharmacological agent for the treatment and management of Alzheimer's and Parkinson's disease. The overall neuroprotective effects and different possible underlying mechanisms related to naringenin are discussed. In the light of substantial evidence for naringenin's neuroprotective efficacy in several experimental paradigms, this review suggests that this molecule should be investigated further as a viable candidate for the management of Alzheimer's and Parkinson's disease, with an emphasis on mechanistic and clinical trials to determine its efficacy. PRACTICAL APPLICATIONS: Naringenin is a flavanone, aglycone of Naringin, predominantly found in citrus fruits with a variety of pharmacological actions. Naringenin has been shown to exhibit remarkable therapeutic efficacy and has emerged as a potential therapeutic agent for the management of a variety of diseases such as various heart, liver, and metabolic disorders. Similarly, it has shown efficacy in neurodegenerative illnesses. Therefore, this review enables us to better understand the neuroprotective effects and different possible underlying mechanisms of naringenin. Also, this review provides a new indication to manage the symptoms of NDs like AD and PD. Furthermore, naringenin will be useful in the field of medicine as a new active ingredient for the treatment of neurodegenerative disorders like AD and PD.
    Keywords:  Alzheimer's disease; Parkinson's disease; naringenin; neurodegenerative disorders
    DOI:  https://doi.org/10.1111/jfbc.14415
  69. Front Pharmacol. 2022 ;13 910292
    System Xc -/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy.
    Feng-Jiao Li, Hui-Zhi Long, Zi-Wei Zhou, Hong-Yu Luo, Shuo-Guo Xu, Li-Chen Gao.
      The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc -), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc -/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc -/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc -/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.
    Keywords:  drug resistance; ferroptosis; solid tumor; system Xc -/GSH/GPX4 axis; therapy
    DOI:  https://doi.org/10.3389/fphar.2022.910292
  70. EXCLI J. 2022 ;21 840-851
    Effects of curcumin on low-density lipoprotein oxidation: From experimental studies to clinical practice.
    Fatemeh Baratzadeh, Alexandra E Butler, Prashant Kesharwani, Seyed Adel Moallem, Amirhossein Sahebkar.
      Atherosclerosis is the most frequent cause of death globally. Oxidized low-density lipoprotein (ox-LDL) has an essential role in the formation of atherosclerotic plaques and foamy macrophages. Ox-LDL increases the uptake of cholesterol by macrophages and is the major cause of blood flow disruption. Ox-LDL is produced during oxidative stress and treatment with antioxidants could inhibit the production and function of ox-LDL. Curcumin is a potent antioxidant and has a strong track record in the treatment of numerous diseases. Recent studies indicate that Curcumin exerts a lipid-lowering effect, and can modulate the formation of atherosclerotic plaque. The current review focuses upon the role of Curcumin in oxidation of LDL and foam cell formation in atherosclerotic lesions.
    Keywords:  Curcuma longa; Curcumin; Turmeric; anti-ox-LDL; ox-LDL; oxidized low density lipoprotein
    DOI:  https://doi.org/10.17179/excli2022-4878
  71. Front Oncol. 2022 ;12 938502
    Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy.
    Yuheng Zou, Hongying Zhang, Feng Bi, Qiulin Tang, Huanji Xu.
      Cholesterol metabolism is often dysregulated in cancer. Squalene monooxygenase (SQLE) is the second rate-limiting enzyme involved in cholesterol synthesis. Since the discovery of SQLE dysregulation in cancer, compelling evidence has indicated that SQLE plays a vital role in cancer initiation and progression and is a promising therapeutic target for cancer treatment. In this review, we provide an overview of the role and regulation of SQLE in cancer and summarize the updates of antitumor therapy targeting SQLE.
    Keywords:  cancer treatment; cell proliferation and migration; cholesterol metabolism; drug target; squalene epoxidase
    DOI:  https://doi.org/10.3389/fonc.2022.938502
  72. Transl Cancer Res. 2022 Aug;11(8): 2553-2561
    Tumor-treating fields in combination with sorafenib curtails the growth of colorectal carcinoma by inactivating AKT/STAT3 signaling.
    Eun Ho Kim, Won Seok Lee, Hoon-Kyu Oh.
       Background: Tumor-treating fields (TTFields) have been extensively used to treat various cancers as well as glioblastoma multiforme (GBM), owing to their antimitotic effects. Furthermore, sorafenib is also extensively used to treat hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC) and is under phase II/III clinical trials for other solid tumors. Hence, this investigation aimed to assess the efficacy of combination therapy with TTFields and sorafenib for colorectal carcinoma (CRC).
    Methods: Human CRC HCT116 and SW480 cells were subjected to cell viability assay, followed by the assessment of their cell death using fluorescence-activated cell sorting (FACS) analysis. Furthermore, the expression of proteins involved in AKT/STAT3 signaling and apoptosis was assessed via western blotting.
    Results: Combination treatment inhibited cell proliferation and induced apoptosis via Reactive oxygen species (ROS) generation, evident from caspase-3 cleavage in CRC cells and suppressed the AKT/STAT3 signaling pathway, as evident from downregulation of BCL-2 after post-treatment. The present results indicate that combination treatment with TTFields and sorafenib inactivates AKT/STAT3 signaling pathway, thus altering the expression of BCL-2, thus inducing apoptosis and inhibiting the growth of CRC cells.
    Conclusions: Thus, combination treatment with TTFields and sorafenib is clinically applicable for treating metastatic CRC, although safety examination in patients with CRC will required to be achieved before this protocol can be implemented clinically for TTFields-sensitizer.
    Keywords:  AKT; STAT3; Tumor-treating fields (TTFields); colorectal carcinoma (CRC); sorafenib
    DOI:  https://doi.org/10.21037/tcr-21-1853
  73. Saudi J Biol Sci. 2022 Oct;29(10): 103426
    Exploration of metabolic responses towards hypoxia mimetic DMOG in cancer cells by using untargeted metabolomics.
    Mohammad Imran Khan.
      Hypoxia is considered as one of the most crucial elements of tumor microenvironment. The hypoxia inducible transcription factors (HIF-1/2) are used by the cancer cells to adapt hypoxic microenvironment through regulating the expression of various target genes, including metabolic enzymes. Dimethyloxalylglycine (DMOG), a hypoxic mimetic used for HIF stabilisation in cell and animal models, also demonstrates multiple metabolic effects. In past, it was shown that in cancer cells, DMOG treatment alters mitochondrial ATP production, glycolysis, respiration etc. However, a global landscape of metabolic level alteration in cancer cells during DMOG treatment is still not established. In the current work, the metabolic landscape of cancer cells during DMOG treatment is explored by using untargeted metabolomics approach. Results showed that DMOG treatment primarily alters the one carbon and lipid metabolism. The levels of one-carbon metabolism related metabolites like serine, ornithine, and homomethionine levels significantly altered during DMOG treatment. Further, DMOG treatment reduces the global fatty acyls like palmitic acids, stearic acids, and arachidonic acid levels in cancer cell lines. Additionally, we found an alteration in glycolytic metabolites known to be regulated by hypoxia in cancer cell lines. Collectively, the results provided novel insights into the metabolic impact of DMOG on cancer cells and showed that the use of DMOG to induce hypoxia yields similar metabolic features relative to physiological hypoxia.
    Keywords:  Dimethyloxalylglycine (DMOG); Fatty acyls; Hypoxia; Lipidomics; Untargeted Metabolomics
    DOI:  https://doi.org/10.1016/j.sjbs.2022.103426
  74. J Food Sci Technol. 2022 Sep 04. 1-11
    Capsicum fruits as functional ingredients with antimicrobial activity: an emphasis on mechanisms of action.
    Haydee Eliza Romero-Luna, Jhoana Colina, Lorena Guzmán-Rodríguez, Celia Gabriela Sierra-Carmona, Ángela María Farías-Campomanes, Santiago García-Pinilla, María Margarita González-Tijera, Karen Otilia Malagón-Alvira, Audry Peredo-Lovillo.
      Capsicum spp. fruits (CFs) are a basic ingredient in the diet and have been used as active ingredients in the pharmaceutical, cosmetic, and food products, due to their antioxidant, anti-inflammatory, antiseptic, and antimicrobial properties. The antimicrobial activity is the most studied property due to its effectiveness against pathogenic species, however, few studies have focused on the mechanisms of action involved. Therefore, this review discusses the effects generated by the CFs compounds on the viability and metabolism of microorganisms, highlighting the mechanisms by which these compounds exert their antimicrobial effects. The information provided shows that CFs are mainly source of capsaicinoids and phenolic compounds responsible for the inhibition of bacteria, yeasts, and fungi, through an increase in the permeabilization of the membrane and cell wall. Also, these compounds show an antiviral effect associated with the inactivation of virus binding proteins, preventing their replication and infection. Despite this, there is still a lack of information about the mechanisms that regulate the interactions between CFs compounds and food-important-microorganisms. Therefore, future research should focus on new antimicrobial compounds from CFs for their subsequent use against novel infectious agents, mainly virus of importance in health such as SARS-CoV-2.
    Keywords:  Capsaicin; Hydroxycinnamic acid; Lactic acid bacteria; Virus; Yeast
    DOI:  https://doi.org/10.1007/s13197-022-05578-y
  75. Curr Drug Targets. 2022 Sep 15.
    An Insight into Diverse Activities and Targets of Flavonoids.
    Prashant Tiwari, Rakhi Mishra, Avijit Mazumder, Rupa Mazumder, Ayushi Singh.
       BACKGROUND: Flavonoids belong to the chemical class of polyphenols and are in the category of secondary metabolites imparting a wide protective effect against acute and chronic diseases.
    OBJECTIVE: The study aims to investigate and summarize the information of various flavonoids which were extracted, isolated from various sources, and possess different pharmacological properties by acting on multiple targets.
    METHODS: This comprehensive review summarizes the research information related to flavonoids and their pharmacological action targets from various sources like PubMed. google scholar and google websites.
    RESULT: Extracted information in the paper discusses various therapeutic effects of flavonoids isolated from medicinal plant sources which have the property to inhibit several enzymes which finally results in health benefits like anti-cancer, anti-bacterial, antioxidant, anti-allergic, and anti-viral effects. This study also showed the different solvents and methods involved in the extraction and characterization of the isolated phytochemical constituents.
    CONCLUSION: The findings showed the contribution of several flavonoids in the management and inhibition of various acute and chronic sicknesses by acting on different sites in the body. This study may lead to gaining the interest for more research on the bioactives of different medicinal plants for the discovery of new lead compounds or further improvement of the efficacy of the existing compound.
    Keywords:  Bioactive; Flavonoids; Medicinal Plants; Phytochemicals; Secondary Metabolites; Targets
    DOI:  https://doi.org/10.2174/1389450123666220915121236
  76. Cancer Cell Int. 2022 Sep 15. 22(1): 284
    Recent advances and limitations of mTOR inhibitors in the treatment of cancer.
    Eunus S Ali, Kangkana Mitra, Shamima Akter, Sarker Ramproshad, Banani Mondal, Ishaq N Khan, Muhammad Torequl Islam, Javad Sharifi-Rad, Daniela Calina, William C Cho.
      The PI3K-Akt-mechanistic (formerly mammalian) target of the rapamycin (mTOR) signaling pathway is important in a variety of biological activities, including cellular proliferation, survival, metabolism, autophagy, and immunity. Abnormal PI3K-Akt-mTOR signalling activation can promote transformation by creating a cellular environment conducive to it. Deregulation of such a system in terms of genetic mutations and amplification has been related to several human cancers. Consequently, mTOR has been recognized as a key target for the treatment of cancer, especially for treating cancers with elevated mTOR signaling due to genetic or metabolic disorders. In vitro and in vivo, rapamycin which is an immunosuppressant agent actively suppresses the activity of mTOR and reduces cancer cell growth. As a result, various sirolimus-derived compounds have now been established as therapies for cancer, and now these medications are being investigated in clinical studies. In this updated review, we discuss the usage of sirolimus-derived compounds and other drugs in several preclinical or clinical studies as well as explain some of the challenges involved in targeting mTOR for treating various human cancers.
    Keywords:  Cancer; Rapamycin; Targeted therapy; mTOR inhibitors; mTOR pathway; mTORC1; mTORC2
    DOI:  https://doi.org/10.1186/s12935-022-02706-8
  77. Pharmacol Res. 2022 Sep 09. pii: S1043-6618(22)00387-5. [Epub ahead of print] 106442
    Bufalin for an innovative therapeutic approach against cancer.
    Laura Soumoy, Ghanem E Ghanem, Sven Saussez, Fabrice Journe.
      Bufalin is an endogenous cardiotonic steroid, first discovered in toad venom but also found in the plasma of healthy humans, with anti-tumour activities in different cancer types. The current review is focused on its mechanisms of action and highlights its very large spectrum of effects both in vitro and in vivo. All leads to the conclusion that bufalin mediates its effects by affecting all the hallmarks of cancer and seems restricted to cancer cells avoiding side effects. Bufalin decreases cancer cell proliferation by acting on the cell cycle and inducing different mechanisms of cell death including apoptosis, necroptosis, autophagy and senescence. Bufalin also moderates metastasis formation by blocking migration and invasion as well as angiogenesis and by inducing a phenotype switch towards differentiation and decreasing cancer cell stemness. Regarding its various mechanisms of action in cancer cells, bufalin blocks overactivated signalling pathways and modifies cell metabolism. Moreover, bufalin gained lately a huge interest in the field of drug resistance by both reversing various drug resistance mechanisms and affecting the immune microenvironment. Together, these data support bufalin as a quite promising new anti-cancer drug candidate.
    Keywords:  Bufalin (PubChem CID: 9547215); bufalin; cancer; cardiotonic steroid; digoxin (PubChem CID: 2724385); marinobufagenin (PubChem CID: 11969465); ouabain (PubChem CID: 439501)
    DOI:  https://doi.org/10.1016/j.phrs.2022.106442
  78. Mol Cancer Res. 2022 Sep 16. pii: MCR-22-0250. [Epub ahead of print]
    Subtype and site specific-induced metabolic vulnerabilities in prostate cancer.
    Federica Mossa, Daniele Robesti, Ramachandran Sumankalai, Eva Corey, Mark Titus, Yuqi Kang, Jianhua Zhang, Alberto Briganti, Francesco Montorsi, Christopher P Vellano, Joseph R Marszalek, Daniel E Frigo, Christopher J Logothetis, Taranjit S Gujral, Eleonora Dondossola.
      Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive-variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759's inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone. Implications: These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0250
  79. Math Biosci. 2022 Sep 12. pii: S0025-5564(22)00098-0. [Epub ahead of print] 108909
    A simulation of parental and glycolytic tumor phenotype competition predicts observed responses to pH changes and increased glycolysis after anti-VEGF therapy.
    Frederika Rentzeperis, Naomi Miller, Arig Ibrahim-Hashim, Robert J Gillies, Robert A Gatenby, Dorothy Wallace.
      Clinical cancers are typically spatially and temporally heterogeneous, containing multiple microenvironmental habitats and diverse phenotypes and/or genotypes, which can interact through resource competition and direct or indirect interference. A common intratumoral evolutionary pathway, probably initiated as adaptation to hypoxia, leads to the "Warburg phenotype" which maintains high glycolytic rates and acid production, even in normoxic conditions. Since individual cancer cells are the unit of Darwinian selection, intraspecific competition dominates intratumoral evolution. Thus, elements of the Warburg phenotype become key "strategies" in competition with cancer cell populations that retain the metabolism of the parental normal cells. Here we model the complex interactions of cell populations with Warburg and parental phenotypes as they compete for access to vasculature, while subject to direct interference by Warburg-related acidosis. In this competitive environment, vasculature delivers nutrients, removes acid and necrotic detritus, and responds to signaling molecules (VEGF and TNF-α). The model is built in a nested fashion and growth parameters are derived from monolayer, spheroid, and xenograft experiments on prostate cancer. The resulting model of in vivo tumor growth reaches a steady state, displaying linear growth and coexistence of both glycolytic and parental phenotypes consistent with experimental observations. The model predicts that increasing tumor pH sufficiently early can arrest the development of the glycolytic phenotype, while decreasing tumor pH accelerates this evolution and increases VEGF production. The model's predicted dual effects of VEGF blockers in decreasing tumor growth while increasing the glycolytic fraction of tumor cells has potential implications for optimizing angiogenic inhibitors.
    Keywords:  Acidosis; Anti-VEGF; Buffer therapy; Warburg effect
    DOI:  https://doi.org/10.1016/j.mbs.2022.108909
  80. Perspect Biol Med. 2022 ;65(3): 415-425
    Darwinian Repurposing of Molecular Motifs in an Evolving Redox Environment and Its Biomedical Implications.
    Joseph Loscalzo, Dan L Longo.
      The evolution of self-replicating biological species required the prebiotic evolution of fundamental chemical compounds that facilitate critical redox reactions, including chiefly the oxidation of water, the reduction of molecular oxygen, and redox transitions of partially reduced forms of oxygen (reactive oxygen species). The fundamental catalysts for these reactions are porphyrins. Chemically versatile, photoreactive, and redox-active, porphyrins (or their primary precursor, porphin) are believed to have evolved prebiotically in an enthalpically feasible series of reactions. Found throughout biological kingdoms, porphyrins were incorporated in apoproteins in biological evolution and adapted to the specific redox needs of the organisms in which they were active, including photosynthesis, reactive oxygen species metabolism, and oxidative phosphorylation. They did so by virtue of differing transition metal chelates and tetrapyrrole side chains. This article reviews the prebiotic and biotic evolution of porphyrins and porphyrin-bearing apoproteins and suggests that porphyrins' history in evolution reflects a repurposing of molecular motifs as an efficient mechanism for adaptation to a changing redox environment.
    DOI:  https://doi.org/10.1353/pbm.2022.0034
  81. Curr Drug Res Rev. 2022 Sep 13.
    Nanocarriers Based Ocular Therapeutics: Updates, Challenges and Future Prospectives.
    Udesh Kaushal, Malkiet Kaur, Manju Nagpal, Madhusmita Bhuyan, Kailasam Periyana Gounder.
       BACKGROUND: Ocular disorders mainly affect patient's eyesight and quality of life. Formulation scientists have a hurdle when it comes to drug distribution to ocular tissues. Anatomical barriers (static and dynamic), Physiological barriers such as nasolacrimal drainage system, blinking action of eye and metabolic barriers and efflux pumps; are the principal obstacles to medication delivery to the posterior and anterior parts. Over the last twenty years, ophthalmic research has evolved rapidly for the development of innovative, safe, and patient's friendly formulations and drug delivery devices or techniques that may get over these obstacles and sustain drug levels in tissues.
    METHODS: Literature from past ten years hass been collected using various search engines such as sciencedirect, j-gate, google scholar, pubmed, scihub etc. and research data has been complied according to various novel carrier systems.
    RESULTS: Nanocarriers have been shown to be helpful in overcoming the drawbacks of traditional ocular dosing forms. Modification of standard topical solutions by both permeability;and viscosity imparters has resulted in breakthroughs in anterior segment medication delivery. Various nanocarriers liposomes, implants, dendrimers, nanosuspensions, nanoparticles, solid lipid nanocarriers, niosomes and proniosomes have been studied for enhanced penetration and successful targeted drug administration to various ocular locations.
    CONCLUSION: Recently developed nanocarriers for ocular delivery proved to be cost-effective, more efficacious and safe sustained release carriers which can be incorporated to suitable dosage forms. In this review, the authors have discussed about various challenges to ocular drug administration. Various recent research reports on advancements in ocular drug delivery based on modified drug delivery carriers have been analyzed and included. Additionally, marketed formulations and patents literature on ocular drug delivery have been added as a part to support the review content and writing.
    Keywords:  Ocular barriers; dendrimers; implants; liposomes; niosomes; topical
    DOI:  https://doi.org/10.2174/2589977514666220913120718
  82. Comb Chem High Throughput Screen. 2022 Sep 09.
    Discovery and Activity Evaluation of the Inhibitory Effect of Four Kinds Traditional Chinese Medicine Extracts on the CYP3A4 Enzyme.
    Chenyang Ai, Xinxin Miao, Lili Wang, Jun He.
       BACKGROUND AND OBJECTIVE: Traditional Chinese medicines that have inhibitory effects on the CYP3A4 enzymes were screened and their inhibitory effects were verified with in vitro bioassay.
    METHODS: The computer virtual screening methods, including the CYP3A4 enzyme pharmacophore model and the molecular docking method were used to rapidly screen the potential CYP3A4 inhibitors in Traditional Chinese Medicine Database (TCMD), and then in vitro experiments were conducted to validate the computational data.
    RESULTS: A total of 413 chemical components in TCMD that have potential inhibitory effects on the CYP3A4 enzyme were screened, and four kinds of traditional Chinese medicines (Abrus precatorius, Andrographis paniculata, Angelica pubescens f.biserrata and Lithospermum erythrorhizon) contained the most potential CYP3A4 inhibitors; The results of the in vitro experiments showed that these four traditional Chinese medicine extracts all had certain degrees of inhibition on the CYP3A4 enzyme, with IC50 values of 5.15, 14.97, 15.2, and 24.21 μg/ml, respectively.
    CONCLUSION: The extracts of Abrus precatorius, Andrographis paniculata, Angelica pubescens f. biserrata and Lithospermum erythrorhizon had certain inhibitory effects on the CYP3A4 enzyme, and attention should be paid to the possible adverse reactions when they were used in combination with the CYP3A4 enzyme-substrate drugs. A combination of computational approaches might be a useful tool to identify potential inhibitors of the CYP3A4 enzyme from traditional Chinese medicine.
    Keywords:  CYP3A4 enzyme inhibitors; Pharmacophore model; TCMD; molecular docking
    DOI:  https://doi.org/10.2174/1386207325666220909100935
  83. Bioact Mater. 2023 Mar;21 157-174
    Recent advances in engineered polymeric materials for efficient photodynamic inactivation of bacterial pathogens.
    Sathishkumar Gnanasekar, Gopinath Kasi, Xiaodong He, Kai Zhang, Liqun Xu, En-Tang Kang.
      Nowadays, infectious diseases persist as a global crisis by causing significant destruction to public health and the economic stability of countries worldwide. Especially bacterial infections remain a most severe concern due to the prevalence and emergence of multi-drug resistance (MDR) and limitations with existing therapeutic options. Antibacterial photodynamic therapy (APDT) is a potential therapeutic modality that involves the systematic administration of photosensitizers (PSs), light, and molecular oxygen (O2) for coping with bacterial infections. Although the existing porphyrin and non-porphyrin PSs were effective in APDT, the poor solubility, limited efficacy against Gram-negative bacteria, and non-specific distribution hinder their clinical applications. Accordingly, to promote the efficiency of conventional PSs, various polymer-driven modification and functionalization strategies have been adopted to engineer multifunctional hybrid phototherapeutics. This review assesses recent advancements and state-of-the-art research in polymer-PSs hybrid materials developed for APDT applications. Further, the key research findings of the following aspects are considered in-depth with constructive discussions: i) PSs-integrated/functionalized polymeric composites through various molecular interactions; ii) PSs-deposited coatings on different substrates and devices to eliminate healthcare-associated infections; and iii) PSs-embedded films, scaffolds, and hydrogels for regenerative medicine applications.
    Keywords:  1O2, Singlet oxygen; APDT, Antibacterial photodynamic therapy; APTT, Antibacterial photothermal therapy; Antibacterial photodynamic therapy; BODIPY, Boron dipyrromethene; BP, Black phosphorus; Biomaterials; CS, Chitosan; CUR, Curcumin; CV, Crystal violet; Ce6, Chlorin e6; Conjugation; HYP, Hypocrellin; Hp, Hematoporphyrin; Hydrogels; ICG, Indocyanine green; MB, Methylene blue; MRSA, Methicillin-resistant Staphylococcus aureus; PCL, Poly(ε-caprolactone); PDA, Polydopamine; PDI, Photodynamic inactivation; PEG, Poly(ethylene glycol); PEI, Polyethylamine; PPIX, Protoporphyrin IX; PSs, Photosensitizers; PVA, Poly(vinyl alcohol); Photosensitizers; Polymers; RB, Rose bengal; ROS, Reactive oxygen species; α-CD, α-cyclodextrin
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.08.011
  84. J Food Sci. 2022 Sep 13.
    Single-layer and double-layer zein-gum arabic nanoencapsulations: Preparation, structural characterization, thermal properties, and controlled release in the gastrointestinal tract.
    Xueying Huang, Xiaohan Ge, Yi Wang.
      Encapsulation is one of the most convenient ways to increase the solubility of hydrophobic compounds and enhance the protection of sensitive compounds. The development of natural and edible encapsulation systems is a challenge for the food industry. This study explored two kinds of nanoparticles (NPs) made by zein and gum arabic (GA) and investigated the protective and controlled release effect of the formed NPs on rutin. Single-layer NPs (ZG) formed with a zein and GA mixture and double-layer NPs (ZWG) with one inner layer of zein and one outer layer of GA were prepared with a series of mass ratios of zein to GA. The particle size, polydispersity index, and zeta potential were obtained, and the structure and morphology of the NPs were observed using scanning electron microscopy. As shown by the differential scanning calorimeter and thermogravimetric analysis, the heat resistance of ZG is higher than the heat resistance of ZWG. ZG showed slower release of rutin in the simulated gastric and small intestinal solutions than ZWG. These results will help in understanding the different behaviors of protection and controlled release of layered NPs made by mixtures of biopolymers, which can be directly applied to the design of delivery systems of sensitive bioactive compounds in the food industry.
    Keywords:  controlled release; encapsulation; gum arabic; rutin; thermal properties; zein
    DOI:  https://doi.org/10.1111/1750-3841.16316
  85. Biomed Mater. 2022 Sep 16.
    Peptide-based assembled nanostructures that can direct cellular responses.
    Haofu Huang, Kristi Lynn Kiick.
      Natural originated materials have been well-studied over the past several decades owing to their higher biocompatibility compared to the traditional polymers. Peptides, consisting of amino acids, are among the most popular programable building blocks, which is becoming a growing interest in nanobiotechnology. Structures assembled using those biomimetic peptides allow the exploration of chemical sequences beyond those been routinely used in biology. In this Review, we discussed the most recent experimental discoveries on the peptide-based assembled nanostructures and their potential application at the cellular level such as drug delivery. In particular, we explored the fundamental principles of peptide self-assembly and the most recent development in improving their interactions with biological systems. We believe that as the fundamental knowledge of the peptide assemblies evolves, the more sophisticated and versatile nanostructures can be built, with promising biomedical applications.
    Keywords:  Anti-tumor drug targetting; Drug delivery; Nanoparticles; Peptide; Secondary structure; Self-assembly; cellular uptake
    DOI:  https://doi.org/10.1088/1748-605X/ac92b5
  86. Mol Biol Rep. 2022 Sep 12.
    Effects of thiostrepton alone or in combination with selumetinib on triple-negative breast cancer metastasis.
    Funda Demirtas Korkmaz, Irem Dogan Turacli, Guldal Esendagli, Abdullah Ekmekci.
       OBJECTIVE: FoxM1 transcription factor contributes to tumor metastasis and poor prognosis in many cancers including triple-negative breast cancer (TNBC). In this study, we examined the effects of FoxM1 inhibitor Thiostrepton (THIO) alone or in combination with MEK inhibitor Selumetinib (SEL) on metastatic parameters in vitro and in vivo.
    METHODS: Cell viability was determined by MTT assay. Immunoblotting and immunohistochemistry was used to assess metastasis-related protein expressions in 4T1 cells and its allograft tumor model in BALB/c mice. In vivo uPA activity was determined by enzymatic methods.
    RESULTS: Both inhibitors were effective on the expressions of FoxM1, ERK, p-ERK, Twist, E-cadherin, and Vimentin alone or in combination in vitro. THIO significantly decreased 4T1 cell migration and changed the cell morphology from mesenchymal-like to epithelial-like structure. THIO was more effective than in combination with SEL in terms of metastatic protein expressions in vivo. THIO alone significantly inhibited mean tumor growth, decreased lung metastasis rate and tumor foci, however, no significant changes in these parameters were observed in the combined group. Immunohistochemically, FoxM1 expression intensity was decreased with THIO and its combination with SEL in the tumors.
    CONCLUSIONS: This study suggests that inhibiting FoxM1 as a single target is more effective than combined treatment with MEK in theTNBC allograft model. The therapeutic efficacy of THIO should be investigated with further studies on appropriate drug delivery systems.
    Keywords:  FoxM1; Metastasis; Selumetinib; Thiostrepton; Triple negative breast cancer
    DOI:  https://doi.org/10.1007/s11033-022-07751-0
  87. J Hematol Oncol. 2022 Sep 14. 15(1): 133
    Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets.
    Rui Qin, Feng-Ming You, Qian Zhao, Xin Xie, Cheng Peng, Gu Zhan, Bo Han.
      Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by genetic signals or drug interventions. Meanwhile, RCD is closely related to the occurrence and therapy of multiple human cancers. Generally, RCD subroutines are the key signals of tumorigenesis, which are contributed to our better understanding of cancer pathogenesis and therapeutics. Indole alkaloids derived from natural sources are well defined for their outstanding biological and pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, and 3,3'-diindolylmethane, which are currently used in the clinic or under clinical assessment. Moreover, such compounds play a significant role in discovering novel anticancer agents. Thus, here we systemically summarized recent advances in indole alkaloids as anticancer agents by targeting different RCD subroutines, including the classical apoptosis and autophagic cell death signaling pathways as well as the crucial signaling pathways of other RCD subroutines, such as ferroptosis, mitotic catastrophe, necroptosis, and anoikis, in cancer. Moreover, we further discussed the cross talk between different RCD subroutines mediated by indole alkaloids and the combined strategies of multiple agents (e.g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy.
    Keywords:  Anoikis; Apoptosis; Autophagy; Cancer; Ferroptosis; Indole alkaloids; Mitotic catastrophe; Necroptosis; Regulated cell death (RCD); Target therapy
    DOI:  https://doi.org/10.1186/s13045-022-01350-z
  88. AAPS PharmSciTech. 2022 Sep 15. 23(7): 255
    Fusion of Tumor-Derived Exosomes with Long-Circulating and pH-Sensitive Liposomes Loaded with Doxorubicin for the Treatment of Breast Cancer.
    E R Gomes, A T Carvalho, T C Barbosa, L L Ferreira, H D R Calado, A P Sabino, M C Oliveira.
      Doxorubicin (DOX) is a chemotherapeutic agent that has been used in the treatment of breast cancer. However, serious toxic effects have limited its use, mainly cardiotoxicity. To minimize the adverse effects, liposomal preparations containing DOX have been developed. These preparations can reach the target in the tumor region as well as bypass the resistance-related problems. An alternative to increased therapeutic efficacy may be the fusion of liposomes with exosomes released from tumor cells to facilitate membrane and fusion interactions, achieving greater cell uptake. Thus, the purpose of this study was the fusion of exosomes derived from breast tumor cells with long-circulating and pH-sensitive liposomes loading DOX (ExoSpHL-DOX) for the treatment of breast cancer. The mean diameter of ExoSpHL-DOX was 100.8 ± 7.8 nm, the polydispersity index was 0.122 ± 0.004, and the encapsulated DOX content was equal to 83.5 ± 2.5%. The fusion of exosomes with long-circulating and pH-sensitive liposomes was confirmed by Fourier transform infrared spectroscopy, Raman spectroscopy, and nano-flow cytometry. The physicochemical characteristics of ExoSpHL-DOX were maintained for 60 days, at 4 °C. The study of the release of DOX from ExoSpHL-DOX in dilution media with different pH values showed the pH sensitivity characteristic of the nanosystem, since 96.6 ± 0.2% of DOX was released from ExoSpHL-DOX at pH 5.0, while at pH 7.4, the release was 70.1 ± 1.7% in the medium. The cytotoxic study against the breast cancer cell line demonstrated that ExoSpHL-DOX treatment significantly reduced the cancer cell viability.
    Keywords:  Breast cancer; Doxorubicin; Exosomes; Fusion; Liposomes
    DOI:  https://doi.org/10.1208/s12249-022-02349-y
  89. Drug Deliv. 2022 Dec;29(1): 2995-3008
    Hepatocyte-targeting and tumor microenvironment-responsive liposomes for enhanced anti-hepatocarcinoma efficacy.
    Dongliang Cheng, Zhiwei Wen, Hui Chen, Shiyuan Lin, Wei Zhang, Xin Tang, Wei Wu.
      To increase the antitumor drug concentration in the liver tumor site and improve the therapeutic effects, a functionalized liposome (PPP-LIP) with tumor targetability and enhanced internalization after matrix metalloproteinase-2 (MMP2)-triggered cell-penetrating peptide (TATp) exposure was modified with myrcludex B (a synthetic HBV preS-derived lipopeptide endowed with compelling liver tropism) for liver tumor-specific delivery. After intravenous administration, PPP-LIP was mediated by myrcludex B to reach the hepatocyte surface. The MMP2-overexpressing tumor microenvironment deprotected PEG, exposing it to TATp, facilitating tumor penetration and subsequent efficient destruction of tumor cells. In live imaging of small animals and cellular uptake, PPP-LIP was taken up much more than typical unmodified liposomes in the ICR mouse liver and liver tumor cells. Hydroxycamptothecin (HCPT)-loaded PPP-LIP showed a better antitumor effect than commercially available HCPT injections among MTT, three-dimensional (3 D) tumor ball, and tumor-bearing nude mouse experiments. Our findings indicated that PPP-LIP nanocarriers could be a promising tumor-targeted medication delivery strategy for treating liver cancers with elevated MMP2 expression.
    Keywords:  Sodium taurocholate cotransporting polypeptide; enzyme sensitive liposomes; hydroxycamptothecin; liver targeting; matrix metalloproteinase-2
    DOI:  https://doi.org/10.1080/10717544.2022.2122635
  90. Front Nutr. 2022 ;9 974896
    Regulation of dietary polyphenols on cancer cell pyroptosis and the tumor immune microenvironment.
    Xiaoxia Huang, Yao Wang, Wenhui Yang, Jing Dong, Lin Li.
      Cancer is a major public health problem that threatens human life worldwide. In recent years, immunotherapy has made great progress in both clinical and laboratory research. But the high heterogeneity and dynamics of tumors makes immunotherapy not suitable for all cancers. Dietary polyphenols have attracted researchers' attention due to their ability to induce cancer cell pyroptosis and to regulate the tumor immune microenvironment (TIME). This review expounds the regulation of dietary polyphenols and their new forms on cancer cell pyroptosis and the TIME. These dietary polyphenols include curcumin (CUR), resveratrol (RES), epigallocatechin gallate (EGCG), apigenin, triptolide (TPL), kaempferol, genistein and moscatilin. New forms of dietary polyphenols refer to their synthetic analogs and nano-delivery, liposomes. Studies in the past decade are included. The result shows that dietary polyphenols induce pyroptosis in breast cancer cells, liver cancer cells, oral squamous cells, carcinoma cells, and other cancer cells through different pathways. Moreover, dietary polyphenols exhibit great potential in the TIME regulation by modulating the programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) axis, enhancing antitumor immune cells, weakening the function and activity of immunosuppressive cells, and targeting tumor-associated macrophages (TAMs) to reduce their tumor infiltration and promote their polarization toward the M1 type. Dietary polyphenols are also used with radiotherapy and chemotherapy to improve antitumor immunity and shape a beneficial TIME. In conclusion, dietary polyphenols induce cancer cell pyroptosis and regulate the TIME, providing new ideas for safer cancer cures.
    Keywords:  antitumor immunity; curcumin; dietary polyphenols; pyroptosis; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fnut.2022.974896
  91. Cancer Sci. 2022 Sep 17.
    Gankyrin and TIGAR cooperatively accelerate glucose metabolism toward PPP and TCA cycle in hepatocellular carcinoma.
    Chun Yang, Xiao-Wen Cui, Zhi-Wen Ding, Tian-Yi Jiang, Xiao-Fan Feng, Yu-Fei Pan, Yun-Kai Lin, Tai-Yu Shang, Qing Wang, Jian Pan, Jian Wang, Hong-Yang Wang, Li-Wei Dong.
      Oncogene-derived metabolic reprogramming is important for anabolic growth of cancer cells, which is now considered not to be simply rely on glycolysis and passively caused by mitochondrial damage. The present work focused on gankyrin, a relatively specific oncogene in hepatocellular carcinoma (HCC), and its impact on glycolysis and mitochondrial homeostasis. Metabolomics, RNA-seq analysis and subsequent conjoint analysis illustrated that gankyrin regulated pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle and mitochondrial function and homeostasis, which process pivotal roles in tumor development. Mechanistically, gankyrin was found to modulate HCC metabolic reprogramming via TIGAR. Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1α. The loop between gankyrin, Nrf2 and TIGAR accelerated glucose metabolism toward PPP and TCA cycle, which provided vital building blocks, such as NADPH, ATP and ribose of tumor and further facilitated progression of HCC.
    Keywords:  Gankyrin; TIGAR; metabolism reprogram; mitochondrial function; pentose phosphate pathway
    DOI:  https://doi.org/10.1111/cas.15593
  92. Front Pharmacol. 2022 ;13 997918
    Review of phytomedicine, phytochemistry, ethnopharmacology, toxicology, and pharmacological activities of Cymbopogon genus.
    Jonnea Japhet Tibenda, Qiong Yi, Xiaobo Wang, Qipeng Zhao.
      The Cymbopogon genus belongs to the Andropoganeae family of the family Poaceae, which is famous for its high essential oil concentration. Cymbopogon possesses a diverse set of characteristics that supports its applications in cosmetic, pharmaceuticals and phytotherapy. The purpose of this review is to summarize and connect the evidence supporting the use of phytotherapy, phytomedicine, phytochemistry, ethnopharmacology, toxicology, pharmacological activities, and quality control of the Cymbopogon species and their extracts. To ensure the successful completion of this review, data and studies relating to this review were strategically searched and obtained from scientific databases like PubMed, Google Scholar, ResearchGate, ScienceDirect, and Elsevier. Approximately 120 acceptable reviews, original research articles, and other observational studies were included and incorporated for further analysis. Studies showed that the genus Cymbopogon mainly contained flavonoids and phenolic compounds, which were the pivotal pharmacological active ingredients. When combined with the complex β-cyclodextrin, phytochemicals such as citronellal have been shown to have their own mechanism of action in inhibiting the descending pain pathway. Another mechanism of action described in this review is that of geraniol and citral phytochemicals, which have rose and lemon-like scents and can be exploited in soaps, detergents, mouthwash, cosmetics, and other products. Many other pharmacological effects, such as anti-protozoal, anti-bacterial, anti-inflammatory and anti-cancer have been discussed sequentially, along with how and which phytochemicals are responsible for the observed effect. Cymbopogon species have proven to be extremely valuable, with many applications. Its phytotherapy is proven to be due to its rich phytochemicals, obtained from different parts of the plant like leaves, roots, aerial parts, rhizomes, and even its essential oils. For herbs of Cymbopogon genus as a characteristic plant therapy, significant research is required to ensure their efficacy and safety for a variety of ailments.
    Keywords:  Cymbopogon; essential oils; pharmacological activity; phytochemistry; phytomedicine
    DOI:  https://doi.org/10.3389/fphar.2022.997918
  93. Biotechnol Appl Biochem. 2022 Sep 16.
    Nanophytosomes of Hesperidin and of Hesperetin: Preparation, characterization and in vivo evaluation.
    Fatemeh Omidfar, Fatemeh Gheybi, Javid Davoodi, Mostafa Amirinejad, Ali Badiee.
      Hesperidin and Hesperetin are two important plant flavanones abundantly found in citrus fruit. They have discovered many biological activities to treat diseases, including cancer, diabetes, and alzheimer. Despite their various benefits, they have poor solubility, which reduces their bioavailability and absorption. In this study, nanophytosomes have been utilized to improve their payload's solubility and bioavailability. In the current study, hesperetin or hesperidin was complexed with Phospholipon 90G with a 2:1 or 3:1 molar ratio, respectively. The formation of associations between active compounds and phospholipid were confirmed by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and Nuclear magnetic resonance (NMR) techniques. Dynamic light scattering (DLS) data shows that the prepared associations in the presence of body fluids can make nanoparticles in the range of 200 - 250 nm. In addition, oral administration was demonstrated that C max of hesperidin and hesperetin was increased (up to 4 times) after complexation with the lipid. It is concluded that phospholipid association may be used as a suitable and straightforward strategy to improve therapeutic activities of hesperidin and hesperetin by increasing their solubility and bioavailability Nano-phytosomes-loaded hesperidin and hesperetin as a natural flavonoid was synthesized. phytosomes as an emergent promising nano vesicular are able to increase the permeability of natural constituents Nanophytosomes as an efficient carrier system significantly enhanced the bioavailability and absorption of hesperidin and hesperetin. This article is protected by copyright. All rights reserved.
    Keywords:  Complex; Hesperetin; Hesperidin; flavonoids; phosphatidylcholine; phospholipid
    DOI:  https://doi.org/10.1002/bab.2404
  94. Front Immunol. 2022 ;13 973601
    Cancer cell membrane-wrapped nanoparticles for cancer immunotherapy: A review of current developments.
    Qi Jiang, Mixue Xie, Ruyin Chen, Feifei Yan, Chanqi Ye, Qiong Li, Shuaishuai Xu, Wei Wu, Yunlu Jia, Peng Shen, Jian Ruan.
       Background: As the forefront of nanomedicine, bionic nanotechnology has been widely used for drug delivery in order to obtain better efficacy but less toxicity for cancer treatments. With the rise of immunotherapy, the combination of nanotechnology and immunotherapy will play a greater potential of anti-tumor therapy. Due to its advantage of homologous targeting and antigen library from source cells, cancer cell membrane (CCM)-wrapped nanoparticles (CCNPs) has become an emerging topic in the field of immunotherapy.
    Key scientific concepts of review: CCNP strategies include targeting or modulating the tumor immune microenvironment and combination therapy with immune checkpoint inhibitors and cancer vaccines. This review summarizes the current developments in CCNPs for cancer immunotherapy and provides insight into the challenges of transferring this technology from the laboratory to the clinic as well as the potential future of this technology.
    Conclusion: This review described CCNPs have enormous potential in cancer immunotherapy, but there are still challenges in terms of translating their effects in vitro to the clinical setting. We believe that these challenges can be addressed in the future with a focus on individualized treatment with CCNPs as well as CCNPs combined with other effective treatments.
    Keywords:  cancer cell membrane; drug delivery; immunotherapy; membrane-wrapped; nanoparticle; nanovaccine
    DOI:  https://doi.org/10.3389/fimmu.2022.973601
  95. In Vivo. 2022 Sep-Oct;36(5):36(5): 2020-2031
    Chemosensitizing Effect and Efficacy of Wilforlide A in Combination With Docetaxel in Drug-resistant Prostate Cancer.
    Zhijun Wang, Steven Yeung, Shanchao Yang, Ying Huang, Moses Sing Sum Chow.
       BACKGROUND/AIM: Prostate cancer is currently the second most common cancer in men and chemotherapy is the main treatment for metastatic castrate-resistant prostate cancers (mCRPC). However, chemoresistance leading to treatment failure is inevitable. Thus, therapeutic approaches that can overcome chemoresistance are important areas of research for cancer chemotherapy.
    MATERIALS AND METHODS: In the present study, six components of tripterygium wilfordii including celastrol, triptolide, pristimerin, triptonide, demethylzeylasteral, and wilforlide A were screened for their chemosensitizing effect on drug-resistant prostate cancer cell lines PC3 and DU145. The most active compound was further investigated on its potential mechanism of action and in vivo efficacy using a SCID mouse model.
    RESULTS: Among the six components only wilforlide A significantly enhanced sensitivity to docetaxel (by reducing the IC50 in resistant prostate cancer cell lines). Wilforlide A inhibited P-glycoprotein efflux transporter and downregulated cyclin E2 splice variant 1 mRNA, both have been known as mechanisms of resistance. The chemosensitizing effect was further verified using a xenograft mouse model. In the high-dose treatment group, the combination of wilforlide A and docetaxel significantly retarded tumor growth of resistant prostate cancer, although neither docetaxel nor wilforlide A monotreatment groups showed any effect.
    CONCLUSION: Wilforlide A was found to enhance the chemosensitizing effect of docetaxel both in vitro and in vivo. Further studies are warranted to verify wilforlide A as a new drug candidate to overcome docetaxel resistance in prostate cancer.
    Keywords:  Wilforlide A; chemosensitization; docetaxel; prostate cancer; resistance
    DOI:  https://doi.org/10.21873/invivo.12928
  96. Drug Des Devel Ther. 2022 ;16 2981-2993
    Levistilide a Induces Ferroptosis by Activating the Nrf2/HO-1 Signaling Pathway in Breast Cancer Cells.
    Shangwen Jing, Yantong Lu, Jing Zhang, Yan Ren, Yousheng Mo, Dongdong Liu, Lining Duan, Zhongyu Yuan, Changjun Wang, Qi Wang.
       Introduction: Breast cancer (BC) is the leading female malignancy, with one million new cases diagnosed worldwide per year. However, the current treatment options for BC patients have difficulty achieving satisfactory efficacy. Ferroptosis is a new mode of regulated cell death that plays a key role in the inhibition of tumorigenesis. Levistilide A (LA), as an active compound extracted from Chuanxiong Rhizoma, might prevent the development of tumors by regulating the critical cellular processes of ferroptosis.
    Methods: In this study, the underlying mechanisms of LA on ferroptosis in BC were explored in vitro. The effect of LA on the viability and mitochondrial function of BC cells was determined. Moreover, the effect of LA on the expression levels of key molecules involved in ferroptosis and the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway was evaluated.
    Results: LA significantly reduced cell viability and damaged the mitochondrial structure and function of BC cells in a dose-dependent manner. Furthermore, LA treatment markedly enhanced reactive oxygen species (ROS)-induced ferroptosis by activating the Nrf2/HO-1 signaling pathway.
    Conclusion: These findings suggest that LA may be a potential lead compound for breast cancer therapy by inducing ferroptosis in tumor cells.
    Keywords:  Nrf2/HO-1 signaling pathway; breast cancer; ferroptosis; levistilide A
    DOI:  https://doi.org/10.2147/DDDT.S374328
  97. Curr Nutr Rep. 2022 Sep 13.
    Is Vitamin D Important in Anxiety or Depression? What Is the Truth?
    Şerife Akpınar, Makbule Gezmen Karadağ.
       PURPOSE OF REVIEW: Depression and anxiety are mood disorders that affect health and therefore quality of life and increase the global burden of disease. One of the possible mechanisms in the pathophysiology of these mood disorders has been reported as oxidative stress and inflammation. In the light of this information, it is important to determine the relationship between antioxidant nutrients (such as vitamin D) and these diseases. There are points where the brain regions involved in the pathophysiology of depression and anxiety and vitamin D metabolism intersect.
    RECENT FINDINGS: Low vitamin D levels are associated with increased symptoms of depression and anxiety. For this reason, vitamin D screening should be performed in the prevention and treatment planning of these mood disorders. Vitamin D, which has antioxidant properties and activity in brain tissue, is important for mood disorders preventions or treatments but serum levels must be followed.
    Keywords:  Antioxidant; Anxiety; Cholecalciferol; Depression; Mood disorders; Vitamin D
    DOI:  https://doi.org/10.1007/s13668-022-00441-0
  98. J Biomol Struct Dyn. 2022 Sep 12. 1-23
    Pharmacological features, health benefits and clinical implications of honokiol.
    Fatima Khatoon, Sabeeha Ali, Vijay Kumar, Abdelbaset Mohamed Elasbali, Hassan H Alhassan, Salem Hussain Alharethi, Asimul Islam, Md Imtaiyaz Hassan.
      Honokiol (HNK) is a natural polyphenolic compound extracted from the bark and leaves of Magnolia grandiflora. It has been traditionally used as a medicinal compound to treat inflammatory diseases. HNK possesses numerous health benefits with a minimal level of toxicity. It can cross the blood-brain barrier and blood-cerebrospinal fluid, thus having significant bioavailability in the neurological tissues. HNK is a promising bioactive compound possesses neuroprotective, antimicrobial, anti-tumorigenic, anti-spasmodic, antidepressant, analgesic, and antithrombotic features . HNK can prevent the growth of several cancer types and haematological malignancies. Recent studies suggested its role in COVID-19 therapy. It binds effectively with several molecular targets, including apoptotic factors, chemokines, transcription factors, cell surface adhesion molecules, and kinases. HNK has excellent pharmacological features and a wide range of chemotherapeutic effects, and thus, researchers have increased interest in improving the therapeutic implications of HNK to the clinic as a novel agent. This review focused on the therapeutic implications of HNK, highlighting clinical and pharmacological features and the underlying mechanism of action.Communicated by Ramaswamy H. Sarma.
    Keywords:  Alzheimer’s disease; Anticancer agents; HNK; apoptosis; diabetes; natural products; neurodegenerative diseases; pharmacological features
    DOI:  https://doi.org/10.1080/07391102.2022.2120541
  99. Front Bioeng Biotechnol. 2022 ;10 973080
    The potential of oxygen and nitrogen species-regulating drug delivery systems in medicine.
    Michał Sołtan, Dorota Bartusik-Aebisher, David Aebisher.
      The focus of this review is to present most significant advances in biomaterials used for control of reactive oxygen/nitrogen species (ROS/RNS, RONS) in medicine. A summary of the main pathways of ROS production and the main pathways of RNS production are shown herein. Although the physiological and pathological roles of RONS have been known for at least 2decades, the potential of their control in management of disease went unappreciated. Recently, advances in the field of biochemical engineering and materials science have allowed for development of RONS-responsive biomaterials for biomedical applications, which aim to control and change levels of reactive species in tissue microenvironments. These materials utilize polymers, inorganic nanoparticles (NPs), or organic-inorganic hybrids. Thus, biomaterials like hydrogels have been developed to promote tissue regeneration by actively scavenging and reducing RONS levels. Their promising utility comes from thermo- and RONS-sensitivity, stability as a delivery-medium, ease for incorporation into other materials and facility for injection. Their particular attractiveness is attributed to drug release realized in targeted tissues and cells with elevated RONS levels, which leads to enhanced treatment outcomes and reduced adverse effects. The mechanism of their action depends on the functional groups employed and their response to oxidation, and may be based on solubility changes or cleavage of chemical bonds. When talking about antioxidants, one should also mention oxidative stress, which we call the imbalance between antioxidants and reactive oxygen species, which occurs due to a deficiency of endogenous antioxidants and a low supply of exogenous antioxidants. This study is a review of articles in English from the databases PubMed and Web of Science retrieved by applying the search terms "Oxygen Species, Nitrogen Species and biomaterials" from 1996 to 2021.
    Keywords:  biomaterials; biomedical applications; nitrogen species; oxygen; oxygen species
    DOI:  https://doi.org/10.3389/fbioe.2022.973080
  100. Front Pharmacol. 2022 ;13 988226
    Editorial: Chemosensitizing effect of natural products against cancers: Applications in enhancing chemotherapy and immunotherapy.
    Nand K Roy, Devesh Tewari, Maria Teresa Esposito.
      
    Keywords:  cancer; chemosensitization; chemotherapy; immunotherapy; natural products
    DOI:  https://doi.org/10.3389/fphar.2022.988226
  101. J Pharm Anal. 2022 Aug;12(4): 541-555
    Interactions between gut microbiota and berberine, a necessary procedure to understand the mechanisms of berberine.
    Hao Cheng, Juan Liu, Yuzhu Tan, Wuwen Feng, Cheng Peng.
      Berberine (BBR), an isoquinoline alkaloid, has been found in many plants, such as Coptis chinensis Franch and Phellodendron chinense Schneid. Although BBR has a wide spectrum of pharmacological effects, its oral bioavailability is extremely low. In recent years, gut microbiota has emerged as a cynosure to understand the mechanisms of action of herbal compounds. Numerous studies have demonstrated that due to its low bioavailability, BBR can interact with the gut microbiota, thereby exhibiting altered pharmacological effects. However, no systematic and comprehensive review has summarized these interactions and their corresponding influences on pharmacological effects. Here, we describe the direct interactive relationships between BBR and gut microbiota, including regulation of gut microbiota composition and metabolism by BBR and metabolization of BBR by gut microbiota. In addition, the complex interactions between gut microbiota and BBR as well as the side effects and personalized use of BBR are discussed. Furthermore, we provide our viewpoint on future research directions regarding BBR and gut microbiota. This review not only helps to explain the mechanisms underlying BBR activity but also provides support for the rational use of BBR in clinical practice.
    Keywords:  Berberine; Gut microbiota; Oral bioavailability; Short chain fatty acids; Traditional Chinese medicines
    DOI:  https://doi.org/10.1016/j.jpha.2021.10.003
  102. Int J Biol Macromol. 2022 Sep 09. pii: S0141-8130(22)01959-6. [Epub ahead of print]221 508-522
    pH-responsive glycodendrimer as a new active targeting agent for doxorubicin delivery.
    Ali Soltani, Mehdi Faramarzi, Fatemeh Farjadian, Seyed Aboutaleb Mousavi Parsa, Homayon Ahmad Panahi.
      The present study synthesized a new kind of pH-responsive active targeting glycodendrimer (ATGD) for doxorubicin delivery to cancerous cells. First, the glycodendrimer was synthesized based on the cultivation of chitosan dendrons on amine-functionalized, silica-grafted cellulose nanocrystals. Afterward, glycodendrimer was conjugated with folic acid to provide a folate receptor-targeting agent. The response surface method was employed to obtain the optimum conditions for the preparation of doxorubicin-loaded ATGD. The effect of doxorubicin/ATGD ratio, temperature, and pH on doxorubicin loading capacity was evaluated, and high loading capacity was achieved under optimized conditions. After determining doxorubicin release pattern at acidic and physiological pH, ATGD cytotoxicity was surveyed by MTT assay. Based on the results, the loading behavior of doxorubicin onto ATGD was in good agreement with monolayer-physisorption, and drug release was Fickian diffusion-controlled. ATGD could release the doxorubicin much more at acidic pH than physiological pH, corresponding to pH-responsive release behavior. Results of MTT assay confirmed the cytotoxicity of doxorubicin-loaded ATGD in cancer cells, while ATGD (without drug) was biocompatible with no tangible toxicity. These results suggested that ATGD has the potential for the treatment of cancer.
    Keywords:  Cellulose nanocrystals; Chitosan; Doxorubicin; Glycodendrimer; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.037
  103. Food Funct. 2022 Sep 15.
    Cactaceae plants as sources of active bioavailable phytochemicals.
    Emmanuel Aispuro-Hernández, Marcela J Vergara-Jiménez, Feliznando I Cárdenas-Torres, Miguel A Martínez-Téllez, Noé Ontiveros.
      Arid-land plants from the Cactaceae family are endemic to the Americas and cultivated worldwide. Cactaceous plants and their fruits contain phenolic compounds, betalains, vitamins, carotenoids, minerals, and soluble fiber. Edible cactaceous matrices can be considered functional foods since their consumption may confer health benefits. These plants could be a source of novel bioactive compounds relevant to the area of phytomedicine. However, consumption of high concentrations of active molecules is not necessarily correlated to beneficial physiological effects because phytochemicals must be released from the food matrices under physiological conditions, resist digestion-associated chemical transformations, and remain in their active state in systemic circulation until the target tissues are reached. Notably, although digestion may either increase or decrease the bioactive phytochemicals' activity and stability, non-absorbed compounds may also be relevant for human health. Additionally, food matrices' type and composition and their technological processing operations may influence the compounds' release, stability, and accessibility. Thus, this review provides insights on the feasibility of using Cactaceae plants as sources of functional compounds. It is focused on compounds' bioactivity, bioaccessibility, and overall bioavailability after their metabolic transformation. Also, it addresses the influence of food processing on bioactive compounds. Many Cactaceae species are unexplored, and our understanding of how they confer health benefits is limited. To better understand the physiological relevance, nutraceutical potential, and therapeutic feasibility of cactaceous bioactive phytochemicals, future research should focus on the metabolic stability and safety of these compounds, as well as their assimilation mechanisms (absorption, distribution, and metabolic fate).
    DOI:  https://doi.org/10.1039/d2fo01863b
  104. J Hematol Oncol. 2022 Sep 12. 15(1): 132
    Enhancing the therapeutic efficacy of nanoparticles for cancer treatment using versatile targeted strategies.
    Hailong Tian, Tingting Zhang, Siyuan Qin, Zhao Huang, Li Zhou, Jiayan Shi, Edouard C Nice, Na Xie, Canhua Huang, Zhisen Shen.
      Poor targeting of therapeutics leading to severe adverse effects on normal tissues is considered one of the obstacles in cancer therapy. To help overcome this, nanoscale drug delivery systems have provided an alternative avenue for improving the therapeutic potential of various agents and bioactive molecules through the enhanced permeability and retention (EPR) effect. Nanosystems with cancer-targeted ligands can achieve effective delivery to the tumor cells utilizing cell surface-specific receptors, the tumor vasculature and antigens with high accuracy and affinity. Additionally, stimuli-responsive nanoplatforms have also been considered as a promising and effective targeting strategy against tumors, as these nanoplatforms maintain their stealth feature under normal conditions, but upon homing in on cancerous lesions or their microenvironment, are responsive and release their cargoes. In this review, we comprehensively summarize the field of active targeting drug delivery systems and a number of stimuli-responsive release studies in the context of emerging nanoplatform development, and also discuss how this knowledge can contribute to further improvements in clinical practice.
    Keywords:  Active targeting; Cancer treatment; Drug delivery; Stimuli-responsive materials; Targeted strategies
    DOI:  https://doi.org/10.1186/s13045-022-01320-5
  105. Carbohydr Polym. 2022 Nov 15. pii: S0144-8617(22)00896-7. [Epub ahead of print]296 119991
    Waxy maize starch nanoparticles incorporated tea polyphenols to stabilize Pickering emulsion and inhibit oil oxidation.
    Ran Wang, Jiang Zhou.
      Waxy maize starch (WMS) and tea polyphenols (TPs) were combined to prepare WMS/TP nanoparticles through precipitation. Physicochemical properties and emulsifying capacity of the WMS/TP nanoparticles were investigated. The results showed that the addition of TPs enhanced the hydrophobicity of the WMS nanoparticles, and the size of the WMS/TP nanoparticles increased with increasing TP addition (from 5 % to 15 %). The emulsions stabilized by the WMS/TP nanoparticles exhibited excellent physical stability. After 15 days of storage, the emulsified phase volume fraction remained at 100 % in the emulsion stabilized by the WMS/TP nanoparticles (15 % of TPs). Moreover, the WMS/TP nanoparticles also enhanced the oxidative stability of the emulsions characterized by a lower peroxide value and thiobarbituric acid reactive substances. The results of this study demonstrate that WMS/TP nanoparticles are potential food-grade Pickering emulsifiers with the capacity not only to stabilize emulsions but also to inhibit oil oxidation of the emulsions.
    Keywords:  Nanoparticle emulsifier; Oxidative stability; Pickering emulsion; Starch; Tea polyphenols
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119991
  106. Front Pharmacol. 2022 ;13 844782
    Exosomes: A novel insight into traditional Chinese medicine.
    Chao Mo, Jie Zhao, Jingyan Liang, Huiling Wang, Yu Chen, Guodong Huang.
      Exosomes are small extracellular vesicles and play an essential role in the mediation of intercellular communication both in health and disease. Traditional Chinese medicine (TCM) has historically been used to maintain human health and treat various diseases up till today. The interplay between exosomes and TCM has attracted researchers' growing attention. By integrating the available evidence, TCM formulas and compounds isolated from TCM as exosome modulators have beneficial effects on multiple disorders, such as tumors, kidney diseases, and hepatic disease, which may associate with inhibiting cells proliferation, anti-inflammation, anti-oxidation, and attenuating fibrosis. Exosomes, a natural delivery system, are essential in delivering compounds isolated from TCM to target cells or tissues. Moreover, exosomes may be the potential biomarkers for TCM syndromes, providing strategies for TCM treatment. These findings may provide a novel insight into TCM from exosomes and serve as evidence for better understanding and development of TCM.
    Keywords:  biomarker; delivery carrier; exosome; modulator; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2022.844782
  107. Signal Transduct Target Ther. 2022 Sep 16. 7(1): 324
    The evolving view of thermogenic fat and its implications in cancer and metabolic diseases.
    Xinpeng Yin, Yuan Chen, Rexiati Ruze, Ruiyuan Xu, Jianlu Song, Chengcheng Wang, Qiang Xu.
      The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually. Most of them are listed on the table of high-risk factors for malignancy, and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients. Importantly, adipose tissue is fundamental to the occurrence and development of these metabolic disorders. White adipose tissue stores excessive energy, while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat. In addition to thermogenesis, beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients, like glucose, fatty acids, and amino acids. Accordingly, strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight, diabetes, and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance. With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis, the roles of thermogenic adipose tissue in tumors have been revealed gradually. On the one hand, enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia. On the other hand, locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy. Here, we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat. In addition, we discuss the multiple roles of thermogenic adipocytes in different tumors. Ultimately, we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.
    DOI:  https://doi.org/10.1038/s41392-022-01178-6
  108. Drug Resist Updat. 2022 Sep 07. pii: S1368-7646(22)00064-4. [Epub ahead of print]64 100865
    Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer.
    Renjith P Johnson, Chandrahas Koumar Ratnacaram, Lalit Kumar, Jobin Jose.
      Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial-mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.
    Keywords:  Combinatorial fapproaches; Inflammatory pathways; Nanotherapeutics; Prostate cancer
    DOI:  https://doi.org/10.1016/j.drup.2022.100865
  109. Appl Biochem Biotechnol. 2022 Sep 12.
    Combination of Peglated-H1/HGFK1 Nanoparticles and TAE in the Treatment of Hepatocellular Carcinoma.
    Dazhi Gao, Xiangxian Xu, Ling Liu, Li Liu, Xiang Zhang, Xianxian Liang, Lanqi Cen, Qian Liu, Xiaoli Yuan, Zhenghong Yu.
      Transarterial embolization (TAE) constitutes the gold standard for the treatment of hepatocellular carcinoma. The effect of combination of TAE and peglated-H1/HGFK1 nanoparticles was explored on hepatocellular carcinoma. MTT and Annexin V-FITC were used to determine the cell viability and apoptosis of HepG2, ml-1, LO2, and VX2 cells after the treatment of HGFK1. Next, the orthotopic rabbit was selected to establish the in situ models of VX2 hepatocellular carcinoma. Nanoparticles were synthesized with peglated-PH1 and used to deliver HGFK1 overexpressing plasmids. MRI was performed to monitor tumor volume after being treated with TAE. The protein expression levels of CD31, CD90, and Ki67 were determined by immunohistochemistry. H&E and TUNEL staining were used to determine the necrosis and apoptosis in vivo. HGFK1 significantly inhibited the proliferation and increased the apoptosis of HepG2 and ml-1 cells (P < 0.05). MRI on 14 days after modeling suggested that the tumor showed ring enhancement. MRI on 7 days and 14 days after interventional therapy showed that tumor volume was significantly inhibited after the treatment with TAE and HGFK1 (P < 0.05). The immunohistochemical results 7 days after interventional therapy indicated that the expressions of CD31, CD90, and Ki67 were significantly lower after treatment with TAE and HGFK1 (P < 0.05). TAE and HGFK1 all extended the survival period of rabbits (P < 0.05). PH1/HGFK1 nanoparticle is an innovative and effective embolic agent, which could limit angiogenesis post-TAE treatment. The combination of TAE with PH1/HGFK1 is a promising strategy and might alter the way that surgeons manage hepatocellular carcinoma (HCC).
    Keywords:  Combination therapy; Hepatocellular carcinoma; Nanoparticles; PH1/HGFK1; Transarterial embolization
    DOI:  https://doi.org/10.1007/s12010-022-04153-7
  110. Curr Med Chem. 2022 Sep 15.
    Medicinal prospects of targeting tyrosinase: A feature review.
    Yuanyuan Wang, Baichen Xiong, Shuaishuai Xing, Ying Chen, Qinghong Liao, Jun Mo, Yao Chen, Qi Li, Haopeng Sun.
      Tyrosinase is a bifunctional polyphenol oxidase (PPO), catalyzing two oxidative reactions: monophenols to o-quinones (monophenolase activity) and o-diphenols to o-quinones (diphenolase activity). As tyrosinase is the rate-limiting enzyme for the melanogenesis process, it is an attractive target for melanogenesis inhibition. Aiming at skin whitening, anticancer, Parkinson's disease (PD) treatment, antibacterial, fruit and vegetable preservation and other anti-pigmentation effect, medicinal chemists have exploited diverse tyrosinase inhibitors through various approaches. In addition to discovering inhibitors with novel scaffold, good activity and high safety, researchers also focused on developing strategies for synergistic effects of multiple inhibitors and simultaneously regulating multiple targets to treat cancer or neurodegenerative diseases. This review focused on multiple natural and synthetic tyrosinase inhibitors which could contribute to preventing fruit and vegetable browning, skin whitening, antibacterial, anticancer, Parkinson's Disease etc.
    Keywords:  Antibacterial; Anticancer; Fruit and vegetable preservation; PD treatment; Skin whitening; Tyrosinase inhibitors
    DOI:  https://doi.org/10.2174/0929867329666220915123714
  111. ACS Nano. 2022 Sep 13.
    Computer-Aided Design of Lasso-like Self-Assembling Anticancer Peptides with Multiple Functions for Targeted Self-Delivery and Cancer Treatments.
    Pengfei Pei, Long Chen, Ruru Fan, Xi-Rui Zhou, Shan Feng, Hangrui Liu, Quanqiang Guo, Huiwei Yin, Qiang Zhang, Fude Sun, Liang Peng, Peng Wei, Chengzhi He, Renzhong Qiao, Zai Wang, Shi-Zhong Luo.
      Anticancer peptides are promising drug candidates for cancer treatment, but the short circulation time and low delivery efficiency limit their clinical applications. Herein, we designed several lasso-like self-assembling anticancer peptides (LASAPs) integrated with multiple functions by a computer-aided approach. Among these LASAPs, LASAP1 (CRGDKGPDCGKAFRRFLGALFKALSHLL, 1-9 disulfide bond) was determined to be superior to the others because it can self-assemble into homogeneous nanoparticles and exhibits improved stability in serum. Thus, LASAP1 was chosen for proving the design idea. LASAP1 can self-assemble into nanoparticles displaying iRGD on the surface because of its amphiphilic structure and accumulate to the tumor site after injection because of the EPR effect and iRGD targeting to αVβ3 integrin. The nanoparticles could disassemble in the acidic microenvironment of the solid tumor, and cleaved by the overexpressed hK2, which was secreted by prostate tumor cells, to release the effector peptide PTP-7b (FLGALFKALSHLL), which was further activated by the acidic pH. Therefore, LASAP1 could target the orthotopic prostate tumor in the model mice after intraperitoneal injection and specifically inhibit tumor growth, with low systematic toxicity. Combining the multiple targeting functions, LASAP1 represents a promising design of self-delivery of peptide drugs for targeted cancer treatments.
    Keywords:  anticancer peptide; multitargeting; nanoparticle; self-assembling; self-delivery
    DOI:  https://doi.org/10.1021/acsnano.2c01014
  112. Chin Med. 2022 Sep 15. 17(1): 108
    Potential role of tea drinking in preventing hyperuricaemia in rats: biochemical and molecular evidence.
    Siyao Sang, Lufei Wang, Taotao Liang, Mingjie Su, Hui Li.
       BACKGROUND: Lifestyle and diet play a significant role in hyperuricaemia. Accumulating evidence indicates that tea consumption is associated with hyperuricaemia and gout. However, diverse compounds in different types of tea make it quite difficult to determine the relevant molecular mechanism. Here, we compared the effects of six types of tea on hyperuricaemia induced by potassium oxonate (PO) and hypoxanthine in rats and investigated the possible underlying mechanisms.
    METHODS: Rats were randomly assigned to ten groups: the control, hyperuricaemia model, benzbromarone positive control, traditional Chinese medicine Simiao San positive control, green tea, yellow tea, black tea, white tea, red tea, and cyan tea treatment groups. After 21 days, uric acid (UA), xanthine oxidase (XOD), alanine aminotransferase (ALT),blood urea nitrogen (BUN), and creatinine (CRE) were assessed. Serum levels of interleukin-1β (IL-1β) were measured with an enzyme-linked immunosorbent assay. Haematoxylin-eosin staining and immunohistochemistry were used to assess liver and kidney injury.
    RESULTS: The levels of UA, CRE, and BUN in the treatment group were decreased to varying degrees. There was a significant reduction in UA, CRE, and BUN levels for yellow tea compared to the positive control drugs. Yellow tea suppressed XOD activity and alleviated hepatic and kidney injury. Network pharmacology and untargeted metabolomics indicated that ten yellow tea bioactive ingredients and 35 targets were responsible for preventing hyperuricaemia, which was mediated by 94 signalling pathways, including IL-1β and TNF.
    CONCLUSION: These findings indicate that green tea cannot reduce the serum uric acid level of hyperuricaemic rats. Yellow tea can significantly improve hyperuricaemia by regulating the inflammatory response, autophagy, and apoptosis. This study provides a potential candidate for the treatment of hyperuricaemia and a basis for selecting therapeutic tea for patients with hyperuricaemia.
    Keywords:  Hyperuricaemia; Inflammation; Kidney injury; Tea; Uric acid
    DOI:  https://doi.org/10.1186/s13020-022-00664-x
  113. J Control Release. 2022 Sep 08. pii: S0168-3659(22)00585-5. [Epub ahead of print]
    Self-assembly hydrogels of therapeutic agents for local drug delivery.
    Jun Zheng, Xianwen Song, Zhaoyu Yang, Chao Yin, Weikang Luo, Chunyang Yin, Yaqiong Ni, Yang Wang, Yi Zhang.
      Advanced drug delivery systems are of vital importance to enhance therapeutic efficacy. Among various recently developed formulations, self-assembling hydrogels composed of therapeutic agents have shown promising potential for local drug delivery owing to their excellent biocompatibility, high drug-loading efficiency, low systemic toxicity, and sustained drug release behavior. In particular, therapeutic agents self-assembling hydrogels with well-defined nanostructures are beneficial for direct delivery to the target site via injection, not only improving drug availability, but also extending their retention time and promoting cellular uptake. In brief, the self-assembly approach offers better opportunities to improve the precision of pharmaceutical treatment and achieve superior treatment efficacies. In this review, we intend to cover the recent developments in therapeutic agent self-assembling hydrogels. First, the molecular structures, self-assembly mechanisms, and application of self-assembling hydrogels are systematically outlined. Then, we summarize the various self-assembly strategies, including the single therapeutic agent, metal-coordination, enzyme-instruction, and co-assembly of multiple therapeutic agents. Finally, the potential challenges and future perspectives are discussed. We hope that this review will provide useful insights into the design and preparation of therapeutic agent self-assembling hydrogels.
    Keywords:  Local drug delivery; Molecule structure; Self-assembling hydrogels; Self-assembly mechanisms; Therapeutic agents
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.001
  114. Sci Rep. 2022 Sep 15. 12(1): 15489
    Deciphering the therapeutical potentials of rosmarinic acid.
    Sally El Kantar, Ali Yassin, Bilal Nehmeh, Louis Labaki, Sara Mitri, Fatima Naser Aldine, Aaron Hirko, Sergio Caballero, Eileen Monck, Alejandra Garcia-Maruniak, Elias Akoury.
      Lemon balm is herbal tea used for soothing stomach cramps, indigestion, and nausea. Rosmarinic acid (RA) is one of its chemical constituents known for its therapeutic potentials against cancer, inflammatory and neuronal diseases such as the treatment of neurofibromatosis or prevention from Alzheimer's diseases (AD). Despite efforts, recovery and purification of RA in high yields has not been entirely successful. Here, we report its aqueous extraction with optimal conditions and decipher the structure by nuclear magnetic resonance (NMR) spectroscopy. Using various physical-chemical and biological assays, we highlight its anti-aggregation inhibition potentials against the formation of Tau filaments, one of the hallmarks of AD. We then examine its anti-cancer potentials through reduction of the mitochondrial reductase activity in tumor cells and investigate its electrochemical properties by cyclic voltammetry. Our data demonstrates that RA is a prominent biologically active natural product with therapeutic potentials for drug discovery in AD, cancer therapy and inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41598-022-19735-y
  115. Life Sci. 2022 Sep 11. pii: S0024-3205(22)00656-7. [Epub ahead of print]308 120956
    Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms.
    Hager H Shaaban, Ibrahim Alzaim, Ahmed El-Mallah, Rania G Aly, Ahmed F El-Yazbi, Ahmed Wahid.
      Non-alcoholic fatty liver disease (NAFLD) is an important health threat that is strongly linked to components of metabolic syndrome, particularly the low-grade inflammatory changes. Significantly, several of the available anti-diabetic drug classes demonstrate a considerable anti-inflammatory effect, and hence might be of benefit for NAFLD patients. In this study, we used a rat model of diet-induced NAFLD to examine the potential effect of metformin, pioglitazone, dapagliflozin and their combinations on NAFLD manifestations. Rats were fed an atherogenic diet containing 1.25 % cholesterol, 0.5 % cholic acid and 60 % cocoa butter for 6 weeks causing a number of metabolic and hepatic alterations including insulin resistance, dyslipidemia, systemic inflammation, increased hepatic oxidative stress and lipid peroxidation, hepatic steatosis, lobular inflammation, as well as increased markers of liver inflammation and hepatocyte apoptosis. Drug treatment, which started at the third week of NAFLD induction and continued for three weeks, not only ameliorated the observed metabolic impairment, but also functional and structural manifestations of NAFLD. Specifically, anti-diabetic drug treatment reversed markers of systemic and hepatic inflammation, oxidative stress, hepatic fibrosis, and hepatocyte apoptosis. Our findings propose that anti-diabetic drugs with a potential anti-inflammatory effect can ameliorate the manifestations of NAFLD, and thus may provide a therapeutic option for such a condition that is closely associated with metabolic diseases. The detailed pharmacology of these classes in aspects linked to the observed impact on NAFLD requires to be further investigated and translated into clinical studies for tailored therapy specifically targeting NAFLD.
    Keywords:  Dapagliflozin; Metabolic syndrome; Metformin; NAFLD; Pioglitazone
    DOI:  https://doi.org/10.1016/j.lfs.2022.120956
  116. Bioact Mater. 2023 Mar;21 86-96
    In situ forming oxygen/ROS-responsive niche-like hydrogel enabling gelation-triggered chemotherapy and inhibition of metastasis.
    Shi-Xiong Chen, Ji Zhang, Fengfeng Xue, Wei Liu, Yichen Kuang, Bingxin Gu, Shaoli Song, Hangrong Chen.
      Though the development of the diverse hypoxia-activated prodrugs (HAPs) has made great progresses in the last several decades, current cancer therapy based on HAPs still suffers many obstacles, e.g., poor therapeutic outcome owing to hard deep reaching to hypoxic region, and the occurrence of metastasis due to hypoxia. Inspired by engineered niches, a novel functional chitosan polymer (CS-FTP) is synthesized for construction of a hydrogel-based bio-niche (CS-FTP-gel) in aiming at remodeling tumor hypoxic microenvironment. The CS-FTP polymers are crosslinked to form a niche-like hydrogel via enzyme-mediated oxygen-consumable dimerization after injected into tumor, in which a HAP (i.e., AQ4N) could be physically encapsulated, resulting in enhanced tumor hypoxia to facilitate AQ4N-AQ4 toxic transformation for maximizing efficacy of chemotherapy. Furthermore, Pazopanib (PAZ) conjugated onto the CS backbone via ROS-sensitive linker undergoes a stimuli-responsive release behavior to promote antiangiogenesis for tumor starvation, eventually contributing to the inhibition of lung metastasis and synergistic action with AQ4N-based chemotherapy for an orthotopic 4T1 breast tumor model. This study provides a promising strategy for hypoxia-based chemotherapy and demonstrates an encouraging clinical potential for multifunctional hydrogel applicable for antitumor treatment.
    Keywords:  Antimetastases; Bio-niches; Hypoxia-activated prodrugs; Hypoxia-inducible hydrogels
    DOI:  https://doi.org/10.1016/j.bioactmat.2022.08.002
  117. Int J Biol Macromol. 2022 Sep 10. pii: S0141-8130(22)01969-9. [Epub ahead of print]
    Bimetallic silver-platinum (AgPt) nanoparticles and chitosan fabricated cotton gauze for enhanced antimicrobial and wound healing applications.
    Anbazhagan Sathiyaseelan, Kandasamy Saravanakumar, Myeong-Hyeon Wang.
      Wound healing is a significant clinical and socioeconomic problem that is often affected by microbial infection. Inappropriate monitoring leads to unfavorable concerns for surrounding tissues. Cotton gauzes have been used as low-cost wound dressing material but prolong healing owing to secondary bacterial infections. Hence, we prepared the bimetallic silver and platinum nanoparticles (AgPt NPs) using citric acid (CA) as a reducing agent and then coated them on chitosan (CS) fabricated cotton gauze (CG) for enhanced antibacterial and wound healing applications. The synthesis of AgPt NPs was evidenced UV-Visible spectroscopy, FE-TEM, and elemental mapping analysis. The average size of AgPt NPs was 21.48 ± 6.32 nm and spherical in structure. Besides, AgPt NPs showed a hydrodynamic size of 63.64 (d.nm) with a polydispersity index of 0.220 and a zeta potential of -28.1 mV. The FT-IR and XRD analysis demonstrated the functional changes and crystalline properties of AgPt NPs. The antimicrobial efficacy of AgPt NPs against bacteria, yeast, and filamentous fungi was significantly higher when compared to the standard antibiotic. Furthermore, the AgPt NPs-CS/CG exhibited a substantial hydrophobic nature with better antimicrobial and antioxidant activity. In addition, pH-dependent Ag and Pt release from the AgPt NPs-CS/CG was determined by ICP-MS analysis. The treatment of AgPt NPs-CS/CG augmented the in vitro wound healing in mouse embryonic fibroblast cells (NIH3T3). Hence, we concluded that AgPt NPs-CS/CG could be used to enhance antimicrobial and wound healing applications.
    Keywords:  Antimicrobial; Chitosan; Core-shell; Cotton fabrics; Platinum nanoparticles; Silver nanoparticles
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.045
  118. Comb Chem High Throughput Screen. 2022 Sep 08.
    The genus Ageratina (Asteraceae) in America: An insight into its chemistry, and pharmacological potential.
    Isabel Rivero-Cruz, José Alberto Gutiérrez-González, Araceli Pérez-Vásquez, José Luis Villaseñor, Rachel Mata.
       BACKGROUND: Ageratina is an American genus of the tribe Eupatorieae (Asteraceae) comprising about 320 species. In Mexico, some species of this genus are highly valued for their medicinal properties, particularly A. pichinchensis, A. petiolaris and A. grandifolia. Furthermore, herbal preparations of A. pichinchensis are available for treating several mycoses.
    AIM AND OBJECTIVE: The present review is aimed to summarize the chemical and pharmacological properties of 36 species of Ageratina genus up to April 2022.
    METHODS: Data were recorded using online scientific databases including Scopus, PubMed, Google Scholar, Taylor and Francis Imprints, National Center for Biotechnology Information, Science Direct, JSTOR, and SciFinder. The information was assembled from research articles, relevant books on herbal medicinal plants and the history of medicinal plants from Mexico, theses, reports, and web pages.
    RESULTS: The specialized metabolites present in Ageratina genus belong to different chemical classes including flavonoids, benzyl benzoates, benzofurans, chromenes, and terpenoids. The chromenes, benzofurans, and benzyl benzoates are the metabolites most widespread in the genus. So far, the species more thoroughly investigated is A. adenophora. Ageratina has received little attention from the pharmacological point of view. The studies are limited to 10 species. The biological studies have been conducted with extracts and/or compounds isolated from plants collected mainly in China and Mexico. The results revealed that the extracts and metabolites possess several biological activities, which include antiviral, antioxidant, antimicrobial, anti-inflammatory, antinociceptive, antifeedant, larvicidal, acaricidal, antidiabetic, antiprotozoal, and wound-healing properties. In the case of A. pichinchensis, A. petiolaris, and A. grandifolia, the pharmacological studies provided evidence for their use for treating gastrointestinal complaints and diabetes. Furthermore, herbal preparations of A. pichinchensis are now widely used for alleviating onicomycoses. A. adenophora, endemic to Mexico, is the most investigated species, chemically and biologically, however some hepatotoxicity effect has been recorded.
    CONCLUSION: This review recapitulates information on the Ageratina genus highlighting on the phytochemistry and biological activities of the species investigated so far. It is important to point out that, the pharmacological potential of this large genus remains largely unexplored.
    Keywords:  Ageratina; botany; pharmacological properties; phytochemistry; toxicology
    DOI:  https://doi.org/10.2174/1386207325666220908093541
  119. Mol Nutr Food Res. 2022 Sep 16. e2200167
    Spicy Food and Chili Peppers and Multiple Health Outcomes: Umbrella Review.
    Zhimin Ao, Zongyue Huang, Hong Liu.
       BACKGROUND: Spicy foods and chili peppers contain the primary ingredient capsaicin, which has potential health benefits. However, their efficacy in some health outcomes is also fiercely disputed, and some side effects have been confirmed. Scope and approach: To assess the quality and strength of the associations between spicy food and chili pepper consumption and different health outcomes. An umbrella review was performed in humans.
    KEY FINDINGS AND CONCLUSIONS: 11 systematic reviews and meta-analyses with a total of 27 findings were identified. The health effect of consuming spicy food and chili peppers is unclear. Furthermore, the characteristics and context of different world regions and populations should be carefully considered. Direct correlations exist in esophageal cancer, gastric cancer, and gallbladder cancer. However, negative connections were reported in metabolism, mortality and cardiovascular disease. Dose-response analysis revealed a significant nonlinear relationship between gastric cancer risk and capsaicin intake. The consumption of spicy foods and chili peppers is typically safe. However, high-quality proof is available to confirm this conclusion. This article is protected by copyright. All rights reserved.
    Keywords:  Capsicum consumption; Health; Meta-Analysis; Spicy food consumption; Umbrella review
    DOI:  https://doi.org/10.1002/mnfr.202200167
  120. Front Pharmacol. 2022 ;13 990665
    Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche.
    Jiayan Shi, Jia Xu, Yang Li, Bowen Li, Hui Ming, Edouard C Nice, Canhua Huang, Qifu Li, Chuang Wang.
      Based on the bidirectional interactions between neurology and cancer science, the burgeoning field "cancer neuroscience" has been proposed. An important node in the communications between nerves and cancer is the innervated niche, which has physical contact with the cancer parenchyma or nerve located in the proximity of the tumor. In the innervated niche, autophagy has recently been reported to be a double-edged sword that plays a significant role in maintaining homeostasis. Therefore, regulating the innervated niche by targeting the autophagy pathway may represent a novel therapeutic strategy for cancer treatment. Drug repurposing has received considerable attention for its advantages in cost-effectiveness and safety. The utilization of existing drugs that potentially regulate the innervated niche via the autophagy pathway is therefore a promising pharmacological approach for clinical practice and treatment selection in cancer neuroscience. Herein, we present the cancer neuroscience landscape with an emphasis on the crosstalk between the innervated niche and autophagy, while also summarizing the underlying mechanisms of candidate drugs in modulating the autophagy pathway. This review provides a strong rationale for drug repurposing in cancer treatment from the viewpoint of the autophagy-mediated innervated niche.
    Keywords:  autophagy; cancer neuroscience; cancer treatment; drug repurposing; innervated niche
    DOI:  https://doi.org/10.3389/fphar.2022.990665
  121. J Gastrointestin Liver Dis. 2022 Sep 16. 31(3): 344-354
    Enhancing Metformin Effects by Adding Gut Microbiota Modulators to Ameliorate the Metabolic Status of Obese, Insulin-Resistant Hosts.
    Elena Maria Seicaru, Ioana Rada Popa Ilie, Adrian Cătinean, Alexandra Marioara Crăciun, Cristina Ghervan.
      Obesity is a systemic disease and represents one of the leading causes of death worldwide by constituting the main risk factor for a series of non-communicable diseases such as type 2 diabetes mellitus (T2DM), cardiovascular diseases and dyslipidemia. Lifestyle interventions have been attempting to prevent T2DM and obesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiota and its important role in the host's metabolism provides a new key for improving metabolic health. Modulating the composition of the gut microbiota was proposed as a method to manage these metabolic diseases and most frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action of metformin, the most commonly prescribed drug for treating T2DM, is mediated in part by the gut microbiota, although this interplay may also be responsible for the frequent gastrointestinal adverse effects of metformin. Thus, adding a gut microbiota modulator (GMM), such as probiotics or prebiotics, to metformin therapy could amplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the various therapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolic parameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existing clinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.
    DOI:  https://doi.org/10.15403/jgld-4248
  122. Front Pharmacol. 2022 ;13 982424
    Recent advances of IDH1 mutant inhibitor in cancer therapy.
    Wangqi Tian, Weitong Zhang, Yifan Wang, Ruyi Jin, Yuwei Wang, Hui Guo, Yuping Tang, Xiaojun Yao.
      Isocitrate dehydrogenase (IDH) is the key metabolic enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG). Two main types of IDH1 and IDH2 are present in humans. In recent years, mutations in IDH have been observed in several tumors, including glioma, acute myeloid leukemia, and chondrosarcoma. Among them, the frequency of IDH1 mutations is higher than IDH2. IDH1 mutations have been shown to increase the conversion of α-KG to 2-hydroxyglutarate (2-HG). IDH1 mutation-mediated accumulation of 2-HG leads to epigenetic dysregulation, altering gene expression, and impairing cell differentiation. A rapidly emerging therapeutic approach is through the development of small molecule inhibitors targeting mutant IDH1 (mIDH1), as evidenced by the recently approved of the first selective IDH1 mutant inhibitor AG-120 (ivosidenib) for the treatment of IDH1-mutated AML. This review will focus on mIDH1 as a therapeutic target and provide an update on IDH1 mutant inhibitors in development and clinical trials.
    Keywords:  2-HG; hypermethylation; isocitrate dehydrogenase mutation; mIDH1 inhibitors; natural product
    DOI:  https://doi.org/10.3389/fphar.2022.982424
  123. Pharmacol Res. 2022 Sep 12. pii: S1043-6618(22)00385-1. [Epub ahead of print] 106440
    Berberine for Gastric Cancer Prevention and Treatment: Multi-step Actions on the Correa's Cascade Underlie its Therapeutic Effects.
    Qingsong Liu, Jianyuan Tang, Shuanglan Chen, Shuangyuan Hu, Caifei Shen, Juyi Xiang, Nianzhi Chen, Jundong Wang, Xiao Ma, Yi Zhang, Jinhao Zeng.
      Gastric carcinoma (GC) is a complex multifactorial disease occurring as sequential events commonly referred to as the Correa's cascade, a stepwise progression from non-active or chronic active gastritis, to gastric precancerous lesions, and finally, adenocarcinoma. Therefore, the identification of novel agents with multi-step actions on the Correa's cascade and those functioning as multiple phenotypic regulators are the future direction for drug discovery. Recently, berberine (BBR) has gained traction owing to its pharmacological properties, including anti-inflammatory, anti-cancer, anti-ulcer, antibacterial, and immunopotentiation activities. In this article, we investigated and summarized the multi-step actions of BBR on Correa's cascade and its underlying regulatory mechanism in gastric carcinogenesis for the first time, along with a discussion on the strength of BBR to prevent and treat GC. A systematic search was performed using the Web of Science, ScienceDirect, PubMed, Google Scholar, and Embase databases. Following literature selection based on inclusion and exclusion criteria, 34 BBR articles were finally included in this study. BBR was found to suppress H. pylori infection, control mucosal inflammation, and promote ulcer healing. In the gastric precancerous lesion phase, BBR could reverse mucosal atrophy and prevent lesions in intestinal metaplasia and dysplasia by regulating inflammatory cytokines, promoting cell apoptosis, regulating macrophage polarization, and regulating autophagy. Additionally, the therapeutic action of BBR on GC was partly realized through the inhibition of cell proliferation, migration, and angiogenesis; induction of apoptosis and autophagy, and enhancement of chemotherapeutic drug sensitivity. BBR exerted multi-step actions on the Correa's cascade, thereby halting and even reversing gastric carcinogenesis in some cases. Thus, BBR could be used to prevent and treat GC. In conclusion, the therapeutic strategy underlying BBR's multi-step action in the trilogy of Correa's cascade may include "prevention of gastric mucosal inflammation (Phase 1); reversal of gastric precancerous lesions (Phase 2), and rescue of GC (Phase 3)." The NF-κB, PI3K/Akt, and MAPK signaling pathways may be the key signaling transduction pathways underlying the treatment of gastric carcinogenesis using BBR. The advantage of BBR over conventional drugs is its multifaceted and long-term effects. This review is expected to provide preclinical evidence for using BBR to prevent gastric carcinogenesis and treat gastric cancer.
    Keywords:  Berberine (PubChem CID: 2353); Correa’s cascade; atrophic gastritis; berberine; dysplasia; gastric carcinoma; gastric precancerous lesions; intestinal metaplasia
    DOI:  https://doi.org/10.1016/j.phrs.2022.106440
  124. ACS Omega. 2022 Sep 06. 7(35): 30657-30672
    Emerging ROS-Modulating Technologies for Augmentation of the Wound Healing Process.
    Suryanarayana Polaka, Pratik Katare, Bhakti Pawar, Nupur Vasdev, Tanisha Gupta, Kuldeep Rajpoot, Pinaki Sengupta, Rakesh Kumar Tekade.
      Reactive oxygen species (ROS) is considered a double-edged sword. The slightly elevated level of ROS helps in wound healing by inhibiting microbial infection. In contrast, excessive ROS levels in the wound site show deleterious effects on wound healing by extending the inflammation phase. Understanding the ROS-mediated molecular and biomolecular mechanisms and their effect on cellular homeostasis and inflammation thus substantially improves the possibility of exogenously augmenting and manipulating wound healing with the emerging antioxidant therapeutics. This review comprehensively delves into the relationship between ROS and critical phases of wound healing and the processes underpinning antioxidant therapies. The manuscript also discusses cutting-edge antioxidant therapeutics that act via ROS scavenging to enhance chronic wound healing.
    DOI:  https://doi.org/10.1021/acsomega.2c02675
  125. Food Microbiol. 2022 Dec;pii: S0740-0020(22)00140-X. [Epub ahead of print]108 104116
    Carvacrol encapsulation into nanoparticles produced from chia and flaxseed mucilage: Characterization, stability and antimicrobial activity against Salmonella and Listeria monocytogenes.
    Fabiola Ayres Cacciatore, Caroline Maders, Bibiana Alexandre, Cristian Mauricio Barreto Pinilla, Adriano Brandelli, Patrícia da Silva Malheiros.
      Carvacrol is a natural antimicrobial with excellent antimicrobial properties against several foodborne pathogens. Encapsulation can increase carvacrol stability and solubility, and mask its pronounced odor. Mucilages have been studied as wall material for nanoparticles due to their high retention capacity of bioactive compounds and ease of chemical modifications to improve their stability. In this study, 1.67 mg/mL of carvacrol encapsulated into chia mucilage nanoparticles (CMNP) and flaxseed mucilage nanoparticles (FMNP) were produced by high-energy emulsification technique and tested against Listeria monocytogenes and Salmonella. Encapsulation efficiency around 98% of carvacrol was obtained for both formulations. CMNP showed a diameter size of 179 nm and zeta potential of -11.4 mV. Bacterial Inactivation Concentration (BIC) of CMNP was 0.42 mg/mL against Salmonella and 0.83 mg/mL against L. monocytogenes. FMNP showed diameter size of 165.3 nm and zeta potential of -12.6 mV. BIC of FMNP was 0.83 mg/mL against both microorganisms. Scanning electron microscopy analysis showed that the nanoparticles are spherically shaped. Concentrations of BIC and ½ BIC were used to evaluate the kinetics of bacterial growth in the presence of antimicrobials (CMNP, FMNP and carvacrol solution). The results of this test showed that viable counts of Salmonella and L.monocytogenes were below the detection limit (1.69 log CFU/mL) after 2 h incubation (37 °C) using CMNP at the BIC. The wall material, rehydrated chia and flaxseed mucilages, reduced L. monocytogenes growth during 24 h. However, unloaded nanoparticles kept the viable counts of both microorganisms 2-5 log CFU/mL below the control curve of microbial growth during the 48 h experiment, suggesting that nanostructured mucilages potentiate antimicrobial properties. The results indicate that CMNP and FMNP have potential for use as food preservatives.
    Keywords:  Antimicrobial activity; Essential oil; Listeria; Mucilage; Nanoparticle; Salmonella
    DOI:  https://doi.org/10.1016/j.fm.2022.104116
  126. J Adv Res. 2022 09;pii: S2090-1232(21)00236-8. [Epub ahead of print]40 263-276
    Targeted delivery of Chinese herb pair-based berberine/tannin acid self-assemblies for the treatment of ulcerative colitis.
    Shiyun Chen, Zhejie Chen, Yi Wang, Wei Hao, Qin Yuan, Hefeng Zhou, Caifang Gao, Yitao Wang, Xu Wu, Shengpeng Wang.
       INTRODUCTION: Ulcerative colitis (UC) is a chronic recurrent idiopathic disease characterized by damage to the colonic epithelial barrier and disruption of inflammatory homeostasis. At present, there is no curative therapy for UC, and the development of effective and low-cost therapies is strongly advocated.
    OBJECTIVES: Multiple lines of evidence support that tannic acid (TA) and berberine (BBR), two active ingredients derived from Chinese herb pair (Rhei Radix et Rhizoma and Coptidis Rhizoma), have promising therapeutic effects on colonic inflammation. This study aims to develop a targeted delivery system based on BBR/TA-based self-assemblies for the treatment of UC.
    METHODS: TA and BBR self-assemblies were optimized, and hyaluronic acid (HA) was coated to achieve targeted colon delivery via HA-cluster of differentiation 44 (CD44) interactions. The system was systematically characterized and dextran sodium sulfate (DSS)-induced mouse colitis model was further used to investigate the biodistribution behavior, effect and mechanism of the natural system.
    RESULTS: TA and BBR could self-assemble into stable particles (TB) and HA-coated TB (HTB) further increased cellular uptake and accumulation in inflamed colon lesions. Treatment of HTB inhibited pro-inflammatory cytokine levels, restored expression of tight junction-associated proteins and recovered gut microbiome alteration, thereby exerting anti-inflammatory effects against DSS-induced acute colitis.
    CONCLUSION: Our targeted strategy may provide a convenient and powerful platform for UC and reveal new modes of application of herbal combinations.
    Keywords:  Berberine; Drug delivery; Gut microbiome; Tannin acid; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.jare.2021.11.017
  127. Adv Exp Med Biol. 2022 ;1390 155-167
    Vitamin D and Gut Health.
    James C Fleet.
      Vitamin D is a conditionally required nutrient that can either be obtained from skin synthesis following UVB exposure from the diet. Once in the body, it is metabolized to produce the endocrine hormone, 1,25 dihydroxyvitamin D (1,25(OH)2D), that regulates gene expression in target tissues by interacting with a ligand-activated transcription factor, the vitamin D receptor (VDR). The first, and most responsive, vitamin D target tissue is the intestine. The classical intestinal role for vitamin D is the control of calcium metabolism through the regulation of intestinal calcium absorption. However, studies clearly show that other functions of the intestine are regulated by the molecular actions of 1,25(OH)2 D that are mediated through the VDR. This includes enhancing gut barrier function, regulation of intestinal stem cells, suppression of colon carcinogenesis, and inhibiting intestinal inflammation. While research demonstrates that there are both classical, calcium-regulating and non-calcium regulating roles for vitamin D in the intestine, the challenge facing biomedical researchers is how to translate these findings in ways that optimize human intestinal health.
    Keywords:  Absorption; Calcium; Cancer; Inflammation; Stem cell; Tight junction; VDR; Vitamin D
    DOI:  https://doi.org/10.1007/978-3-031-11836-4_9
  128. Odontology. 2022 Sep 13.
    Curcumin nanoparticles: the topical antimycotic suspension treating oral candidiasis.
    Souzy Kamal Anwar, Sarah Nasser Abd Elmonaem, Eglal Moussa, Aliaa Gamaleldin Aboulela, Marwa Morsy Essawy.
      Phytotherapeutics is widely used nowadays as an alternative to the current antifungal drugs to reduce their side effects. Curcumin, with its wide therapeutic array as antioxidant and anti-inflammatory agent, is one of the natural compounds that ha..s an antifungal effect, especially when being used at nanoscale to increase its bioavailability. Our research aimed to evaluate clinically and microbiologically the effect of using topical nanocurcumin suspension to treat oral candidiasis. After 4 days from induction of oral candidiasis (baseline), we randomly divided 39 female BALB/c mice into three groups of 13 animals; nanocurcumin, nystatin, and sham groups. All animals in nanocurcumin and nystatin groups received topical treatment twice daily for 10 days. Then, we performed clinical and microbiological evaluations at baseline, day 5, and day 10. By the end of treatment, our results revealed that nanocurcumin promoted a significant reduction in the number of candida colonies. There was no statistically significant difference neither clinically nor microbiologically between nanocurcumin and nystatin groups. In conclusion, nanocurcumin has a good antifungal effect as nystatin, however, its therapeutic efficacy takes a longer time to appear than nystatin. The enhanced bioavailability of curcumin at the nanoscale qualifies this nano-herb as a promising alternative therapy for oral candidiasis, evading nystatin-associated morbidity.
    Keywords:  Nanocurcumin; Nanotechnology; Nystatin; Oral candidiasis
    DOI:  https://doi.org/10.1007/s10266-022-00742-4
  129. Trends Pharmacol Sci. 2022 Sep 08. pii: S0165-6147(22)00177-8. [Epub ahead of print]
    Nanodelivery of cGAS-STING activators for tumor immunotherapy.
    Jianfeng Guo, Leaf Huang.
      Activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has great potential to promote antitumor immunity. Development of activators for the cGAS-STING pathway (cGAS-STING activators) has profoundly revolutionized tumor immunotherapy. However, successful clinical application of cGAS-STING activators is contingent on having appropriate systems to achieve safe, effective, and specific delivery. There is an increasing emphasis on the design and application of nano drug delivery systems (NDDS) that can facilitate the delivery potential of cGAS-STING activators. In this review, we discuss barriers for translational development of cGAS-STING activators (DNA damaging drugs and STING agonists) and recent advances of NDDS for these agents in tumor immunotherapy.
    Keywords:  antitumor immunity; cGAS-STING; drug delivery; immunotherapy; nanoparticle
    DOI:  https://doi.org/10.1016/j.tips.2022.08.006
  130. Front Pharmacol. 2022 ;13 980945
    Exploring potential antidiabetic and anti-inflammatory flavonoids from Euphorbia humifusa with an integrated strategy.
    Tojofaniry Fabien Rakotondrabe, Minxia Fan, Mingquan Guo.
      E. humifusa Willd, a monoecious annual plant, native to Eastern Asia, has been traditionally attributed to the treatment and prevention of miscellaneous diseases, including diabetes mellitus and its associated complications. Earlier studies have supported this species' pharmacological efficacies including its antibacterial, antidiabetic, and anti-inflammatory properties. Even so, the underlying bioactive components with their mechanisms of action associated with its antidiabetic and anti-inflammatory effects remain elusive. The preamble in vitro assessments of the crude extract and its different fractions revealed that the n-butanol fraction (EHNB) exhibited the best activity, which was subsequently subjected to a rapid screening of candidate ligands through bio-affinity ultrafiltration with the two enzyme targets: α-glucosidase (α-Glu) and cycloxygenase-2 (COX-2) combined with UPLC/QTOF-MS. As a result, 7 compounds were identified from EHNB, among them, vitexin and astragalin were screened out as the most active ligand compounds. Vitexin showed great specific binding (SB) affinity values of 1.26 toward α-Glu and 1.32 toward COX-2, while astragalin showed 1.32 and 1.36, respectively. The docking simulation results exhibited strong interactions of vitexin and astragalin with the key residues of the enzyme targets, suggesting their possible mechanisms of action. The in vitro antidiabetic validation revealed noticeable half-maximal inhibitory effects (IC50) of 36.38 ± 3.06 µM for vitexin and 42.47 ± 4.13 µM for astragalin, much better than that of the positive drug acarbose (109.54 ± 14.23 µM). Similarly, these two compounds showed the inhibitory activity against COX-2 with the half-maximal inhibitory effects (IC50) at 27.91 ± 1.74 µM and 49.05 ± 1.49 µM, respectively. Therefore, these two flavonoid compounds (vitexin and astragalin) were speculated as potential antidiabetic and anti-inflammatory compounds from E. humifusa. Taken together, the integrated strategy applied to E. humifusa led to the fast identification of two potential double-acting flavonoids and enlightened its antidiabetic and anti-inflammatory uses. Besides these findings, the integrated strategy in this study could also be used to facilitate the rapid discovery and development of active candidates from other traditional herbal medicines against multi-drug targets and to aid in revealing their mechanisms of action for their traditional uses.
    Keywords:  Euphorbia humifusa; anti-inflammatory; antidiabetic; bio-affinity; flavonoid; ligand
    DOI:  https://doi.org/10.3389/fphar.2022.980945
  131. Mol Biomed. 2022 Sep 16. 3(1): 28
    Natural polyphenol self-assembled pH-responsive nanoparticles loaded into reversible hydrogel to inhibit oral bacterial activity.
    Yunyun Qi, Jinxiang Yang, Yaping Chi, Peng Wen, Zhongying Wang, Shiyi Yu, Rui Xue, Jingmin Fan, Hong Li, Wen Chen, Xinjun Wang, Yan Zhang, Gang Guo, Bo Han.
      Periodontitis is one of the most prevalent chronic inflammatory diseases and Polyphenols isolated from Turkish gall play a major role in the treatment of inflammatory diseases for their antibacterial, anti-inflammatory and antioxidant activities. In this work, Turkish Galls effective constituent (TGEC, T) was prepared into nanoparticles (T-NPs) by principle of oxidative self-polymerization. The pH-sensitive T-NPs was encapsulated into thermosensitive type in-situ hydrogel, and 42.29 ± 1.12% of effective constituent from T-NPs were continuously released within 96 h under the periodontitis environment. In addition, the weakly alkaline oral micro-environment of patients with periodontitis is more conducive to the sustained release of effective constituent, which is 10.83% more than that of healthy periodontal environment. The bacteriostatic test showed that T-NPs had stronger antibacterial activity on oral pathogens than that of TGEC. Compared with TGEC, the minimum inhibitory concentration (MIC) of T-NPs against P. gingivalis and A. viscosus was reduced by 50% and 25%, respectively. Interestingly, T-NPs induced bacteria lysis by promoting the excessive production of ROS without periodontal tissue damage caused by excessive oxidation reaction. In conclusion, a simple method of preparing microspheres with natural polyphenols was developed, which provides beneficial reference for one-step prepared drug carriers from effective components of natural product, likewise the method offers a green and effective solution to synthesis a new adjuvant therapy drugs for treatment of gingivitis associated with periodontal pockets.
    Keywords:  Anti-bacterial; Anti-oxidation; Nanoparticles; Natural polyphenols; Oxidative self-polymerization; pH sensitive
    DOI:  https://doi.org/10.1186/s43556-022-00082-3
  132. Oxid Med Cell Longev. 2022 ;2022 9966750
    Flavonols and Flavones as Potential anti-Inflammatory, Antioxidant, and Antibacterial Compounds.
    Maria do Socorro S Chagas, Maria D Behrens, Carla J Moragas-Tellis, Gabriela X M Penedo, Adriana R Silva, Cassiano F Gonçalves-de-Albuquerque.
      Plant preparations have been used to treat various diseases and discussed for centuries. Research has advanced to discover and identify the plant components with beneficial effects and reveal their underlying mechanisms. Flavonoids are phytoconstituents with anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial properties. Herein, we listed and contextualized various aspects of the protective effects of the flavonols quercetin, isoquercetin, kaempferol, and myricetin and the flavones luteolin, apigenin, 3',4'-dihydroxyflavone, baicalein, scutellarein, lucenin-2, vicenin-2, diosmetin, nobiletin, tangeretin, and 5-O-methyl-scutellarein. We presented their structural characteristics and subclasses, importance, occurrence, and food sources. The bioactive compounds present in our diet, such as fruits and vegetables, may affect the health and disease state. Therefore, we discussed the role of these compounds in inflammation, oxidative mechanisms, and bacterial metabolism; moreover, we discussed their synergism with antibiotics for better disease outcomes. Indiscriminate use of antibiotics allows the emergence of multidrug-resistant bacterial strains; thus, bioactive compounds may be used for adjuvant treatment of infectious diseases caused by resistant and opportunistic bacteria via direct and indirect mechanisms. We also focused on the reported mechanisms and intracellular targets of flavonols and flavones, which support their therapeutic role in inflammatory and infectious diseases.
    DOI:  https://doi.org/10.1155/2022/9966750
  133. Front Mol Biosci. 2022 ;9 964295
    Drug affinity-responsive target stability unveils filamins as biological targets for artemetin, an anti-cancer flavonoid.
    Giusy Ferraro, Raffaella Belvedere, Antonello Petrella, Alessandra Tosco, Björn Stork, Stefano Salamone, Alberto Minassi, Federica Pollastro, Elva Morretta, Maria Chiara Monti.
      Artemetin is a valuable 5-hydroxy-3,6,7,3',4'-pentamethoxyflavone present in many different medicinal plants with very good oral bioavailability and drug-likeness values, owing to numerous bioactivities, such as anti-inflammatory and anti-cancer ones. Here, a multi-disciplinary plan has been settled and applied for identifying the artemetin target(s) to inspect its mechanism of action, based on drug affinity-responsive target stability and targeted limited proteolysis. Both approaches point to the disclosure of filamins A and B as direct artemetin targets in HeLa cell lysates, also giving detailed insights into the ligand/protein-binding sites. Interestingly, also 8-prenyl-artemetin, which is an artemetin more permeable semisynthetic analog, directly interacts with filamins A and B. Both compounds alter filamin conformation in living HeLa cells with an effect on cytoskeleton disassembly and on the disorganization of the F-actin filaments. Both the natural compound and its derivative are able to block cell migration, expectantly acting on tumor metastasis occurrence and development.
    Keywords:  anti-cancer; bioactive natural compounds; cytoskeleton; drug affinity-responsive target stability; proteomics
    DOI:  https://doi.org/10.3389/fmolb.2022.964295
  134. Photodiagnosis Photodyn Ther. 2022 Sep 12. pii: S1572-1000(22)00404-5. [Epub ahead of print] 103118
    Photodynamic therapy for treating infected skin wounds: A systematic review and meta-analysis from randomized clinical trials.
    Analú Barros de Oliveira, Túlio Morandin Ferrisse, Carla Raquel Fontana, Fernanda Gonçalves Basso, Fernanda Lourenção Brighenti.
       BACKGROUND: Infected skin wounds represent a public health problem that affects 20 million people worldwide. Photodynamic therapy (PDT) is a treatment option with excellent results against several infections.
    OBJECTIVE: This study aimed to perform a systematic review and meta-analysis on PDT efficacy for treating infected wounds based on randomized clinical trials (RCTs).
    METHODS: PubMed, Scopus, Web of Science, SciELO, and the Cochrane library were searched. The Delphi List criteria and the Revised Cochrane risk-of-bias (Rob 2) were used for evaluating the quality of clinical trials. Meta-analyses were performed with the random-effect model. The odds ratio was the effect measure for binary outcomes, while the standard mean difference was used for continuous outcomes. The trim-and-fill method was used to detect small-study effects. The quality of evidence was verified for each outcome.
    RESULTS: Only four out of 573 articles were selected for the qualitative and quantitative analyses. The most frequent cause of infected wounds was impaired venous circulation (75%). All studies used red LED light. PDT reduced healing time and improved the healing process and wound oxygenation. Patients treated with PDT showed 15% to 17% (p=0.0003/ I2=0%) lower microbial cell viability in the wound and a significantly smaller wound size (0.72 cm2/p=0.0187/I2=0%) than patients treated with placebo or red-light exposure. There was a high level of evidence for each meta-analysis outcome.
    CONCLUSION: PDT can be an excellent alternative treatment for infected skin wounds.
    Keywords:  Infected skin wounds; Infection; Meta-analysis; Photodynamic therapy; Systematic review
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103118
  135. Front Neurosci. 2022 ;16 977374
    Research progress on the pharmacological effects of matrine.
    Yanan Sun, Lu Xu, Qihan Cai, Mengmeng Wang, Xinliang Wang, Siming Wang, Zhiyu Ni.
      Matrine possesses anti-cancer properties, as well as the prevention and treatment of allergic asthma, and protection against cerebral ischemia-reperfusion injury. Its mechanism of action may be (1) regulation of cancer cell invasion, migration, proliferation, and cell cycle to inhibit tumor growth; (2) reduction of oxidized low-density lipoprotein and advanced glycation end products from the source by exerting anti-inflammatory and antioxidant effects; (3) protection of brain damage and cortical neurons by regulating apoptosis; (4) restoration of the intestinal barrier and regulation of the intestinal microbiota. This article aims to explore matrine's therapeutic potential by summarizing comprehensive information on matrine's pharmacology, toxicity, and bioavailability.
    Keywords:  gut and gut microbes; matrine; pharmacokinetics; pharmacological action; toxicology
    DOI:  https://doi.org/10.3389/fnins.2022.977374
  136. J Food Biochem. 2022 Sep 15. e14390
    Diosgenin: An ingress towards solving puzzle for diabetes treatment.
    Prajya Arya, Pradyuman Kumar.
      The consumption and composition of food in daily life predict our health in long run. The relation of diabetes to sweets is quite popular. Diabetes hampers the glucose and insulin regulation in the human body by damaging pancreatic β cells. Diabetes has a strong potential towards altering cellular mechanisms of organs causing unlawful performance. Diabetes alters pathways like TLR4, AChE, NF-ĸB, LPL, and PPAR at different sites that affect the normal cellular machinery and cause damage to the local tissue and organ. The long-lasting effect of diabetes was observed in vascular, cardia, nervous, skeletal, reproductive, hepatic, ocular, and renal systems. The increasing awareness of diabetes and its concern has awakened the common people more enthusiastically. Due to rising harm from diabetes, scientific researchers tend to have more eyes toward it. While searching for diabetes solutions, fenugreek diosgenin could pop up with some positive effects in curing the same. Diosgenin helps to lower the scathe of diabetes by modifying cellular pathways in favor of healthy bodily functions. Diosgenin altered the pathways for renewal of pancreatic β cells for better insulin secretion, initiate GLUT4, enhanced DHEA, modify ER-α-mediated PI3K/Akt pathways. Diosgenin can be an appropriate insult for diabetes in a much evolving way for a healthy lifestyle. PRACTICAL APPLICATIONS: Diabetes is one of the most death causing diseases in the medical world. Regrettably the cure of diabetes is yet to be found. Various scientific team working on the same to look after the most appropriate way for diabetes treatment. There is enormous growth of nutraceutical in the market claiming for cure of different metabolic disorders. Among various bioactive compound fenugreek's diosgenin could took a leap over other in curing and preventing the damage caused by diabetes to different organs. The role of diosgenin in curing various metabolic disorders is quite popular from some time. This article also emphasizes over beneficiary effect of diosgenin in curing the damages caused by diabetes by altering cellular metabolism processes. Hence diosgenin could be a better way for researchers to develop a method for diabetes treatment.
    Keywords:  Cellular mechanism; Diabetes; Diabetes effect; Diosgenin; Metabolic disorder
    DOI:  https://doi.org/10.1111/jfbc.14390
  137. J Control Release. 2022 Sep 07. pii: S0168-3659(22)00586-7. [Epub ahead of print]
    Stealth nanoparticles in oncology: Facing the PEG dilemma.
    Sara Zalba, Timo L M Ten Hagen, Carmen Burgui, María J Garrido.
      Nanoparticles (Nps) have revolutionized the landscape of many treatments, by modifying not only pharmacokinetic properties of the encapsulated agent, but also providing a significant protection of the drug from non-desired interactions, and reducing side-effects of the enclosed therapeutic, enabling co-encapsulation of possibly synergistic compounds or activities, allowing a controlled release of content and improving the therapeutic effect. Nevertheless, in systemic circulation, Nps suffer a rapid removal by opsonisation and the action of Mononuclear phagocyte system (MPS). To overcome this problem, different polymers, in particular Polyethyleneglycol (PEG), have been used to cover the surface of these nanocarriers forming a hydrophilic layer that allows the delay of the removal. These advantages contrast with some drawbacks such as the difficulty to interact with cell membranes and the development of immunological reactions, conforming the known, "PEG dilemma". To address and minimize this phenomenon, different strategies have been applied. Therefore, this review aims to summarize the state of the art of Pegylation strategies, comment in depth on the principal characteristics of PEG and describe the main alternatives, which are the use of cleavable PEG, addition of different polymers or even use other derivatives of cell membranes to camouflage Nps.
    Keywords:  Alternatives; Cancer; Nanoparticles; PEG; PEG dilemma; Pharmacokinetics; Stealth
    DOI:  https://doi.org/10.1016/j.jconrel.2022.09.002
  138. Nutr Cancer. 2022 Sep 14. 1-6
    Dietary Phytochemical Index and the Risk of Breast Cancer: A Case-Control Study.
    Aylin Acikgoz Pinar, Emine Yildiz, Kadri Altundag.
      High intakes of phytochemical-rich foods might have beneficial effects on reducing breast cancer risk. In this study, we assessed the association between the dietary phytochemical index (PI) and breast cancer risk in a sample of premenopausal Turkish women. This case-control study was conducted on 70 newly diagnosed breast cancer cases and matched 70 healthy controls. Dietary intake was assessed using a validated food frequency questionnaire and dietary phytochemical indexes were calculated with two different methods. The mean PI score of participants was 19.9 ± 9.52 and 23.0 ± 8.95 in cases and controls, respectively (p = 0.046). After adjusting for energy intake, the risk of breast cancer significantly increased by 29.5% in the third quartile as compared to the fourth quartile of dietary PI (OR = 0.295, 95%CI = 0.106-0.822). Higher dietary PI was negatively associated with breast cancer risk; therefore, dietary PI may be suggested as an important contributor to dietary intake for breast cancer.
    DOI:  https://doi.org/10.1080/01635581.2022.2122518
  139. Prog Biophys Mol Biol. 2022 Sep 12. pii: S0079-6107(22)00092-X. [Epub ahead of print]
    Insulin fibrillation: Strategies for inhibition.
    Minoo Qafary, Fatemeh Rashno, Khosro Khajeh, Mohammad Khaledi, Ali A Moosavi-Movahedi.
      Insulin and its homologous are the most utilized protein drugs due to their role in diabetic patients' treatment. Insulin forms amyloid-like fibrils in vivo at the injection site. Therefore, the study of its fibrillation mechanism and designing efficient inhibitors have high importance in the pharmaceutical industry. Insulin fibrils are formed at both acidic and neutral pH in vitro. Overall, this process involves the dissociation of hexameric form to monomeric, partially dissociating the native monomeric form, nuclei formation, and finally converting oligomers to large ordered aggregates. Intermediate and terminal species are different pathologically. This review is focused on the research works dedicated to the inhibition of insulin fibril formation. The inhibitors include various polyphenols, natural compounds, nanoparticles, and synthetic chemicals/peptides, as well as the classification of inhibitors targets concerning protein fibrillation. Although most inhibitors stabilize the native structure of the protein and prevent the formation of partially folded species, there are other inhibitors that hinder other steps in the course of fibrillation. Also, several inhibitors were able to dissociate the pre-existing fibrils. Finding inhibition strategies could be beneficial for developing new inhibitors that are more efficient and can block the amyloid pathway in a specific desired stage.
    Keywords:  Fibrillation; Inhibition mechanisms; Inhibition strategies; Insulin; Nanoparticles; Natural compounds; Polyphenols
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2022.09.001
  140. Ther Adv Med Oncol. 2022 ;14 17588359221118019
    Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies.
    Anthony Turpin, Cindy Neuzillet, Elise Colle, Nelson Dusetti, Rémy Nicolle, Jérôme Cros, Louis de Mestier, Jean-Baptiste Bachet, Pascal Hammel.
      Mortality from pancreatic ductal adenocarcinoma (PDAC) is increasing worldwide and effective new treatments are urgently needed. The current treatment of metastatic PDAC in fit patients is based on two chemotherapy combinations (FOLFIRINOX and gemcitabine plus nab-paclitaxel) which were validated more than 8 years ago. Although almost all treatments targeting specific molecular alterations have failed so far when administered to unselected patients, encouraging results were observed in the small subpopulations of patients with germline BRCA 1/2 mutations, and somatic gene fusions (neurotrophic tyrosine receptor kinase, Neuregulin 1, which are enriched in KRAS wild-type PDAC), KRAS G12C mutations, or microsatellite instability. While targeted tumor metabolism therapies and immunotherapy have been disappointing, they are still under investigation in combination with other drugs. Optimizing pharmacokinetics and adapting available chemotherapies based on molecular signatures are other promising avenues of research. This review evaluates the current expectations and limits of available treatments and analyses the existing trials. A permanent search for actionable vulnerabilities in PDAC tumor cells and microenvironments will probably result in a more personalized therapeutic approach, keeping in mind that supportive care must also play a major role if real clinical efficacy is to be achieved in these patients.
    Keywords:  KRAS; NRG1; NTRK; PARP; immunotherapy; metastatic; pancreatic cancer; precision medicine
    DOI:  https://doi.org/10.1177/17588359221118019
  141. MedComm (2020). 2022 Dec;3(4): e164
    Targeting cancer cachexia: Molecular mechanisms and clinical study.
    Yong-Fei Wang, Zi-Yi An, Dong-Hai Lin, Wei-Lin Jin.
      Cancer cachexia is a complex systemic catabolism syndrome characterized by muscle wasting. It affects multiple distant organs and their crosstalk with cancer constitute cancer cachexia environment. During the occurrence and progression of cancer cachexia, interactions of aberrant organs with cancer cells or other organs in a cancer cachexia environment initiate a cascade of stress reactions and destroy multiple organs including the liver, heart, pancreas, intestine, brain, bone, and spleen in metabolism, neural, and immune homeostasis. The role of involved organs turned from inhibiting tumor growth into promoting cancer cachexia in cancer progression. In this review, we depicted the complicated relationship of cancer cachexia with the metabolism, neural, and immune homeostasis imbalance in multiple organs in a cancer cachexia environment and summarized the treatment progress in recent years. And we discussed the molecular mechanism and clinical study of cancer cachexia from the perspective of multiple organs metabolic, neurological, and immunological abnormalities. Updated understanding of cancer cachexia might facilitate the exploration of biomarkers and novel therapeutic targets of cancer cachexia.
    Keywords:  cancer cachexia; exercise; innervation; interorgan communication; metabolism; muscle wasting
    DOI:  https://doi.org/10.1002/mco2.164
  142. J Nanobiotechnology. 2022 Sep 15. 20(1): 412
    Overcoming the blood-brain barrier for the therapy of malignant brain tumor: current status and prospects of drug delivery approaches.
    Ksenia Mitusova, Oleksii O Peltek, Timofey E Karpov, Albert R Muslimov, Mikhail V Zyuzin, Alexander S Timin.
      Besides the broad development of nanotechnological approaches for cancer diagnosis and therapy, currently, there is no significant progress in the treatment of different types of brain tumors. Therapeutic molecules crossing the blood-brain barrier (BBB) and reaching an appropriate targeting ability remain the key challenges. Many invasive and non-invasive methods, and various types of nanocarriers and their hybrids have been widely explored for brain tumor treatment. However, unfortunately, no crucial clinical translations were observed to date. In particular, chemotherapy and surgery remain the main methods for the therapy of brain tumors. Exploring the mechanisms of the BBB penetration in detail and investigating advanced drug delivery platforms are the key factors that could bring us closer to understanding the development of effective therapy against brain tumors. In this review, we discuss the most relevant aspects of the BBB penetration mechanisms, observing both invasive and non-invasive methods of drug delivery. We also review the recent progress in the development of functional drug delivery platforms, from viruses to cell-based vehicles, for brain tumor therapy. The destructive potential of chemotherapeutic drugs delivered to the brain tumor is also considered. This review then summarizes the existing challenges and future prospects in the use of drug delivery platforms for the treatment of brain tumors.
    Keywords:  Blood–brain barrier; Brain tumor; Cell therapy; Cell-based vehicles; Glioblastoma; Glioma; Invasive and non-invasive methods; Nanocarriers; Targeting vectors; Therapeutic drugs; Viral-like particles
    DOI:  https://doi.org/10.1186/s12951-022-01610-7
  143. Chem Biol Interact. 2022 Sep 10. pii: S0009-2797(22)00382-9. [Epub ahead of print] 110177
    Combination treatment with cyclosporin A and arsenic trioxide induce synergistic cell death via non-apoptotic pathway in uterine cervical cancer cells.
    Pei-Ju Wu, I-Lun Hsin, Wei-Li Hung, Maw-Sheng Lee, Po-Hui Wang, Jiunn-Liang Ko.
      Cyclosporin A is an immunosuppressive drug with anti-cancer effect. Arsenic trioxide (As2O3), a well-known cancer-inhibiting drug, induced cytotoxicity via apoptosis and autophagy. The aim of this study is to evaluate the effect of combinational treatment with cyclosporin A and arsenic trioxide on cell viability inhibition in cervical cancer cells. Using MTT assay and combination index, combinational treatment with cyclosporin A and arsenic trioxide induced a synergistic cytotoxic effect in Caski and SiHa cells. Cyclosporin A and arsenic trioxide triggered cell death via non-apoptotic pathway by using annexin V/propidium iodide (PI) assay. Cyclosporin A and arsenic trioxide combined treatment decreased mitochondrial membrane potential and increase reactive oxygen species (ROS) generation. This co-treatment increased LC3B-II expression and autophagosome formation in cervical cancer cells. This study first demonstrated that combinational treatment with cyclosporin A and As2O3 trigger synergistic cytotoxic effect via autophagy in cervical cancer cells.
    Keywords:  Arsenic trioxide; Autophagy; Cyclosporin A; Mitochondrial membrane potential; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cbi.2022.110177
  144. Front Mol Biosci. 2022 ;9 937865
    Metabolic profiling of induced acute pancreatitis and pancreatic cancer progression in a mutant Kras mouse model.
    Tatiana J Carneiro, Joana Pinto, Eva M Serrao, António S Barros, Kevin M Brindle, Ana M Gil.
      Untargeted Nuclear Magnetic Resonance (NMR) metabolomics of polar extracts from the pancreata of a caerulin-induced mouse model of pancreatitis (Pt) and of a transgenic mouse model of pancreatic cancer (PCa) were used to find metabolic markers of Pt and to characterize the metabolic changes accompanying PCa progression. Using multivariate analysis a 10-metabolite metabolic signature specific to Pt tissue was found to distinguish the benign condition from both normal tissue and precancerous tissue (low grade pancreatic intraepithelial neoplasia, PanIN, lesions). The mice pancreata showed significant changes in the progression from normal tissue, through low-grade and high-grade PanIN lesions to pancreatic ductal adenocarcinoma (PDA). These included increased lactate production, amino acid changes consistent with enhanced anaplerosis, decreased concentrations of intermediates in membrane biosynthesis (phosphocholine and phosphoethanolamine) and decreased glycosylated uridine phosphates, reflecting activation of the hexosamine biosynthesis pathway and protein glycosylation.
    Keywords:  KRAS; PanIN; metabolomics; nuclear magnetic resonance (1H-NMR); pancreatic cancer; pancreatic ductal adenocarcinoma; pancreatitis
    DOI:  https://doi.org/10.3389/fmolb.2022.937865
  145. Int J Biol Macromol. 2022 Sep 09. pii: S0141-8130(22)01988-2. [Epub ahead of print]
    A self-healing hydrogel based on oxidized microcrystalline cellulose and carboxymethyl chitosan as wound dressing material.
    Huishuang Yin, Peiqin Song, Xingyu Chen, Huihua Huang.
      As the food processing by-products, hericium erinaceus residues (HER) and pineapple peel (PP) are good sources of cellulose and chitosan that can be prepared into hydrogels for structuring a drug delivery system. Hydrogel is one new type biomaterial for drug delivery with excellent absorbent ability applied in wound dressing. In this research, one composite self-healing hydrogel with pH sensitivity for drug delivery system based on the Schiff-base reaction was fabricated. Therein aldehyde group of oxidized microcrystalline cellulose (OMCC) from PP were crosslinked with amino group of carboxymethyl chitosan (CMCS) from HER via Schiff-base reaction for structuring hydrogels. The structures of the prepared hydrogels were characterized. Meanwhile, its blood clotting activity and physical properties were investigated. The hydrogels show some favorable performances with suitable gel time (54 s of minimum), distinguish swelling rate (about 31.18 g/g), good mechanical, self-healing characteristic and well coagulation effect. The cumulative release of the rutin-loaded hydrogel OMCM-54 reached about 80 % within 6 h, suggesting the well-controlled release of rutin by crosslinking degree between the modified OMCC and CMCS based on Schiff-base reaction. The novel biomaterial based on hericium erinaceus residues and pineapple peel shows its potential use as wound dressing.
    Keywords:  Cellulose/chitosan hydrogel; Hericium erinaceus residue; Pineapple peel; Schiff-base reaction; Self-healing ability; Wound dressing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.09.060
  146. Nat Prod Res. 2022 Sep 10. 1-5
    Chrysin inhibits the cell viability, induces apoptosis and modulates expression of genes related to epigenetic events in bladder cancer cells.
    Ana Paula Braga Lima, André Sacramento Melo, Gabriel Monteze Ferreira, Glenda Nicioli da Silva.
      This study was conducted with the aim of exploring the molecular and cellular mechanisms of action of the chrysin (natural flavonoid compound) on bladder tumour cell lines with different status of TP53 (RT4, 5637 and T24). The cells were treated with different concentrations of chrysin (20, 40, 60, 80 and 100 µM) to analyze the cell viability, nuclear division index, mutagenicity, apoptosis rates and expression of genes related to epigenetic events (DNMT1, HAT1 and HDAC1). Results showed that the treatment with chrysin reduced the cell viability and caused apoptosis, regardless TP53. Moreover, in the TP53-mutated cell lines, chrysin modulated the expression of the DNMT1, HAT1 and HDAC1 epigenetic genes, which might be a plus to the death observed in the cells with p53 mutation.
    Keywords:  Flavonoid; IDN; TP53; bladder tumor; cell death; epigenetic events
    DOI:  https://doi.org/10.1080/14786419.2022.2121825
  147. Adv Drug Deliv Rev. 2022 Sep 08. pii: S0169-409X(22)00421-5. [Epub ahead of print] 114531
    Liposomal formulations for treating lysosomal storage disorders.
    Judit Tomsen-Melero, Josep Merlo-Mas, Aida Carreño, Santi Sala, Alba Córdoba, Jaume Veciana, Elisabet González-Mira, Nora Ventosa.
      Lysosomal storage disorders (LSD) are a group of rare life-threatening diseases caused by a lysosomal dysfunction, usually due to the lack of a single enzyme required for the metabolism of macromolecules, which leads to a lysosomal accumulation of specific substrates, resulting in severe disease manifestations and early death. There is currently no definitive cure for LSD, and despite the approval of certain therapies, their effectiveness is limited. Therefore, an appropriate nanocarrier could help improve the efficacy of some of these therapies. Liposomes show excellent properties as drug carriers, because they can entrap active therapeutic compounds offering protection, biocompatibility, and selectivity. Here, we discuss the potential of liposomes for LSD treatment and conduct a detailed analysis of promising liposomal formulations still in the preclinical development stage from various perspectives, including treatment strategy, manufacturing, characterization, and future directions for implementing liposomal formulations for LSD.
    Keywords:  Compressed fluids; Drug delivery; Enzyme replacement therapy; Gene therapy; Liposome processing; Liposomes; Lysosomal storage disorders; Nanocarriers; Nanovesicles
    DOI:  https://doi.org/10.1016/j.addr.2022.114531
  148. Colloids Surf B Biointerfaces. 2022 Aug 27. pii: S0927-7765(22)00489-1. [Epub ahead of print]219 112806
    Dual-functional polyetheretherketone surface with programmed sequential drug release coating.
    Wei-Hong Yin, Chang-Hai Zhou, Xiao-Jie Ju, Yi Deng, Lu Zhang, Rui Xie, Wei Wang, Zhuang Liu, Liang-Yin Chu.
      The poor bacteriostasis and osseointegration properties of bioinert polyetheretherketone (PEEK) hinder its clinical application. This work reports a simple and versatile strategy for fabricating dual-functional coating with programmed sequential drug release properties on porous PEEK surfaces. The dual-drug-loaded composite coating composed of drug-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and drug-loaded polyvinyl alcohol (PVA) gel can be immobilized on the surface of sulfonated PEEK by a cyclic freeze-thaw method. Based on the swelling of PVA and the slow degradation of PLGA, the composite coating can realize rapid release of antibacterial drugs and sustained release of osteogenic drugs. The in vitro antibacterial evaluations show that the porous PEEK modified with drug-loaded composite gel coating exhibits an early effective fight against Staphylococcus aureus (S.aureus). The results of in vitro cell experiments show that the PEEK materials modified by the composite gel coating can well support the normal growth, adhesion and proliferation of cells. In addition, the PEEK material coated with the drug-loaded composite gel is found to have positive effects on the osteogenic differentiation of cells in detections of alkaline phosphatase (ALP) activity of cells and the amount of calcium deposition on the surface of the material. The results demonstrate that the proposed porous PEEK modified with dual-drug-loaded composite gel coating simultaneously exhibits excellent osseointegration and exerts early effective antibacterial activity. This dual-functional PEEK material has great application potential in clinical bone tissue repair.
    Keywords:  Antibacterial activity; Composite gel coating; Osseointegration; Polyetheretherketone; Programmed sequential drug release
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112806
  149. Gut. 2022 Sep 16. pii: gutjnl-2021-326575. [Epub ahead of print]
    Diet fuelling inflammatory bowel diseases: preclinical and clinical concepts.
    Timon E Adolph, Jingwan Zhang.
      The diet and gut microbiota have been extensively interrogated as a fuel for gut inflammation in inflammatory bowel diseases (IBDs) in the last few years. Here, we review how specific nutrients, typically enriched in a Western diet, instigate or deteriorate experimental gut inflammation in a genetically susceptible host and we discuss microbiota-dependent and independent mechanisms. We depict the study landscape of nutritional trials in paediatric and adult IBD and delineate common grounds for dietary advice. Conclusively, the diet reflects a critical rheostat of microbial dysbiosis and gut inflammation in IBD. Dietary restriction by exclusive enteral nutrition, with or without a specific exclusion diet, is effectively treating paediatric Crohn's disease, while adult IBD trials are less conclusive. Insights into molecular mechanisms of nutritional therapy will change the perception of IBD and will allow us to enter the era of precision nutrition. To achieve this, we discuss the need for carefully designed nutritional trials with scientific rigour comparable to medical trials, which also requires action from stake holders. Establishing evidence-based dietary therapy for IBD does not only hold promise to avoid long-term immunosuppression, but to provide a widely accessible therapy at low cost. Identification of dietary culprits disturbing gut health also bears the potential to prevent IBD and allows informed decision making in food politics.
    Keywords:  diet; dietary factors; gut inflammation; inflammatory bowel disease; intestinal microbiology
    DOI:  https://doi.org/10.1136/gutjnl-2021-326575
  150. Nat Prod Res. 2022 Sep 12. 1-18
    Asian herbal medicine and chronic urticaria: which are the therapeutic perspectives?
    Luca Gammeri, Claudia Panzera, Fabrizio Calapai, Nicola Cicero, Sebastiano Gangemi.
      Chronic urticaria (CU) is a pathologic condition marked by the emergence of wheals, angioedema, or both for more than six weeks. The improper activation and degranulation of mast cells is the triggering event, which results in the production of various mediators such as histamine, leukotrienes, PAF, chemokines, and cytokines. Antihistamines are currently the most common pharmacological treatment for urticaria, but corticosteroids and monoclonal antibodies can also be employed. Patients who have been taking antihistamines for a long time are often looking for alternatives. Whole plants, portions of plants, or single extracted active compounds are all used in phytomedicine. Plant elements are frequently combined to create formulations that can be utilized to treat a variety of pathological disorders. Anti-inflammatory and/or anti-allergic properties are found in several herbs regularly used in herbal formulations. Antioxidant properties are also present in some of the constituents. Exogenous antioxidants have been shown to improve the progression of autoimmune disorders in numerous studies. The aim of this review is to identify the most common herbs used to treat chronic urticaria, and to characterize their efficacy, mechanisms of action, and risk/benefit ratio in comparison to western treatment, and also to find less often used formulations and assess their therapeutic efficacy, safety profile, and potential for wider use.
    Keywords:  Chronic urticaria; antioxidants; immune system; inflammation; phytomedicine
    DOI:  https://doi.org/10.1080/14786419.2022.2122055
  151. J Food Sci. 2022 Sep 13.
    Onion (Allium cepa L.) peel: A review on the extraction of bioactive compounds, its antioxidant potential, and its application as a functional food ingredient.
    Manoj Kumar, Mrunal D Barbhai, Muzaffar Hasan, Sangram Dhumal, Surinder Singh, Ravi Pandiselvam, Nadeem Rais, Suman Natta, Marisennayya Senapathy, Neha Sinha, Ryszard Amarowicz.
      Functional food development is rapidly increasing as a result of consumer consciousness concerning healthy and nutritious foods. In turn, research exploring novel ingredients for formulating functional foods has been accelerated. Onion peel or skin is a byproduct obtained from onion processing that contains abundant phytochemicals, contributing to its antioxidant potential. The main focus of this review is to highlight different extraction techniques (both conventional and nonconventional) that can be implemented to extract the bioactive compounds from onion peel and assess their antioxidant activity. Furthermore, this review highlights the major areas for the application of onion peel and its extract as prospective functional ingredients, thus aiding in the preparation of designer foods with additional health benefits. The use of onion peel could also assist in redesigning popularly consumed processed foods, such as baked products, noodles or pasta, as packaging material, meat quality improvers, colorants, and juice clarifiers. This review serves as a preliminary document that can assist in exploring different ways of incorporating bioactive onion peels or skin into the functional food industry and concludes that future research can assist in the effective and efficient utilization of this resource.
    Keywords:  antioxidants; extraction techniques; functional food; onion peel; onion skin
    DOI:  https://doi.org/10.1111/1750-3841.16297
  152. Probl Endokrinol (Mosk). 2022 Jun 01. 68(4): 78-91
    [Time-restricted eating as a novel strategy for treatment of obesity and it's comorbid conditions].
    M A Berkovskaya, O Y Gurova, I A Khaykina, V V Fadeev.
      The article provides a review of the current literature about time-restricted eating (TRE) as a new tool for the treatment of obesity and comorbid conditions. The search for new nutritional strategies in obesity, one of which is TRE, is due to the weak adherence of patients to hypocaloric diets in the long term, as well as the available data on the importance of -desynchronization of food intake with natural circadian rhythms in the development and progression of obesity and cardio--metabolic complications. The article describes the main mechanisms that regulate the circadian rhythms of food intake and nutrient absorption, substantiates the importance of adhering to a physiological diet for maintaining metabolic health. The main part of the review is devoted to reviewing the currently available researches on the effectiveness of various strategies of intermittent energy restriction for weight loss and the correction of metabolic parameters. Potential mechanisms of  the -effect of TRE on health are discussed, including those mediated by an unintentional decrease in caloric intake and changes in eating behavior, and differences in the effectiveness of early and late TRE. The article contains a detailed discussion of the potential problems and contradictions associated with the use of time-restricted eating in clinical practice, namely: the limitations and inconsistencies of the available clinical trials, the lack of data on long-term efficacy and safety, social and psychological limitations that impede the widespread use of TRE.
    DOI:  https://doi.org/10.14341/probl13078
  153. Heliyon. 2022 Sep;8(9): e10452
    Dietary phytochemicals alter hypopharyngeal gland size in honey bee (Apis mellifera L.) workers.
    Elina L Niño, Seiji Yokota, William H O Stacy, H S Arathi.
      Honey bees are the most efficient pollinators of several important fruits, nuts and vegetables and are indispensable for the profitable production of these crops. Health and performance of honey bee colonies have been declining for decades due to a combination of factors including poor nutrition, agrochemicals, pests and diseases. Bees depend on a diversity of plants for nutrition as pollen is the predominant protein and lipid source, and nectar, the source of carbohydrates for larval development. Additionally, pollen and nectar also contain small amounts of plant secondary metabolites or phytochemicals that are primarily plant defense compounds. Bees have coevolved to benefit from these compounds as seen by the improved longevity, pathogen tolerance and gut microbiome abundance in worker bees whose diets were supplemented with select phytochemicals. Here we investigate the impact of four phytochemicals, known to benefit bees, - caffeine, kaempferol, gallic acid and p-coumaric acid, on hypopharyngeal gland (HPG) size of nurse bees. Newly emerged bees were provided with 25 ppm of each of the four phytochemicals in 20% (w/v) sucrose solution and the size of HPGs were measured after a 10 d period. Bees that received p-coumaric acid or kaempferol showed a significant increase in HPG size. A significant decrease in HPG size was seen in bees receiving caffeine or gallic acid. The implication of our findings on worker bee ontogeny, transitioning from nurses to foragers and relevance to foraging related competencies are discussed. It is critical that bees have access to phytochemicals to ensure colony health and performance. Such access could be through natural habitats that provide a diversity of pollen and nectar sources or through dietary supplements for bee colonies.
    Keywords:  Caffeine; Gallic acid; Honey bees; Hypopharyngeal glands (HPG); Kaempferol; Phytochemicals; p-coumaric acid
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10452
  154. Cell Mol Life Sci. 2022 Sep 14. 79(10): 517
    Metabolic reprogramming in the OPA1-deficient cells.
    Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.
      OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.
    Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation
    DOI:  https://doi.org/10.1007/s00018-022-04542-5
  155. Adv Colloid Interface Sci. 2022 Sep 06. pii: S0001-8686(22)00174-9. [Epub ahead of print]308 102772
    Bioactive-loaded nanodelivery systems for the feed and drugs of livestock; purposes, techniques and applications.
    Shahida Anusha Siddiqui, Nur Alim Bahmid, Ahmed Taha, Abdel-Moneim Eid Abdel-Moneim, Abdelrazeq M Shehata, Chen Tan, Mohammad Saeed Kharazmi, Yuan Li, Elham Assadpour, Roberto Castro-Muñoz, Seid Mahdi Jafari.
      Advances in animal husbandry and better performance of livestock results in growing demands for feed and its nutrients, bioactive compounds (bioactives), such as vitamins, minerals, proteins, and phenolics, along with drugs/vaccines. To protect the feed bioactives in unintended circumstances, they can be encapsulated to achieve desired efficacy in animal feeding and nanoencapsulation gives more potential for better protection, absorption and targeted delivery of bioactives. This study reviews structures, properties, and methods of nanoencapsulation for animal feedings and relevant drugs. Essential oil (EOs) and plant extracts are mostly encapsulated bioactives and phytochemicals for poultry diets and chitosan is found as most effective nanocarrier to load EOs and plant extracts. Nanoparticles (NPs) and nanocapsules are frequently studied nanocarriers, which are mostly processed by using the ionotropic/ionic gelation. Nanofibers, nanohydrogels and nanoemulsions are not found yet for their application in feed bioactives. These nanocarriers can have an improved protection, stability, and controlled release of feed bioactives which benefits to additional nutrition for the growth of livestock regardless of the low stability and water solubility of bioactives. For ruminants' feeds, nano-minerals, vitamins, phytochemicals, essential fatty acids, and drugs are encapsulated by NPs to facilitate the delivery to target organs through direct penetration, to improve their bioavailability, to generate more efficient absorption in cells and tissues, and protect them from rapid degradation. Furthermore, safety and regulatory issues, as well as advantages and disadvantages of nanoencapsulation application in animal feeds are also discussed. The review shows an accurate design of NPs can largely mask safety issues with straightforward approaches and awareness of safety concerns is fundamental for better designing of nanoencapsulation systems and commercialization. This review gives an insight of understanding and potential of nanoencapsulation in ruminants and poultry feedings to obtain a better bioavailability of the nutrients and bioactives with improved safety and awareness for better designing of nanoencapsulating systems.
    Keywords:  Animal drugs; Animal feed; Bioactive compounds; Nanoencapsulation; Poultry; Ruminants
    DOI:  https://doi.org/10.1016/j.cis.2022.102772
  156. Front Pharmacol. 2022 ;13 933655
    Disulfiram in glioma: Literature review of drug repurposing.
    Shiyu Zhong, Shengyu Liu, Xin Shi, Xudong Zhang, Kunhang Li, Guojun Liu, Lishuai Li, Shanwei Tao, Bowen Zheng, Weichen Sheng, Ziyin Ye, Qichen Xing, Qingqing Zhai, Lijie Ren, Ying Wu, Yijun Bao.
      Gliomas are the most common malignant brain tumors. High-grade gliomas, represented by glioblastoma multiforme (GBM), have a poor prognosis and are prone to recurrence. The standard treatment strategy is tumor removal combined with radiotherapy and chemotherapy, such as temozolomide (TMZ). However, even after conventional treatment, they still have a high recurrence rate, resulting in an increasing demand for effective anti-glioma drugs. Drug repurposing is a method of reusing drugs that have already been widely approved for new indication. It has the advantages of reduced research cost, safety, and increased efficiency. Disulfiram (DSF), originally approved for alcohol dependence, has been repurposed for adjuvant chemotherapy in glioma. This article reviews the drug repurposing method and the progress of research on disulfiram reuse for glioma treatment.
    Keywords:  disulfiram; drug repurposing; glioblastoma multiforme; gliomas; temozolomide
    DOI:  https://doi.org/10.3389/fphar.2022.933655
  157. Curr Med Chem. 2022 Sep 15.
    Ancient Wheats as Promising Nutraceuticals for the Prevention of Chronic and Degenerative Diseases.
    Giovanna Basile, Azzurra Chiara De Maio, Alessia Catalano, Jessica Ceramella, Domenico Iacopetta, Daniela Bonofiglio, Carmela Saturnino, Maria Stefania Sinicropi.
      In the context of a balanced diet, wheat, mainly when used as whole grains, is a good source of nutrients, including fibers and bioactive compounds. Cereals belong to the Poaceae family and are crucial for maintaining a healthy status, granted by their nutritional and chemical properties. Recent studies have demonstrated that the intake of whole grains and grain-based products may reduce the risk of oxidative stress, thus lowering chronic and age-related disorders, such as obesity, cardiovascular diseases, type II diabetes and cancer. Indeed, several studies report that the regular whole grain consumption is associated with lower levels of total and LDL-cholesterol, triglycerides, fasting glucose, blood pressure and body mass index. Moreover, ancient wheat species have acquired increasing interest for human health, as they contain several nutraceutical compounds, such as vitamins, minerals and others. The numerous phytochemicals present in ancient wheat (polyphenols, carotenoids, phytosterols and phenolic compounds) provide, in fact, antioxidant properties, which are essential in the prevention of various chronic and degenerative diseases. The aim of this review is to report the existing information on ancient wheat species, discussing their composition and nutraceuticals properties compared with modern varieties and highlight the beneficial impact on human health.
    Keywords:  Wheat; ancient wheat; antioxidants; carotenoids; cereals; ferulic acid; human health; nutraceuticals; whole grain
    DOI:  https://doi.org/10.2174/0929867329666220915122216
  158. Cell Biol Int. 2022 Sep 13.
    Exosomes to control glioblastoma multiforme: Investigating the effects of mesenchymal stem cell-derived exosomes on C6 cells in vitro.
    Houman Parsaei, Mir Javad Moosavifar, Mina Eftekharzadeh, Reihaneh Ramezani, Mahmood Barati, Soheil Mirzaei, Maliheh Nobakht.
      Glioblastoma multiforme (GBM) is a common, aggressive, fast-growing tumor of the central nervous system that currently has no effective treatment. Although stem cell therapy has shown promising in vitro achievements, the blood-brain barrier (BBB) has always been a major hurdle to clinical success. To overcome this challenge, exosomes have been targeted as attractive drug delivery agents in numerous studies since they are small enough to enter the BBB. Furthermore, exosomes' characteristics and compositions are directly determined by the parent cell and these heritable traits affect their cell interactions. This article focuses on exosomes as an alternative to stem cell therapy to regulate glioma cell activity. Exosomes were isolated from rat bone marrow mesenchymal stem cells (rBMMSCs) by ultracentrifugation method and then characterized via western blot, dynamic light scattering, scanning, and transmission electron microscopy. Next, various concentrations of the exosomes were incubated with C6 cells and their effects at different time points were evaluated in vitro. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Annexin/Pi assay results confirmed that the isolated exosomes cause cell death mostly through apoptosis, and a linear correlation was observed between exosomes' concentration and their cytotoxicity. Following that, the scratch test, colony formation test, and Transwell assay confirmed exosomes' significant impact on the migration and invasion behavior of C6 cells. For the first time, rBMMSC-derived exosomes have been used as a single treatment for GBM rather than in combination with other treatments or as a pharmaceutical carrier.
    Keywords:  cancer; central nervous system; exosomes; glioblastoma multiforme; mesenchymal stem cells
    DOI:  https://doi.org/10.1002/cbin.11884
  159. Biologicals. 2022 Sep 13. pii: S1045-1056(22)00048-3. [Epub ahead of print]
    Metabolic reprogramming and alteration of the redox state in hyper-productive MDCK cells for influenza a virus production.
    Qian Ye, Xuping Liu, Yuxiang Wan, Wen-Song Tan, Liang Zhao.
      Influenza is a global public health issue leading to widespread morbidity and mortality with devastating economic loss annually. Madin-Darby Canine Kidney (MDCK) cell line has been a major cell line for influenza vaccine applications. Though many details of the host metabolic responses upon influenza A virus (IAV) infection have been documented, little is known about the metabolic reprogramming features of a hyper-productive host for IAV vaccine production. In this study, a MDCK cell clone H1 was shown to have a particular high productivity of 30 × 103 virions/cell. The glucose and amino acid metabolism of H1 were evaluated, indicating that the high producer had a particular metabolic reprogramming phenotype compared to its parental cell line (P): elevated glucose uptake, superior tricarboxylic acid cycle flux, moderate amino acid consumption, and better regulation of reactive oxygen species. Combined with the stronger mitochondrial function and mild antiviral and inflammatory responses characterized previously, our results indicated that the high producer had a sufficient intracellular energy supply, and balanced substrate distribution for IAV and host protein synthesis as well as the intracellular redox status. Understanding of these metabolic alterations paves the way for the rational cell line development and reasonable process optimization for high-yield influenza vaccine production.
    Keywords:  Influenza a virus; MDCK cells; Metabolic reprogramming; Productive cell line; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.biologicals.2022.08.004
  160. Front Mol Biosci. 2022 ;9 966007
    Current progress of ferroptosis study in ovarian cancer.
    Zhuomin Tan, Hui Huang, Wenyan Sun, Ya Li, Yinnong Jia.
      Tumors are the leading cause of death all over the world, among which ovarian cancer ranks the third in gynecological malignancies. The current treatment for ovarian cancer is liable to develop chemotherapy resistance and high recurrence rate, in which a new strategy is demanded. Ferroptosis, a newly discovered manner of regulatory cell death, is shown to be induced by massive iron-dependent accumulation of lipid reactive oxygen species. With the in-depth study of ferroptosis, its associated mechanism with various tumors is gradually elucidated, including ovarian tumor, which probably promotes the application of ferroptosis in treating ovarian cancer. To this end, this review will focus on the history and current research progress of ferroptosis, especially its regulation mechanism, and its potential application as a novel treatment strategy for ovarian cancer.
    Keywords:  FSP1-CoQ10-NAD (P) H; GCH1–BH4; ROS; System-Xc−; ferroptosis; inducer; inhibitor; ovarian cancer
    DOI:  https://doi.org/10.3389/fmolb.2022.966007
  161. Cell Rep. 2022 Sep 13. pii: S2211-1247(22)01194-9. [Epub ahead of print]40(11): 111362
    Adipocyte mesenchymal transition contributes to mammary tumor progression.
    Qingzhang Zhu, Yi Zhu, Chelsea Hepler, Qianbin Zhang, Jiyoung Park, Christy Gliniak, Gervaise H Henry, Clair Crewe, Dawei Bu, Zhuzhen Zhang, Shangang Zhao, Thomas Morley, Na Li, Dae-Seok Kim, Douglas Strand, Yingfeng Deng, Jacob J Robino, Oleg Varlamov, Ruth Gordillo, Mikhail G Kolonin, Christine M Kusminski, Rana K Gupta, Philipp E Scherer.
      Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment.
    Keywords:  CP: Cancer; CP: Metabolism; adipocyte; breast cancer; de-differentiation; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111362
  162. Front Pharmacol. 2022 ;13 961941
    How zoledronic acid improves osteoporosis by acting on osteoclasts.
    Biao Wang, Yi Zhan, Liang Yan, Dingjun Hao.
      Osteoporosis is called a silent disease, because it is difficult to detect until comprehensive examinations for osteoporosis are performed or osteoporotic fractures occur. Zoledronic acid is currently the first-line anti-osteoporotic drug, with good efficacy and treatment compliance. A major advantage of zoledronic acid is that intravenous zoledronic acid often guarantees a therapeutic effect for up to 1 year after infusion. The reasons why zoledronic acid is effective in improving osteoporosis are that it can inhibit osteoclast differentiation and induce osteoclast apoptosis, thus suppressing bone resorption and increasing bone density. The story between zoledronic acid and osteoclasts has been written long time ago. Both the canonical receptor activator of the receptor activator of nuclear factor-κB ligand (RANKL) pathway and the non-canonical Wnt pathway are the main pathways by which zoledronic acid inhibits osteoclast differentiation. Farnesyl pyrophosphate synthase (FPPS), reactive oxygen species (ROS), and ferroptosis that was first proposed in 2012, are all considered to be closely associated with zoledronic acid-induced osteoclast apoptosis. Here, we provide a brief review of the recent progress on the study of zoledronic acid and osteoclasts, and hope to elaborate how zoledronic acid improves osteoporosis by acting on osteoclasts.
    Keywords:  apoptosis; differentiation; osteoclasts; osteoporosis; signaling; signaling pathways; zoledronic acid
    DOI:  https://doi.org/10.3389/fphar.2022.961941
  163. Otolaryngol Clin North Am. 2022 Sep 07. pii: S0030-6665(22)00073-1. [Epub ahead of print]
    Natural Alternatives and the Common Cold and Influenza.
    Varun S Patel, Michael D Seidman.
      The use of complementary and integrative medicine has increased . It is estimated that one-third of the population of the United States uses some form of alternative medicine. Physicians should consider integrative medicine therapies . Alternative medical therapies for the common cold and influenza include herbal supplements, dietary supplements, diet, and other adjunct therapies. However, it is important to research and study these therapies. Therefore, communication with patients and other health care providers is important. This will ensure effective and positive patient care experiences. Further randomized clinical trials are necessary to further establish the role of various alternative options.
    Keywords:  COVID treatment; Dietary supplements; Herbal remedies; Influenza; Viral illness
    DOI:  https://doi.org/10.1016/j.otc.2022.06.009
  164. J Mater Chem B. 2022 Sep 16.
    ROS generation strategy based on biomimetic nanosheets by self-assembly of nanozymes.
    Pinghua Ling, Pei Yang, Xianping Gao, Xinyu Sun, Feng Gao.
      Reactive oxygen species (ROS) play an important role in physiology and have been applied in tumor therapy. However, insufficient endogenous H2O2 and hypoxia in cancer cells can lead to limited ROS production and poor therapeutic efficacy. Herein, we develop a biomimetic nanosheet material based on the self-assembly of nanozymes that could supply H2O2 under acidic conditions and catalyze a cascade of intracellular biochemical reactions to produce ROS under both normoxic and hypoxic conditions without any external stimuli. In this system, the copper peroxide nanosheets (CPNS), which are pH-responsive, were prepared through coordination of H2O2 to Cu2+ and then modified using ultrafine Pt NPs to form CPNS@Pt. The CPNS could decompose under acidic conditions, allowing the simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. On the other hand, Pt NPs were also released. The released Pt NPs behave as an oxidase mimic and catalase mimic. In this way, the well-defined CPNS@Pt can not only relieve hypoxic conditions but also generate ROS to induce cell apoptosis, thereby paving the way for the development of a nanozyme with multienzyme activity as a therapeutic strategy.
    DOI:  https://doi.org/10.1039/d2tb01639g
  165. Nutr Hosp. 2022 Sep 06.
    Is Ramadan fasting associated with low scores of Healthy Eating Index?
    Melahat Sedanur Macit, Zeynep Uzdil, Yasemin ErtaŞ ÖztÜrk, Pınar Sökülmez-Kaya.
       BACKGROUND: intermittent fasting diets that reduce or completely restrict food intake for specific periods have become more popular in recent years. Fasting in Ramadan is also an example of these intermittent fasting practices. In fasting practices focusing on the duration of nutrition, less emphasis was placed on the information on the dietary pattern.
    OBJECTIVE: this study aims to evaluate the Healthy Eating Index (HEI) and diet quality in fasting individuals in Ramadan.
    MATERIAL AND METHODS: this study was a cross-sectional study, conducted with adults aged 18-65 years. Food consumption record was taken with a 24-h-record with food consumption form. Diet quality and adequacy were assessed with the HEI, Nutrient Adequacy Ratio (NAR), and Average Adequacy Ratio (MAR) from food consumption records.
    RESULTS: according to study results, HEI and NAR Ca scores were statistically significantly lower in the fasting group than in the non-fasting group (p < 0.05). In the non-fasting group, HEI scores showed a negative correlation with body mass index (BMI) (kg/m2) and waist-hip ratio (r = -0.023, r = -0.148, p < 0.05).
    CONCLUSION: this study claimed that fasting might be associated with low scores of HEI. These results suggest that specific nutritional recommendations should be developed for fasting individuals.
    DOI:  https://doi.org/10.20960/nh.04042
  166. Malays J Med Sci. 2022 Aug;29(4): 28-42
    Natural Food for Sarcopenia: A Narrative Review.
    Nurul Syahidah Mohd Nazri, Divya Vanoh, Kah Leng Soo.
      Sarcopenia is a syndrome characterised by progressive loss of skeletal muscle mass and strength. Proper nutrition is essential for management of sarcopenia. Thus, this article aims to review the association between dietary pattern or food groups consisting of natural food and sarcopenia. A literature search was performed using four databases namely PubMed, Scopus, Sage and ScienceDirect. The search terms used were 'fruits', 'vegetables', 'egg', 'fish', 'chicken', 'protein food', 'ulam', 'fresh herbs', 'sarcopenia', 'elderly and 'older adults'. A total of 18 studies were included in the final review. Adherence to Mediterranean and Japanese dietary pattern were associated with lower prevalence of sarcopenia whereas Western dietary pattern was significantly associated with higher risk of sarcopenia. For food groups, there is a significant association between dietary protein intake and sarcopenia. There are also significant associations between the intake of vegetables, fruits or both vegetables and fruits, and lower risk of sarcopenia. Consumption of natural food comprising of high-quality protein, fruits and vegetables have been associated with protection against muscle wasting and sarcopenia. Therefore, it is possible that a well-planned diet may works just as effectively as or possibly better than individual nutrient supplements for the prevention and treatment for sarcopenia among older adults.
    Keywords:  dietary pattern; food; fruits; sarcopenia; vegetables
    DOI:  https://doi.org/10.21315/mjms2022.29.4.4
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