bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–08–21
150 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Micelles as potential drug delivery systems for colorectal cancer treatment.
  2. Self-Assembled Aza-Boron-Dipyrromethene for Ferroptosis-Boosted Sonodynamic Therapy.
  3. A systematic review of anti-cancer roles and mechanisms of kaempferol as a natural compound.
  4. Potential mechanisms of quercetin in cancer prevention: focus on cellular and molecular targets.
  5. Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.
  6. A comprehensive review of beetroot (Beta vulgaris L.) bioactive components in the food and pharmaceutical industries.
  7. Molecularly Self-Engineered Nanoamplifier for Boosting Photodynamic Therapy via Cascade Oxygen Elevation and Lipid ROS Accumulation.
  8. The role of size in PEGylated liposomal doxorubicin biodistribution and anti-tumour activity.
  9. High efficacy of tamoxifen-loaded L-lysine coated magnetic iron oxide nanoparticles in cell cycle arrest and anti-cancer activity for breast cancer therapy.
  10. Treatment of cancer with antipsychotic medications: Pushing the boundaries of schizophrenia and cancer.
  11. Fucoxanthin: A Promising Phytochemical on Diverse Pharmacological Targets.
  12. The promising interplay between sonodynamic therapy and nanomedicine.
  13. Multifunctional graphene oxide nanoparticles for drug delivery in cancer.
  14. Combinatorial chemosensitive Nanomedicine approach for the treatment of Breast cancer.
  15. Targeted Delivery of Chemo-Sonodynamic Therapy via Brain Targeting, Glutathione-Consumable Polymeric Nanoparticles for Effective Brain Cancer Treatment.
  16. A Critical Scrutiny on Liposomal Nanoparticles Drug Carriers as Modelled by Topotecan Encapsulation and Release in Treating Cancer.
  17. Pharmacokinetic behaviors of soft nanoparticulate formulations of chemotherapeutics.
  18. Physicochemical Characterization of Chitosan-Decorated Finasteride Solid Lipid Nanoparticles for Skin Drug Delivery.
  19. A review on the current status of homeopathy in the clinical management of cancer.
  20. Bystander effect in photosensitized prostate cancer cells with a different grade of malignancy: The role of nitric oxide.
  21. Catalase-Like Nanozymes: Classification, Catalytic Mechanisms, and Their Applications.
  22. Impact of solid lipid nanoparticles on 3T3 fibroblasts viability and lipid profile: the effect of curcumin- and resveratrol-loading.
  23. Surface-tailoring of emulsomes for boosting brain delivery of vinpocetine via intranasal route: in vitro optimization and in vivo pharmacokinetic assessment.
  24. Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders.
  25. Mitochondrial targeted hierarchical drug delivery system based on HA-modified liposomes for cancer therapy.
  26. Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer.
  27. Lipid metabolism in ferroptosis and ferroptosis-based cancer therapy.
  28. Differential molecular mechanistic behavior of HDACs in cancer progression.
  29. Curcumin Combats Against Organophosphate Pesticides Toxicity: A Review of the Current Evidence and Molecular Pathways.
  30. Tubiechong：A review on ethnomedicinal uses, bioactive chemical constituents and pharmacological activities.
  31. Onion anthocyanins: Extraction, stability, bioavailability, dietary effect, and health implications.
  32. Natural medicines of targeted rheumatoid arthritis and its action mechanism.
  33. Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical: improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats.
  34. Polymeric and small molecule-conjugates of temozolomide as improved therapeutic agents for glioblastoma multiforme.
  35. Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy.
  36. Glutathione-depleting polymer delivering chlorin e6 for enhancing photodynamic therapy.
  37. Medicine-food herb: Angelica sinensis, a potential therapeutic hope for Alzheimer's disease and related complications.
  38. Novel natural inhibitors targeting KRAS G12C by computational study.
  39. Matrine induces autophagy in human neuroblastoma cells via blocking the AKT-mTOR pathway.
  40. Green Route Synthesis and Characterization Techniques of Silver Nanoparticles and Their Biological Adeptness.
  41. Triple negative breast cancer: approved treatment options and their mechanisms of action.
  42. Reactive oxygen species scavenging nanofibers with chitosan-stabilized Prussian blue nanoparticles for enhanced wound healing efficacy.
  43. Gentian violet induces apoptosis and ferroptosis via modulating p53 and MDM2 in hepatocellular carcinoma.
  44. A Molecular Approach Of The Caloric Restriction And Vitamins For Cancer Prevention.
  45. Modulation of diverse oncogenic signaling pathways by oroxylin A: An important strategy for both cancer prevention and treatment.
  46. Multifaceted role of polyphenols in the treatment and management of neurodegenerative diseases.
  47. Research progress in elucidating the mechanisms underlying resveratrol action on lung cancer.
  48. Conquering oncogenic KRAS and its bypass mechanisms.
  49. Synthesis and preparation of vitamin A coupled butein-loaded solid lipid nanoparticles for liver fibrosis therapy in rats.
  50. Sphingosine-1-phosphate-lyase deficiency affects glucose metabolism in a way that abets oncogenesis.
  51. Nanogel-Based Transdermal Drug Delivery System: A Therapeutic Strategy with Under Discussed Potential.
  52. Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor-resistant pancreatic ductal adenocarcinoma.
  53. Cucumber-Derived Nanovesicles Containing Cucurbitacin B for Non-Small Cell Lung Cancer Therapy.
  54. Research progress on the role of PKM2 in the immune response.
  55. Role of exosomes in tumor growth, chemoresistance and immunity: state-of-the-art.
  56. Photoredox catalysis may be a general mechanism in photodynamic therapy.
  57. Intraperitoneal administration of thermosensitive hydrogel Co-loaded with norcantharidin nanoparticles and oxaliplatin inhibits malignant ascites of hepatocellular carcinoma.
  58. Ionizing Radiation-Induced Ferroptosis Based on Nanomaterials.
  59. Exploring the anticancer activities of novel bioactive compounds derived from endophytic fungi: mechanisms of action, current challenges and future perspectives.
  60. Physiopathological Mechanisms Involved In The Development Of Hypertension Associated With Gut Dysbiosis And The Effect Of Nutritional/Pharmacological Interventions.
  61. Phytochemistry and pharmacology of sea buckthorn (Elaeagnus rhamnoides; syn. Hippophae rhamnoides): progress from 2010 to 2021.
  62. Curcumin activates Nrf2/HO-1 signaling to relieve diabetic cardiomyopathy injury by reducing ROS in vitro and in vivo.
  63. Chlorogenic acid: A dietary phenolic acid with promising pharmacotherapeutic potential.
  64. Evaluation of wound-healing efficiency of a functional Chitosan/Aloe vera hydrogel on the improvement of re-epithelialization in full thickness wound model of rat.
  65. Coating a Self-Assembly Nanoconstruct with a Neutrophil Cell Membrane Enables High Specificity for Triple Negative Breast Cancer Treatment.
  66. Combinatorial therapeutic approaches of photodynamic therapy and immune checkpoint blockade for colon cancer treatment.
  67. PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.
  68. Efficacy of methanolic extracts of some medicinal plants on wound healing in diabetic rats.
  69. Development of andrographolide-loaded solid lipid nanoparticles for lymphatic targeting: Formulation, optimization, characterization, in vitro, and in vivo evaluation.
  70. D-mannose functionalized MgAl-LDH/Fe-MOF nanocomposite as a new intelligent nanoplatform for MTX and DOX co-drug delivery.
  71. Iridoids as a potential hepatoprotective class - a review.
  72. Matcha green tea targets the gut-liver axis to alleviate obesity and metabolic disorders induced by a high-fat diet.
  73. Obesity, cancer risk, and time-restricted eating.
  74. Introducing potato starch-ecofriendly silver nanoparticles as a novel binary system for nanoencapsulation of riboflavin.
  75. Research progress on the mechanism of action of hesperetin in cerebral ischemia: a narrative review.
  76. Human serum albumin-based nanoparticles alter raloxifene administration and improve bioavailability.
  77. Meaning and Significance of "Alkalization Therapy for Cancer".
  78. A narrative review on the role of carbon nanoparticles in oncology.
  79. Effect of vitamin D supplementation on the incidence and prognosis of depression: An updated meta-analysis based on randomized controlled trials.
  80. Black Seed (Nigella sativa): A Favourable Alternative Therapy for Inflammatory and Immune System Disorders.
  81. Oxidative degradation in pharmaceuticals: Mechanism and stabilization of a spray-dried amorphous drug - A case study.
  82. Development, characterization and in vitro antimicrobial evaluation of novel flavonoids entrapped micellar topical formulations of neomycin sulfate.
  83. Induction of ferroptosis in head and neck cancer: A novel bridgehead for fighting cancer resilience.
  84. Chondroitin sulfate microspheres anchored with drug-loaded liposomes play a dual antioxidant role in the treatment of osteoarthritis.
  85. Utility of Intravenous Curcumin Nanodelivery Systems for Improving In Vivo Pharmacokinetics and Anticancer Pharmacodynamics.
  86. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
  87. Nucleic acid-based therapy for brain cancer: Challenges and strategies.
  88. Regulated cell death (RCD) in cancer: key pathways and targeted therapies.
  89. Celecoxib nanocrystal-loaded dissolving microneedles with highly efficient for osteoarthritistreatment.
  90. Influence of Elasticity of Hydrogel Nanoparticles on Their Tumor Delivery.
  91. Protein-Based Drug Delivery Nanomedicine Platforms: Recent Developments.
  92. The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accummulation, and PKC activity in male rat liver.
  93. Differing effects of oral conjugated equine estrogen and transdermal estradiol on vitamin D metabolism in postmenopausal women: a 4-year longitudinal study.
  94. Network Pharmacology Research and Dual-omic Analyses Reveal the Molecular Mechanism of Natural Product Nodosin Inhibiting Muscle-Invasive Bladder Cancer in Vitro and in Vivo.
  95. The Effects of Methanol Extracts of Hyssopus officinalis on Model of Induced Glioblastoma Multiforme (GBM) in Rats.
  96. EXPRESSION OF OSTEOPONTIN AND OSTEONECTIN IN BREAST AND PROSTATE CANCER CELLS WITH DIFFERENT SENSITIVITY TO DOXORUBICIN.
  97. Association between the mediterranean diet and cognitive health among healthy adults: A systematic review and meta-analysis.
  98. Relationship between Intestinal Microflora and Hepatocellular Cancer Based on Gut-Liver Axis Theory.
  99. Saffron as a promising therapy for diabetes and Alzheimer's disease: mechanistic insights.
  100. The Preventive and Therapeutic Effects of Ajwa Date Fruit Extract Against Acute Diclofenac Toxicity-Induced Colopathy: An Experimental Study.
  101. pH-Sensitive Twin Liposomes Containing Quercetin and Laccase for Tumor Therapy.
  102. An expanding horizon of complex injectable products: development and regulatory considerations.
  103. Antileishmanial Agents Co-loaded in Transfersomes with Enhanced Macrophage Uptake and Reduced Toxicity.
  104. A pH-Responsive Cluster Metal-organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.
  105. Identification of potential targets of the curcumin analog CCA-1.1 for glioblastoma treatment : integrated computational analysis and in vitro study.
  106. Hyperthermia based individual in situ recombinant vaccine enhances lymph nodes drainage for de novo antitumor immunity.
  107. Novel Light Delivery Method for Performing Transbronchial Photodynamic Therapy Ablation to Treat Peripheral Lung Cancer: A Pilot Study.
  108. Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth.
  109. The construction of self-protective ferritin nanocage to cross dynamic gastrointestinal barriers with improved delivery efficiency.
  110. Vitamin D intakes and health outcomes in infants and preschool children: Summary of an evidence report.
  111. Stimuli-responsive nanoassemblies for targeted delivery against tumor and its microenvironment.
  112. Nanosponges Based Drug Delivery System for the Cosmeceutical Applications of Stabilized Ascorbic Acid.
  113. Drug metabolism and drug transport of the 100 most prescribed oral drugs.
  114. Research Advances of Lactoferrin in Electrostatic Spinning, Nano Self-Assembly, and Immune and Gut Microbiota Regulation.
  115. The short-term effects of berberine in the liver: narrow margins between benefits and toxicity.
  116. Remdesivir-loaded bis-MPA hyperbranched dendritic nanocarriers for pulmonary delivery.
  117. Therapeutic Uses and Pharmacological Properties of Shallot (Allium ascalonicum): A Systematic Review.
  118. Recent applications of nanoparticles in organic transformations.
  119. Zinc sulfide-chitosan hybrid nanoparticles as a robust surface for immobilization of Sillago sihama α-amylase.
  120. Antioxidants (selenium and garlic) alleviated the adverse effects of tramadol on the reproductive system and oxidative stress markers in male rabbits.
  121. Curcumin, but not its degradation products, in combination with silibinin is primarily responsible for the inhibition of colon cancer cell proliferation.
  122. Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake.
  123. Metronidazole nanosuspension loaded dissolving microarray patches: An engineered composite pharmaceutical system for the treatment of skin and soft tissue infection.
  124. Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy.
  125. Regular exercise combined with ferulic acid exhibits antiobesity effect and regulates metabolic profiles in high-fat diet-induced mice.
  126. Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy.
  127. Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection.
  128. Lingguizhugan Decoction Targets Intestinal Microbiota and Metabolites to Reduce Insulin Resistance in High-Fat Diet Rats.
  129. Sustained release of chlorogenic acid-loaded nanomicelles alleviates bone loss in mouse periodontitis.
  130. Glycation-induced age-related illnesses, antiglycation and drug delivery strategies.
  131. Nanotrains of DNA Copper Nanoclusters That Triggered a Cascade Fenton-Like Reaction and Glutathione Depletion to Doubly Enhance Chemodynamic Therapy.
  132. Genetics of Dravet Syndrome and its Targeted Therapy by Nanomedicine: A Roadmap for Future Treatment of Drug Resistant Seizures.
  133. Enzyme-manipulated hydrogelation of small molecules for biomedical applications.
  134. Systemic immune effects of anesthetics and their intracellular targets in tumors.
  135. Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies.
  136. Photobiomodulation and photodynamic therapy-induced switching of autophagy and apoptosis in human dermal fibroblasts.
  137. Editorial: Metabolism of anti-cancer drugs: Interplay involving pharmacology and pharmacokinetics.
  138. Recent ring distortion reactions for diversifying complex natural products.
  139. Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation.
  140. Prostate-specific membrane antigen targeted, glutathione-sensitive nanoparticles loaded with docetaxel and enzalutamide for the delivery to prostate cancer.
  141. Mitochondria-targeted alginate/triphenylphosphonium-grafted-chitosan for treatment of hepatocellular carcinoma.
  142. Lipid and Lipoprotein Metabolism.
  143. The benefits of vitamin A as a complementary treatment for oncology patients: a systematic review.
  144. High fat diets induce early changes in gut microbiota that may serve as markers of ulterior altered physiological and biochemical parameters related to metabolic syndrome. Effect of virgin olive oil in comparison to butter.
  145. Targeting purine metabolism in ovarian cancer.
  146. Anti-cancer effect of in vivo inhibition of nitric oxide synthase in a rat model of breast cancer.
  147. Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.
  148. A pH-sensitive field-effect transistor for monitoring of cancer cell external acid environment.
  149. A Supramolecular Self-Assembling Nanoagent by Inducing Intracellular Aggregation of PSMA for Prostate Cancer Molecularly Targeted Theranostics.
  150. Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches.
  1. World J Gastroenterol. 2022 Jul 07. 28(25): 2867-2880
    Micelles as potential drug delivery systems for colorectal cancer treatment.
    Zaynab Fatfat, Maamoun Fatfat, Hala Gali-Muhtasib.
      Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.
    Keywords:  Chemotherapy; Colorectal cancer; Combination cancer therapy; Drug delivery; Gene therapy; Polymeric micelles
    DOI:  https://doi.org/10.3748/wjg.v28.i25.2867
  2. Angew Chem Int Ed Engl. 2022 Aug 18.
    Self-Assembled Aza-Boron-Dipyrromethene for Ferroptosis-Boosted Sonodynamic Therapy.
    Changwen You, Xingguang Li, Dongqiong Wang, Hongzhong Chen, Lei Liang, Yu Chen, Yanli Zhao, Huijing Xiang.
      The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza-boron-dipyrromethene dye (denoted as Aza-BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza-BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (1O2) generation significantly induces cancer-cell death and suppresses tumor proliferation with a high inhibition rate of 97.5%.
    Keywords:  Cysteine Starvation * Ferroptosis * Organic Nanomedicine * Sonodynamic Therapy * Tumor Therapy
    DOI:  https://doi.org/10.1002/anie.202210174
  3. Cancer Cell Int. 2022 Aug 20. 22(1): 260
    A systematic review of anti-cancer roles and mechanisms of kaempferol as a natural compound.
    Elham Amjad, Babak Sokouti, Solmaz Asnaashari.
      It has been shown in multiple experimental and biological investigations that kaempferol, an edible flavonoid generated from plants, may be used as an anti-cancer drug and has been shown to have anti-cancer properties. Many signaling pathways are altered in cancer cells, resulting in cell growth inhibition and death in various tumor types. Cancer is a multifaceted illness coordinated by multiple external and internal mechanisms. Natural extracts with the fewest side effects have piqued the attention of researchers in recent years, attempting to create cancer medicines based on them. An extensive array of natural product-derived anti-cancer agents have been examined to find a successful method. Numerous fruits and vegetables have high levels of naturally occurring flavonoid kaempferol, and its pharmacological and biological effects have been studied extensively. Certain forms of cancer are sensitive to kaempferol-mediated anti-cancer activity, although complete research is needed. We have endeavored to concentrate our review on controlling carcinogenic pathways by kaempferol in different malignancies. Aside from its extraordinary ability to modify cell processes, we have also discussed how kaempferol has the potential to be an effective therapy for numerous tumors.
    Keywords:  Anti-cancer; Kaempferol; Mechanisms; Natural compounds; Signaling pathways
    DOI:  https://doi.org/10.1186/s12935-022-02673-0
  4. Cancer Cell Int. 2022 Aug 15. 22(1): 257
    Potential mechanisms of quercetin in cancer prevention: focus on cellular and molecular targets.
    Parina Asgharian, Abbas Pirpour Tazekand, Kamran Hosseini, Haleh Forouhandeh, Tohid Ghasemnejad, Maryam Ranjbar, Muzaffar Hasan, Manoj Kumar, Sohrab Minaei Beirami, Vahideh Tarhriz, Saiedeh Razi Soofiyani, Latipa Kozhamzharova, Javad Sharifi-Rad, Daniela Calina, William C Cho.
      Over the past few years, the cancer-related disease has had a high mortality rate and incidence worldwide, despite clinical advances in cancer treatment. The drugs used for cancer therapy, have high side effects in addition to the high cost. Subsequently, to reduce these side effects, many studies have suggested the use of natural bioactive compounds. Among these, which have recently attracted the attention of many researchers, quercetin has such properties. Quercetin, a plant flavonoid found in fresh fruits, vegetables and citrus fruits, has anti-cancer properties by inhibiting tumor proliferation, invasion, and tumor metastasis. Several studies have demonstrated the anti-cancer mechanism of quercetin, and these mechanisms are controlled through several signalling pathways within the cancer cell. Pathways involved in this process include apoptotic, p53, NF-κB, MAPK, JAK/STAT, PI3K/AKT, and Wnt/β-catenin pathways. In addition to regulating these pathways, quercetin controls the activity of oncogenic and tumor suppressor ncRNAs. Therefore, in this comprehensive review, we summarized the regulation of these signalling pathways by quercetin. The modulatory role of quercetin in the expression of various miRNAs has also been discussed. Understanding the basic anti-cancer mechanisms of these herbal compounds can help prevent and manage many types of cancer.
    Keywords:  Malignant tumors; Molecular targets; Pharmacology; Quercetin; Signalling pathways
    DOI:  https://doi.org/10.1186/s12935-022-02677-w
  5. Small. 2022 Aug 15. e2202369
    Covalent Organic Framework Nanocarriers of Singlet Oxygen for Oxygen-Independent Concurrent Photothermal/Photodynamic Therapy to Ablate Hypoxic Tumors.
    Debabrata Dutta, Jingbo Wang, Xiang Li, Qinghao Zhou, Zhishen Ge.
      Photodynamic therapy (PDT) of cancers is seriously restricted by tumor hypoxia. In addition to the intrinsic hypoxic microenvironment, continuous photoirradiation further aggravates intratumoral hypoxia, thereby reducing the PDT effect significantly. Oxygen-independent PDT is recognized as an efficient approach to overcome this issue. Herein, singlet oxygen (1 O2 )-stored covalent organic framework (COF) nanoparticles loading the near-infrared (NIR) dye cypate, which realize oxygen-independent 1 O2 production for concurrent photothermal therapy (PTT) and PDT under NIR irradiation, are presented. The cypate-loading COF nanoparticles are prepared by using the photosensitizers and 1 O2 -stored molecules via formation of Schiff base bonds, followed by coverage of poly(vinyl pyrrolidone). The COF nanoparticles significantly improve the photostability and photothermal conversion efficiency of cypate by protecting them from photodegradation under NIR irradiation. Upon 660 nm laser irradiation, 1 O2 is produced by the photosensitizer motifs and is successfully stored by the 1 O2 -stored moieties. After intravenous injection and tumor accumulation, the COF nanoparticles can generate heat quickly upon 808 nm irradiation which induces the efficient release of the stored 1 O2 to ablate tumors via O2 -independent concurrent PTT/PDT. Accordingly, the COF nanocarriers of 1 O2 provide a paradigm to develop O2 -independent concurrent PTT/PDT for precise cancer treatment upon NIR irradiation.
    Keywords:  covalent organic frameworks; hypoxia; photodynamic therapy; photothermal therapy; singlet oxygen
    DOI:  https://doi.org/10.1002/smll.202202369
  6. Crit Rev Food Sci Nutr. 2022 Aug 16. 1-33
    A comprehensive review of beetroot (Beta vulgaris L.) bioactive components in the food and pharmaceutical industries.
    Muthu Thiruvengadam, Ill-Min Chung, Ramkumar Samynathan, S R Harish Chander, Baskar Venkidasamy, Tanmay Sarkar, Maksim Rebezov, Olga Gorelik, Mohammad Ali Shariati, Jesus Simal-Gandara.
      Beetroot is rich in various bioactive phytochemicals, which are beneficial for human health and exert protective effects against several disease conditions like cancer, atherosclerosis, etc. Beetroot has various therapeutic applications, including antioxidant, antibacterial, antiviral, and analgesic functions. Besides the pharmacological effects, food industries are trying to preserve beetroots or their phytochemicals using various food preservation methods, including drying and freezing, to preserve their antioxidant capacity. Beetroot is a functional food due to valuable active components such as minerals, amino acids, phenolic acid, flavonoid, betaxanthin, and betacyanin. Due to its stability, nontoxic and non-carcinogenic and nonpoisonous capabilities, beetroot has been used as an additive or preservative in food processing. Beetroot and its bioactive compounds are well reported to possess antioxidant, anti-inflammatory, antiapoptotic, antimicrobial, antiviral, etc. In this review, we provided updated details on (i) food processing, preservation and colorant methods using beetroot and its phytochemicals, (ii) synthesis and development of several nanoparticles using beetroot and its bioactive compounds against various diseases, (iii) the role of beetroot and its phytochemicals under disease conditions with molecular mechanisms. We have also discussed the role of other phytochemicals in beetroot and their health benefits. Recent technologies in food processing are also updated. We also addressed on molecular docking-assisted biological activity and screening for bioactive chemicals. Additionally, the role of betalain from different sources and its therapeutic effects have been listed. To the best of our knowledge, little or no work has been carried out on the impact of beetroot and its nanoformulation strategies for phytocompounds on antimicrobial, antiviral effects, etc. Moreover, epigenetic alterations caused by phytocompounds of beetroot under several diseases were not reported much. Thus, extensive research must be carried out to understand the molecular effects of beetroot in the near future.
    Keywords:  Beetroot; betalain; bioactive compounds; biomedical uses; food processing; molecular mechanisms; nanoparticles
    DOI:  https://doi.org/10.1080/10408398.2022.2108367
  7. ACS Appl Mater Interfaces. 2022 Aug 17.
    Molecularly Self-Engineered Nanoamplifier for Boosting Photodynamic Therapy via Cascade Oxygen Elevation and Lipid ROS Accumulation.
    Shenwu Zhang, Xinxin Sun, Ziyue Wang, Jin Sun, Zhonggui He, Bingjun Sun, Cong Luo.
      Photodynamic therapy (PDT) has been extensively explored as a noninvasive cancer treatment modality. However, the dilemma of tumor hypoxia and short half-life of singlet oxygen (1O2) severely restrict the therapeutic efficacy of PDT. Herein, we develop a facile three-in-one PDT nanoamplifier (AA@PPa/Hemin NPs) assembled by pyropheophorbide a (PPa), hemin, and arachidonic acid (AA). Interestingly, AA not only acts as an enabler to facilitate the assembly of PPa and hemin in the construction of ternary hybrid nanoassemblies but also acts as a lipid reactive oxygen species (ROS) amplifier for robust PDT. In tumor cells, hemin plays the role of a catalase-like catalyst that accelerates the production of oxygen (O2) from hydrogen peroxide (H2O2), significantly alleviating tumor hypoxia. Under laser irradiation, vast amounts of 1O2 generated by PPa trigger the peroxidation of AA to produce large amounts of cytotoxic lipid ROS, immensely amplifying the efficiency of PDT by promptly eliciting cellular oxidative stress. As expected, AA@PPa/Hemin NPs exert potent antitumor activity in a 4T1 breast-tumor-bearing BALB/c mice xenograft model. Such a cascade nanohybrid amplifier provides a novel codelivery platform for accurate and effective PDT of cancer.
    Keywords:  cascade nanoamplifier; cytotoxic lipid ROS; hypoxia alleviation; molecularly self-engineered; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsami.2c09209
  8. IET Nanobiotechnol. 2022 Aug 18.
    The role of size in PEGylated liposomal doxorubicin biodistribution and anti-tumour activity.
    Saba Dadpour, Amin Mehrabian, Mahdieh Arabsalmani, Elaheh Mirhadi, Anis Askarizadeh, Mohammad Mashreghi, Mahmoud Reza Jaafari.
      The size of nanoliposome-encapsulated drugs significantly affects their therapeutic efficacy, biodistribution, targeting ability, and toxicity profile for the cancer treatment. In the present study, the biodistribution and anti-tumoral activity of PEGylated liposomal Doxorubicin (PLD) formulations with different sizes were investigated. First, 100, 200, and 400 nm PLDs were prepared by remote loading procedure and characterised for their size, zeta potential, encapsulation efficacy, and release properties. Then, in vitro cellular uptake and cytotoxicity were studied by flow cytometry and MTT assay, and compared with commercially available PLD Caelyx® . In vivo studies were applied on BALB/c mice bearing C26 colon carcinoma. The cytotoxicity and cellular uptake tests did not demonstrate any statistically significant differences between PLDs. The biodistribution results showed that Caelyx® and 100 nm liposomal formulations had the most doxorubicin (Dox) accumulation in the tumour tissue and, as a result, considerably suppressed tumour growth compared with 200 and 400 nm PLDs. In contrast, larger nanoparticles (200 and 400 nm formulations) had more accumulation in the liver and spleen. This study revealed that 90 nm Caelyx® biodistribution profile led to the stronger anti-tumour activity of the drug and hence significant survival extension, and showed the importance of vesicle size in the targeting of nanoparticles to the tumour microenvironment for the treatment of cancer.
    Keywords:  Biodistribution; Cancer; EPR effect; Nanoparticle size; PEGylated liposomal doxorubicin; Therapeutic efficacy
    DOI:  https://doi.org/10.1049/nbt2.12094
  9. Bioimpacts. 2022 ;12(4): 301-313
    High efficacy of tamoxifen-loaded L-lysine coated magnetic iron oxide nanoparticles in cell cycle arrest and anti-cancer activity for breast cancer therapy.
    Soheila Rostami, Farzaneh Tafvizi, Hamid Reza Kheiri Manjili.
      Introduction: Due to the side effects of drugs, the development of nanoscale drug delivery systems has led to a significant improvement in medicinal therapies due to drug pharmacokinetics changes, decreased toxicity, and increased half-life of the drug. This study aimed to synthesize tamoxifen (TMX)-loaded L-lysine coated magnetic iron oxide nanoparticles as a nano-carrier to investigate its cytotoxic effects and anti-cancer properties against MCF-7 cancer cells. Methods: Magnetic Fe3O4 nanoparticles were synthesized and coated with L-lysine (F-Lys NPs). Then, TMX was loaded onto these NPs. The characteristics of synthesized nanoparticles (F-Lys-TMX NPs) were evaluated by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), differential scanning calorimetry (DSC), vibrating sample magnetometer (VSM), and thermogravimetric analysis (TGA). The drug release was analyzed at pH 5.8 and pH 7.4. The MCF-7 cells were exposed to F-Lys-TMX NPs, F-Lys NPs, and TMX for 24, 48, and 72 hours. To evaluate the cytotoxic potential of designed nanoparticles, MTT and apoptosis assays, real-time PCR, and cell cycle analysis was carried out. Results: The F-Lys-TMX NPs had spherical morphology with a size ranging from 9 to 30 nm. By increasing the nanoparticles concentration and treatment time, more cell proliferation inhibition and apoptosis induction were observed in F-Lys-TMX NPs-treated cells compared to the TMX. The expression levels of ERBB2, cyclin D1, and cyclin E genes were down-regulated and expression levels of the caspase-3 and caspase-9 genes were up-regulated. Studies on the drug release revealed a slow and controlled pH-dependent release of the nanoparticles. Cell cycle analysis indicated that F-Lys-TMX NPs could arrest the cells at the G0/G1 phase. Conclusion: The findings suggest that F-Lys-TMX NPs are more effective and have the potential for cell proliferation inhibition and apoptosis induction compared to the TMX. Hence, F-Lys-TMX NPs can be considered as an anti-cancer agent against MCF-7 breast cancer cells.
    Keywords:  Apoptosis; L-lysine; MCF-7 cell line; Magnetic iron oxide nanoparticles; Tamoxifen
    DOI:  https://doi.org/10.34172/bi.2021.23337
  10. Neurosci Biobehav Rev. 2022 Aug 12. pii: S0149-7634(22)00298-6. [Epub ahead of print]141 104809
    Treatment of cancer with antipsychotic medications: Pushing the boundaries of schizophrenia and cancer.
    James S Brown.
      Over a century ago, the phenothiazine dye, methylene blue, was discovered to have both antipsychotic and anti-cancer effects. In the 20th-century, the first phenothiazine antipsychotic, chlorpromazine, was found to inhibit cancer. During the years of elucidating the pharmacology of the phenothiazines, reserpine, an antipsychotic with a long historical background, was likewise discovered to have anti-cancer properties. Research on the effects of antipsychotics on cancer continued slowly until the 21st century when efforts to repurpose antipsychotics for cancer treatment accelerated. This review examines the history of these developments, and identifies which antipsychotics might treat cancer, and which cancers might be treated by antipsychotics. The review also describes the molecular mechanisms through which antipsychotics may inhibit cancer. Although the overlap of molecular pathways between schizophrenia and cancer have been known or suspected for many years, no comprehensive review of the subject has appeared in the psychiatric literature to assess the significance of these similarities. This review fills that gap and discusses what, if any, significance the similarities have regarding the etiology of schizophrenia.
    Keywords:  Antipsychotic agents; Drug therapy; Neoplasms; Pharmacology; Phenothiazines; Psychotic disorders; Schizophrenia
    DOI:  https://doi.org/10.1016/j.neubiorev.2022.104809
  11. Front Pharmacol. 2022 ;13 929442
    Fucoxanthin: A Promising Phytochemical on Diverse Pharmacological Targets.
    Mumtaza Mumu, Ayan Das, Talha Bin Emran, Saikat Mitra, Fahadul Islam, Arpita Roy, Md Mobarak Karim, Rajib Das, Moon Nyeo Park, Deepak Chandran, Rohit Sharma, Mayeen Uddin Khandaker, Abubakr M Idris, Bonglee Kim.
      Fucoxanthin (FX) is a special carotenoid having an allenic bond in its structure. FX is extracted from a variety of algae and edible seaweeds. It has been proved to contain numerous health benefits and preventive effects against diseases like diabetes, obesity, liver cirrhosis, malignant cancer, etc. Thus, FX can be used as a potent source of both pharmacological and nutritional ingredient to prevent infectious diseases. In this review, we gathered the information regarding the current findings on antimicrobial, antioxidant, anti-inflammatory, skin protective, anti-obesity, antidiabetic, hepatoprotective, and other properties of FX including its bioavailability and stability characteristics. This review aims to assist further biochemical studies in order to develop further pharmaceutical assets and nutritional products in combination with FX and its various metabolites.
    Keywords:  anti-inflammatory activity; anticancer activity; antimicrobial activity; enzyme inhibition; fucoxanthin; phytochemicals
    DOI:  https://doi.org/10.3389/fphar.2022.929442
  12. Adv Drug Deliv Rev. 2022 Aug 16. pii: S0169-409X(22)00385-4. [Epub ahead of print] 114495
    The promising interplay between sonodynamic therapy and nanomedicine.
    Roberto Canaparo, Federica Foglietta, Nadia Barbero, Loredana Serpe.
      Sonodynamic therapy (SDT) is a non-invasive approach for cancer treatment in which chemical compounds, named sonosensitizers, are activated by non-thermal ultrasound (US), able to deeply penetrate into the tissues. Despite increasing interest, the underlying mechanisms by which US triggers the sonosensitizer therapeutic activity are not yet clearly elucidate, slowing down SDT clinical application. In this review we will discuss the main mechanisms involved in SDT with particular attention to the sonosensitizers involved for each described mechanism, in order to highlight how much important are the physicochemical properties of the sonosensitizers and their cellular localization to predict their bioeffects. Moreover, we will also focus our attention on the pivotal role of nanomedicine providing the sonodynamic anticancer approach with the ability to shape US-responsive agents to enhance specific sonodynamic effects as the sonoluminescence-mediated anticancer effects. Indeed, SDT is one of the biomedical fields that has significantly improved in recent years due to the increased knowledge of nanosized materials. The shift of the nanosystem from a delivery system for a therapeutic agent to a therapeutic agent in itself represents a real breakthrough in the development of SDT. In doing so, we have also highlighted potential areas in this field, where substantial improvements may provide a valid SDT implementation as a cancer therapy.
    Keywords:  Sonodynamic therapy; cancer; drug delivery systems; nanomedicine; nanosonosensitizer; sonoluminescence; sonosensitizer; ultrasound
    DOI:  https://doi.org/10.1016/j.addr.2022.114495
  13. J Control Release. 2022 Aug 13. pii: S0168-3659(22)00515-6. [Epub ahead of print]350 26-59
    Multifunctional graphene oxide nanoparticles for drug delivery in cancer.
    Asif Mohd Itoo, Sree Lakshmi Vemula, Mahima Tejasvni Gupta, Mahesh Vilasrao Giram, Sangishetty Akhil Kumar, Balaram Ghosh, Swati Biswas.
      Recent advancements in nanotechnology have enabled us to develop sophisticated multifunctional nanoparticles or nanosystems for targeted diagnosis and treatment of several illnesses, including cancers. To effectively treat any solid tumor, the therapy should preferably target just the malignant cells/tissue with minor damage to normal cells/tissues. Graphene oxide (GO) nanoparticles have gained considerable interest owing to their two-dimensional planar structure, chemical/mechanical stability, excellent photosensitivity, superb conductivity, high surface area, and good biocompatibility in cancer therapy. Many compounds have been functionalized on the surface of GO to increase their biological applications and minimize cytotoxicity. The review presents an overview of the physicochemical characteristics, strategies for various modifications, toxicity and biocompatibility of graphene and graphene oxide, current trends in developing GO-based nano constructs as a drug delivery cargo and other biological applications, including chemo-photothermal therapy, chemo-photodynamic therapy, bioimaging, and theragnosis in cancer. Further, the review discusses the challenges and opportunities of GO, GO-based nanomaterials for the said applications. Overall, the review focuses on the therapeutic potential of strategically developed GO nanomedicines and comprehensively discusses their opportunities and challenges in cancer therapy.
    Keywords:  Anticancer; Cancer; Drug delivery; Graphene oxide; Nanomedicine; Photothermal
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.011
  14. Curr Mol Med. 2022 Aug 19.
    Combinatorial chemosensitive Nanomedicine approach for the treatment of Breast cancer.
    Priya Gupta, Yub Raj Neupane, Suhel Parvez, Kanchan Kohli, Yasmin Sultana.
      Breast cancer is the most commonly diagnosed type of cancer and ranks second among cancer that leads to death. From becoming the foremost reason for global concern, this multifactorial disease is being treated by conventional chemotherapies that are associated with severe side effects with chemoresistance being the ruling reason. Exemestane, an aromatase inhibitor that has been approved by the US FDA for the treatment of breast cancer in post-menopausal women acts by inhibiting the aromatase enzyme, in turn, inhibiting the production of estrogen. However, clinical application of exemestane remains limited due to its poor aqueous solubility and low oral bioavailability. Furthermore, the treatment regime of exemestane often leads to thinning of the mineral density of bone. Thymoquinone, a natural compound derived from the oil of the seeds of Nigella sativa Linn possesses the dual property of being a chemosensitizer and chemotherapeutic agent. In addition, it has been found to exhibit potent bone protection properties as evidenced by several studies. To mitigate the limitations associated with exemestane and to deliver to the cancerous cells overcoming chemoresistance, the present hypothesis, has been put forth, wherein a natural chemosensitizer and chemotherapeutic agent thymoquinone will be incorporated into a lipid nanocarrier along with exemestane for combinatorial delivery to cancer cells. Additionally, thymoquinone being bone protecting will help in ousting the untoward effect of exemestane at the same time delivering it to the required malignant cells, safeguarding the healthy cells, reducing the offsite toxicity, and providing potent synergistic action.
    Keywords:  Breast cancer; Chemoresistance; Chemosensitizer; Combinatorial delivery.; Exemestane; Thymoquinone
    DOI:  https://doi.org/10.2174/1566524023666220819122948
  15. Adv Sci (Weinh). 2022 Aug 15. e2203894
    Targeted Delivery of Chemo-Sonodynamic Therapy via Brain Targeting, Glutathione-Consumable Polymeric Nanoparticles for Effective Brain Cancer Treatment.
    Haoan Wu, Xingchun Gao, Yuanyuan Luo, Jiang Yu, Gretchen Long, Zhaozhong Jiang, Jiangbing Zhou.
      Glioblastoma (GBM) is the most aggressive tumor of the central nervous system and remains universally lethal due to lack of effective treatment options and their inefficient delivery to the brain. Here the development of multifunctional polymeric nanoparticles (NPs) for effective treatment of GBM is reported. The NPs are synthesized using a novel glutathione (GSH)-reactive poly (2,2″-thiodiethylene 3,3″-dithiodipropionate) (PTD) polymer and engineered for brain penetration through neutrophil elastase-triggered shrinkability, iRGD-mediated targeted delivery, and lexiscan-induced autocatalysis. It is found that the resulting lexiscan-loaded, iRGD-conjugated, shrinkable PTD NPs, or LiPTD NPs, efficiently penetrate brain tumors with high specificity after intravenous administration. Furthermore, it is demonstrated that LiPTD NPs are capable of efficient encapsulation and delivery of chemotherapy doxorubicin and sonosensitizer chlorin e6 to achieve combined chemotherapy and sonodynamic therapy (SDT). It is demonstrated that the capability of GSH depletion of LiPTD NPs further augments the tumor cell killing effect triggered by SDT. As a result, treatment with LiPTD NPs effectively inhibits tumor growth and prolongs the survival of tumor-bearing mice. This study may suggest a potential new approach for effective GBM treatment.
    Keywords:  GSH; blood-brain barrier; brain tumor; chemo-sonodynamic; shrinkable nanoparticles
    DOI:  https://doi.org/10.1002/advs.202203894
  16. Evid Based Complement Alternat Med. 2022 ;2022 7702512
    A Critical Scrutiny on Liposomal Nanoparticles Drug Carriers as Modelled by Topotecan Encapsulation and Release in Treating Cancer.
    Hilla Mills, Ronald Acquah, Nova Tang, Luke Cheung, Susanne Klenk, Ronald Glassen, Magali Pirson, Alain Albert, Duong Trinh Hoang, Thang Nguyen Van.
      The medical field is looking for drugs and/or ways of delivering drugs without harming patients. A number of severe drug side effects are reported, such as acute kidney injury (AKI), hepatotoxicity, skin rash, and so on. Nanomedicine has come to the rescue. Liposomal nanoparticles have shown great potential in loading drugs, and delivering drugs to specific targeted sites, hence achieving a needed bioavailability and steady state concentration, which is achieved by a controlled drug release ability by the nanoparticles. The liposomal nanoparticles can be conjugated to cancer receptor tags that give the anticancer-loaded nanoparticles specificity to deliver anticancer agents only at cancerous sites, hence circumventing destruction of normal cells. Also, the particles are biocompatible. The drugs are shielded by attack from the liver and other cytochrome P450 enzymes before reaching the desired sites. The challenge, however, is that the drug release is slow by these nanoparticles on their own. Scientists then came up with several ways to enhance drug release. Magnetic fields, UV light, infrared light, and so on are amongst the enhancers used by scientists to potentiate drug release from nanoparticles. In this paper, synthesis of liposomal nanoparticle formulations (liposomal-quantum dots (L-QDs), liposomal-quantum dots loaded with topotecan (L-QD-TPT)) and their analysis (cytotoxicity, drug internalization, loading efficiency, drug release rate, and the uptake of the drug and nanoparticles by the HeLa cells) are discussed.
    DOI:  https://doi.org/10.1155/2022/7702512
  17. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 18. e1846
    Pharmacokinetic behaviors of soft nanoparticulate formulations of chemotherapeutics.
    Mahua Sarkar, Yang Wang, Oscar Ekpenyong, Dong Liang, Huan Xie.
      Chemotherapeutic treatment with conventional drug formulations pose numerous challenges, such as poor solubility, high cytotoxicity and serious off-target side effects, low bioavailability, and ultimately subtherapeutic tumoral concentration leading to poor therapeutic outcomes. In the field of Nanomedicine, advances in nanotechnology have been applied with great success to design and develop novel nanoparticle-based formulations for the treatment of various types of cancer. The approval of the first nanomedicine, Doxil® (liposomal doxorubicin) in 1995, paved the path for further development for various types of novel delivery platforms. Several different types of nanoparticles, especially organic (soft) nanoparticles (liposomes, polymeric micelles, and albumin-bound nanoparticles), have been developed and approved for several anticancer drugs. Nanoparticulate drug delivery platform have facilitated to overcome of these challenges and offered key advantages of improved bioavailability, higher intra-tumoral concentration of the drug, reduced toxicity, and improved efficacy. This review introduces various commonly used nanoparticulate systems in biomedical research and their pharmacokinetic (PK) attributes, then focuses on the various physicochemical and physiological factors affecting the in vivo disposition of chemotherapeutic agents encapsulated in nanoparticles in recent years. Further, it provides a review of the current landscape of soft nanoparticulate formulations for the two most widely investigated anticancer drugs, paclitaxel, and doxorubicin, that are either approved or under investigation. Formulation details, PK profiles, and therapeutic outcomes of these novel strategies have been discussed individually and in comparison, to traditional formulations. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
    Keywords:  chemotherapeutics; doxorubicin; paclitaxel; pharmacokinetics; soft nanoparticles
    DOI:  https://doi.org/10.1002/wnan.1846
  18. Biomed Res Int. 2022 ;2022 7792180
    Physicochemical Characterization of Chitosan-Decorated Finasteride Solid Lipid Nanoparticles for Skin Drug Delivery.
    Muhammad Sohaib, Shefaat Ullah Shah, Kifayat Ullah Shah, Kifayat Ullah Shah, Nauman Rahim Khan, Malik Muhammad Irfan, Zahid Rasul Niazi, Abdulsalam A Alqahtani, Ali Alasiri, Ismail A Walbi, Sajid Mahmood.
      Finasteride is considered the drug of choice for androgenic alopecia and benign prostate hyperplasia. The aim of the study was to formulate nanodrug carriers of finasteride with enhanced retentive properties in the skin. The finasteride was formulated as solid lipid nanoparticles that were decorated with different concentrations of chitosan for improved retentive properties. Solid lipid nanoparticles (SLNs) were synthesized by "high-speed homogenization technique" using stearic acid as a solid lipid while PEG-6000 and Tween-80 were used as surfactants. The SLNs were evaluated for particle size, polydispersity index (PDI), zeta potential, drug entrapment efficiency, and drug release behavior. The mean particle size of SLNs was in the range of 10.10 nm to 144.2 nm. The PDI ranged from 0.244 to 0.412 while zeta potential was in the range of 8.9 mV to 62.6 mV. The drug entrapment efficiency in chitosan undecorated formulations was 48.3% while an increase in drug entrapment was observed in chitosan-decorated formulations (51.1% to 62%). The in vitro drug release studies of SLNs showed an extended drug release for 24 hours after 4 hours of initial burst release. The extended drug release was observed in chitosan-coated SLNs in comparison with uncoated nanoparticles. The permeation and retention study revealed higher retention of drug in the skin and low permeation with chitosan-decorated SLNs that ranged from 39.4 μg/cm2 to 13.2 μg/cm2. TEM images depicted spherical shape of SLNs. The stability study confirmed stable formulations in temperature range of 5°C and 40°C for three months. It is concluded from this study that the SLNs of finasteride were successfully formulated and chitosan decoration enhanced the drug retention in the skin layers. Therefore, these formulations could be used in androgenic alopecia and benign prostate hyperplasia to avoid the side effects, drug degradation, and prolonged use of drug with conventional oral therapy.
    DOI:  https://doi.org/10.1155/2022/7792180
  19. Curr Drug Targets. 2022 Aug 16.
    A review on the current status of homeopathy in the clinical management of cancer.
    Ajay Tangelloju, Rudra Chakravarti, Rajveer Singh, Bireswar Bhattacharya, Arijit Ghosh, Sujit Kumar Bhutia, Velayutham Ravichandiran, Dipanjan Ghosh.
      Homeopathy is a widely practiced alternate system of medicine around the world that employs small doses of various medicines to promote auto-regulation and self-healing. It is among the most commonly used alternative approaches in cancer as well as other diseases, among other alternate therapeutic systems. It is widely used as palliative and as supportive therapy in cancer patients. Few cases have been reported on patients using homeopathy after surgery, radiotherapy, and chemotherapy, generally for overcoming side effects. The dose of Homoeopathic medicines and their mechanism of action in cancer has also been documented while the clinical trials on the effects of Homoeopathy in the treatment of cancer are rare. It is found that the anticancer potential of homeopathic medicines are reported for different cancer types which show their efficacy through apoptosis and immune system modulation. Homeopathic treatment is an add-on to conventional therapy, with almost no interaction with the conventional drugs due to the small dose, and is largely attributed towards improving life by providing symptomatic relief, increasing survival time and boosting patient's immunity. This review explores the accountability of homeopathic system of medicine by highlighting some of the most commonly used homeopathic drugs for different types of cancers.
    Keywords:  Alternative therapeutics; Apoptosis; Cancer; Homeopathy; Palliative care; clinical trial
    DOI:  https://doi.org/10.2174/1389450123666220816151547
  20. Nitric Oxide. 2022 Aug 12. pii: S1089-8603(22)00085-4. [Epub ahead of print]128 25-36
    Bystander effect in photosensitized prostate cancer cells with a different grade of malignancy: The role of nitric oxide.
    Mariachiara Gani, Luigi E Xodo, Valentina Rapozzi.
      Photodynamic therapy (PDT) is a therapeutic modality based on the simultaneous action of three elements: photosensitizer, light and oxygen. This triad generates singlet oxygen and reactive oxygen species that can reduce the mass of a tumor. PDT is also able to stimulate iNOS, the enzyme that generates nitric oxide (NO). The role of NO in PDT-treated cancer cells has been investigated in several studies. They showed that low iNOS/NO levels stimulate signaling pathways that promote tumor survival, while high iNOS/NO levels arrest tumor growth. There is increasing evidence that ROS/RNS control both proliferation and migration of cells in the vicinity of PDT-treated tumor cells (so-called bystander cells). In this work, we addressed the question of how NO, which is generated by weak PDT, affects bystander cells. We used a conditioned medium: medium of PDT-treated tumor cells containing the stressors produced by the cells was added to untreated cells mimicking the neighboring bystander cells to investigate whether the conditioned medium affects cell proliferation. We found that low-level NO in prostate cancer cells affects the bystander tumor cells in a manner that depends on their malignancy grade.
    Keywords:  Bystander effect; GSNOR; Nitric oxide; Photodynamic therapy; Prostate cancer cells; S-nitrosylation; Tumor malignancy
    DOI:  https://doi.org/10.1016/j.niox.2022.08.002
  21. Small. 2022 Aug 15. e2203400
    Catalase-Like Nanozymes: Classification, Catalytic Mechanisms, and Their Applications.
    Deting Xu, Liyuan Wu, Haodong Yao, Lina Zhao.
      The field of nanozymes has developed rapidly over the past decade. Among various oxidoreductases mimics, catalase (CAT)-like nanozyme, acting as an essential part of the regulation of reactive oxygen species (ROS), has attracted extensive research interest in recent years. However, CAT-like nanozymes are not as well discussed as other nanozymes such as peroxidase (POD)-like nanozymes, etc. Compared with natural catalase or artificial CAT enzymes, CAT-like nanozymes have unique properties of low cost, size-dependent properties, high catalytic activity and stability, and easy surface modification, etc., which make them widely used in various fields, especially in tumor therapy and disease treatment. Consequently, there is a great requirement to make a systematic discussion on CAT-like nanozymes. In this review, some key aspects of CAT-like nanozymes are deeply summarized as: 1) Typical CAT-like nanozymes classified by different nanomaterials; 2) The catalytic mechanisms proposed by experimental and theoretical studies; 3) Extensive applications in regard to tumor therapy, cytoprotection and sensing. Therefore, it is prospected that this review will contribute to the further design of CAT-like nanozymes and optimize their applications with much higher efficiency than before.
    Keywords:  cancer therapy; catalase CAT-like nanozymes; catalytic mechanisms; classifications
    DOI:  https://doi.org/10.1002/smll.202203400
  22. J Appl Toxicol. 2022 Aug 17.
    Impact of solid lipid nanoparticles on 3T3 fibroblasts viability and lipid profile: the effect of curcumin- and resveratrol-loading.
    Antonella Rosa, Mariella Nieddu, Giulia Pitzanti, Rosa Pireddu, Francesco Lai, Maria Cristina Cardia.
      This study focused on the impact in 3T3 fibroblasts of several types of empty and curcumin- and resveratrol-loaded solid lipid nanoparticles (SLN) on cell viability and lipid metabolism in relation to their lipid content and encapsulated drug. SLN, prepared by hot homogenization/ultrasonication, were characterized with respect to size, polydispersity index, and zeta potential. Compritol® 888 ATO at different concentrations (4%, 5%, 6% wt/wt) was chosen as lipid matrix while Poloxamer 188 (from 2.2 to 3.3% wt/wt) and Transcutol (TRC; 2 or 4%) were added as nanoparticle excipients. Prepared SLN were able to encapsulate high drug amount (encapsulation efficiency percentage of about 97-99%). All empty SLN did not show cytotoxicity (by MTT assay, at 24 h of incubation) in 3T3 cells independently of the lipid and TRC amount, while a viability reduction in the range 5-11% and 12-27% was observed in 3T3 cells treated with curcumin-loaded and resveratrol-loaded SLN, respectively. SLN without TRC did not affect cell lipid metabolism, independently from the lipid content. Empty and loaded SLN formulated with 4% of Compritol and 4% of TRC significantly affected, after 24 h of incubation at the dose of 5 mL/mL, cell polar lipids (phospholipids and free cholesterol) and fatty acid profile, with respect to control cells. Loaded compounds significantly modulated the impact of the corresponding empty formulation on cell lipids. Therefore, the combined impact on lipid metabolism of SLN and loaded drug should be taken in consideration in the evaluation of the toxicity, potential application, and therapeutic effects of new formulations.
    Keywords:  Nanoparticles; SLN; cytotoxicity; fibroblasts; lipid profile modulation
    DOI:  https://doi.org/10.1002/jat.4379
  23. Drug Deliv. 2022 Aug 08. 29(1): 2671-2684
    Surface-tailoring of emulsomes for boosting brain delivery of vinpocetine via intranasal route: in vitro optimization and in vivo pharmacokinetic assessment.
    Hibah M Aldawsari, Shaimaa M Badr-Eldin, Nourah Y Assiri, Nabil A Alhakamy, Anna Privitera, Filippo Caraci, Giuseppe Caruso.
      Vinpocetine (VNP), a semisynthetic active pharmaceutical ingredient, is used for oral management of cerebrovascular diseases because of its ability to enhance the blood flow to the brain. However, despite that, the therapeutic application of VNP is restricted due to its reduced bioavailability and diminished brain levels that could be attributed to its low aqueous solubility, short half-life, and presystemic metabolism exposure. Accordingly, the goal of this work was to explore the ability of surface-tailored intranasal emulsomes to boost brain delivery of the drug. A 3221 factorial design was implemented to explore the impact of phospholipid (PL) to solid lipid weight ratio, PL to cholesterol molar ratio, and type of solid lipid on vesicle size, zeta potential, drug entrapment, and release efficiency of the new developed VNP emulsomes. Tailoring of the optimized emulsomal surface formulation was performed using either cationization or PEGylation approaches to boost blood-brain barrier penetration. The pharmacokinetic assessment in rats showed significantly improved bioavailability of VNP emulsomal formulations compared to the oral market product. Additionally, surface-tailored emulsomes exhibited significantly higher brain levels compared to the optimized emulsomes. Based on these findings, the proposed surface-tailored emulsomes could be considered as a promising platform for achieving high brain levels of VNP following intranasal administration.
    Keywords:  PEGylation; Vinpocetine; brain delivery; cationization; pharmacokinetics; surface-tailored intranasal emulsomes
    DOI:  https://doi.org/10.1080/10717544.2022.2110996
  24. Adv Drug Deliv Rev. 2022 Aug 12. pii: S0169-409X(22)00375-1. [Epub ahead of print] 114485
    Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders.
    A C Correia, A R Monteiro, R Silva, J N Moreira, J M Sousa Lobo, A C Silva.
      The main limitation to the success of central nervous system (CNS) therapies lies in the difficulty for drugs to cross the blood-brain barrier (BBB) and reach the brain. Regarding its structure and enzymatic complexity, crossing the BBB is a challenge, although several alternatives have been identified. For instance, the use of drugs encapsulated in lipid nanoparticles has been described as one of the most efficient approaches to bypass the BBB, as they allow the passage of drugs through this barrier, improving brain bioavailability. In particular, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been a focus of research related to drug delivery to the brain. These systems provide protection of lipophilic drugs, improved delivery and bioavailability, having a major impact on treatments outcomes. In addition, the use of lipid nanoparticles administered via routes that transport drugs directly into the brain seems a promising solution to avoid the difficulties in crossing the BBB. For instance, the nose-to-brain route has gained considerable interest, as it has shown efficacy in 3D human nasal models and in animal models. This review addresses the state of the art on the use of lipid nanoparticles to modify the pharmacokinetics of drugs employed in the management of neurological disorders. A description of the structural components of the BBB, the role of the neurovascular unit and limitations for drugs to entry into the CNS is first addressed, along with the developments to increase drug delivery to the brain, with a special focus on lipid nanoparticles. In addition, the obstacle of BBB complexity in the creation of new effective drugs for the treatment of the most prevalent neurological disorders is also addressed. Finally, the proposed strategies for lipid nanoparticles to reach the CNS, crossing or circumventing the BBB, are described. Although promising results have been reported, especially with the nose-to-brain route, they are still ongoing to assess its real efficacy in vivo in the management of neurological disorders.
    Keywords:  Blood-brain barrier; Central nervous system; Lipid nanoparticles; NLC; Nanostructured lipid carriers; Neurological disorders; Nose-to-brain; SLN; Solid lipid nanoparticles
    DOI:  https://doi.org/10.1016/j.addr.2022.114485
  25. Eur J Med Chem. 2022 Aug 05. pii: S0223-5234(22)00550-5. [Epub ahead of print]241 114648
    Mitochondrial targeted hierarchical drug delivery system based on HA-modified liposomes for cancer therapy.
    Huiting Chen, Zhou Fang, Mengdi Song, Kehai Liu.
      Chemotherapy targeting mitochondrial is a faster and more sensitive anti-tumor therapy strategy. In this study, a hierarchical drug delivery system HA-GDT-Lip was constructed by coupling glycyrrhetinic acid (GA), triphenylphosphine (TPP), and doxorubicin (DOX), encapsulating them in cationic liposomes (CLs), then coating the surface of CLs with HA. HA-GDT-Lip nanoparticles can be accumulated in tumor tissue through the EPR effect, then achieve tumor cell-specific endocytosis mediated by the CD44 receptor, DOX can be successfully delivered into mitochondria through the combined action of GA and TPP. Physicochemical properties analysis showed that HA-GDT-Lip nanoparticles were uniform in size and spherical in shape. In vitro cell experiments showed that HA-GDT-Lip had high cell uptake efficiency and mitochondrial targeting ability. In addition, HA-GDT-Lip could induce MPTP opening and accelerate cell apoptosis. Meanwhile, HA-GDT-Lip showed excellent antitumor activity and in vivo safety in tumor-bearing nude mice. In conclusion, HA-GDT-Lip may serve as a promising mitochondrial delivery system to reduce the side effects of anticancer drugs and improve their antitumor efficacy.
    Keywords:  Doxorubicin; Drug delivery; Glycyrrhetinic acid; Hyaluronic acid; Mitochondrial targeting; Triphenylphosphine
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114648
  26. Acta Pharm Sin B. 2022 Aug;12(8): 3354-3366
    Dual-responsive nanoparticles with transformable shape and reversible charge for amplified chemo-photodynamic therapy of breast cancer.
    Wenfeng Jia, Rui Liu, Yushan Wang, Chuan Hu, Wenqi Yu, Yang Zhou, Ling Wang, Mengjiao Zhang, Huile Gao, Xiang Gao.
      Herein, we designed a dual-response shape transformation and charge reversal strategy with chemo-photodynamic therapy to improve the blood circulation time, tumor penetration and retention, which finally enhanced the anti-tumor effect. In the system, hydrophobic photosensitizer chlorin e6 (Ce6), hydrophilic chemotherapeutic drug berberrubine (BBR) and matrix metalloproteinase-2 (MMP-2) response peptide (PLGVRKLVFF) were coupled by linkers to form a linear triblock molecule BBR-PLGVRKLVFF-Ce6 (BPC), which can self-assemble into nanoparticles. Then, positively charged BPC and polyethylene glycol-histidine (PEG-His) were mixed to form PEG-His@BPC with negative surface charge and long blood circulation time. Due to the acidic tumor microenvironment, the PEG shell was detached from PEG-His@BPC attributing to protonation of the histidine, which achieved charge reversal, size reduction and enhanced tumor penetration. At the same time, enzyme cutting site was exposed, and the spherical nanoparticles could transform into nanofibers following the enzymolysis by MMP-2, while BBR was released to kill tumors by inducing apoptosis. Compared with original nanoparticles, the nanofibers with photosensitizer Ce6 retained within tumor site for a longer time. Collectively, we provided a good example to fully use the intrinsic properties of different drugs and linkers to construct tumor microenvironment-responsive charge reversal and shape transformable nanoparticles with synergistic antitumor effect.
    Keywords:  Breast cancer; Carrier-free nanoparticles; Charge reversal; Chemo-photodynamic therapy; MMP-2 response; Self-delivery; Shape transformation; pH response
    DOI:  https://doi.org/10.1016/j.apsb.2022.03.010
  27. Front Oncol. 2022 ;12 941618
    Lipid metabolism in ferroptosis and ferroptosis-based cancer therapy.
    Yonghao Sun, Zuoxing Xue, Tao Huang, Xiangyu Che, Guangzhen Wu.
      Ferroptosis refers to iron-dependent, specialized, and regulated-necrosis mediated by lipid peroxidation, which is closely related to a variety of diseases, including cancer. Tumor cells undergo extensive changes in lipid metabolism, including lipid peroxidation and ferroptosis. Changes in lipid metabolism are critical for the regulation of ferroptosis and thus have important roles in cancer therapy. In this review, we introduce the characteristics of ferroptosis and briefly analyze the links between several metabolic mechanisms and ferroptosis. The effects of lipid peroxides, several signaling pathways, and the molecules and pathways involved in lipid metabolism on ferroptosis were extensively analyzed. Finally, our review highlights some ferroptosis-based treatments and presents some methods and examples of how these treatments can be combined with other treatments.
    Keywords:  ferroptosis; lipid metabolism; lipid peroxidation; tumor; tumor therapy
    DOI:  https://doi.org/10.3389/fonc.2022.941618
  28. Med Oncol. 2022 Aug 16. 39(11): 171
    Differential molecular mechanistic behavior of HDACs in cancer progression.
    Tashvinder Singh, Prabhsimran Kaur, Paramdeep Singh, Sandeep Singh, Anjana Munshi.
      Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs' role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.
    Keywords:  Angiogenesis; Cancer; Histone deacetylases; Metabolism; Metastasis; Stemness potential
    DOI:  https://doi.org/10.1007/s12032-022-01770-4
  29. Curr Med Chem. 2022 Aug 17.
    Curcumin Combats Against Organophosphate Pesticides Toxicity: A Review of the Current Evidence and Molecular Pathways.
    Amir Masoud Jafari-Nozad, Amirsajad Jafari, Michel Aschner, Tahereh Farkhondeh, Saeed Samarghandian.
      Organophosphate compounds are regarded as a class of pesticides that are used in farming. Their extensive use, especially in developing countries, is a serious public health problem. Numerous studies have shown the effects of these toxins on various parts of the human and other vertebrates' bodies, including the cardiovascular, hepatobiliary, renal, and reproductive systems. Curcumin is a polyphenol compound obtained from the rhizome of the Curcuma longa. Curcumin has been known as a dietary spice, food additive, and traditional medicine since many years ago. In recent decades, the medicinal characteristics, clinical aspects, and biological activity of Curcumin have been extensively examined. The most examined positive characteristics of Curcumin are its anti-inflammatory and anti-oxidant qualities. This review will deal with the pharmacological properties of Curcumin as well as an update of currently available studies in terms of Curcumin's uses and function against organophosphate pesticides-induced toxicity on different human organs.
    Keywords:  Curcumin; Organophosphate; Pesticides; Toxicity
    DOI:  https://doi.org/10.2174/0929867329666220817125800
  30. J Ethnopharmacol. 2022 Aug 13. pii: S0378-8741(22)00681-X. [Epub ahead of print]298 115642
    Tubiechong：A review on ethnomedicinal uses, bioactive chemical constituents and pharmacological activities.
    Xiang Fu, Bing-Hao Shao, Xue Wei, Hui-Hui Wang, Xing Chen, Tian-Tian Zhao, Chun-Mei Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Tubiechong comprises mainly Eupolyphaga and Steleophaga is widely distributed in China. It has been used in the traditional medicine systems in Asian countries specially in China，Japan and Singapore for thousand years.
    AIM OF THE REVIEW: The aim of this work is to review the scientific work about Tubiechong regarding their ethnomedicinal uses, bioactive chemical constituents and pharmacological activities.
    MATERIALS AND METHODS: Relevant literature of Tubiechong was collected for its traditional uses, pharmacological activities, and bioactive compounds released from inception until May 2022. The online databases such as Web of Science, PubMed, Google Scholar, Science Direct, Scopus, SciFinder Scholar, Springer Link, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP database were used as electronic search engines for articles with the various specific keywords. Additionally, references from ancient texts and local information such as PhD and MSc theses, books, and Chinese journals were also included.
    RESULTS: The clinical researches have revealed that Tubiechong alone has been successfully used to treat bone disease, ache, sprain, herpes zoster, paronychia and so on. Tubichong's main clinical application is to form formulations with other herbs. The most widely used 34 kinds of Chinese patent medicine containing Tubiechong were included in Chinese Pharmacopoeia (2020 Edition) for the treatment of traumatic injury, low back pain, cardiovascular disease, tumors or mass and nodule, cervical spondylopathy, osteoarthritis and psoriasis. Its other derived formulas have been used in the clinical treatment of various diseases, such as blood stasis, hepatic cirrhosis, cyclomastopathy, chronic active hepatitis, nephropathy, gynaecopathia, cancer diseases. To date, the bioactive substances reported are limited to protein and peptides, fatty acids, polysaccharides and alkaloids from Eupolyphaga sinensis Walker. So far, the pharmacological activities of Tubiechong and its various extracts have been evaluated, including anticoagulant and antithrombotic, anticancer, bone repair, immunomodulation, analgesia, antioxidant, antihyperlipidemic, antimicrobial and protective and repair functions for damage to the liver, heart, brain and skin. As an edible insect, its safety has also been confirmed by acute toxicity tests and 30-day feeding trials.
    CONCLUSION: Tubiechong is an important insect medicine with the effect of promoting blood circulation and removing blood stasis, which has been used in traditional Chinese medicine for thousands of years for the treatment of trauma and abdominal lumps, and has now been clinically extended to the treatment of a variety of diseases. Its multiple pharmacological activities indicate that it has great potential for development and application. However, its chemical constituents with pharmacological activity require further excavation and detailed study. In addition, the in-depth molecular pharmacological mechanisms deserve further explanation.
    Keywords:  Bioactive chemical constituents; Ethnomedicinal uses; Eupolyphaga; Pharmacological activities; Tubiechong
    DOI:  https://doi.org/10.1016/j.jep.2022.115642
  31. Front Nutr. 2022 ;9 917617
    Onion anthocyanins: Extraction, stability, bioavailability, dietary effect, and health implications.
    Mahesh Kumar Samota, Madhvi Sharma, Kulwinder Kaur, Sarita, Dinesh Kumar Yadav, Abhay K Pandey, Yamini Tak, Mandeep Rawat, Julie Thakur, Heena Rani.
      Anthocyanins are high-value compounds, and their use as functional foods and their natural colorant have potential health benefits. Anthocyanins seem to possess antioxidant properties, which help prevent neuronal diseases and thereby exhibit anti-inflammatory, chemotherapeutic, cardioprotective, hepatoprotective, and neuroprotective activities. They also show different therapeutic effects against various chronic diseases. Anthocyanins are present in high concentrations in onion. In recent years, although both conventional and improved methods have been used for extraction of anthocyanins, nowadays, improved methods are of great importance because of their higher yield and stability of anthocyanins. In this review, we compile anthocyanins and their derivatives found in onion and the factors affecting their stability. We also analyze different extraction techniques of anthocyanins. From this point of view, it is very important to be precisely aware of the impact that each parameter has on the stability and subsequently potentiate its bioavailability or beneficial health effects. We present up-to-date information on bioavailability, dietary effects, and health implications of anthocyanins such as antioxidant, antidiabetic, anticancerous, antiobesity, cardioprotective, and hepatoprotective activities.
    Keywords:  anthocyanins; bioavailability; dietary effects; extraction techniques; health effects
    DOI:  https://doi.org/10.3389/fnut.2022.917617
  32. Front Immunol. 2022 ;13 945129
    Natural medicines of targeted rheumatoid arthritis and its action mechanism.
    Xueling Liu, Zhiguo Wang, Hua Qian, Wenhua Tao, Ying Zhang, Chunyan Hu, Weiwei Mao, Qi Guo.
      Rheumatoid arthritis (RA) is an autoimmune disease involving joints, with clinical manifestations of joint inflammation, bone damage and cartilage destruction, joint dysfunction and deformity, and extra-articular organ damage. As an important source of new drug molecules, natural medicines have many advantages, such as a wide range of biological effects and small toxic and side effects. They have become a hot spot for the vast number of researchers to study various diseases and develop therapeutic drugs. In recent years, the research of natural medicines in the treatment of RA has made remarkable achievements. These natural medicines mainly include flavonoids, polyphenols, alkaloids, glycosides and terpenes. Among them, resveratrol, icariin, epigallocatechin-3-gallate, ginsenoside, sinomenine, paeoniflorin, triptolide and paeoniflorin are star natural medicines for the treatment of RA. Its mechanism of treating RA mainly involves these aspects: anti-inflammation, anti-oxidation, immune regulation, pro-apoptosis, inhibition of angiogenesis, inhibition of osteoclastogenesis, inhibition of fibroblast-like synovial cell proliferation, migration and invasion. This review summarizes natural medicines with potential therapeutic effects on RA and briefly discusses their mechanisms of action against RA.
    Keywords:  alkaloids; autoimmune disease; flavonoids; glycosides; natural medicines; polyphenols; rheumatoid arthritis; terpenes
    DOI:  https://doi.org/10.3389/fimmu.2022.945129
  33. Drug Deliv. 2022 Dec;29(1): 2694-2704
    Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical: improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats.
    Mohammed H Elkomy, Hussein M Eid, Mohammed Elmowafy, Khaled Shalaby, Ameeduzzafar Zafar, Mohamed A Abdelgawad, Mostafa E Rateb, Mohammed R A Ali, Izzeddin Alsalahat, Heba A Abou-Taleb.
      Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (-) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity.
    Keywords:  Berberine; bile salts; bilosomes; bioavailability; diabetes mellitus; optimization; pharmacokinetics
    DOI:  https://doi.org/10.1080/10717544.2022.2110997
  34. J Control Release. 2022 Aug 16. pii: S0168-3659(22)00529-6. [Epub ahead of print]
    Polymeric and small molecule-conjugates of temozolomide as improved therapeutic agents for glioblastoma multiforme.
    Reena Jatyan, Prabhjeet Singh, Deepak Kumar Sahel, Y G Karthik, Anupama Mittal, Deepak Chitkara.
      Temozolomide (TMZ), an imidazotetrazine, is a second-generation DNA alkylating agent used as a first-line treatment of glioblastoma multiforme (GBM). It was approved by FDA in 2005 and declared a blockbuster drug in 2008. Although TMZ has shown 100% oral bioavailability and crosses the blood-brain barrier effectively however it suffers from limitations such as a short half-life (~1.8 h), rapid metabolism, and less accumulation in the brain (~10-20%). Additionally, development of chemoresistance has been associated with its use. Since it is a potential chemotherapeutic agent with an unmet medical need, advanced delivery strategies have been explored to overcome the associated limitations of TMZ. Nanocarriers including liposomes, solid lipid nanoparticles (SLNs), nanostructure lipid carriers (NLCs), and polymeric nanoparticles have demonstrated their ability to improve its circulation time, stability, tissue-specific accumulation, sustained release, and cellular uptake. Because of the appreciable water solubility of TMZ (~5 mg/ml), the physical loading of TMZ in these nanocarriers is always challenging. Alternatively, the conjugation approach, wherein TMZ has been conjugated to polymers or small molecules, has been explored with improved outcomes in vitro and in vivo. This review emphasized the practical evidence of the conjugation strategy to improve the therapeutic potential of TMZ in the treatment of glioblastoma multiforme.
    Keywords:  Conjugates; Glioblastoma Multiforme; Polymer drug conjugates; Prodrugs; Temozolomide
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.024
  35. J Control Release. 2022 Aug 15. pii: S0168-3659(22)00524-7. [Epub ahead of print]
    Delivery of DNA octahedra enhanced by focused ultrasound with microbubbles for glioma therapy.
    Yuanyuan Shen, Mengni Hu, Wen Li, Yiling Chen, Yiluo Xu, Litao Sun, Dongzhe Liu, Siping Chen, Yueqing Gu, Yi Ma, Xin Chen.
      DNA nanostructures, with good biosafety, highly programmable assembly, flexible modification, and precise control, are tailored as drug carriers to deliver therapeutic agents for cancer therapy. However, they face considerable challenges regarding their delivery into the brain, mainly due to the blood-brain barrier (BBB). By controlling the acoustic parameters, focused ultrasound combined with microbubbles (FUS/MB) can temporarily, noninvasively, and reproducibly open the BBB in a localized region. We investigated the delivery outcome of pH-responsive DNA octahedra loading Epirubicin (Epr@DNA-Octa) via FUS/MB and its therapeutic efficiency in a mouse model bearing intracranial glioma xenograft. Using FUS/MB to locally disrupt the BBB or the blood-tumor barrier (BTB) and systemic administration of Epr@DNA-Octa (Epr@DNA-Octa + FUS/MB) (2 mg/kg of loaded Epr), we achieved an Epr concentration of 292.3 ± 10.1 ng/g tissue in glioma, a 4.4-fold increase compared to unsonicated animals (p < 0.001). The in vitro findings indicated that Epr released from DNA strands accumulated in lysosomes and induced enhanced cytotoxicity compared to free Epr. Further two-photon intravital imaging of spatiotemporal patterns of the DNA-Octa leakage revealed that the FUS/MB treatment enhanced DNA-Octa delivery across several physiological barriers at microscopic level, including the first extravasation across the BBB/BTB and then deep penetration into the glioma center and engulfment of DNA-Octa into the tumor cell body. Longitudinal in vivo bioluminescence imaging and histological analysis indicated that the intracranial glioma progression in nude mice treated with Epr@DNA-Octa + FUS/MB was effectively retarded compared to other groups. The beneficial effect on survival was most significant in the Epr@DNA-Octa + FUS/MB group, with a 50% increase in median survival and a 73% increase in the maximum survival compared to control animals. Our work demonstrates the potential viability of FUS/MB as an alternative strategy for glioma delivery of anticancer drugs using DNA nanostructures as the drug delivery platform for brain cancer therapy.
    Keywords:  Blood-brain barrier; DNA nanostructure; Drug delivery; Focused ultrasound; Glioma
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.019
  36. RSC Adv. 2022 Jul 21. 12(33): 21609-21620
    Glutathione-depleting polymer delivering chlorin e6 for enhancing photodynamic therapy.
    Shi-Yin Wang, Guo Chen, Ji-Feng Chen, Jin Wang, Shao-Hui Deng, Du Cheng.
      The therapeutic effect of photodynamic therapy (PDT) is highly dependent on the intracellular production of reactive oxygen species (ROS). However, the ROS generated by photosensitizers can be consumed by the highly concentrated glutathione (GSH) in tumor cells, severely impairing the therapeutic effect of PDT. Herein, we synthesized a GSH-scavenging copolymer to deliver photosensitizer chlorin e6 (Ce6). The pyridyl disulfide groups, which have faster reactivity with the thiol groups of GSH than other disulfide groups, were grafted onto a hydrophobic block to encapsulate the Ce6. Under NIR irradiation, the Ce6 generated ROS to kill tumor cells, and the pyridyl disulfide groups depleted the GSH to prevent ROS consumption, which synergistically enhanced the therapeutic effect of PDT. In vitro and in vivo experiments confirmed the combinatory antitumor effect of Ce6-induced ROS generation and the pyridyl disulfide group-induced GSH depletion. Therefore, the pyridyl disulfide group-grafted amphiphilic copolymer provides a more efficient strategy for enhancing PDT and has promising potential for clinical application.
    DOI:  https://doi.org/10.1039/d2ra01877b
  37. Food Funct. 2022 Aug 19.
    Medicine-food herb: Angelica sinensis, a potential therapeutic hope for Alzheimer's disease and related complications.
    Yu Long, Dan Li, Shuang Yu, Ai Shi, Jie Deng, Jing Wen, Xiao-Qiu Li, Yin Ma, Yu-Lu Zhang, Song-Yu Liu, Jin-Yan Wan, Nan Li, Ming Yang, Li Han.
      Alzheimer's disease (AD) is a progressive neurodegenerative disease, which has brought a huge burden to the world. The current therapeutic approach of one-molecule-one-target strategy fails to address the issues of AD because of multiple pathological features of AD. Traditionally, the herb of Angelica sinensis (AS) comes from the root of an umbrella plant Angelica sinensis (Oliv.) Diels. As a typical medicine-food herb, studies have shown that AS can alleviate AD and AD-complications by multiple targets through the various foundations of pharmaceutical material and dietary supply basis. Therefore, this review summarizes the pharmacological effects of AS for the treatment of AD and AD-complications for the first time. AS contains many effective components, such as ligustilide, z-ligustilide, n-butylidenephthalide, α-pinene, p-cymene, myrcene, ferulic acid, vanillic acid and coniferyl ferulate. It is found that AS, AS-active compounds and AS-compound recipes mainly treat AD through neuroprotective, anti-inflammation, and anti-oxidant effects, improving mitochondrial dysfunction, anti-neuronal apoptosis, regulating autophagy, regulating intestinal flora and enhancing the central cholinergic system, which shows the multi-component and multi-target effect of AS. The role of dietary supplement components in AS for AD intervention is summarized, including vitamin B12, folic acid, arginine, and oleic acid, which can improve the symptoms of AD. Besides, this review focuses on the safety and toxicity evaluation of AS, which provides a basis for its application. This review will provide further support for the research on AD and the application of medicine-food herb AS in a healthy lifestyle in the future.
    DOI:  https://doi.org/10.1039/d2fo01287a
  38. Anticancer Drugs. 2022 Aug 12.
    Novel natural inhibitors targeting KRAS G12C by computational study.
    Yuting Jiang, Wanting Chen, Xinhui Wang, Baolin Zhou, Haoqun Xie, Yuanyuan Hou, Zhen Guo, Bo Yu, Sheng Zhong, Xing Su.
      Ideal leading and nominee compounds with inhibiting effects on KRAS G12C were selected from the ZINC database, laying a cornerstone for the progress of anticancer drugs. A variety of computational virtual screening methods were utilized to screen possible inhibitors of KRAS G12C. LibDock was utilized to estimate 17 930 compounds and the top 20 were nominated for additional study, which was absorption, distribution, metabolism, and excretion and harmfulness prediction. Molecule docking was employed to prove the binding connection between certain ligands and KRAS G12C. Natural novel compounds ZINC000012494057 and ZINC000003789195 were selected to bind stably with KRAS G12C. In addition, they had lower scores in Ames mutagenicity, rodent carcinogenicity, cytochrome P450 2D6(CYP2D6) tolerance, and non-developmental toxicity potential. Molecular dynamic simulations demonstrate that the combination of ZINC000012494057 and ZINC000003789195 with KRAS G12C has more favorable potential energy, which provides conditions for their stable existence in the natural environment. Natural compounds ZINC000012494057 and ZINC000003789195 were identified as KRAS G12C potential inhibitors. These two compounds have been verified to have enormous importance for the progress of anticancer medicines.
    DOI:  https://doi.org/10.1097/CAD.0000000000001317
  39. Med Oncol. 2022 Aug 16. 39(11): 167
    Matrine induces autophagy in human neuroblastoma cells via blocking the AKT-mTOR pathway.
    Nanjing Liu, Chunmei Yang, Li Yang, Ting Li, Maoyuan Gong, Haobiao Wang, Jun Zhang, Hui Zhao, Lin Zou, Xiaoyan He.
      Neuroblastoma (NB) is one of the most common malignant solid tumors in children. Despite significant advances in the treatment strategy, the long-term survival rate of NB patients is only 50%. Developing new agents for NB patients deserves attention. Recent research indicates that matrine, a natural quinolizidine alkaloid component extracted from the traditional Chinese medicine Sophora root, is widely used for various diseases, including antitumor effects against a variety of cancers. However, the effect of matrine on NB is unknown. Herein, we found that matrine exerted antiproliferative activity in human NB cells in dose- and time-dependent manner. Matrine triggered autophagy in NB cells by blocking the AKT-mTOR signaling pathway and suppressing the phosphorylation of AKT and mTOR. 3-Methyladenine (3-MA), a PI3K inhibitor, protected against matrine-induced inhibition of cell proliferation, further supporting that the antitumor activity of matrine was at least partly autophagy-dependent. In vivo, matrine reduced tumor growth of SK-N-DZ cells in a dose-dependent manner. Matrine treatment significantly declined the phosphorylation of AKT and mTOR and enhanced the LC3 II/GAPDH ratio in NB xenografts. Altogether, our work uncovered the molecular mechanism underlying matrine-induced autophagy in NB and provided implications for matrine as a potential therapeutic agent against NB.
    Keywords:  Autophagy; Cell proliferation; Matrine; Neuroblastoma
    DOI:  https://doi.org/10.1007/s12032-022-01762-4
  40. ACS Omega. 2022 Aug 09. 7(31): 27004-27020
    Green Route Synthesis and Characterization Techniques of Silver Nanoparticles and Their Biological Adeptness.
    Nitin Kumar Sharma, Jyotsna Vishwakarma, Summi Rai, Taghrid S Alomar, Najla AlMasoud, Ajaya Bhattarai.
      The development of the most reliable and green techniques for nanoparticle synthesis is an emerging step in the area of green nanotechnology. Many conventional approaches used for nanoparticle (NP) synthesis are expensive, deadly, and nonenvironmental. In this new era of nanotechnology, to overcome such concerns, natural sources which work as capping and reducing agents, including bacteria, fungi, biopolymers, and plants, are suitable candidates for synthesizing AgNPs. The surface morphology and applications of AgNPs are significantly pretentious to the experimental conditions by which they are synthesized. Available scattered information on the synthesis of AgNPs comprises the influence of altered constraints and characterization methods such as FTIR, UV-vis, DLS, SEM, TEM, XRD, EDX, etc. and their properties and applications. This review focuses on all the above-mentioned natural sources that have been used for AgNP synthesis recently. The green routes to synthesize AgNPs have established effective applications in various areas, including biosensors, magnetic resonance imaging (MRI), cancer treatment, surface-enhanced Raman spectroscopy (SERS), antimicrobial agents, drug delivery, gene therapy, DNA analysis, etc. The existing boundaries and prospects for metal nanoparticle synthesis by the green route are also discussed herein.
    DOI:  https://doi.org/10.1021/acsomega.2c01400
  41. J Cancer Res Clin Oncol. 2022 Aug 17.
    Triple negative breast cancer: approved treatment options and their mechanisms of action.
    Aditya Mandapati, Kiven Erique Lukong.
       PURPOSE: Breast cancer, the most prevalent cancer worldwide, consists of 4 main subtypes, namely, Luminal A, Luminal B, HER2-positive, and Triple-negative breast cancer (TNBC). Triple-negative breast tumors, which do not express estrogen, progesterone, and HER2 receptors, account for approximately 15-20% of breast cancer cases. The lack of traditional receptor targets contributes to the heterogenous, aggressive, and refractory nature of these tumors, resulting in limited therapeutic strategies.
    METHODS: Chemotherapeutics such as taxanes and anthracyclines have been the traditional go to treatment regimens for TNBC patients. Paclitaxel, docetaxel, doxorubicin, and epirubicin have been longstanding, Food and Drug Administration (FDA)-approved therapies against TNBC. Additionally, the FDA approved PARP inhibitors such as olaparib and atezolizumab to be used in combination with chemotherapies, primarily to improve their efficiency and reduce adverse patient outcomes. The immunotherapeutic Keytruda was the latest addition to the FDA-approved list of drugs used to treat TNBC.
    RESULTS: The following review aims to elucidate current FDA-approved therapeutics and their mechanisms of action, shedding a light on the various strategies currently used to circumvent the treatment-resistant nature of TNBC cases.
    CONCLUSION: The recent approval and use of therapies such as Trodelvy, olaparib and Keytruda has its roots in the development of an understanding of signaling pathways that drive tumour growth. In the future, the emergence of novel drug delivery methods may help increase the efficiency of these therapies whiel also reducing adverse side effects.
    Keywords:  Atezolizumab; BRCA1 and BRCA2; Breast cancer; Doxorubicin; ER; Epirubicin chemotherapy; HER2; Immunotherapy; Keytruda; Olabarib; PARP inhibitors; TNBC; Taxol
    DOI:  https://doi.org/10.1007/s00432-022-04189-6
  42. Int J Biol Macromol. 2022 Aug 10. pii: S0141-8130(22)01728-7. [Epub ahead of print]219 835-843
    Reactive oxygen species scavenging nanofibers with chitosan-stabilized Prussian blue nanoparticles for enhanced wound healing efficacy.
    Hyeryeon Oh, Dongwan Son, Jin Sil Lee, Myungwoong Kim, Daekyung Sung, Hoik Lee, Won Il Choi.
      Chronic inflammatory wounds pose therapeutic challenges in the biomedical field. Polymeric nanofibrous matrices provide extracellular-matrix-like structures to facilitate wound healing; however, wound infection and the subsequent accumulation of reactive oxygen species (ROS) delay healing. Therefore, we herein developed electrospun nanofibers (NFs), composed of chitosan-stabilized Prussian blue (PBChi) nanoparticles (NPs) and poly(vinyl alcohol) (PVA), with ROS scavenging activity to impart antioxidant and wound healing properties. The PBChi NPs were prepared using chitosan with different molecular weights, and their weight ratio with respect to PVA was optimized to yield PBChi-NP-coated PVA NFs with well-defined NF structures. In situ and in vitro antioxidant activity assays showed that the PBChi/PVA NFs could effectively remove ROS. Particularly, PBChi/PVA NFs with a lower chitosan molecular weight exhibited greater antioxidant activity. The hydroxyl radical scavenging activity of PBChi10k/PVA NFs was 60.4 %, approximately two-fold higher than that of PBChi100k/PVA NFs. Further, at the concentration of 10 μg/mL, they could significantly lower the in vitro ROS level by up to 50.7 %. The NFs caused no significant reduction in cell viability, owing to the excellent biocompatibility of PVA with PBChi NPs. Treatment using PBChi/PVA NFs led to faster cell proliferation in in vitro scratch wounds, reducing their size from 202 to 162 μm. The PBChi/PVA NFs possess notable antioxidant and cell proliferation properties as ROS-scavenging wound dressings.
    Keywords:  Chitosan; Electrospinning; Nanofiber; Prussian blue; Reactive oxygen species scavenging; Wound healing
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.08.033
  43. Am J Cancer Res. 2022 ;12(7): 3357-3372
    Gentian violet induces apoptosis and ferroptosis via modulating p53 and MDM2 in hepatocellular carcinoma.
    Jingyi Chen, Fangxin Zhao, Hongxin Yang, Jianxun Wen, Ying Tang, Fang Wan, Xuan Zhang, Jianqiang Wu.
      Hepatocellular carcinoma (HCC) is the fifth most common malignancies with limited curative options and poor prognosis. Gentian violet (GV) has recently been found to have anti-tumor properties with promising clinical applications. However, its anti-tumor effect and the underlying functional mechanisms in HCC have not been investigated. In this study, we found that GV induced ferroptosis and apoptosis, inhibited cell proliferation, migration and invasion in a dose-dependent manner in vitro, and significantly attenuated the growth of HCC in vivo. Both ferroptosis inhibitor Ferrostain-1 (Fer-1) and apoptosis inhibitor Z-VAD-KFM (Z-VAD) partially attenuated GV-induced growth-inhibitory effects, while combined treatment of Fer-1 and Z-VAD completely abolished GV's activities. Increased levels of intracellular reactive oxygen species (ROS) were detected after GV treatment. Interestingly, GV elevated the expression levels of both p53 and its negative regulator MDM2, which was dependent on the expression of the dehydrogenase/reductase protein Hep27. Simultaneously silencing both the MDM2 and p53 genes by siRNAs abolished ROS production and partially rescued the cell death induced by GV treatment. Our data demonstrate a GV-Hep27-MDM2-p53 signaling cascade that regulates ferroptosis and apoptosis. Furthermore, our findings provide insights into understanding the anti-tumor function of GV and present the basis of new therapeutic strategies for the treatment of HCC.
    Keywords:  Gentian violet; MDM2; ferroptosis; hepatocellular carcinoma; p53
  44. Anticancer Agents Med Chem. 2022 Aug 19.
    A Molecular Approach Of The Caloric Restriction And Vitamins For Cancer Prevention.
    Carmen Rubio, Fernando Gatica, Paola Rodríguez-Quintero, Zayra Morales, Héctor Romo-Parra.
      Each year, cancer claims the lives of around 10.0 million people around the world. Food components have been shown to alter numerous particular intracellular signaling events that frequently go awry during carcinogenesis. Many studies suggest that dietary behaviors involving the consumption of antioxidant-rich foods, as well as caloric restriction, may play an important role in cancer prevention. Gene expression patterns, such as genetic polymorphisms, can influence the response to food components by altering their specific action on targets, as well as absorption, metabolism, and distribution, among other things. This review discusses two significant cancer prevention techniques: a vitamin-rich diet and caloric restriction. It also discusses the possible molecular interactions between the two dietary strategies and the first clues of a probable synergy that would come from combining caloric restriction with antioxidant use. Caloric restriction diets have positive effects on life expectancy and the avoidance of age-related illnesses. As a result, this manuscript is based on the degenerative nature of cancer and intends to shed light on the biochemical features of not just calorie restriction but also vitamins. Both are thought to have an effect on oxidative stress, autophagy, and signaling pathways involved in energy metabolism and mitochondrial functions.
    Keywords:  Antioxidants; Caloric Restriction; Cancer Prevention; Diet; Vitamins
    DOI:  https://doi.org/10.2174/1871520622666220819092503
  45. Phytomedicine. 2022 Aug 01. pii: S0944-7113(22)00448-2. [Epub ahead of print]105 154369
    Modulation of diverse oncogenic signaling pathways by oroxylin A: An important strategy for both cancer prevention and treatment.
    Anjana Sajeev, Mangala Hegde, Uzini Devi Daimary, Aviral Kumar, Sosmitha Girisa, Gautam Sethi, Ajaikumar B Kunnumakkara.
       BACKGROUND: Regardless of major advances in diagnosis, prevention and treatment strategies, cancer is still a foreboding cause due to factors like chemoresistance, radioresistance, adverse side effects and cancer recurrence. Therefore, continuous development of unconventional approaches is a prerequisite to overcome foregoing glitches. Natural products have found their way into treatment of serious health conditions, including cancer since ancient times. The compound oroxylin A (OA) is one among those with enormous potential against different malignancies. It is a flavonoid obtained from the several plants such as Oroxylum indicum, Scutellaria baicalensis and S. lateriflora, Anchietea pyrifolia, and Aster himalaicus.
    PURPOSE: The main purpose of this study is to comprehensively elucidate the anticancerous effects of OA against various malignancies and unravel their chemosensitization and radiosensitization potential. Pharmacokinetic and pharmacodynamic studies of OA have also been investigated.
    METHOD: The literature on antineoplastic effects of OA was searched in PubMed and Scopus, including in vitro and in vivo studies and is summarized based on a systematic review protocol prepared according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The term "oroxylin A" was used in combination with "cancer" and all the title, abstracts and keywords appeared were considered.
    RESULTS: In Scopus, a total of 157 articles appeared out of which 103 articles that did not meet the eligibility criteria were eliminated and 54 were critically evaluated. In PubMed, from the 85 results obtained, 26 articles were eliminated and 59 were included in the preparation of this review. Mounting number of studies have illustrated the anticancer effects of OA, and its mechanism of action.
    CONCLUSION: OA is a promising natural flavonoid possessing wide range of pleiotropic properties and is a potential anticancer agent. It has a great potential in the treatment of multiple cancers including brain, breast, cervical, colon, esophageal, gall bladder, gastric, hematological, liver, lung, oral, ovarian, pancreatic and skin. However, lack of pharmacokinetic studies, toxicity assessments, and dose standardization studies and adverse effects limit the optimization of this compound as a therapeutic agent.
    Keywords:  Cancer; Chemosensitization; Molecular mechanism; Oroxylin A; Oroxylum indicum; Pharmacokinetics
    DOI:  https://doi.org/10.1016/j.phymed.2022.154369
  46. Chemosphere. 2022 Aug 16. pii: S0045-6535(22)02513-9. [Epub ahead of print] 136020
    Multifaceted role of polyphenols in the treatment and management of neurodegenerative diseases.
    Fahadul Islam, Md Mohaimenul Islam, Atkia Farzana Khan Meem, Mohamed H Nafady, Md Rezaul Islam, Aklima Akter, Saikat Mitra, Fahad A Alhumaydhi, Talha Bin Emran, Ameer Khusro, Jesus Simal-Gandara, Aziz Eftekhari, Fatemeh Karimi, Mehdi Baghayeri.
      Neurodegenerative diseases (NDDs) are conditions that cause neuron structure and/or function to deteriorate over time. Genetic alterations may be responsible for several NDDs. However, a multitude of physiological systems can trigger neurodegeneration. Several NDDs, such as Huntington's, Parkinson's, and Alzheimer's, are assigned to oxidative stress (OS). Low concentrations of reactive oxygen and nitrogen species are crucial for maintaining normal brain activities, as their increasing concentrations can promote neural apoptosis. OS-mediated neurodegeneration has been linked to several factors, including notable dysfunction of mitochondria, excitotoxicity, and Ca2+ stress. However, synthetic drugs are commonly utilized to treat most NDDs, and these treatments have been known to have side effects during treatment. According to providing empirical evidence, studies have discovered many occurring natural components in plants used to treat NDDs. Polyphenols are often safer and have lesser side effects. As, epigallocatechin-3-gallate, resveratrol, curcumin, quercetin, celastrol, berberine, genistein, and luteolin have p-values less than 0.05, so they are typically considered to be statistically significant. These polyphenols could be a choice of interest as therapeutics for NDDs. This review highlighted to discusses the putative effectiveness of polyphenols against the most prevalent NDDs.
    Keywords:  Nanoformulations; Neurodegeneration; Neuroprotection; Oxidative stress; Polyphenols
    DOI:  https://doi.org/10.1016/j.chemosphere.2022.136020
  47. Curr Pharm Biotechnol. 2022 Aug 18.
    Research progress in elucidating the mechanisms underlying resveratrol action on lung cancer.
    Rui Xin, Biao Shen, Zhong-Yan Huang, Ji-Bin Liu, Sha Li, Geng-Xi Jiang, Jie Zhang, Ya-Hong Cao, Da-Zhi Zou, Wen Li, Chun-Guang Li, Yu-Shui Ma, Da Fu.
      Resveratrol has several functions, including protection of the heart and nervous system and exerts antidiabetic, anti-inflammatory, anti-aging, and antitumor effects. It is reported to impede the occurrence and development of tumors in cancer cell lines, animal models, and clinical studies. In vitro and in vivo experiments show that it exerts preventive or adjuvant therapeutic effects in pancreatic, colorectal, prostate, liver, and lung cancers. Mechanistic research reports show that resveratrol can induce tumor cell apoptosis and autophagy, inhibit cell cycle and angiogenesis, regulate nuclear factors and cyclooxygenase signal transduction pathways, and inhibit carcinogens' metabolic activation and alter tumor-related expression patterns; anti-oxidation affects tumor cell proliferation, metastasis, and apoptosis. However, the exact mechanism underlying its action remains unclear. This review highlights multiple aspects of the biological impacts and mechanisms underlying resveratrol action on the occurrence and development of lung cancer.
    Keywords:  anti-tumor activity; development; lung cancer; occurrence; resveratrol; treatment
    DOI:  https://doi.org/10.2174/1389201023666220818085945
  48. Theranostics. 2022 ;12(13): 5691-5709
    Conquering oncogenic KRAS and its bypass mechanisms.
    Pingping Hou, Y Alan Wang.
      Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors. Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities. Yet, no matter how a cancer is addicted to a specific target - cancer's genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions. Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.
    Keywords:  KRAS; MEK; RAF; cancer; targeted therapy resistance
    DOI:  https://doi.org/10.7150/thno.71260
  49. Int J Pharm. 2022 Aug 11. pii: S0378-5173(22)00617-2. [Epub ahead of print] 122063
    Synthesis and preparation of vitamin A coupled butein-loaded solid lipid nanoparticles for liver fibrosis therapy in rats.
    Somayeh Mahdinloo, Salar Hemmati, Hadi Valizadeh, Mohammad Mahmoudian, Javad Mahmoudi, Leyla Roshangar, Muhammad Sarfraz, Parvin Zakeri-Milani.
      The development of a therapeutic system for hepatic fibrosis has become a research hotspot to date. Butein, a simple chalcone derivative, displays anti-fibrotic effects through different pathways. However, impurities, low solubility, and low concentration in the target tissue hinder therapy with herbal ingredients. Hepatic stellate cells (HSCs), the vitamin A (VA) storage cells, as the main contributors to liver fibrogenesis, are not readily accessible to drugs owing to their anatomical location. Targeted delivery of therapeutics to the activated HSCs is therefore critical for successful treatment. For these reasons, the current study aimed at increasing butein delivery to the liver. Hence, high purity butein was synthesized in three steps. A novel VA-Myrj52 ester conjugate was also synthesized using all-trans retinoic acid and a hydrophilic emulsifier (Myrj52) as a targeting agent. Next, butein was encapsulated inside the novel VA-modified solid lipid nanoparticles (VA-SLNs) and studied in vitro and in vivo. According to our evaluations, negatively charged SLNs with a mean diameter of 150 nm and entrapment efficacy of 75% were successful in liver fibrosis amelioration. Intraperitoneal (i.p.) injection of VA-SLNs in fibrotic rats, for four weeks long, reduced serum AST and ALT by 58% (P, 0.001) and 72% (P, 0.05), respectively, concerning the CCl4 group. Additionally, histologic damage score decline and normalization of tissue oxidative stress markers collectively confirmed the efficacy of formulations in hepatic fibrosis and kidney damage amelioration.
    Keywords:  Butein; Liver fibrosis; Solid lipid nanoparticle; Targeted therapy; Vitamin A
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122063
  50. Mol Oncol. 2022 Aug 06.
    Sphingosine-1-phosphate-lyase deficiency affects glucose metabolism in a way that abets oncogenesis.
    Sumaiya Y Afsar, Shah Alam, Carina Fernandez Gonzalez, Gerhild van Echten-Deckert.
      Sphingosine-1-phosphate (S1P), a bioactive signaling lipid, is involved in several vital processes, including cellular proliferation, survival and migration, as well as neovascularization and inflammation. Its critical role in the development and progression of cancer is well documented. The metabolism of S1P, which exerts its effect mainly via five G protein-coupled receptors (S1PR1-5 ), is tightly regulated. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism and exhibits remarkably decreased enzymatic activity in tumor samples. In this study, we used SGPL1-deficient (Sgpl1-/- ) mouse embryonic fibroblasts (MEFs) and investigated the impact of S1P on glucose metabolism. Accumulated S1P activates, via its receptors (S1PR1-3 ), hypoxia-inducible factor 1 and stimulates the expression of proteins involved in glucose uptake and breakdown, indicating that Sgpl1-/- cells, like cancer cells, prefer to convert glucose to lactate even in the presence of oxygen. Accordingly, their rate of proliferation is significantly increased. Activation of the Akt/mTOR pathway and hence down-regulation of autophagy indicate that these changes do not negatively affect the cellular energy status. In summary, we report on a newly identified role of the S1P/S1PR1-3 axis in glucose metabolism in SGPL1-deficient MEFs.
    Keywords:  HIF-1; S1P-lyase; aerobic glycolysis; autophagy; cancer; sphingosine-1-phosphate
    DOI:  https://doi.org/10.1002/1878-0261.13300
  51. Curr Top Med Chem. 2022 Aug 18.
    Nanogel-Based Transdermal Drug Delivery System: A Therapeutic Strategy with Under Discussed Potential.
    Lubna Tariq, Azher Arafah, Shafat Ali, Saba Beigh, Mashooq Ahmad Dar, Tanvir Ul Hassan Dar, Aqib Iqbal Dar, Rana M Alsaffar, Mubashir Hussain Masoodi, Muneeb U Rehman.
      The application of nanoparticles in medication delivery has revolutionized the field of therapeutic biology. To improve medical efficacy, currently, drug nanocarriers are employed to control the release and stability, expand its circulation time, or protect it from cell clearance or premature breakdown. A crosslinked polymeric framework is used to crosslink the hydrogel nanoparticle dispersions for safer and stable delivery on target sites. Nanogels have developed in the last two decades as potential biomaterials with a wide variety of applications. Later attributes of nanogels are mainly due to large surface areas, retention of molecules, size flexibility, and water-based formulations that have made them popular as drug delivery vehicles, as seen by several in vivo uses. The gel matrix containing the nanoparticle drug demonstrated a considerable increase in drug penetration in transdermal drug and topical delivery methods. This review aims to understand why and how nanogels are considered so innovative as a drug delivery method. It also examines their preparation methods and applications in the pharmaceutical and biomedical fields and discusses the benefits of nanogels, including swelling capacity and stimulus stimuli sensitivity. Nanogels, on the other hand, have recently been investigated for applications outside the field of biomedicine. Since there are many possible uses for nanogels, we have comprehensively reviewed the current state of the art for all feasible nanogel applications and manufacturing methods.
    Keywords:  Gel matrix; Hydrogels; Nanogels; Nanotechnology; Therapeutics; Transdermal drug delivery system
    DOI:  https://doi.org/10.2174/1568026622666220818112728
  52. Front Oncol. 2022 ;12 926437
    Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor-resistant pancreatic ductal adenocarcinoma.
    Parmanand Malvi, Vipin Rawat, Romi Gupta, Narendra Wajapeyee.
      Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.
    Keywords:  LDHA; cancer metabolism; chromatin accessibility; metabolomics; transcriptomics
    DOI:  https://doi.org/10.3389/fonc.2022.926437
  53. Int J Nanomedicine. 2022 ;17 3583-3599
    Cucumber-Derived Nanovesicles Containing Cucurbitacin B for Non-Small Cell Lung Cancer Therapy.
    Tingting Chen, Bingxiang Ma, Shi Lu, Lupeng Zeng, Huaying Wang, Wanhua Shi, Linying Zhou, Yaokun Xia, Xi Zhang, Jing Zhang, Jinghua Chen.
       Purpose: In recent years, a variety of nanoparticles with excellent anticancer and delivery properties have emerged for cancer therapy. However, potential toxicity, high production cost and complex preparation procedures have been obstacles to their use in biomedicine. Here, we obtained cucumber-derived nanovesicles (CDNVs) at high yield and low cost by simple juicing and ultracentrifugation. The anticancer effects of CDNVs were evaluated in vitro and in vivo.
    Methods: Transmission electron microscope, nanoparticle tracking analysis and laser particle size analysis were used to characterize the morphology, diameter and zeta potential of CDNVs, respectively. The anticancer effects of CDNVs in vitro were evaluated by MTT and apoptosis assays. The mechanism was further explored by measuring the protein levels of signal transducer and activator of transcription 3 pathway, reactive oxygen species, cell cycle distribution and caspase activity. In-vivo anticancer efficacy was evaluated by measuring tumor volume and weight of mice in three different treatment groups (CDNVs, cucurbitacin B and PBS).
    Results: CDNVs inhibited proliferation of human non-small cell lung cancer cells by suppressing signal transducer and activator of transcription 3 activation, generating reactive oxygen species, promoting cell cycle arrest, and activating the caspase pathway. These CDNVs exhibited strong anticancer effects both in vitro and in vivo, and reduced the rate of tumor growth without obvious toxicity to mouse visceral organs. Compared with an equivalent dose of cucurbitacin B, CDNVs exerted stronger anticancer effects in vitro and in vivo.
    Conclusion: These results demonstrate that CDNVs suppress tumor growth. This study addresses the development of cancer therapeutic drugs using plant-derived nanovesicles that are cost-efficient, simple to produce in high yields, and provide an alternative approach to drug isolation that may help advance sustainability of medicinal plants.
    Keywords:  ROS; STAT3; anticancer; cucurbitacin B
    DOI:  https://doi.org/10.2147/IJN.S362244
  54. Front Immunol. 2022 ;13 936967
    Research progress on the role of PKM2 in the immune response.
    Chunyan Liu, Chenchen Liu, Rong Fu.
      Pyruvate kinase (PK) is a key enzyme that catalyzes the dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate, and is responsible for the production of ATP during glycolysis. As another important isozyme of PK, pyruvate kinase M2 (PKM2) exists in cells with high levels of nucleic acid synthesis, such as normal proliferating cells (e.g., lymphocytes and intestinal epithelial cells), embryonic cells, adult stem cells, and tumor cells. With further research, PKM2, as an important regulator of cellular pathophysiological activity, has attracted increasing attention in the process of autoimmune response and inflammatory. In this re]view, we examine the contribution of PKM2 to the human immune response. Further studies on the immune mechanisms of PKM2 are expected to provide more new ideas and drug targets for immunotherapy of inflammatory and autoimmune diseases, guiding drug development and disease treatment.
    Keywords:  PKM2; immune response; inflammatory diseases; metabolic reprogramming; proinflammatory cytokines
    DOI:  https://doi.org/10.3389/fimmu.2022.936967
  55. J Drug Target. 2022 Aug 16. 1-35
    Role of exosomes in tumor growth, chemoresistance and immunity: state-of-the-art.
    Seyedeh Maryam Hosseinikhah, Fatemeh Gheybi, Seyedeh Alia Moosavian, Mohammad-Ali Shahbazi, Mahmoud Reza Jaafari, Mika Sillanpää, Prashant Kesharwani, Seyedeh Hoda Alavizadeh, Amirhossein Sahebkar.
      Cancer is one of the most lethal diseases, and limited available treatment options contribute to its high mortality rate. Exosomes are considered membrane-bound nanovesicles that include different molecules such as lipids, proteins, and nucleic acids. Virtually most cells could release exosomes via exocytosis in physiological and pathological conditions. Tumor-derived exosomes (TDEs) play essential roles in tumorigenesis, proliferation, progression, metastasis, immune escape, and chemoresistance by transferring functional biological cargos, triggering different autocrine, and paracrine signaling cascades. Due to their antigen-presenting properties, exosomes are widely used as biomarkers and drug carriers and have a prominent role in cancer immunotherapy. They offer various advantages in carrier systems (e.g., in chemotherapy, siRNA, and miRNA), delivery of diagnostic agents owing to their stability, loading of hydrophobic and hydrophilic agents, and drug targeting. Novel exosomes-based carriers can be generated as intelligent systems using various sources and crosslinking chemistry extracellular vesicles (EVs). Exosomes studded with targeting ligands, including peptides, can impart in targeted delivery of cargos to tumor cells. In this review, we comprehensively summarized the important role of tumor-derived exosomes in dictating cancer pathogenesis and resistance to therapy. We have therefore, investigated in further detail the pivotal role of tumor-derived exosomes in targeting various cancer cells and their applications, and prospects in cancer therapy and diagnosis. Additionally, we have implicated the potential utility and significance of tumor exosomes-based nanoparticles as an efficient and novel therapeutic carrier and their applications in treating advanced cancers.
    Keywords:  Chemoresistance; Diagnosis; Drug delivery; Immunomodulation; Tumor-derived exosomes
    DOI:  https://doi.org/10.1080/1061186X.2022.2114000
  56. Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2210504119
    Photoredox catalysis may be a general mechanism in photodynamic therapy.
    Mingle Li, Yunjie Xu, Zhongji Pu, Tao Xiong, Haiqiao Huang, Saran Long, Subin Son, Le Yu, Nem Singh, Yunkang Tong, Jonathan L Sessler, Xiaojun Peng, Jong Seung Kim.
      Elucidating the underlying photochemical mechanisms of action (MoA) of photodynamic therapy (PDT) may allow its efficacy to be improved and could set the stage for the development of new classes of PDT photosensitizers. Here, we provide evidence that "photoredox catalysis in cells," wherein key electron transport pathways are disrupted, could constitute a general MoA associated with PDT. Taking the cellular electron donor nicotinamide adenine dinucleotide as an example, we have found that well-known photosensitizers, such as Rose Bengal, BODIPY, phenoselenazinium, phthalocyanine, and porphyrin derivatives, are able to catalyze its conversion to NAD+. This MoA stands in contrast to conventional type I and type II photoactivation mechanisms involving electron and energy transfer, respectively. A newly designed molecular targeting photocatalyst (termed CatER) was designed to test the utility of this mechanism-based approach to photosensitizer development. Photoexcitation of CatER induces cell pyroptosis via the caspase 3/GSDME pathway. Specific epidermal growth factor receptor positive cancer cell recognition, high signal-to-background ratio tumor imaging (SBRTI = 12.2), and good tumor growth inhibition (TGI = 77.1%) are all hallmarks of CatER. CatER thus constitutes an effective near-infrared pyroptotic cell death photo-inducer. We believe the present results will provide the foundation for the synthesis of yet-improved phototherapeutic agents that incorporate photocatalytic chemistry into their molecular design.
    Keywords:  NADH; photodynamic therapy; photoredox catalysis; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2210504119
  57. Drug Deliv. 2022 Dec;29(1): 2713-2722
    Intraperitoneal administration of thermosensitive hydrogel Co-loaded with norcantharidin nanoparticles and oxaliplatin inhibits malignant ascites of hepatocellular carcinoma.
    Susu Xiao, Yu Wang, Wenqiong Ma, Ping Zhou, Biqiong Wang, Zhouxue Wu, Qian Wen, Kang Xiong, Yanlin Liu, Shaozhi Fu.
      Malignant ascites is a common complication of some advanced cancers. Although intraperitoneal (IP) administration of chemotherapy drugs is routinely used to treat cancerous ascites, conventional drugs have poor retention and therefore need to be administered frequently to maintain a sustained anti-tumor effect. In this study, a thermosensitive hydrogel composite loaded with norethindrone nanoparticles (NPs) and oxaliplatin (N/O/Hydrogel) was developed to inhibit ascites of hepatocellular carcinoma (HCC) through IP injection. N/O/Hydrogel induced apoptosis in the H22 cells in vitro, and significantly inhibited ascites formation, tumor cell proliferation and micro-angiogenesis in a mouse model of advanced HCC with ascites, and prolonged the survival of tumor-bearing mice. Histological examination of the major organs indicated that the hydrogel system is safe. Taken together, the N/O/Hydrogel system is a promising platform for in-situ chemotherapy of malignant ascites.
    Keywords:  Thermosensitive hydrogel; hepatocellular carcinoma; malignant ascites; nanoparticles; norcantharidin; oxaliplatin
    DOI:  https://doi.org/10.1080/10717544.2022.2111480
  58. Int J Nanomedicine. 2022 ;17 3497-3507
    Ionizing Radiation-Induced Ferroptosis Based on Nanomaterials.
    Shenghong Zhang, Jiajia Zhang, Xin Fan, Hanhui Liu, Mengqin Zhu, Mengdie Yang, Xiaoyi Zhang, Han Zhang, Fei Yu.
      Ferroptosis is an iron-dependent form of regulated cell death (RCD), that is associated with peroxidative damage to cellular membranes. A promising therapeutic method is to target ferroptosis. Nanomaterial-induced ferroptosis attracts enormous attention. Nevertheless, there are still certain shortcomings in ferroptosis, such as inadequate triggered immunogenic cell death to suit clinical demands. Various investigations have indicated that ionizing radiation (IR) can further induce ferroptosis. Consequently, it is a potential strategy for cancer therapy that combines nanomaterials and IR to induce ferroptosis. Initially, we discuss various ferroptosis inducers based on nanomaterials in this review. Furthermore, mechanisms of IR-induced ferroptosis are briefly introduced. Ultimately, we assess the feasibility of combining nanomaterials with IR to induce ferroptosis, paving the way for future research.
    Keywords:  ROS; combined therapy; lipid peroxidation; nanoparticles; radiation therapy
    DOI:  https://doi.org/10.2147/IJN.S372947
  59. Am J Cancer Res. 2022 ;12(7): 2897-2919
    Exploring the anticancer activities of novel bioactive compounds derived from endophytic fungi: mechanisms of action, current challenges and future perspectives.
    Rubina Kousar, Muhammad Naeem, Mohamad Ikhwan Jamaludin, Ammara Arshad, Aisyah Nazirah Shamsuri, Nelofar Ansari, Samreen Akhtar, Abu Hazafa, Jalal Uddin, Ajmal Khan, Ahmed Al-Harrasi.
      Cancer is the second leading cause of death all around the world. The natural compounds derived from the endophytic flora of fungi are possible solutions to cancer treatment because they are safe for health, cost-effective, biocompatible and have fewer toxicity issues. The active ingredients in endophytic fungi that are responsible for anti-cancer activities are alkaloids, terpenoids, glycosides, saponin, peptides, steroids, phenols, quinones, and flavonoids. This review highlights the anti-cancer activities of entophytic fungus against human papillary thyroid carcinoma (IHH4), human pancreatic (PANC-1), ovarian (OVCAR-3), hepatic (HepG2), lung (A-549), human lymphoma (U937), human skin carcinoma (A431), breast (MCF-7), and Kaposi's sarcoma. The emerging evidence suggested that bioactive compounds isolated from endophytic fungi showed their anti-cancer activities by revealing the disturbance of the microtubule network caused by increased levels of Bax and Bcl-2 proteins that triggers cell cycle arrest at the G2-M phase, by inhibiting the DNA replication via binding with topoisomerase II, by regulating the activity of extracellular signal-regulated kinase and NF-kB, by evaluating the levels of p21, p27, and cyclins B/D1/E that led to cell death by apoptosis and cell cycle arrest. This review will assist readers in better comprehending bioactive chemicals and the beneficial interaction between the fungal endophytes and medicinal plants.
    Keywords:  Endophyte fungi; anti-tumor; apoptosis; bioactive compounds; cancer; cell cycle arrest; signalling pathways; treatment
  60. Biochem Pharmacol. 2022 Aug 16. pii: S0006-2952(22)00307-0. [Epub ahead of print] 115213
    Physiopathological Mechanisms Involved In The Development Of Hypertension Associated With Gut Dysbiosis And The Effect Of Nutritional/Pharmacological Interventions.
    Virna Margarita Martín Giménez, Natalia Lucía Rukavina Mikusic, Hyun Jin Lee, Sebastián García Menéndez, Marcelo Roberto Choi, Walter Manucha.
      The gut microbiota dysbiosis represents a triggering factor for cardiovascular diseases, including hypertension. In addition to the harmful impact caused by hypertension on different target organs, gut dysbiosis is capable of causing direct damage to critical organs such as the brain, heart, blood vessels, and kidneys. In this sense, it should be noted that pharmacological and nutritional interventions may influence gut microbiota composition, either inducing or preventing the development of hypertension. Some of the most important nutritional interventions at this level are represented by pro-, pre-, post- and/or syn-biotics, as well as polysaccharides, polyunsaturated fatty acids ω-3, polyphenols and fiber contained in different foods. Meanwhile, certain natural and synthetic active pharmaceutical ingredients, including antibiotics, antihypertensive and immunosuppressive drugs, vegetable extracts and vitamins, may also have a key role in the modulation of both gut microbiota and cardiovascular health. Additionally, gut microbiota may influence drugs and food-derived bioactive compounds metabolism, positively or negatively affecting their biological behavior facing established hypertension. The understanding of the complex interactions between gut microbiome and drug/food response results of great importance to developing improved pharmacological therapies for hypertension prevention and treatment. The purpose of this review is to critically outline the most relevant and recent findings on cardiovascular, renal and brain physiopathological mechanisms involved in the development of hypertension associated with changes in gut microbiota, besides the nutritional and pharmacological interventions potentially valuable for the prevention and treatment of this prevalent pathology. Finally, harmful food/drug interventions on gut microbiota are also described.
    Keywords:  cardiovascular disease; gut microbiota dysbiosis; hypertension; inflammation; nutrition; pharmacological intervention
    DOI:  https://doi.org/10.1016/j.bcp.2022.115213
  61. Phytochem Rev. 2022 Aug 11. 1-31
    Phytochemistry and pharmacology of sea buckthorn (Elaeagnus rhamnoides; syn. Hippophae rhamnoides): progress from 2010 to 2021.
    Jerzy Żuchowski.
      Sea buckthorn (Elaeagnus rhamnoides; syn. Hippophae rhamnoides) is a thorny shrub or a small tree belonging to the Elaeagnaceae family, native to Eurasia. Sea buckthorn fruit is rich in vitamins and minerals, oils from the seeds and fruit flesh find use in medicine and the cosmetic industry or as nutraceutical supplements. Fruit, leaves and other parts of buckthorn have been used in traditional medicine, especially in China, Tibet, Mongolia, and Central Asia countries, and are a rich source of many bioactive substances. Due to its health-promoting and medicinal properties, the plant has been extensively investigated for several decades, and its phytochemical composition and pharmacological properties are well characterized. The years 2010-2021 brought significant progress in phytochemical research on sea buckthorn. Dozens of new compounds, mainly phenolics, were isolated from this plant. Numerous pharmacological studies were also performed, investigating diverse aspects of the biological activity of different extracts and natural products from sea buckthorn. This review focuses on the progress in research on sea buckthorn specialized metabolites made in this period. Pharmacological studies on sea buckthorn are also discussed. In addition, biosynthetic pathways of the main groups of these compounds have been shortly described.
    Graphical abstract:
    Keywords:  Elaeagnus rhamnoides; Hippophae rhamnoides; Pharmacology; Phytochemistry; Sea buckthorn
    DOI:  https://doi.org/10.1007/s11101-022-09832-1
  62. FASEB J. 2022 Sep;36(9): e22505
    Curcumin activates Nrf2/HO-1 signaling to relieve diabetic cardiomyopathy injury by reducing ROS in vitro and in vivo.
    Xia Wu, Xueliang Zhou, Songqing Lai, Jichun Liu, Jianwei Qi.
      The hallmark feature of Diabetes mellitus (DM) is hyperglycemia which can lead to excess production of reactive oxygen species (ROS) in the myocardium, contributing to diabetic cardiomyopathy (DCM). Nuclear factor erythroid2-related factor2 (Nrf2), a transcriptional activator, enhances its ability to resist oxidative stress by activating multiple downstream anti-oxidants, anti-inflammatory proteins, and detoxifying enzymes. However, the mechanism of Nrf2 signaling in HG-induced DCM is unclear. In this study, we used HG pretreated H9c2 cells as the experimental basis in vitro, and established a high fat-diet, streptozotocin (STZ) induced Type 2 diabetic rat model in vivo. Meanwhile, we used shRNA-Nrf2 and curcumin (CUR) (as an activator) to affect H9c2 cells, to verify the role of the Nrf2 signaling pathway in DCM. The results showed that the excessive production of ROS caused by HG, which could inhibit the activation of Nrf2-related signaling, resulting in a decrease in cell energy metabolism and an increase in cell apoptosis. Surprisingly, we found that the activation of the Nrf2 signaling pathway significantly increased cardiomyocyte viability, reduced ROS formation, increased antioxidant enzyme activity, and inhibited cardiomyocyte apoptosis. In conclusion, these findings conclusively infer that CUR activation of the Nrf2/HO-1 signaling pathway exerts myocardial protection by reducing ROS formation.
    Keywords:  Nrf2/HO-1 signaling; curcumin; diabetic cardiomyopathy; hyperglycemia; reactive oxygen species
    DOI:  https://doi.org/10.1096/fj.202200543RRR
  63. Curr Med Chem. 2022 Aug 16.
    Chlorogenic acid: A dietary phenolic acid with promising pharmacotherapeutic potential.
    Amit Kumar Singh, Rajeev K Singla, Abhay K Pandey.
      Phenolic acids are now receiving a great deal of interest as pervasive human dietary constituents that have various therapeutic applications against chronic and age-related diseases. One such phenolic acid that is being utilized in traditional medicine is chlorogenic acid (CGA). It is one of the most readily available phytochemicals that can be isolated from the leaves and fruits of plants such as coffee beans (CoffeaarabicaL.), apples (Malus spp.), artichoke (Cynara cardunculus L.), carrots (Daucus carota L.), betel (Piper betle L.), burdock (Arctium spp.) and so on. Despite its low oral bioavailability (about 33%), CGA has drawn considerable attention due to its wide range of biological activities and numerous molecular targets.Several studies have reported that the antioxidant and antiinflammatory potential of CGA mainly account for its broad-spectrum pharmacological attributes. CGA has been implicated in exerting beneficial role against dysbiosis by encouraging the growth of beneficial GUT microbes. At biochemical level its therapeutic action is mediated by free radical scavenging efficacy, modulation of glucose and lipid metabolism, down-regulation of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α),interleukin-6 (IL-6), IL-1β, and interferon gamma (IFN-γ), upregulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and inhibition ofthe activity of nuclear factor- κβ (NF-κβ) and thus help inmanagement of diabetes, cardiovascular diseases, neurodegenerative disorder, cancer, hypertension etc. This review highlights the natural sources of CGA, its bioavailability, metabolism, pharmacotherapeutic potential and underlying mechanisms of action for clinical usefulness of CGA in the management of health disorders.
    Keywords:  Anticancer; Chlorogenic acid; Natural product; Neuroprotective; Phenolic acid; caffeic acid
    DOI:  https://doi.org/10.2174/0929867329666220816154634
  64. J Tissue Viability. 2022 Jul 31. pii: S0965-206X(22)00083-3. [Epub ahead of print]
    Evaluation of wound-healing efficiency of a functional Chitosan/Aloe vera hydrogel on the improvement of re-epithelialization in full thickness wound model of rat.
    Jebreil Movaffagh, Majid Khatib, Seddigheh Fazli Bazzaz, Zhila Taherzadeh, Maryam Hashemi, Atieh Seyedian Moghaddam, Seyyed Abbas Tabatabaee, Mohammad Azizzadeh, Nafiseh Jirofti.
       OBJECTIVE: Chitosan-based hydrogels as wound dressings are expected to improve the efficiency of the wound-healing process. Fabrication of the composite structure of Aloe vera and biopolymeric hydrogels has been demonstrated to promote the wound-healing process through protection against a wide spectrum of microbes, and enhanced cell adhesion and differentiation. Therefore, the present study investigates to development of improved CHO/Aloe hydrogel for improving the wound-healing process in an animal model.
    MATERIALS AND METHODS: CHO hydrogel with Aloe was prepared, and its properties were evaluated in terms of viscosity, antibacterial activity, and ints In-vivo wound-healing efficiency in full-thickness wounds of rat models. Physical examination of wound-healing efficiency of CHO/Aleo hydrogel was evaluated by analyzing total wound closure, recovery percentage, and the epiderm thickness of wounds. Histological evaluation was performed using hematoxylin and eosin staining to evaluate the re-epithelialization, inflammatory response, granulation tissue formation, and fibrotic tissue formation.
    RESULTS: The results showed a significantly higher wound-healing rate of the CHO/Aleo group compared to other groups at 3,7,14 days (p < 0.05). After 14 days of treatment, the best healing effect was observed in the CHO/Aleo gel with the highest tissue tension compared with other groups (p < 0.05). Histological findings indicated a significant difference in inflammatory response between control and treatment groups after three days of treatment (p < 0.05). Epidermal thickness was also significantly thicker in the CHO/Aleo gel group than others (p < 0.05).
    CONCLUSION: The present study an improved the effective topical drug-delivery system by CHO/Aloe hydrogel with the potential to reduce inflammation over time, allowing the body to recover more quickly and better re-epithelialization for improving the wound-healing procedures.
    Keywords:  Aloe vera; Chitosan; Histological; Hydrogel; Wound-healing
    DOI:  https://doi.org/10.1016/j.jtv.2022.07.009
  65. ACS Appl Bio Mater. 2022 Aug 17.
    Coating a Self-Assembly Nanoconstruct with a Neutrophil Cell Membrane Enables High Specificity for Triple Negative Breast Cancer Treatment.
    Pallabita Chowdhury, Prashanth Kumar Bhusetty Nagesh, T J Hollingsworth, Meena Jaggi, Subhash Chand Chauhan, Murali Mohan Yallapu.
      Breast cancer is one of the most commonly diagnosed cancers in American women. Triple negative breast cancer is among the most advanced and aggressive forms of breast cancer. Treatment options are limited for such cancers, making chemotherapy a convenient and effective treatment. Although these therapies can reduce morbidity and mortality, it is often followed by systemic side effects or relapse. Nanoparticles (NPs) have been considered for drug delivery approaches due to their ability to target various disease sites. Herein, we aim to develop a biomimetic NP construct (cell membrane-cloaked NPs) that exhibits specific affinity with triple negative breast cancer cells. In this regard, we designed biomimetic supramolecular nanoconstructs composed of a poly(vinyl pyrrolidone)-tannic acid (PVP-TA NPs/ PVT NPs) core and biofunctionalized with neutrophil cell membranes (PVT-NEU NPs). In this study, we have synthesized a PVT-NEU NP construct, characterized it, and evaluated it for improved targeting and therapeutic benefits in in vitro and in vivo models. Analysis of PVT-NEU NPs confirms the presence of the core of PVP-TA NPs coated with activated human neutrophil membranes. The study results confirmed that PVT-NEU NPs demonstrated an enhanced interaction and targeting with the tumor cells, thus improving the therapeutic activity of a model therapeutic agent (paclitaxel). Altogether, this study suggests the potential of biomimetic NPs as a promising therapeutic option for targeted drug delivery for advanced-stage breast cancer and other similar diseased conditions.
    Keywords:  biomimetic nanoparticles; breast cancer treatment; chemotherapy; membrane-cloaked nanoparticles; nanomedicine; nanoparticles; triple negative breast cancer
    DOI:  https://doi.org/10.1021/acsabm.2c00614
  66. Mol Biomed. 2022 Aug 17. 3(1): 26
    Combinatorial therapeutic approaches of photodynamic therapy and immune checkpoint blockade for colon cancer treatment.
    Yang Hao, Chih Kit Chung, Zili Gu, Timo Schomann, Xiaoxu Dong, Ruben V Huis In 't Veld, Marcel G M Camps, Peter Ten Dijke, Ferry A Ossendorp, Luis J Cruz.
      Photodynamic therapy (PDT) has shown impressive therapeutic effects on various types of cancers by reactive oxygen species (ROS) generation and induction of immune responses. However, under certain conditions, the immune responses induced by PDT are not always sufficient to eradicate the remaining tumor cells. On the other hand, the photosensitizer indocyanine green (ICG) can mediate PDT under near-infrared (NIR) illumination, thereby enhancing the penetration depth of the excitation light into the tumor. We found that ICG is rapidly taken up in vitro by colorectal MC38 and CT26 tumor cells and it promotes PDT-mediated cell-killing effects. Our results furthermore revealed that ICG induces immunogenic cell death (ICD), as dendritic cells (DCs) were found to engulf ICG-PDT-treated tumor cells and undergo phenotypic maturation. ICG accumulated in tumors 2 h after administration, as measured by fluorescence and photoacoustic imaging. Considering the advantages of ICG as a photosensitizer, we sought to design a therapy that combines PDT and immune checkpoint blockade to maximize tumor control. To this end, a 25% thermosensitive polymer 407 hydrogel was included as a co-delivery platform for this treatment scheme. NIR-PDT under 808 nm irradiation in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4)/programmed death-ligand 1 (PD-L1) checkpoint blockade prolonged survival rate of colorectal tumor-bearing mice by inducing a series of immune responses, like the phagocytosis of tumor debris by macrophages and DCs, and induction of acute inflammation, leukocyte infiltration, maturation and activation of DCs. Altogether, our work presents a NIR-triggered PDT strategy in combination with immune checkpoint blockade. Compared to a single treatment, the combination treatment increased efficiency to inhibit solid tumor growth and improved the survival rate of tumor-bearing mice.
    Keywords:  Immune checkpoint blockade inhibitors; Immunogenic cell death; Indocyanine green; Photodynamic therapy; Poloxamer 407 (P407) hydrogel
    DOI:  https://doi.org/10.1186/s43556-022-00086-z
  67. Biochem Biophys Res Commun. 2022 Aug 05. pii: S0006-291X(22)01109-3. [Epub ahead of print]625 167-173
    PINK1-dependent and Parkin-independent mitophagy is involved in reprogramming of glycometabolism in pancreatic cancer cells.
    Natsumi Miyazaki, Reika Shiratori, Taichi Oshima, Zhiheng Zhang, Robert Valencia, Joshua Kranrod, Liye Fang, John M Seubert, Kousei Ito, Shigeki Aoki.
      Cancer cells rely on glycolysis to generate ATP for survival. However, inhibiting glycolysis is insufficient for the eradication of cancer cells because glycolysis-suppressed cells undergo metabolic reprogramming toward mitochondrial oxidative phosphorylation. We previously described that upon glycolytic suppression in pancreatic cancer cells, intracellular glycometabolism is shifted toward mitochondrial oxidative phosphorylation in an autophagy-dependent manner for cellular survival. Here, we hypothesized that mitophagy, which selectively degrades mitochondria via autophagy, is involved in mitochondrial activation under metabolic reprogramming. We revealed that glycolytic suppression notably increased mitochondrial membrane potential and mitophagy in a pancreatic cancer cell model (PANC-1). PTEN-induced kinase 1 (PINK1), a ubiquitin kinase that regulates mitophagy in healthy cells, regulated mitochondrial activation through mitophagy by glycolytic suppression. However, Parkin, a ubiquitin ligase regulated by PINK1 in healthy cells to induce mitophagy, was not involved in the PINK1-dependent mitophagy of the cancer glycometabolism. These results imply that cancer cells and healthy cells have different regulatory pieces of machinery for mitophagy, and inhibition of cancer-specific mechanisms may be a potential strategy for cancer therapy targeting metabolic reprogramming.
    Keywords:  Glycometabolism; Mitophagy; PINK1; Pancreatic cancer; Parkin
    DOI:  https://doi.org/10.1016/j.bbrc.2022.08.004
  68. Heliyon. 2022 Aug;8(8): e10071
    Efficacy of methanolic extracts of some medicinal plants on wound healing in diabetic rats.
    Ahmad Z Alsarayreh, Sawsan A Oran, Jumah M Shakhanbeh, Khaled M Khleifat, Yaseen T Al Qaisi, Ibrahim I Alfarrayeh, Ayah M Alkaramseh.
       Background: One of the primary health concerns for diabetes individuals is wounds. The used drugs have several side effects, urging the need for new natural sources for therapeutics.
    Materials and methods: This study was designed to estimate the wound healing potential of the methanolic extract of Globularia arabica and Malva sylvestris leaves and Rhus coriaria fruits. plant extracts were orally administered to the rats to determine their effect on the wound-healing process.
    Results: Plant extracts significantly increased the contraction of the wound in non-diabetic and diabetic rats (P < 0.05) and increased the fibroblast's proliferation and migration resulting in a faster healing process. The plant extracts have no cytotoxic effects. The proliferation assay exhibited the lowest cell mortality after treatment with plant extract.
    Conclusion: These findings may indicate that the methanolic leaf extract of the above plants can be used as new therapeutics for wound healing in diabetic patients.
    Keywords:  Cytotoxicity; Diabetes; Medicinal plants; Wound healing; Wounds
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e10071
  69. Drug Deliv Transl Res. 2022 Aug 17.
    Development of andrographolide-loaded solid lipid nanoparticles for lymphatic targeting: Formulation, optimization, characterization, in vitro, and in vivo evaluation.
    Saurabh Shrivastava, Chanchal Deep Kaur.
      Andrographolide, the primary bioactive constituent of Andrographis paniculata, is a promising natural substance with numerous pharmacotherapy uses. Low water solubility, short half-life, and low permeability necessitate the development of a delivery system that enhances its entrapment efficiency, bioavailability, lymphatic targeting, and by-pass hepatic effect. The andrographolide-loaded solid lipid nanoparticles were fabricated by melt-emulsification and ultrasonication and optimized with Design-Expert software. In the optimal formulation, Glycerol monostearate as the solid lipid and Poloxamer 407 and Span 60 as surfactants were used. Optimum AND-SLN was observed to have a mean particle size, polydispersity index, zeta potential, and entrapment efficiency of 193.84 nm, 0.211, - 22.8 mV, and 83.70% respectively. An optimized formulation was characterized by examining surface morphology, X-ray diffraction, and differential scanning calorimetry. In vitro studies have shown sustained drug release from AND-SLN for up to 24 h. The stability studies showed that there was no significant change in the mean particle size and entrapment efficiency after storage at 4 ± 2 °C and 25 ± 2 °C/60 ± 5% RH. In in vivo pharmacokinetics studies, AND-SLN was found to have enhanced bioavailability and specificity in the spleen and thymus compared to plasma, providing evidence that the formulations could enhance target specificity and bioavailability in comparison to pure drugs. The H&E staining of the liver, spleen, and thymus treated with the AND-SLN revealed no signs of damage histopathologically. Thus, AND-SLN possess a high potential for improved efficacy and are an efficient vehicle for delivering drugs to the lymphatic system.
    Keywords:  Andrographolide; In vivo evaluation; Lymphatic targeting; Nanocarriers; Solid lipid nanoparticles
    DOI:  https://doi.org/10.1007/s13346-022-01230-6
  70. Int J Pharm. 2022 Aug 12. pii: S0378-5173(22)00666-4. [Epub ahead of print] 122112
    D-mannose functionalized MgAl-LDH/Fe-MOF nanocomposite as a new intelligent nanoplatform for MTX and DOX co-drug delivery.
    Malihe Pooresmaeil, Hassan Namazi.
      Commonly the directly administered chemotherapy drugs lack targeting in tumor treatment. Thus, trying to improve cancer treatment efficiency led us to design a new intelligent system for cancer treatment. Considering these, in the current work, at first, the 2-aminoterephthalic acid (NH2-BDC) intercalated layered double hydroxides (MgAl-(NH2-BDC) LDH) were synthesized simply. Afterward, the in situ growth of the iron-based metal-organic frameworks in the presence of MgAl-(NH2-BDC) LDH occurred (MgAl-LDH/Fe-MOF). In the end, the reaction of MgAl-LDH/Fe-MOF with D-mannose (D-Man) achieved the MgAl-LDH/Fe-MOF/D-Man ternary hybrid nanostructure. Scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) analysis confirmed the formation of the monodisperse Fe-MOF with nanosize in the presence of MgAl-LDH. Importantly, methotrexate (MTX) and doxorubicin (DOX) entrapment efficiency reached respectively about 28 wt% and 21% for MgAl-LDH/Fe-MOF/D-Man. The in vitro drug release experiments revealed a higher drug release at pH 5.0 in comparison with pH 7.4 which revealed its promising potential for anticancer drug delivery applications. Bioassay results revealed that the co-drug-loaded MgAl-LDH/Fe-MOF/D-Man has higher cytotoxicity on MDA-MB 231 cells. At last, fluorescence microscopy and flow cytometric analysis confirmed the successful uptake of MgAl-LDH/Fe-MOF/D-Man into MDA-MB 231 cell lines, as well as its bioimaging potential. A survey in the published literature approved that this work is the first report on the evaluation of the MgAl-LDH/Fe-MOF/D-Man for targeted co-delivery of both MTX and DOX. Finally, results collectively demonstrate the importance of the biocompatible MgAl-LDH/Fe-MOF/D-Man as a hopeful candidate for biomedicinal applications from the targeted co-drug delivery and bioimaging potential viewpoints.
    Keywords:  Bioimaging potential; D-mannose; Layered double hydroxides; Metal-organic frameworks; Nanocomposite; Targeted co-drug delivery
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122112
  71. Mini Rev Med Chem. 2022 Aug 16.
    Iridoids as a potential hepatoprotective class - a review.
    Raquel Bridi, Gilsane Lino von Poser, Gabriela de Carvalho Meirelles.
       BACKGROUND: Liver disease rates are gradually increasing over the years, becoming a severe public health problem. The indiscriminate use of drugs associated to a rich fat diet, high consumption of alcoholic beverages, as well as the exposure to viral infections and lipid peroxidative products are considered the chief factors for the development of hepatic disorders. Owing to the absence of reliable hepatoprotective drugs in the therapeutic arsenal, since they present a high incidence of adverse reactions and/or lack of efficacy in some cases, liver diseases are widely treated with medicinal plants. Among them, it can be pointed out those plants producing iridoids, which due to their bitter taste, are believed to be good remedies for the liver. Actually, the hepatoprotective effect of iridoids and extracts, rich in these compounds, has been demonstrated, both in vitro and in vivo.
    OBJECTIVE: This review aims to scrutinize the available literature related to the hepatoprotective activity of iridoids.
    METHOD: The information was obtained from scientific databases (Science Direct, PubMed, Web of Science, Scopus, ACS Publications, Wiley Online Library) until December 2021.
    RESULTS AND CONCLUSION: A total of 63 hepatoprotective iridoids were found, being aucubin, catalpol and picroliv, a mixture of two iridoids, the target of a high number of studies, which evince their protective action face to different hepatotoxic agents and detailed action mechanisms.
    Keywords:  anti-inflammatory; antioxidants; hepatotoxicity; iridoids; oxidative stress
    DOI:  https://doi.org/10.2174/1389557522666220816130158
  72. Front Nutr. 2022 ;9 931060
    Matcha green tea targets the gut-liver axis to alleviate obesity and metabolic disorders induced by a high-fat diet.
    Yuefei Wang, Yueer Yu, Lejia Ding, Ping Xu, Jihong Zhou.
      Obesity induced by a high-fat diet (HFD) is an increasing global health problem, leading to many metabolic syndromes. As the emerging food additive rich in tea polyphenols, theanine, caffeine, and so on, matcha green tea has gained more and more popularity for its outstanding potential in ameliorating metabolic disorders. This study investigated the composition and antioxidant activity of matcha green tea and further explored its effects on gut-liver axis homeostasis in an HFD-induced obese mouse model. Male (7-8 weeks old) C57BL/6J mice were divided into four groups with the following dietary supplementation for 8 weeks: a normal chow diet (NCD), a normal chow diet+1.0% matcha (NCM), a high-fat diet (HFD), and a high-fat diet+1.0% matcha (HFM). The results demonstrated that matcha green tea ameliorated the development of obesity, lipid accumulation, and hepatic steatosis induced by HFD. Subsequently, dietary matcha supplementation restored the alterations in fecal bile acid profile and gut microbial composition. Meanwhile, the levels of mRNA expression in hepatocytes demonstrated that matcha intervention made significant regulatory on the multiple metabolic pathways of hosts involved in glucose, lipid, and bile acid metabolism. These findings present new evidence for matcha green tea as an effective nutritional strategy to mitigate obesity and relevant metabolic disorders through the gut-liver axis.
    Keywords:  bile acid; gut microbiota; metabolic regulation; obesity; tea polyphenols
    DOI:  https://doi.org/10.3389/fnut.2022.931060
  73. Cancer Metastasis Rev. 2022 Aug 19.
    Obesity, cancer risk, and time-restricted eating.
    Manasi Das, Nicholas J G Webster.
      Obesity and the associated metabolic syndrome is considered a pandemic whose prevalence is steadily increasing in many countries worldwide. It is a complex, dynamic, and multifactorial disorder that presages the development of several metabolic, cardiovascular, and neurodegenerative diseases, and increases the risk of cancer. In patients with newly diagnosed cancer, obesity worsens prognosis, increasing the risk of recurrence and decreasing survival. The multiple negative effects of obesity on cancer outcomes are substantial, and of great clinical importance. Strategies for weight control have potential utility for both prevention efforts and enhancing cancer outcomes. Presently, time-restricted eating (TRE) is a popular dietary intervention that involves limiting the consumption of calories to a specific window of time without any proscribed caloric restriction or alteration in dietary composition. As such, TRE is a sustainable long-term behavioral modification, when compared to other dietary interventions, and has shown many health benefits in animals and humans. The preliminary data regarding the effects of time-restricted feeding on cancer development and growth in animal models are promising but studies in humans are lacking. Interestingly, several short-term randomized clinical trials of TRE have shown favorable effects to reduce cancer risk factors; however, long-term trials of TRE have yet to investigate reductions in cancer incidence or outcomes in the general population. Few studies have been conducted in cancer populations, but a number are underway to examine the effect of TRE on cancer biology and recurrence. Given the simplicity, feasibility, and favorable metabolic improvements elicited by TRE in obese men and women, TRE may be useful in obese cancer patients and cancer survivors; however, the clinical implementation of TRE in the cancer setting will require greater in-depth investigation.
    Keywords:  Cancer; Dietary interventions time-restricted feeding; Metabolism; Obesity
    DOI:  https://doi.org/10.1007/s10555-022-10061-3
  74. Food Chem. 2022 Aug 10. pii: S0308-8146(22)01872-6. [Epub ahead of print]398 133910
    Introducing potato starch-ecofriendly silver nanoparticles as a novel binary system for nanoencapsulation of riboflavin.
    Neda Farnad, Khalil Farhadi.
      Riboflavin (Rf), an externally supplied nutrient, is highly photosensitive, and should be protected from sunlight once used in food and pharmaceutical manufacturing. The applications of encapsulated Rf have recently developed due to their therapeutic properties. In this study, the use of green silver nanoparticles (AgNPs) synthesized by Rosa damascena mill L. extract to control the encapsulation efficiency of Rf in potato starch was demonstrated for the first time. Starch/Rf, Starch/AgNPs/Rf and Starch/AgNPs nanocapsules were characterized by Fourier-transform infrared, field emission scanning electron microscopy, differential scanning calorimetry, and brunauer-Emmett-Teller techniques. The obtained results showed that the presence of AgNPs reduces Rf nanocapsules size (from 340 to 327 nm), increases the encapsulation efficiency (21.14 ± 0.62 to 92.52 ± 1.32 %) and improves the thermal stability, antibacterial and antioxidant activities. Moreover, UV-vis spectroscopy demonstrated the stronger association of AgNPs/Rf and AgNPs/Rf/Starch nanocapsules with BSA under physiological conditions.
    Keywords:  Antioxidant-antibacterial activities; BSA; Encapsulation; Freeze-drying; Nanocapsules; Potato starch; Riboflavin; Silver nanoparticles
    DOI:  https://doi.org/10.1016/j.foodchem.2022.133910
  75. Ann Transl Med. 2022 Jul;10(14): 806
    Research progress on the mechanism of action of hesperetin in cerebral ischemia: a narrative review.
    Qingchun Mu, Yufei Zhang, Qian Cheng, Hanning Huang, Chunming Huang, Longguang Tang.
       Background and Objective: Ischemic cerebrovascular disease is one of the main diseases threatening human health and survival and is a commonly occurring disease in neurology. Due to its high disability rate, ischemic cerebrovascular disease is one of the most important diseases to be prevented and treated at present. The risk factors of cerebral ischemia include atherosclerosis, hypertension, hyperlipidemia, and blood viscosity caused by thrombocytosis. After cerebral ischemia, cerebral ischemia-reperfusion injury may be induced by oxidative stress (OS), inflammatory reaction, nitric oxide damage, apoptosis, excitatory amino acid toxicity, calcium (Ca2+) overload, and other mechanisms. Hesperidin is a flavanone compound and is a key component in citrus plants. It is a kind of traditional Chinese medicine extract with high levels of Pericarpium, shell, fruit, and green peel. In recent years, Hesperidin has received great attention, compelling evidence has indicated Hesperidin plays a beneficial role in cerebral ischemia.
    Methods: We conducted a literature search for published manuscripts hesperidin in ischemia/reperfusion up to December 2021 in common English databases (i.e., PubMed, EMBASE, Web of Science, SpringerLink, Wiley, Cochrane Library) and Chinese databases [Chinese BioMedical Literature Service System (CBM), WANFANG database, China Knowledge Resource Integrated Database (CNKI)].
    Key Content and Findings: In this article, we reviewed the mechanisms of action of hesperidin in the treatment of cerebral ischemia, including antioxidant stress, anti-inflammatory reaction, anti-atherosclerosis, anti-thrombosis, anti-apoptosis, and nitric oxide regulation.
    Conclusions: In this narrative review, Hesperidin exhibits antioxidant stress, anti-platelet aggregation, vasodilation, anti-atherosclerotic, anti-inflammatory, anti-apoptotic, hypolipidemic, anti-tumor, cardiovascular protection, and nitric oxide-release regulatory properties Such a comprehension of the recent progress of hesperidin will help identify biomarkers for diagnosis and therapeutic targets to cerebral ischemia.
    Keywords:  Hesperetin; apoptosis; atherosclerosis; cerebral ischemia-reperfusion injury; oxidative stress (OS)
    DOI:  https://doi.org/10.21037/atm-22-3136
  76. Drug Deliv. 2022 Dec;29(1): 2685-2693
    Human serum albumin-based nanoparticles alter raloxifene administration and improve bioavailability.
    Shu-Jyuan Yang, Chih-Hao Chang, Tai-Horng Young, Chung-Hao Wang, Tzu-Hao Tseng, Man-Ling Wang.
      Osteoporosis is a disease that reduces bone mass and microarchitecture, which makes bones fragile. Postmenopausal osteoporosis occurs due to estrogen deficiency. Raloxifene is a selective estrogen receptor modulator used to treat postmenopausal osteoporosis. However, it has a low bioavailability, which requires long-term, high-dose raloxifene administration to be effective and causes several side effects. Herein, raloxifene was encapsulated in human serum albumin (HSA)-based nanoparticles (Ral/HSA/PSS NPs) as an intravenous-injection pharmaceutical formulation to increase its bioavailability and reduce the treatment dosage and time. In vitro results indicated that raloxifene molecules were well distributed in HSA-based nanoparticles as an amorphous state, and the resulting raloxifene formulation was stabile during long-term storage duration. The Ral/HSA/PSS NPs were both biocompatible and hemocompatible with a decreased cytotoxicity of high-dose raloxifene. Moreover, the intravenous administration of the prepared Ral/HSA/PSS NPs to rats improved raloxifene bioavailability and improved its half-life in plasma. These raloxifene-loaded nanoparticles may be a potential nanomedicine candidate for treating postmenopausal osteoporosis with lower raloxifene dosages.
    Keywords:  Osteoporosis; human serum albumin; nanoparticle; poly(sodium styrene sulfonate); raloxifene
    DOI:  https://doi.org/10.1080/10717544.2022.2111479
  77. Front Oncol. 2022 ;12 920843
    Meaning and Significance of "Alkalization Therapy for Cancer".
    Hiromi Wada, Reo Hamaguchi, Ryoko Narui, Hiromasa Morikawa.
       Objectives of the Study: Our research aims to answer the following questions. Can cancer progression be stopped by changing the body condition of person with cancer? Can cancer be cured?If cancer progression can be stopped, what is the underlying mechanism?
    Theoretical Rationale for Alkalization Therapy: Almost 70 years ago, Goldblatt H. & Cameron G. reported on the idea of alkalization therapy. Before that, Otto Warburg had been studying the metabolism of cancer and had discovered the essential nature of cancer. He published a review in Science in 1956 under the title "On the origin of cancer cells". From his phenomena described above, we established the theoretical rationale for alkalization therapy, based on the question of "How does cancer form and what is its nature"?
    Limitations of Deductive Methods and Inductive Approaches: In this paper, we describe a method to reconstruct the limitations and weaknesses of modern cancer medicine as Science-based Medicine using an inductive method, and to present a new vision of cancer therapy. How should we treat cancer? (Case presentation): Using a specific clinical case, we present patients in whom were successfully treated with no or few anticancer drugs.
    Summary: The biggest weakness of current cancer treatments is that they only treat the cancer and not the actual patient. The "alkalization therapy" that we advocate does not compete with any of the current standard treatments, but improves the effectiveness of standard treatments, reduces side effects, and lowers medical costs.
    Keywords:  alkalization therapy; bicarbonate; cancer; metabolism; tumor microenvironment; urine pH
    DOI:  https://doi.org/10.3389/fonc.2022.920843
  78. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2022 Aug 17. e1845
    A narrative review on the role of carbon nanoparticles in oncology.
    Meghan M Watt, Parikshit Moitra, Zach Sheffield, Fatemeh Ostadhossein, Elizabeth A Maxwell, Dipanjan Pan.
      The lymphatic system is the first site of metastasis for most tumors and is a common reason for the failure of cancer therapy. The lymphatic system's anatomical properties make it difficult to deliver chemotherapy agents at therapeutic concentrations while avoiding systemic toxicity. Carbon nanoparticles offer a promising alternative for identifying and transporting therapeutic molecules. The larger diameter of lymphatic vessels compared to the diameter of blood vessels, allows carbon nanoparticles to selectively enter the lymphatic system once administered subcutaneously. Carbon nanoparticles stain tumor-draining lymph nodes black following intratumoral injection, making them useful in sentinel lymph node mapping. Drug-loaded carbon nanoparticles allow higher concentrations of chemotherapeutics to accumulate in regional lymph nodes while decreasing plasma drug accumulation. The use of carbon nanoparticles for chemotherapy delivery has been associated with lower mortality, fewer histopathology changes in vital organs, and lower serum concentrations of hepatocellular enzymes. This review will focus on the ability of carbon nanoparticles to target the lymphatics as well as their current and potential applications in sentinel lymph node mapping and oncology treatment regimens. This article is categorized under: Implantable Materials and Surgical Technologies > Nanoscale Tools and Techniques in Surgery.
    Keywords:  cancer; chemotherapeutics; drug delivery; lymphatics; nanoparticles; sentinel lymph node
    DOI:  https://doi.org/10.1002/wnan.1845
  79. Front Public Health. 2022 ;10 903547
    Effect of vitamin D supplementation on the incidence and prognosis of depression: An updated meta-analysis based on randomized controlled trials.
    Fei Xie, Tongmin Huang, Dandi Lou, Rongrong Fu, Chaoxiong Ni, Jiaze Hong, Lingyan Ruan.
       Background: There have been several controversies about the correlation between vitamin D and depression. This study aimed to investigate the relationship between vitamin D supplementation and the incidence and prognosis of depression and to analyze the latent effects of subgroups including population and supplement strategy.
    Methods: A systematic search for articles before July 2021 in databases (PubMed, EMBASE, Web of Science, and the Cochrane Library) was conducted to investigate the effect of vitamin D supplementation on the incidence and prognosis of depression.
    Results: This meta-analysis included 29 studies with 4,504 participants, indicating that the use of vitamin D was beneficial to a decline in the incidence of depression (SMD: -0.23) and improvement of depression treatment (SMD: -0.92). Subgroup analysis revealed that people with low vitamin D levels (<50 nmol/L) and females could notably benefit from vitamin D in both prevention and treatment of depression. The effects of vitamin D with a daily supplementary dose of >2,800 IU and intervention duration of ≥8 weeks were considered significant in both prevention and treatment analyses. Intervention duration ≤8 weeks was recognized as effective in the treatment group.
    Conclusion: Our results demonstrate that vitamin D has a beneficial impact on both the incidence and the prognosis of depression. Whether suffering from depression or not, individuals with low vitamin D levels, dose >2,800 IU, intervention duration ≥8 weeks, and all females are most likely to benefit from vitamin D supplementation.
    Keywords:  depression; incidence; meta-analysis; prognosis; vitamin D supplementation
    DOI:  https://doi.org/10.3389/fpubh.2022.903547
  80. Inflammopharmacology. 2022 Aug 16.
    Black Seed (Nigella sativa): A Favourable Alternative Therapy for Inflammatory and Immune System Disorders.
    Opeyemi Oluwafemi Ojueromi, Ganiyu Oboh, Ayokunle Olubode Ademosun.
      In the recent years, various food additives, medicinal plants, and their bioactive components have been utilized in anti-inflammatory and immunomodulatory therapy. Nigella sativa is a key dietary supplement and food additive which has a strong traditional background. It is also one of the most broadly studied seeds in the global pharmaceutical and nutraceutical sector. N. sativa seeds are potential sources of natural metabolite such as phenolic compounds and alkaloids. The anti-inflammatory and immunomodulatory abilities of these seeds, most peculiarly with reference to some inflammatory and immune mediators, are reviewed. N. sativa and its bioactive compounds modulate inflammatory and immunomodulatory mediators including tumor necrosis factor-alpha (TNF-α), interferon gamma (IFN-γ), nuclear factor kappa B (NF-kB) cyclooxygenase (COX), lipoxygenase (LOX), transforming growth factor beta (TGF-β), interleukins, and immunoglobulin levels. This paper comprehensively describes the biomarkers and signaling pathways underlying the anti-inflammatory and immunomodulatory potential of N. sativa. This review also explains the scientific basis and the pharmacological properties of core bioactive ingredients of N. sativa responsible for these biological activities which indicates that their bioactive components could be possibly regarded as favorable therapy for disorders linked to inflammation and immune-dysregulation.
    Keywords:  Alkaloid; Anti-inflammation; Cytokines; Immunomodulation; N. sativa; Phenolics
    DOI:  https://doi.org/10.1007/s10787-022-01035-6
  81. J Pharm Biomed Anal. 2022 Jul 25. pii: S0731-7085(22)00383-1. [Epub ahead of print]220 114962
    Oxidative degradation in pharmaceuticals: Mechanism and stabilization of a spray-dried amorphous drug - A case study.
    Raghavendhar R Kotha, Kelly Zhang, Peter Yehl, Archana Kumar.
      Drug formulations such as spray drying are often required to improve the physicochemical properties and bioavailability of hydrophobic drugs. However, excipients often carry contaminants/ impurities and may also increase moisture levels in solid formulations, which can have detrimental effects on the drugs, including drug degradation and stability. Hence, achieving adequate shelf life of drug products has been among the most challenging issues for pharmaceuticals. Here we report a case study where we systematically studied the oxidative degradation of a pharmaceutical compound GENE-A, spray-dried and dispersed in hydroxypropyl methylcellulose-acetate succinate polymer matrix. Three different oxidative degradation products were observed, and their mechanisms of formation were investigated via forced degradation studies. Finally, we used several antioxidants based on their mechanisms of action to reduce/ prevent the drug degradation process. Propyl gallate alone and in combination with Ethylenediaminetetraacetic acid completely prevented the formation of two degradation products, whereas there was no significant impact observed on the third one. The results showed that both metal chelators and free radical terminators most effectively prevented drug degradation. This study may address some of the key issues that pharmaceutical companies encounter and offer appropriate solutions to counter the oxidative degradation process of pharmaceuticals.
    Keywords:  Antioxidants; Drug stability; Forced degradation; Oxidative degradation; Pharmaceuticals; Spray-dried formulations
    DOI:  https://doi.org/10.1016/j.jpba.2022.114962
  82. J Pharm Sci. 2022 Aug 14. pii: S0022-3549(22)00349-5. [Epub ahead of print]
    Development, characterization and in vitro antimicrobial evaluation of novel flavonoids entrapped micellar topical formulations of neomycin sulfate.
    Vikrant Abbot, Tamanna Sharma, Varun Bhardwaj, Shailesh Sharma, Poonam Sharma.
      Flavonoids are the secondary metabolites widely used in pharmaceutical industries due to their several health benefits. Quercetin and rutin, well known flavonoids possesses various pharmacological properties but the constraints of poor aqueous solubility and impermeability across cell membranes restricts their use in formulation development. Moreover, the rising problem of antimicrobial resistance has also caused a serious threat to human life, thus demanding the urgent need of developing more effective antimicrobial formulations. In view of this, the present research work is focused on utilizing the most feasible flavonoid-surfactant concentrations obtained from the already reported physico-chemical analysis in developing an improved neomycin topical formulation through drug combinatorial approach. The formulations were subjected for assessment of physical parameters such as determination of pH, viscosity and spreadability. The drug release profile of the formulations was studied through different mathematical models. After evaluation of all the parameters, two best formulations (NQ-T2 [HE] and NR-T1 [HE]) were selected for antimicrobial evaluation studies against different bacterial and fungal clinical isolates. Among the two formulations, NQ-T2 [HE] showed excellent antibacterial activity against the bacterial strains while NR-T1 [HE] also exhibited promising results when compared with the standard formulations. Overall, this study represents a possible solution to enhance the antimicrobial efficacy of neomycin formulations by combining them with flavonoids through micelles assisted drug combination approach.
    Keywords:  Neomycin sulfate; antimicrobial evaluation; drug release; formulation development; mathematical modeling
    DOI:  https://doi.org/10.1016/j.xphs.2022.08.013
  83. Cancer Lett. 2022 Aug 13. pii: S0304-3835(22)00338-X. [Epub ahead of print]546 215854
    Induction of ferroptosis in head and neck cancer: A novel bridgehead for fighting cancer resilience.
    Jaewang Lee, Jong-Lyel Roh.
      Most head and neck cancers (HNCs) originate from mucosal epithelial cells and show epithelial traits. It often changes to a mesenchymal or poorly differentiated state as cancer progresses, leading to invasion, metastasis, and resistance to treatment. The loss of epithelial traits by the epithelial-mesenchymal transition may render resilient cancers vulnerable to a novel non-apoptotic regulated cell death ferroptosis by the iron-dependent accumulation of excessive lipid peroxidation. By regulating mitochondrial or iron metabolism, intracellular ferrous iron and lipid peroxidation accumulation can be boosted, making resistant cancer cells more susceptible to ferroptosis. This article discusses the potential effect of ferroptosis induction as a novel treatment for resilient HNCs.
    Keywords:  Ferroptosis; Head and neck cancer; Iron; Lipid peroxidation; Treatment
    DOI:  https://doi.org/10.1016/j.canlet.2022.215854
  84. Acta Biomater. 2022 Aug 11. pii: S1742-7061(22)00454-8. [Epub ahead of print]
    Chondroitin sulfate microspheres anchored with drug-loaded liposomes play a dual antioxidant role in the treatment of osteoarthritis.
    Yuzhe He, Miao Sun, Jirong Wang, Xiaofu Yang, Changjian Lin, Lujie Ge, Chenting Ying, Kai Xu, An Liu, Lidong Wu.
      Reactive oxygen species (ROS) play a critical role in the pathogenesis of osteoarthritis. The injection of a single antioxidant drug is characterized by low drug utilization and short residence time in the articular cavity, limiting the therapeutic effect of antioxidant drugs on osteoarthritis. Currently, the drug circulation half-life can be extended using delivery vehicles such as liposomes and microspheres, which are widely used to treat diseases. In addition, the composite carriers of liposomes and hydrogel microspheres can combine the advantages of different material forms and show stronger plasticity and flexibility than traditional single carriers, which are expected to become new local drug delivery systems. Chondroitin sulfate, a sulfated glycosaminoglycan commonly found in native cartilage, has good antioxidant properties and degradability and is used to develop an injectable chondroitin sulfate hydrogel by covalent modification with photo-cross-linkable methacryloyl groups (ChsMA). Herein, ChsMA microgels anchored with liquiritin (LQ)-loaded liposomes (ChsMA@Lipo) were developed to delay the progression of osteoarthritis by dual antioxidation. On the one hand, the antioxidant drug LQ wrapped in ChsMA@Lipo microgels exhibits significant sustained-release kinetics due to the double obstruction of the lipid membrane and the hydrogel matrix network. On the other hand, ChsMA can eliminate ROS through degradation into chondroitin sulfate monomers by enzymes in vivo. Therefore, ChsMA@Lipo, as a degradable and dual antioxidant drug delivery platform, is a promising option for osteoarthritis treatment. STATEMENT OF SIGNIFICANCE: : Compared with the traditional single carrier, the composite carriers of hydrogel microspheres and liposome can complement the advantages of different materials, which shows stronger plasticity and flexibility, and is expected to become a new and efficient drug delivery system. ChsMA@Lipo not only attenuates IL-1β-induced ECM degradation in chondrocytes but also inhibits the M1 macrophages polarization and the inflammasome activation. The obtained ChsMA@Lipo alleviates the progression of osteoarthritis in vivo, which is promising for osteoarthritis treatment.
    Keywords:  Antioxidation; Drug delivery; Microsphere; Osteoarthritis; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.actbio.2022.07.052
  85. Mol Pharm. 2022 Aug 16.
    Utility of Intravenous Curcumin Nanodelivery Systems for Improving In Vivo Pharmacokinetics and Anticancer Pharmacodynamics.
    Mahsa Bagheri, Cornelus F van Nostrum, Robbert Jan Kok, Gert Storm, Wim E Hennink, Michal Heger.
      Curcumin nanoformulations for intravenous injection have been developed to offset poor absorption, biotransformation, degradation, and excessive clearance associated with parenteral delivery. This review investigates (1) whether intravenous nanoformulations improve curcumin pharmacokinetics (PK) and (2) whether improved PK yields greater therapeutic efficacy. Standard PK parameters (measured maximum concentration [Cmax], area under the curve [AUC], distribution volume [Vd], and clearance [CL]) of intravenously administered free curcumin in mice and rats were sourced from literature and compared to curcumin formulated in nanoparticles, micelles, and liposomes. The studies that also featured analysis of pharmacodynamics (PD) in murine cancer models were used to determine whether improved PK of nanoencapsulated curcumin resulted in improved PD. The distribution and clearance of free and nanoformulated curcumin were very fast, typically accounting for >80% curcumin elimination from plasma within 60 min. Case-matched analysis demonstrated that curcumin nanoencapsulation generally improved curcumin PK in terms of measured Cmax (n = 27) and AUC (n = 33), and to a lesser extent Vd and CL. However, when the data were unpaired and clustered for comparative analysis, only 5 out of the 12 analyzed nanoformulations maintained a higher relative curcumin concentration in plasma over time compared to free curcumin. Quantitative analysis of the mean plasma concentration of free curcumin versus nanoformulated curcumin did not reveal an overall marked improvement in curcumin PK. No correlation was found between PK and PD, suggesting that augmentation of the systemic presence of curcumin does not necessarily lead to greater therapeutic efficacy.
    Keywords:  absorption, distribution, metabolism, excretion; cancer therapy; drug delivery; micelles; nanomedicine; nanoparticles
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00455
  86. Mol Cell. 2022 Aug 12. pii: S1097-2765(22)00703-1. [Epub ahead of print]
    Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells.
    Yahui Wang, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P Shriver, Gary J Patti.
      Proliferating cells exhibit a metabolic phenotype known as "aerobic glycolysis," which is characterized by an elevated rate of glucose fermentation to lactate irrespective of oxygen availability. Although several theories have been proposed, a rationalization for why proliferating cells seemingly waste glucose carbon by excreting it as lactate remains elusive. Using the NCI-60 cell lines, we determined that lactate excretion is strongly correlated with the activity of mitochondrial NADH shuttles, but not proliferation. Quantifying the fluxes of the malate-aspartate shuttle (MAS), the glycerol 3-phosphate shuttle (G3PS), and lactate dehydrogenase under various conditions demonstrated that proliferating cells primarily transform glucose to lactate when glycolysis outpaces the mitochondrial NADH shuttles. Increasing mitochondrial NADH shuttle fluxes decreased glucose fermentation but did not reduce the proliferation rate. Our results reveal that glucose fermentation, a hallmark of cancer, is a secondary consequence of MAS and G3PS saturation rather than a unique metabolic driver of cellular proliferation.
    Keywords:  NADH shuttles; aerobic glycolysis; cancer metabolism; glycerol 3-phosphate shuttle; isotope-tracer analysis; malate-aspartate shuttle; metabolic flux; metabolomics; the Warburg effect
    DOI:  https://doi.org/10.1016/j.molcel.2022.07.007
  87. J Control Release. 2022 Aug 16. pii: S0168-3659(22)00518-1. [Epub ahead of print]350 80-92
    Nucleic acid-based therapy for brain cancer: Challenges and strategies.
    Zixia Zhang, João Conniot, Joana Amorim, Yiliang Jin, Rajendra Prasad, Xiyun Yan, Kelong Fan, João Conde.
      Nucleic acid-based therapy emerges as a powerful weapon for the treatment of tumors thanks to its direct, effective, and lasting therapeutic effect. Encouragingly, continuous nucleic acid-based drugs have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the tremendous progress, there are few nucleic acid-based drugs for brain tumors in clinic. The most challenging problems lie on the instability of nucleic acids, difficulty in traversing the biological barriers, and the off-target effect. Herein, nucleic acid-based therapy for brain tumor is summarized considering three aspects: (i) the therapeutic nucleic acids and their applications in clinical trials; (ii) the various administration routes for nucleic acid delivery and the respective advantages and drawbacks. (iii) the strategies and carriers for improving stability and targeting ability of nucleic acid drugs. This review provides thorough knowledge for the rational design of nucleic acid-based drugs against brain tumor.
    Keywords:  Blood brain barrier; Brain tumor; Carriers; Drug delivery; Nucleic acid-based therapy
    DOI:  https://doi.org/10.1016/j.jconrel.2022.08.014
  88. Signal Transduct Target Ther. 2022 Aug 13. 7(1): 286
    Regulated cell death (RCD) in cancer: key pathways and targeted therapies.
    Fu Peng, Minru Liao, Rui Qin, Shiou Zhu, Cheng Peng, Leilei Fu, Yi Chen, Bo Han.
      Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s41392-022-01110-y
  89. Int J Pharm. 2022 Aug 12. pii: S0378-5173(22)00662-7. [Epub ahead of print] 122108
    Celecoxib nanocrystal-loaded dissolving microneedles with highly efficient for osteoarthritistreatment.
    Qiuyue Wang, Xuejing Yang, Xun Gu, Fang Wei, Wenyu Cao, Lijie Zheng, Yingying Li, Tao Ma Resoures, Chuanbin Wu, Qingqing Wang.
      Osteoarthritis (OA) is a prevalent degenerative disease that has a significant impact on patients' lives. Celecoxib (CXB) is now primarily used to treat OA with oral dosing. CXB's limited water solubility, on the other hand, restricts its therapeutic application. We developed a delivery system of dissolving microneedles (DMNs) loaded with CXB-nanocrystals (CXB-NCs) for the treatment of OA. Oral administration's inefficiency and injectable administration's poor compliance might be solved using DMNs. Furthermore, carrier-free NCs may dramatically increase the dissolution of drugs with poorly water-solubility, as well as the drug load of DMNs. Antisolvent precipitation was used to make CXB-NCs. CXB-NC@DMNs were prepared by mixing CXB-NCs with hyaluronic acid (HA) that had high mechanical qualities and could permeate the skin efficiently in vitro. The therapeutic effect of oral CXB-NCs was substantially better than that of the same dose of oral CXB in an in vivo pharmacodynamic trial, demonstrating that the preparation of CXB into NCs might greatly increase CXB bioavailability. Furthermore, we discovered that DMNs loaded with low-dose CXB-NCs had similar or even better efficacy than the oral CXB-NCs group. The findings suggested that CXB-NC@DMNs may be a very efficient and promising drug delivery strategy in the treatment of OA.
    Keywords:  celecoxib; dissolving microneedles; nanocrystals; osteoarthritis
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122108
  90. Adv Sci (Weinh). 2022 Aug 18. e2202644
    Influence of Elasticity of Hydrogel Nanoparticles on Their Tumor Delivery.
    Xiangyu Chen, Shuwei Zhang, Jinming Li, Xiaobin Huang, Haochen Ye, Xuezhi Qiao, Zhenjie Xue, Wensheng Yang, Tie Wang.
      Polymeric nanocarriers have a broad range of clinical applications in recent years, but an inefficient delivery of polymeric nanocarriers to target tissues has always been a challenge. These results show that tuning the elasticity of hydrogel nanoparticles (HNPs) improves their delivery efficiency to tumors. Herein, a microfluidic system is constructed to evaluate cellular uptake of HNPs of different elasticity under flow conditions. It is found that soft HNPs are more efficiently taken up by cells than hard HNPs under flow conditions, owing to the greater adhesion between soft HNPs and cells. Furthermore, in vivo imaging reveals that soft HNPs have a more efficient tumor delivery than hard HNPs, and the greater targeting potential of soft HNPs is associated with both prolonged blood circulation and a high extent of cellular adhesion.
    Keywords:  cellular adhesion; cellular uptake; flow conditions; soft hydrogel nanoparticles; tumor targeting
    DOI:  https://doi.org/10.1002/advs.202202644
  91. Pharm Nanotechnol. 2022 Aug 17.
    Protein-Based Drug Delivery Nanomedicine Platforms: Recent Developments.
    Alaa A A Aljabali, Meriem Rezigue, Rawan H Alsharedeh, Mohammad A Obeid, Vijay Mishra, Ángel Serrano-Aroca, Murtaza M Tambuwala.
       BACKGROUND: Naturally occurring protein cages, both viral and non-viral assemblies, have been developed for various pharmaceutical applications. Protein cages are ideal platforms as they are compatible, biodegradable, bioavailable, and amenable to chemical and genetic modification to impart new functionalities for selective targeting or tracking of proteins. The ferritin/apoferritin protein cage, plant-derived viral capsids, the small Heat shock protein, albumin, soy and whey protein, collagen, and gelatin have all been exploited and characterized as drug-delivery vehicles. Protein cages come in many shapes and types with unique features such as unmatched uniformity, size, and conjugations.
    OBJECTIVES: The recent strategic development of drug delivery will be covered in this review, emphasizing polymer-based, specifically protein-based, drug delivery nanomedicine platforms. The potential and drawbacks of each kind of protein-based drug-delivery system will also be highlighted.
    METHODS: Research examining the usability of nanomaterials in the pharmaceutical and medical sectors were identified by employing bibliographic databases and web search engines.
    RESULTS: Rings, tubes, and cages are unique protein structures that occur in the biological environment and might serve as building blocks for nanomachines. Furthermore, numerous virions can undergo reversible structural conformational changes that open or close gated pores, allowing customizable accessibility to their core and ideal delivery vehicles.
    CONCLUSION: Protein cages' biocompatibility and their ability to be precisely engineered indicate they have significant potential in drug delivery and intracellular administration.
    Keywords:  Drug delivery; Nanomedicine; Pharmaceutical nanotechnology; Protein nanoparticles; viruses
    DOI:  https://doi.org/10.2174/2211738510666220817120307
  92. J Physiol. 2022 Aug 16.
    The ketogenic diet prevents steatosis and insulin resistance by reducing lipogenesis, diacylglycerol accummulation, and PKC activity in male rat liver.
    Shailee Jani, Daniel Da Eira, Mateja Stefanovic, Rolando B Ceddia.
       KEY POINTS: The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause insulin resistance and nonalcoholic fatty liver (NAFLD). This study provides evidence that a ketogenic diet (KD) rich in fat and devoid of carbohydrate reduced DAG content and preserved insulin signalling in the liver. The KD shifted metabolism away from lipogenesis by enhancing genes involved in mitochondrial biogenesis and fatty acid oxidations in the liver. The KD also promoted the production of beneficial very long-chain ceramides instead of potentially harmful long-chain ceramides. Through multiple mechanisms, the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD.
    ABSTRACT: Obesity-associated insulin resistance plays a major role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The accumulation of diacylglycerol (DAG), ceramides and inflammation are key factors that cause NAFLD. In recent years, the ketogenic diet (KD) has emerged as an effective non-pharmacological intervention for the treatment of NAFLD and other obesity-related metabolic disorders. What remains undetermined is how the KD affects DAG and ceramides content and insulin sensitivity in the liver. Thus, this research was designed to assess these variables, as well as glucose and fat metabolism and markers of inflammation in livers of rats exposed for 8 weeks to one of the following diets: standard chow (SC), obesogenic high-fat, sucrose-enriched diet (HFS), or a KD. Despite having a higher fat content than the HFS diet, the KD did not cause steatosis and preserved hepatic insulin signalling. The KD reduced DAG content and protein kinase C epsilon (PKCε) activity, but markedly increased liver ceramides content. However, whereas the KD increased ceramide synthase 2 (CerS2) expression, it suppressed CerS6 expression, an effect that promoted the production of beneficial very long-chain ceramides instead of harmful long-chain ceramides. The KD also enhanced the liver expression of key genes involved in mitochondrial biogenesis and fatty acid oxidation (Pgc-1α and Fgf21), suppressed inflammatory genes (Tnfα, Nf-kb, Tlr4, and Il6), and shifted substrate away from de-novo lipogenesis. Thus, through multiple mechanisms the KD exerted anti-steatogenic and insulin-sensitizing effects in the liver, which supports the use of this dietary intervention to treat NAFLD. Abstract figure legend This article is protected by copyright. All rights reserved.
    Keywords:  AKT; NAFLD; TAG; ceramides; glycogen; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1113/JP283552
  93. Menopause. 2022 Aug 16.
    Differing effects of oral conjugated equine estrogen and transdermal estradiol on vitamin D metabolism in postmenopausal women: a 4-year longitudinal study.
    Anna Maria Santoro, Christine A Simpson, Elaine Cong, Andrea Haas, Rebecca R Sullivan, Stephen Parziale, Yanhong Deng, Karl L Insogna.
       OBJECTIVE: The aim of this study was to examine the effect of either conjugated equine estrogen or transdermal estradiol on vitamin D metabolism in postmenopausal women.
    METHODS: Twenty-five women from the Kronos Early Estrogen Prevention Study who were randomized to conjugated equine estrogen 0.45 mg/d and 20 women who were treated with transdermal estradiol 50 mg/d (patch replaced weekly) were analyzed in the present study. All participants received micronized progesterone for 12 days per month.
    RESULTS: There was no significant treatment effect on serum total 25-hydroxyvitamin D over 48 months in either study group, and there were no significant differences between treatment arms. In contrast, at 12 months, directly measured free 25-hydroxyvitamin D was significantly higher in the transdermal estradiol group than in the conjugated equine estrogen group. Directly measured free 25-hydroxyvitamin D subsequently increased significantly from 12 to 48 months in both treatment arms. Calculated free 25-hydroxyvitamin D was also significantly higher in the transdermal estradiol group at 36 months. Vitamin D-binding protein decreased significantly in both treatment groups from 12 to 48 months, but at 48 months, least square mean values were no different based on treatment assignment.
    CONCLUSIONS: Directly measured free 25-hydroxyvitamin D levels, but not serum total 25-hydroxyvitamin D levels, are different within the first 12 months of estrogen replacement depending on the preparation. However, this difference is transient, in that there were no differences at 36 or 48 months. These findings suggest that there may be a short-term benefit to prescribing transdermal estradiol for women who are either vitamin D deficient or vitamin D insufficient.
    DOI:  https://doi.org/10.1097/GME.0000000000002045
  94. J Nat Prod. 2022 Aug 17.
    Network Pharmacology Research and Dual-omic Analyses Reveal the Molecular Mechanism of Natural Product Nodosin Inhibiting Muscle-Invasive Bladder Cancer in Vitro and in Vivo.
    Xiaopeng Hao, Huixia Fan, Jian Yang, Jinfu Tang, Junhui Zhou, Yuyang Zhao, Luqi Huang, Yong Xia.
      Bladder cancer, specifically, muscle-invasive bladder cancer (MIBC), is among the most common malignant tumors. Patients with MIBC who cannot tolerate standard drugs require novel treatments. Targeting apoptosis may help treat cancer, which may be achieved with the use of some natural products. Nodosin, found in Isodon serra (Maxim.) Kudo (known as Xihuangcao), may inhibit bladder cancer cells. Transcriptomics and proteomics dual-omic analyses revealed the network pharmacological mechanism: (1) blocking the S phase by up-regulating RPA2, CLSPN, MDC1, PDCD2L, and E2F6 gene expressions, suppressing cancer cell proliferation; (2) inducing apoptosis and autophagy and restraining ferroptosis by up-regulating HMOX1, G0S2, SQSTM1, FTL, SLC7A11, and AIFM2 gene expressions; (3) preventing cancer cell migration by down-regulating NEXN, LIMA1, CFL2, PALLD, and ITGA3 gene expressions. In vivo, nodosin inhibited bladder cancer cell growth in a model of xenograft tumor in nude mice. This study is the first to report basic research findings on the network pharmacological mechanism of cytotoxicity of bladder cancer cells by nodosin, providing novel evidence for the application of nodosin in the field of oncology; however, other mechanisms may be involved in the effects of nodosin for further research. These findings provide a foundation for the development of novel MIBC drugs.
    DOI:  https://doi.org/10.1021/acs.jnatprod.2c00400
  95. J Mol Neurosci. 2022 Sep;72(9): 2045-2066
    The Effects of Methanol Extracts of Hyssopus officinalis on Model of Induced Glioblastoma Multiforme (GBM) in Rats.
    Sepideh Khaksar, Khadijeh Kiarostami, Shahrzad Alinaghi.
      Given the complexity of pathophysiological processes of brain tumors, ineffective therapies, and high mortality rate, new therapeutic options with less toxicity are necessary. Hyssopus officinalis (hyssop) is an aromatic plant with important biological activities. The aim of this study is to assess the anti-cancer effect of hyssop extract on damages of glioblastoma multiforme. In this study, total flavonoids, phenolic content, and quantification of phenolic compound of hyssop extracts were analyzed. In vitro antioxidant properties of hyssop extract were also examined. In addition, cell viability, apoptosis, and cell cycle were evaluated in C6 glioma cell culture. In vivo, the rats were divided randomly into four main groups: intact, control, vehicle, and treatment groups. 1 × 106 C6 rat glioma cells were implanted into the right caudate nucleus of the rat's brain. The treatment group received the methanol extract of hyssop (100 mg/kg) for 7 days. Evolution of locomotor activity, tumor volume, survival rate, activities of antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)), vascular endothelial growth factor (VEGF) expression, TUNEL-positive cells, p53 and p21 mRNA expression, and histological alterations were performed. The results showed that the methanol extract of hyssop increased the apoptosis and reduced the cell division of C6 glioma cells in cell culture. Moreover, methanol extract decreased the tumor volume and prolonged survival. Also, the activity of SOD and CAT enzymes was reduced in tumor tissue and enhanced in surrounding tissue. TUNEL-positive cells were increased in methanol extract of hyssop group. The expression of p53 and p21 mRNA was upregulated in the treatment group. Moreover, the histological analysis indicated a considerable decrease in invasion of tumor cells and inflammation in the hyssop-treated rats. According to the achieved results, it can be stated that hyssop has sufficient potential to inhibit damage of brain tumors, at least in part, by affecting the oxidative stress and cell proliferation pathways.
    Keywords:  Antioxidant enzymes; Apoptotic cells; Brain tumor; Cell cycle; Cell viability; Hyssopus officinalis; Tumor volume; VEGF; p21; p53
    DOI:  https://doi.org/10.1007/s12031-022-02058-y
  96. Exp Oncol. 2022 08;44(2): 107-112
    EXPRESSION OF OSTEOPONTIN AND OSTEONECTIN IN BREAST AND PROSTATE CANCER CELLS WITH DIFFERENT SENSITIVITY TO DOXORUBICIN.
    T Zadvornyi, N Lukianova, T Borikun, S Gogol, P Virych, O Lykhova, V Chekhun.
       BACKGROUND: According to modern literature, osteopontin (OPN) and osteonectin (ON) are involved not only in the formation of the aggressive phenotype of malignantly transformed cells, but also in the realization of cytotoxic effects of some antitumor drugs.
    AIM: To study the changes of the expression of OPN and ON and their mRNAs (SPP1 and SPARC) upon exposure to doxorubicin (Dox) in breast cancer (BCa) and prostate cancer (PCa) cell lines with different sensitivity to Dox.
    MATERIALS AND METHODS: Cell lines of BCa (MCF-7 and MDA-MB-231) and PCa (LNCaP and DU-145) were cultured in the presence of Dox at IC30 concentrations for 24 h. OPN and ON levels were assessed by immunocytochemical (ICH) and Western blot analysis. SPP1 and SPARC mRNA levels were assessed by quantitative PCR.
    RESULTS: Dox treatment resulted in the significant decrease in the expression of both OPN and ON in MCF-7 and LNCaP cells. Similarly, Dox treatment downregulated both SPP1 and SPARC in MDA-MB-231 and DU-145 cells. Dox did not affect ON expression in MDA-MB-231 and DU-145 cells although the significant decrease in the level of SPARC mRNA has been evident. In contrast, no significant differences in SPP1 and SPARC mRNA levels were detected in LNCaP cells.
    CONCLUSION: The changes in the expression of OPN and ON proteins and their corresponding genes in BCa and PCa cells may be related to the intrinsic mechanisms of Dox effects in cells differing by malignant phenotype and Dox sensitivity.
  97. Front Nutr. 2022 ;9 946361
    Association between the mediterranean diet and cognitive health among healthy adults: A systematic review and meta-analysis.
    Jialei Fu, Li-Juan Tan, Jung Eun Lee, Sangah Shin.
       Background: An increasing prevalence of cognitive disorders warrants comprehensive systematic reviews on the effect of diet on cognitive health. Studies have suggested that the Mediterranean (MeDi) diet has protective effects against metabolic diseases. However, comprehensive systematic reviews on the effect of the MeDi diet on the cognitive decline are limited. We investigated whether adherence to the MeDi diet could lower the risk of the cognitive disorder or improve cognitive function in older adults.
    Methods: In this systematic review and meta-analysis, PubMed, Web of Science, PsycINFO, Scopus, and Cochrane databases were searched from inception to June 2021. Cohort studies and randomized controlled trials (RCTs) were included. The effect sizes were estimated as log risk ratios and standard mean differences (SMDs) with 95% confidence intervals (CIs). The Newcastle-Ottawa score and Cochrane Collaboration's tool were used to assess the risk of bias in cohort studies and RCTs, respectively.
    Results: Of the 1,687 screened studies, 31 cohort studies and five RCTs met the eligibility criteria for qualitative analysis; 26 cohort studies and two RCTs were included in the meta-analysis. In the cohort studies, high adherence to the MeDi diet was associated with lower risk of mild cognitive impairment (MCI) [risk ratio (RR) = 0.75 (0.66-0.86)], and Alzheimer's disease (AD) [RR = 0.71 (0.56-0.89)]. In the RCTs, high adherence to the MeDi diet was associated with better episodic [SMD = 0.20 (0.09-0.30)] and working memories [SMD = 0.17 (0.01-0.32)] than lowest group.
    Conclusion: Adherence to the MeDi diet may reduce the risk of MCI and AD. However, other associations with cognitive outcomes (global cognition, working memory, and episodic memory) remain open to interpretation. Overall, the MeDi diet is recommended to prevent or delay cognitive disorders and improve cognitive function. Further, long-term RCTs are warranted to strengthen the evidence.
    Systematic review registration: [https://www.crd.york.ac.uk], identifier [CRD42021276801].
    Keywords:  Alzheiemer’s disease; Mediterranean diet (MD); cognitive function; dementia; mild cognitive impairment
    DOI:  https://doi.org/10.3389/fnut.2022.946361
  98. Contrast Media Mol Imaging. 2022 ;2022 6533628
    Relationship between Intestinal Microflora and Hepatocellular Cancer Based on Gut-Liver Axis Theory.
    Shipeng Li, Wenfeng Han, Qichen He, Wei Zhang, Youcheng Zhang.
      The intestinal microflora is a bacterial group that lives in the human digestive tract and has a long-term interdependence with the host. Due to the close anatomical and functional relationship between the liver and the intestine, the intestinal flora affects liver metabolism via the intestinal-hepatic circulation, thereby playing an extremely important role in the pathological process of liver inflammation, chronic fibrosis, and liver cancer. In recent years, the rapid development of technologies in high-throughput sequencing and genomics has opened up possibilities for a broader and deeper understanding of the crosstalk between the intestinal flora and the occurrence and development of liver cancer. This review aims to summarize the mechanisms by which the gut microbiota changes the body's metabolism, through the gut-liver axis, thereby affecting the occurrence and development of primary liver cancer. In addition, the potential regulation of intestinal microflora in the treatment of liver cancer is discussed.
    DOI:  https://doi.org/10.1155/2022/6533628
  99. Metab Brain Dis. 2022 Aug 20.
    Saffron as a promising therapy for diabetes and Alzheimer's disease: mechanistic insights.
    Sarvin Sanaie, Saba Nikanfar, Zahra Yousefi Kalekhane, Akbar Azizi-Zeinalhajlou, Saeed Sadigh-Eteghad, Mostafa Araj-Khodaei, Mohammad Hossein Ayati, Sasan Andalib.
      The prevalence of both Alzheimer's disease (AD) and diabetes mellitus is increasing with the societies' aging and has become an essential social concern worldwide. Accumulation of amyloid plaques and neurofibrillary tangles (NFTs) of tau proteins in the brain are hallmarks of AD. Diabetes is an underlying risk factor for AD. Insulin resistance has been proposed to be involved in amyloid-beta (Aβ) aggregation in the brain. It seems that diabetic conditions can result in AD pathology by setting off a cascade of processes, including inflammation, mitochondrial dysfunction, and ROS and advanced glycation end products (AGEs) synthesis. Due to the several side effects of chemical drugs and their high cost, using herbal medicine has recently attracted attention for the treatment of diabetes and AD. Saffron and its active ingredients have been used for its anti-inflammatory, anti-oxidant, anti-diabetic, and anti-AD properties. Therefore, in the present review paper, we take account of the clinical, in vivo and in vitro evidence regarding the anti-diabetic and anti-AD effects of saffron and discuss the preventive or postponing properties of saffron or its components on AD development via its anti-diabetic effects.
    Keywords:  Alzheimer's disease; Diabetes; Herbal medicine; Saffron
    DOI:  https://doi.org/10.1007/s11011-022-01059-5
  100. Drug Des Devel Ther. 2022 ;16 2601-2616
    The Preventive and Therapeutic Effects of Ajwa Date Fruit Extract Against Acute Diclofenac Toxicity-Induced Colopathy: An Experimental Study.
    Shaimaa Mohamed Abdelfattah Hassan, Moutasem Salih Aboonq, Emad A Albadawi, Yasmeen Aljehani, Hytham Mahmoud Abdel-Latif, Reham A Mariah, Noha M Shafik, Tamer M Soliman, Abdelhady Ragab Abdel-Gawad, Faten M Omran, Wafaa A Abdellah, Ahmed Shehata, Husam Shahada, Hussam H Baghdadi, Hanan Yousef Aly, Alfarazdeg Saad, Manal Mohamed Helmy Nabo, Abdullah Almilaibary, Heba M Eltahir, Salah Mohamed El Sayed, Mustafa A M Abu-Elnaga, Yasser M Elbastawisy.
       Background: Studies regarding treatment of acute toxicity with diclofenac (ATD) are quite few. Diclofenac is commonly prescribed in neurology, psychiatry, and general medicine practice. This study investigated possible colon-protective effects exerted by Ajwa date fruit extract (ADFE), a prophetic medicine remedy native to Al-Madinah, Saudi Arabia against ATD. Phytochemicals in ADFE as gallic acid and quercetin have reported protective effects against ATD.
    Methods: Total phenols and flavonoids in ADFE were estimated as equivalents to gallic acid and quercetin. Four experimental groups were allocated each of six rats: control group, ATD group received a single dose of 150 mg diclofenac intraperitoneally, toxicity prevention group received a single dose of ADFE orally followed 4 hours later by diclofenac injection, and toxicity treatment group received a similar diclofenac dose followed 4 hours later by a single dose of ADFE. Four days later, animals were sacrificed. Histological and biochemical examinations were done.
    Results: ADFE has a total phenolic content of 331.7 gallic acid equivalent/gram extract and a total flavonoid content of 70.23 quercetin equivalent/gram. ATD significantly increased oxidative stress markers as serum malondialdehyde (MDA) and hydrogen peroxide (H2O2). Serum MDA and H2O2 were significantly scavenged by ADFE. ATD significantly (p<0.001) decreased antioxidant power as serum total antioxidant capacity and catalase activity. That was reversed by ADFE in both prevention and treatment groups. Histologically, ATD caused complete destruction of colonic crypts architecture, patchy loss of the crypts, loss of the surface epithelium, absent goblet cells and submucosal exudate, heavy infiltration of the lamina propria and submucosa with inflammatory cells, mainly lymphocytes and eosinophils. There were mucosal haemorrhages and submucosal dilated congested blood vessels. All that was prevented and treated using ADFE.
    Conclusion: ADFE is rich in quercetin and gallic acid equivalents that exert potent antitoxic effects. ADFE is strongly recommended for preventive and therapeutic colon effects against ATD.
    Keywords:  Ajwa date extract; acute toxicity; colon; diclofenac; histology; polyphenols and flavonoids
    DOI:  https://doi.org/10.2147/DDDT.S344247
  101. Biomacromolecules. 2022 Aug 17.
    pH-Sensitive Twin Liposomes Containing Quercetin and Laccase for Tumor Therapy.
    Yoonyoung Kim, Kyung Taek Oh, Yu Seok Youn, Eun Seong Lee.
      In this study, functional twin liposomes (TLs) were designed by linking avidin-anchored single liposomes and biotin-anchored single liposomes via avidin-biotin interactions. Here, we first punched a hole on the liposome surface using the liposome magnetoporation method to prepare functional single liposomes, which were used for safely encapsulating quercetin (QER, as a model prodrug) or laccase (LAC, as a bioactive enzyme) inside the liposomes without the use of organic solvents; the pores were then plugged by pH-sensitive glycol chitosan grafted with 3-diethylaminopropylamine (GDEAP) and avidin (or biotin). As a result, single liposomes with QER and biotin-GDEAP were efficiently coupled with other liposomes with LAC and avidin-GDEAP. We demonstrated that the TLs could accelerate QER and LAC release at acidic pH (6.8), improving the LAC-mediated oxidization of QER and significantly elevating tumor cell death, suggesting that this strategy can be used as an efficient method for the programmed action of prodrugs.
    DOI:  https://doi.org/10.1021/acs.biomac.2c00571
  102. Drug Deliv Transl Res. 2022 Aug 14.
    An expanding horizon of complex injectable products: development and regulatory considerations.
    Kanan Panchal, Sumeet Katke, Sanat Kumar Dash, Ankit Gaur, Aishwarya Shinde, Nithun Saha, Neelesh Kumar Mehra, Akash Chaurasiya.
      There has been a constant evolution in the pharmaceutical market concerning the new technologies imbibed in delivering drug substances for various indications. This is either market-driven or technology-driven to improve the overall therapeutic efficacy and patients' quality of life. The pharmaceutical industry has experienced rapid growth in the area of complex injectable products because of their effectiveness in the unmet market. These novel parenteral products, viz, the nanoparticles, liposomes, microspheres, suspensions, and emulsions, have proven their worth as "Safe and Effective" products. However, the underlying challenges involved in the development, scalability, and characterization of these injectable products are critical. Moreover, the guidelines available do not provide a clear understanding of these complex products, making it difficult to anticipate the regulatory requirements. Thus, it becomes imperative to comprehend the criticalities and develop an understanding of these products. This review discusses various complexities involved in the parenteral products such as complex drug substances, excipients, dosage forms, drug administration devices like pre-filled syringes and injector pens, and its different characterization tools and techniques. The review also provides a brief discussion on the regulatory aspects and associated hurdles with other parenteral products.
    Keywords:  Complex injectables; Controlled release; Liposomes; Microspheres; Multivesicular liposome; USFDA
    DOI:  https://doi.org/10.1007/s13346-022-01223-5
  103. AAPS PharmSciTech. 2022 Aug 16. 23(6): 226
    Antileishmanial Agents Co-loaded in Transfersomes with Enhanced Macrophage Uptake and Reduced Toxicity.
    Fatima Zahid, Sibgha Batool, Fakhar Ud-Din, Zakir Ali, Muhammad Nabi, Salman Khan, Omer Salman, Gul Majid Khan.
      The prime objective of this study was to develop amphotericin B (AMB) and rifampicin (RIF) co-loaded transfersomal gel (AMB-RIF co-loaded TFG) for effective treatment of cutaneous leishmaniasis (CL). AMB-RIF co-loaded TF was prepared by the thin-film hydration method and was optimized based on particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (%EE), and deformability index. Similarly, AMB-RIF co-loaded TFG was characterized in terms of rheology, spread ability, and pH. In vitro, ex vivo, and in vivo assays were performed to evaluate AMB-RIF co-loaded TF as a potential treatment option for CL. The optimized formulation had vesicles in nanosize range (167 nm) with suitable PDI (0.106), zeta potential (- 19.05 mV), and excellent %EE of RIF (66%) and AMB (85%). Moreover, it had appropriate deformability index (0.952). Additionally, AMB-RIF co-loaded TFG demonstrated suitable rheological behavior for topical application. AMB-RIF co-loaded TF and AMB-RIF co-loaded TFG showed sustained release of the incorporated drugs as compared to AMB-RIF suspension. Furthermore, RIF permeation from AMB-RIF co-loaded TF and AMB-RIF co-loaded TFG was enhanced fivefold and threefold, whereas AMB permeation was enhanced by eightfold and 6.6-fold, respectively. The significantly different IC50, higher CC50, and FIC50 (p < 0.5) showed synergistic antileishmanial potential of AMB-RIF co-loaded TF. Likewise, reduced lesion size and parasitic burden in AMB-RIF co-loaded TF-treated mouse group further established the antileishmanial effect of the optimized formulation. Besides, AMB-RIF co-loaded TFG showed a better safety profile. This study concluded that TFG may be a suitable carrier for co-delivery of AMB-RIF when administered topically for the treatment of CL.
    Keywords:  amphotericin B; cutaneous leishmaniasis; macrophage; rifampicin; toxicity; transfersomes
    DOI:  https://doi.org/10.1208/s12249-022-02384-9
  104. Adv Mater. 2022 Aug 19. e2203915
    A pH-Responsive Cluster Metal-organic Framework Nanoparticle for Enhanced Tumor Accumulation and Antitumor Effect.
    Ruoyu Cheng, Lingxi Jiang, Han Gao, Zehua Liu, Ermei Mäkilä, Shiqi Wang, Qimanguli Saiding, Lei Xiang, Xiaomei Tang, Minmin Shi, Jia Liu, Libin Pang, Jarno Salonen, Jouni Hirvonen, Hongbo Zhang, Wenguo Cui, Baiyong Shen, Hélder A Santos.
      As a result of the deficient tumor-specific antigens, potential off-target effect, and influence of protein corona, the metal-organic framework nanoparticles have inadequate accumulation in the tumor tissues, limiting the therapeutic effects. In this work, a pH-responsive linker (L) is prepared by covalently modifying oleylamine (OA) with 3-(bromomethyl)-4-methyl-2,5-furandione (MMfu) and poly (ethylene glycol) (PEG). Then, the L is embedded into a solid lipid nano-shell to coat apilimod (Ap)-loaded zeolitic imidazolate framework (Ap-ZIF) to form Ap-ZIF@SLN#L. Under the tumor microenvironment, the hydrophilic PEG and MMfu are removed, exposing the hydrophobic OA on Ap-ZIF@SLN#L, increasing their uptake in cancer cells and accumulation in the tumor. ZIF@SLN#L nanoparticle induced reactive oxygen species (ROS). Ap released from Ap-ZIF@SLN#L significantly promoted intracellular ROS and lactate dehydrogenase generation. Ap-ZIF@SLN#L inhibited tumor growth, increased the survival rate in mice, activated the tumor microenvironment, and improved the infiltration of macrophages and T cells in the tumor, as demonstrated in two different tumor-bearing mice after injections with Ap-ZIF@SLN#TL. Furthermore, mice showed normal physiological responses of the main organs and the normal serum level in alanine aminotransferase and aspartate aminotransferase after treatment with the nanoparticles. Overall, this pH-responsive targeting strategy improves nanoparticle accumulation in tumors with enhanced therapeutic effects. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer; Metal-organic framework; Nanoparticles; Targeting; pH-Responsive targeting
    DOI:  https://doi.org/10.1002/adma.202203915
  105. Sci Rep. 2022 Aug 17. 12(1): 13928
    Identification of potential targets of the curcumin analog CCA-1.1 for glioblastoma treatment : integrated computational analysis and in vitro study.
    Adam Hermawan, Febri Wulandari, Naufa Hanif, Rohmad Yudi Utomo, Riris Istighfari Jenie, Muthi Ikawati, Ahmad Syauqy Tafrihani.
      The treatment of glioblastoma multiforme (GBM) is challenging owing to its localization in the brain, the limited capacity of brain cells to repair, resistance to conventional therapy, and its aggressiveness. Curcumin has anticancer activity against aggressive cancers, such as leukemia, and GBM; however, its application is limited by its low solubility and bioavailability. Chemoprevention curcumin analog 1.1 (CCA-1.1), a curcumin analog, has better solubility and stability than those of curcumin. In this study, we explored potential targets of CCA-1.1 in GBM (PTCGs) by an integrated computational analysis and in vitro study. Predicted targets of CCA-1.1 obtained using various databases were subjected to comprehensive downstream analyses, including functional annotation, disease and drug association analyses, protein-protein interaction network analyses, analyses of genetic alterations, expression, and associations with survival and immune cell infiltration. Our integrative bioinformatics analysis revealed four candidate targets of CCA-1.1 in GBM: TP53, EGFR, AKT1, and CASP3. In addition to targeting specific proteins with regulatory effects in GBM, CCA-1.1 has the capacity to modulate the immunological milieu. Cytotoxicity of CCA-1.1 was lower than TMZ with an IC50 value of 9.8 μM compared to TMZ with an IC50 of 40 μM. mRNA sequencing revealed EGFR transcript variant 8 was upregulated, whereas EGFRvIII was downregulated in U87 cells after treatment with CCA-1.1. Furthermore, a molecular docking analysis suggested that CCA-1.1 inhibits EGFR with various mutations in GBM, which was confirmed using molecular dynamics simulation, wherein the binding between CCA-1.1 with the mutant EGFR L861Q was stable. For successful clinical translation, the effects of CCA-1.1 need to be confirmed in laboratory studies and clinical trials.
    DOI:  https://doi.org/10.1038/s41598-022-18348-9
  106. Acta Pharm Sin B. 2022 Aug;12(8): 3398-3409
    Hyperthermia based individual in situ recombinant vaccine enhances lymph nodes drainage for de novo antitumor immunity.
    Cuixia Zheng, Xinxin Liu, Yueyue Kong, Lei Zhang, Qingling Song, Hongjuan Zhao, Lu Han, Jiannan Jiao, Qianhua Feng, Lei Wang.
      The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes (LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin (SV) adjuvant loaded Au nanocages (AuNCs) as cores (AuNCs/SV) and folic acid modified thermal-sensitive liposomes (FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy (PTT) induced the release of tumor-derived protein antigens (TDPAs) and the shedding of FA-TSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine (AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.
    Keywords:  Au nanocages; De novo antitumor immunity; Lymph node drainage; Photothermal therapy; Recombinant vaccine; Simvastatin; Tumor targeting; Tumor-derived protein antigens
    DOI:  https://doi.org/10.1016/j.apsb.2022.02.026
  107. Photodiagnosis Photodyn Ther. 2022 Aug 10. pii: S1572-1000(22)00349-0. [Epub ahead of print] 103063
    Novel Light Delivery Method for Performing Transbronchial Photodynamic Therapy Ablation to Treat Peripheral Lung Cancer: A Pilot Study.
    Hwailuh Chang, Yu-Chi Chiu, Shih-Wei Lee, Chu-Cheng Yen, Jih-Tung Pai, Cho-Yin Lee, Yen-Lin Wu, Chi-Ming Lee, Yei-San Hsieh.
       BACKGROUND: Photodynamic therapy involves using a tumor-specific photosensitizer and laser illumination and is recommended for treating early, centrally located lung cancers, but it is not a standard treatment for peripheral lung tumor until now. We previously proposed a novel light delivery method, in which lipiodol is perfused into the bronchial tree to increase the scope of illumination via the fiber effect. Herein, we attempted this novel technique under electromagnetic bronchoscope guidance in a hybrid operation room where lipiodol facilitated light diffusion, and evaluated the effectiveness and feasibility of this technique for peripheral lung cancers.
    METHODS: This phase 0 pilot study included three patients with peripheral lung cancers (primary tumors ≤20-mm diameter). The photodynamic therapy was administered using Porfimer sodium as the photosensitizer, and an electromagnetic navigation bronchoscope in a hybrid operating room to guide the catheter to the tumor. This facilitated lipiodol infusion to encase the tumor and permit the transbronchial photodynamic therapy ablation.
    RESULTS: Administering 630 nm 200 J/cm (400mW/500sec) energy through a 3-cm cylindrical diffusing laser fiber was safe; no significant acute complications were observed. Although the treatment outcome was unsatisfactory due to the low light dose, tumor pathology in one case revealed tumor necrosis, with no significant damage to the surrounding lung tissue.
    CONCLUSIONS: Novel light delivery transbronchial photodynamic therapy ablation for peripheral lung tumors is feasible and safe. Additional clinical trials may help determine the best illumination plan and light dose through multiple deliveries from multiple angles.
    Keywords:  Electromagnetic navigation bronchoscope; Lipiodol; Peripheral lung cancer; Photodynamic Therapy; Porfimer sodium
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103063
  108. Adv Sci (Weinh). 2022 Aug 17. e2200750
    Aberrant Cholesterol Metabolism and Wnt/β-Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth.
    Shaoqin Zheng, Jiahui Lin, Zhongqiu Pang, Hui Zhang, Yinuo Wang, Lanjing Ma, Haijiao Zhang, Xi Zhang, Maorong Chen, Xinjun Zhang, Chao Zhao, Jun Qi, Liu Cao, Min Wang, Xi He, Ren Sheng.
      Frizzled (Fzd) proteins are Wnt receptors and play essential roles in development, homeostasis, and oncogenesis. How Wnt/Fzd signaling is coupled to physiological regulation remains unknown. Cholesterol is reported as a signaling molecule regulating morphogen such as Hedgehog signaling. Despite the elusiveness of the in-depth mechanism, it is well-established that pancreatic cancer specially requires abnormal cholesterol metabolism levels for growth. In this study, it is unexpectedly found that among ten Fzds, Fzd5 has a unique capacity to bind cholesterol specifically through its conserved extracellular linker region. Cholesterol-binding enables Fzd5 palmitoylation, which is indispensable for receptor maturation and trafficking to the plasma membrane. In Wnt-addicted pancreatic ductal adenocarcinoma (PDAC), cholesterol stimulates tumor growth via Fzd5-mediated Wnt/β-catenin signaling. A natural oxysterol, 25-hydroxylsterol competes with cholesterol and inhibits Fzd5 maturation and Wnt signaling, thereby alleviating PDAC growth. This cholesterol-receptor interaction and ensuing receptor lipidation uncover a novel mechanism by which Fzd5 acts as a cholesterol sensor and pivotal connection coupling lipid metabolism to morphogen signaling. These findings further suggest that cholesterol-targeting may provide new therapeutic opportunities for treating Wnt-dependent cancers.
    Keywords:   Wnt/β-catenin signaling ; Frizzled receptor; cholesterol; pancreatic cancer
    DOI:  https://doi.org/10.1002/advs.202200750
  109. Food Chem. 2022 Jul 16. pii: S0308-8146(22)01642-9. [Epub ahead of print]397 133680
    The construction of self-protective ferritin nanocage to cross dynamic gastrointestinal barriers with improved delivery efficiency.
    Hai Chen, Liang Ma, Hongjie Dai, Yu Fu, Xueer Han, Yuhao Zhang.
      Ferritin nanocages are promising nanocarriers for food bioactive compound delivery, but gastrointestinal barriers including disassociation by environmental acidity, degradation by protease, pose great challenges for cargo delivery. Herein, a self-protective ferritin that can cross gastrointestinal barriers is prepared through phosphorylation modification at 37 °C for 4 h. The results showed that the conjugation of phosphate group facilitates an acidic pI shift of ferritin from ∼5.0 to ∼4.0, allowing fast aggregation and precipitation in an intact spherical form rather than disassociation into subunits in acidic environments. Meanwhile, after incubation at simulated gastric juice for 30 min, almost 80 % STP-MjFer is retained, thus, the aggregation state and phosphate layers can improve its digestive stability. Besides, curcumin can be encapsulated within its cavity and the retention rate is ∼ 9 times higher than that of MjFer nanocage in simulated gastrointestinal fluid. Overall, the self-protective ferritin nanocarrier displays great potential for cargo delivery in food science.
    Keywords:  Digestive stability; Ferritin; Gastrointestinal barriers; Isoelectric point; Phosphorylation
    DOI:  https://doi.org/10.1016/j.foodchem.2022.133680
  110. Ann Med. 2022 Dec;54(1): 2278-2301
    Vitamin D intakes and health outcomes in infants and preschool children: Summary of an evidence report.
    Andrew R Beauchesne, Kelly Copeland Cara, Danielle M Krobath, Laura Paige Penkert, Shruti P Shertukde, Danielle S Cahoon, Belen Prado, Ruogu Li, Qisi Yao, Jing Huang, Tee Reh, Mei Chung.
       BACKGROUND: A systematic review was commissioned to support an international expert group charged to update the Food and Agriculture Organisation of the United Nations (FAO)/World Health Organisation (WHO)'s vitamin D intake recommendations for children aged 0-4 years.
    MATERIALS AND METHODS: Multiple electronic databases were searched to capture studies published from database inception to the 2nd week of June 2020 according to key questions formulated by the FAO/WHO. Relevant studies were summarised and synthesised by key questions and by health outcomes using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach.
    RESULTS: The 146 included studies examined the effects of different vitamin D intake levels on a variety of health outcomes (e.g. infectious disease, growth, neurodevelopment, rickets, and bone mineral density), and on outcomes for setting vitamin D upper limits (e.g. hypercalcemia, hypercalciuria, and nephrocalcinosis). For most outcomes, the strength of evidence was low or very low. Evidence was rated moderate for the effect of daily vitamin D supplementation on raising serum 25(OH)D concentrations, and a random-effects meta-regression analysis of 28 randomised controlled trials (mostly in infants 0-12 months) showed that each 100 IU/d increase in vitamin D supplementation was associated with an average of 1.92 (95% CI 0.28, 3.56) nmol/L increase in achieved 25-hydroxy-vitaminn D (25[OH]D) concentration (n = 53 intervention arms; p = .022) with large residual heterogeneity (I2 = 99.39%). Evidence was very low on two of the upper limit outcomes - hypercalcemia and hypercalciuria.
    CONCLUSIONS: The evidence report provided the expert group with a foundation and core set of data to begin their work to set vitamin D nutrient reference values. To move the field forward, future studies should use standardised 25(OH)D assay measurements and should examine the relationship between long-term vitamin D status and health outcomes.Key MessagesResults of a large complex systematic review suggest the current totality of evidence from trials and prospective observational studies do not reach sufficient certainty level to support a causal relationship between vitamin D intake and asthma, wheeze, eczema, infectious diseases, or rickets (most trials reported no rickets) in generally healthy infants and young children.In this systematic review, the only body of evidence that reached a moderate level of certainty was regarding the effect of daily vitamin D supplementation (vitamin D3 or D2 supplements to infants/children) on increasing serum 25(OH)D concentrations. However, currently there is no consensus on the definitions of vitamin D status, e.g. deficiency, insufficiency, sufficiency and toxicity, based on serum 25(OH)D concentrations.This systematic review provided an international expert group a foundation and core set of data through intake-response modelling to help set vitamin D nutrient reference values for infants and children up to 4 years of age.
    Keywords:  Vitamin D; asthma; autoimmune diseases; bone density; child development; communicable diseases; infant; nutritional requirements; pre-school child; systematic review
    DOI:  https://doi.org/10.1080/07853890.2022.2111602
  111. Biochim Biophys Acta Rev Cancer. 2022 Aug 14. pii: S0304-419X(22)00104-4. [Epub ahead of print] 188779
    Stimuli-responsive nanoassemblies for targeted delivery against tumor and its microenvironment.
    Chin Siew Sia, Hui Peng Lim, Beng Ti Tey, Bey-Hing Goh, Liang Ee Low.
      Despite the emergence of various cancer treatments, such as surgery, chemotherapy, radiotherapy, and immunotherapy, their use remains restricted owing to their limited tumor elimination efficacy and side effects. The use of nanoassemblies as delivery systems in nanomedicine for tumor diagnosis and therapy is flourishing. These nanoassemblies can be designed to have various shapes, sizes, and surface charges to meet the requirements of different applications. It is crucial for nanoassemblies to have enhanced delivery of payloads while inducing minimal to no toxicity to healthy tissues. In this review, stimuli-responsive nanoassemblies capable of combating the tumor microenvironment (TME) are discussed. First, various TME characteristics, such as hypoxia, oxidoreduction, adenosine triphosphate (ATP) elevation, and acidic TME, are described. Subsequently, the unique characteristics of the vascular and stromal TME are differentiated, and multiple barriers that have to be overcome are discussed. Furthermore, strategies to overcome these barriers for successful drug delivery to the targeted site are reviewed and summarized. In conclusion, the possible challenges and prospects of using these nanoassemblies for tumor-targeted delivery are discussed. This review aims at inspiring researchers to develop stimuli-responsive nanoassemblies for tumor-targeted delivery for clinical applications.
    Keywords:  Nanoassemblies; Stimuli-responsive; Stroma; Targeted delivery; Tumor microenvironment; Vascular
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188779
  112. Curr Drug Deliv. 2022 Aug 16.
    Nanosponges Based Drug Delivery System for the Cosmeceutical Applications of Stabilized Ascorbic Acid.
    Sadia Ahmed Zuberi, Muhammad Ali Sheraz, Syed Abid Ali, Muhammad Raza Shah, Sumbul Mujahid, Sofia Ahmed, Zubair Anwar, Fawaz Jaffar.
       BACKGROUND: L-Ascorbic acid (AA) is a highly unstable compound, thus, limiting its use in pharmaceutical and cosmetic products, particularly at higher concentrations.
    OBJECTIVE: This study aimed to stabilize the highly sensitive molecule (AA) by encapsulating it in β-cyclodextrin nanosponges (β-CD NS) that can be used further in preparing cosmeceuticals products with higher AA concentrations and enhanced stability.
    METHODS: The NS have been synthesized by the melting method. The AA was encapsulated in β-CD NS by the freeze-drying process. The prepared NS were characterized by FTIR spectrometry, SEM, Atomic Force Microscopy (AFM), zeta sizer, Differential Scanning Calorimetry (DSC), and the physical flow characteristics were also studied. The in-vitro drug release was carried out on the Franz apparatus using a combination of two methods: sample & separate and dialysis membrane. The assay was performed using a validated spectrometric method.
    RESULTS: The entrapment efficiency of AA in β-CD NS indicated a good loading capacity (83.57±6.35%). The FTIR, SEM, AFM, and DSC results confirmed the encapsulation of AA in β-CD NS. The particle size, polydispersity index, and zeta potential results ascertained the formation of stabilized monodisperse nanoparticles. The physical flow characteristics showed good flow properties. Around 84% AA has been released from the NS in 4 h following the Korsmeyer-Peppas model. The AA-loaded NS remained stable for nine months when stored at 30±2℃/65±5% RH.
    CONCLUSION: It is concluded that the prepared NS can protect the highly sensitive AA from degradation and provide an extended release of the vitamin. The prepared AA-loaded β-CD NS can be used to formulate other cosmeceutical dosage forms with better stability and effect.
    Keywords:  Ascorbic acid; Freeze-drying; Korsmeyer-Peppas Model; Melting method; Nanosponges; Stability.; β-Cyclodextrin
    DOI:  https://doi.org/10.2174/1567201819666220816093123
  113. Basic Clin Pharmacol Toxicol. 2022 Aug 16.
    Drug metabolism and drug transport of the 100 most prescribed oral drugs.
    Ditte B Iversen, Nanna Elman Andersen, Ann-Cathrine Dalgård Dunvald, Anton Pottegård, Tore B Stage.
      Safe and effective use of drugs requires an understanding of metabolism and transport. We identified the 100 most prescribed drugs in six countries and conducted a literature search on in vitro data to assess contribution of phase I and II enzymes and drug transporters to metabolism and transport. Eighty-nine of the 100 drugs undergo drug metabolism or are known substrates for drug transporters. Phase I enzymes are involved in metabolism of 67 drugs, while phase II enzymes mediate metabolism of 18 drugs. CYP3A4/5 is the most important phase I enzyme involved in metabolism of 43 drugs followed by CYP2D6 (23 drugs), CYP2C9 (23 drugs), CYP2C19 (22 drugs), CYP1A2 (14 drugs), and CYP2C8 (11 drugs). More than half of the drugs (54 drugs) are known substrates for drug transporters. P-glycoprotein (P-gp) is known to be involved in transport of 30 drugs while breast cancer resistance protein (BCRP) facilitates transport of 11 drugs. A considerable proportion of drugs are subject to a combination of phase I metabolism, phase II metabolism, and/or drug transport. We conclude that the majority of the most frequently prescribed drugs depend on drug metabolism or drug transport. Thus, understanding variability of drug metabolism and transport remains a priority.
    Keywords:  ADME; CYP3A4; Drug metabolism; P-gp; drug transport
    DOI:  https://doi.org/10.1111/bcpt.13780
  114. J Agric Food Chem. 2022 Aug 15.
    Research Advances of Lactoferrin in Electrostatic Spinning, Nano Self-Assembly, and Immune and Gut Microbiota Regulation.
    Ying Li, Lezhen Dong, Zhishen Mu, Lingyi Liu, Junsi Yang, Zufang Wu, Daodong Pan, Lianliang Liu.
      Lactoferrin (LF) is a naturally present iron-binding globulin with the structural properties of an N-lobe strongly positively charged terminus and a cage-like structure of nano self-assembly encapsulation. These unique structural properties give it potential for development in the fields of electrostatic spinning, targeted delivery systems, and the gut-brain axis. This review will provide an overview of LF's unique structure, encapsulation, and targeted transport capabilities, as well as its applications in immunity and gut microbiota regulation. First, the microstructure of LF is summarized and compared with its homologous ferritin, revealing both structural and functional similarities and differences between them. Second, the electrostatic interactions of LF and its application in electrostatic spinning are summarized. Its positive charge properties can be applied to functional environmental protection packaging materials and to improving drug stability and antiviral effects, while electrostatic spinning can promote bone regeneration and anti-inflammatory effects. Then the nano self-assembly behavior of LF is exploited as a cage-like protein to encapsulate bioactive substances to construct functional targeted delivery systems for applications such as contrast agents, antibacterial dressings, anti-cancer therapy, and gene delivery. In addition, some covalent and noncovalent interactions of LF in the Maillard reaction and protein interactions and other topics are briefly discussed. Finally, LF may affect immunological function via controlling the gut microbiota. In conclusion, this paper reviews the research advances of LF in electrostatic spinning, nano self-assembly, and immune and gut microbiota regulation, aiming to provide a reference for its application in the food and pharmaceutical fields.
    Keywords:  electrostatic spinning; gut microbiota; gut-brain axis; immunity; lactoferrin; nano self-assembly
    DOI:  https://doi.org/10.1021/acs.jafc.2c04241
  115. Toxicol Lett. 2022 Aug 10. pii: S0378-4274(22)00984-5. [Epub ahead of print]
    The short-term effects of berberine in the liver: narrow margins between benefits and toxicity.
    Evelyn Silva Moreira, Ana Paula Ames-Sibin, Carla Indianara Bonetti, Luana Eloísa Leal, Rosane Marina Peralta, Anacharis Babeto de Sá-Nakanishi, Jurandir Fernando Comar, Adelar Bracht, Lívia Bracht.
      Berberine is a plant alkaloid to which antihyperglycemic properties have been attributed. It is also known as an inhibitor of mitochondrial functions. In this work short-term translation of the latter effects on hepatic metabolism were investigated using the isolated perfused rat liver. Once-through perfusion with a buffered saline solution was done. At low portal concentrations berberine modified several metabolic pathways. It inhibited hepatic gluconeogenesis, increased glycolysis, inhibited ammonia detoxification, increased the cytosolic NADH/NAD+ ratio and diminished the ATP levels. Respiration of intact mitochondria was impaired as well as the mitochondrial pyruvate carboxylation activity. These results can be regarded as evidence that the direct inhibitory effects of berberine on gluconeogenesis, mediated by both energy metabolism and pyruvate carboxylation inhibition, represent most likely a significant contribution to its clinical efficacy as an antihyperglycemic agent. However, safety concerns also arise because all effects occur at similar concentrations and there is a narrow margin between the expected benefits and toxicity. Even mild inhibition of gluconeogenesis is accompanied by diminutions in oxygen uptake and ammonia detoxification and increases in the NADH/NAD+ ratio. All combined, desired and undesired effects could well in the end represent a deleterious combination of events leading to disruption of cellular homeostasis.
    Keywords:  alkaloid; ammonia detoxification; energy metabolism; gluconeogenesis; glycolysis
    DOI:  https://doi.org/10.1016/j.toxlet.2022.08.005
  116. J Drug Deliv Sci Technol. 2022 Sep;75 103625
    Remdesivir-loaded bis-MPA hyperbranched dendritic nanocarriers for pulmonary delivery.
    Eleftherios Halevas, Barbara Mavroidi, Chrysoula Kokotidou, Alexandra Moschona, Marina Sagnou, Anna Mitraki, George Litsardakis, Maria Pelecanou.
      Remdesivir is the only clinically available antiviral drug for the treatment of COVID-19. However, its very limited aqueous solubility confines its therapeutic activity and the development of novel inhaled nano-based drug delivery systems of remdesivir for enhanced lung tissue targeting and efficacy is internationally pursued. In this work 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) hyperbranched dendritic nano-scaffolds were employed as nanocarriers of remdesivir. The produced nano-formulations, empty and loaded, consisted of monodisperse nanoparticles with spherical morphology and neutral surface charge and sizes ranging between 80 and 230 nm. The entrapment efficiency and loading capacity of the loaded samples were 82.0% and 14.1%, respectively, whereas the release of the encapsulated drug was complete after 48 h. The toxicity assays in healthy MRC-5 lung diploid fibroblasts and NR8383 alveolar macrophages indicated their suitability as potential remdesivir carriers in the respiratory system. The novel nano-formulations are non-toxic in both tested cell lines, with IC50 values higher than 400 μΜ after 72 h treatment. Moreover, both free and encapsulated remdesivir exhibited very similar IC50 values, at the range of 80-90 μM, while its aqueous solubility was increased, overall presenting a suitable profile for application in inhaled delivery of therapeutics.
    Keywords:  2,2-bis(hydroxymethyl)propionic acid hyperbranched dendritic nanocarriers; Bioavailable remdesivir nanocarriers; Nontoxic remdesivir nano-formulations; Remdesivir encapsulation and delivery
    DOI:  https://doi.org/10.1016/j.jddst.2022.103625
  117. Front Nutr. 2022 ;9 903686
    Therapeutic Uses and Pharmacological Properties of Shallot (Allium ascalonicum): A Systematic Review.
    Cadmiel Moldovan, Oleg Frumuzachi, Mihai Babotă, Lillian Barros, Andrei Mocan, Simone Carradori, Gianina Crişan.
       Background: Shallot (Allium ascalonicum L.) is a traditional plant species used throughout the world both for culinary purposes and as a folk remedy. To date (i.e., April 2022), there is no report on the main pharmacological activities exerted by shallot preparations and/or extracts.
    Scope and Approach: The aim of this study was to comprehensively review the pharmacological activities exerted by shallot, with rigorous inclusion and exclusion criteria based on the scientific rigor of studies. Prisma guidelines were followed to perform the literature search.
    Key Findings and Conclusions: The literature search yielded 2,410 articles of which 116 passed the required rigorous criteria for inclusion in this review. The extracts exert a potent antioxidant activity both in vitro and in vivo, as well as a strong inhibitory capacity on various pathogens with relevant implications for public health. Moreover, shallot can be used as adjuvant therapy in cardiovascular diseases, diabetes, cancer prevention, and other non-communicable diseases associated with inflammatory and oxidative pathways. Future studies investigating the chemical composition of this species, as well as the molecular mechanisms involved in the empirically observed pharmacological actions are required.
    Keywords:  Allium ascalonicum; Allium cepa var. aggregatum; pharmacological activity; shallot; therapeutic use
    DOI:  https://doi.org/10.3389/fnut.2022.903686
  118. Org Biomol Chem. 2022 Aug 16.
    Recent applications of nanoparticles in organic transformations.
    Muskan, Arya Gangadharan, Pratiksha Goel, Monika Patel, Akhilesh K Verma.
      A variation in the size of metal nanoparticles leads to a difference in their properties. As the size of metal nanoparticles decreases, the surface area increases which leads to an increase in the reactivity of metal nanoparticles. Metals like Au, Ag, Pd, and Pt have interesting properties when used in nanometric dimensions. They function efficiently in significant industrial processes as electrocatalysts and photocatalysts in various organic reactions. Recently, the green biosynthesis of nanoparticles has attracted the attention of researchers. With environmental pollution rising over the past few decades, metal nanoparticle catalysts could be the key to subdue the toxic effects. Being versatile, they can be used to degrade pollutants, develop solar cells, convert toxic nitroaromatic compounds, significantly reduce CO2 emissions per unit of energy, and many more. Owing to their unique properties, nanoparticles have wide applications in biomedicine, for example, gold cages are promising agents for cancer diagnosis and therapy. Transition metal-oxide nanoparticles have been considered one of the best supercapacitor electrodes with high electrochemical performance. In this review, we have summarised fundamental concepts of metal nanoparticles over the last decade's main emphasis from 2010 to 2021. It focuses on the exceptional use of these nanocatalysts in various organic reactions. Additionally, we have also discussed the utility of these reactions and their crucial role in solving the problems of today. Through this article, we hope to provide the necessary framework needed to further advance the applications of metal nanoparticles as catalysts.
    DOI:  https://doi.org/10.1039/d2ob01114j
  119. Colloids Surf B Biointerfaces. 2022 Aug 08. pii: S0927-7765(22)00437-4. [Epub ahead of print]218 112754
    Zinc sulfide-chitosan hybrid nanoparticles as a robust surface for immobilization of Sillago sihama α-amylase.
    Sara Bahri, Ahmad Homaei, Elaheh Mosaddegh.
      In the present study, zinc sulfide-chitosan hybrid nanoparticles synthesized by chemical deposition were used as a matrix for the immobilization of purified α-amylase extracted from Sillago sihama (Forsskal, 1775). In this regard, the size and morphological structure of zinc sulfide-chitosan hybrid nanoparticles before and after the stabilization process were evaluated using FT-IR, DLS methods, as well as SEM and TEM electron microscopy, and EDS analyses. Then, the efficiency of the immobilized enzyme was measured in terms of temperature, optimal pH, stability at the critical temperature, and pH values. Immobilization of α-amylase on zinc sulfide -chitosan hybrid nanoparticles increased the long-term stability, as well as its endurance to critical temperatures and pH values; however, the optimal temperature and pH values of the enzyme were not altered following the immobilization process. The kinetic parameters of the enzyme were also changed during immobilization. Enzyme immobilization increased the Km, whereas decreased the catalytic efficiency (Kcat / Km) of the immobilized enzyme compared with the free enzyme. These results are very important as, in most cases, enzyme immobilization reduces the activity and catalytic efficiency of enzymes. The nano-enzyme produced in this study, due to its high temperature, and pH stability, could be a good candidate for industrial applications, especially in the food industry.
    Keywords:  Hybrid nanoparticles; Industrial applications; Kinetic parameters; Long-term stability
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112754
  120. Sci Rep. 2022 Aug 17. 12(1): 13958
    Antioxidants (selenium and garlic) alleviated the adverse effects of tramadol on the reproductive system and oxidative stress markers in male rabbits.
    Salah A Sheweita, Yassmin A El-Dafrawi, Osama A El-Ghalid, Alaa A Ghoneim, Ahmed Wahid.
      Tramadol has been used by millions of patients as an analgesic drug to relief the severe pain caused by cancers and other diseases. The current study aimed to investigate the protective effects of antioxidants (garlic and selenium) against the toxic effects of tramadol on semen characteristics, steroid hormones, the protein expressions of different cytochrome P450 isozymes [CYP 21A2, CYP 19, and 11A1], and on antioxidant enzyme activities in testes of rabbits. Western immunoblotting, spectrophotometric, and histological methods were used in this study. Tramadol (1.5 mg/kg body weight) was administered orally to male rabbits for up to three months (three times/week), and after pretreatment of rabbits with garlic (800 mg/kg) and/or selenium (1 mg/kg body weight) by 2 h. The present study showed that motilities, semen volumes, morphologies, sperm counts, testosterone, and estrogen levels were significantly decreased after 4, 8, and 12 weeks of tramadol treatment. In addition, the protein expressions of CYP 21A2, CYP 19, and 11A1 were down-regulated in the testes of the tramadol-treated rabbits. On the other hand, pretreatment of rabbits with garlic, selenium, and/or garlic-selenium for 2 h before administration of tramadol restored the downregulated CYP 21A2 and 11A1 to their normal levels after 12 weeks of tramadol treatment. Activities of antioxidant enzymes including glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, superoxide dismutase, and levels of glutathione were inhibited in the testes of tramadol-treated rabbits. On the other hand, free radical levels were significantly increased in the testes of tramadol-treated rabbits for 12 weeks. Interestingly, such changes in the activities of antioxidant enzymes as well as free radical levels caused by tramadol were restored to their normal levels in the rabbits pretreated with either selenium, garlic, and/or their combination. Histopathological investigations showed that tramadol caused substantial vacuolization with the presence of damaged immature spermatozoid in the testes. However, selenium and garlic treatments showed an increase in healthy sperm production with normal mitotic and meiotic divisions. The present study illustrated for the first time the mechanisms of low steroid hormone levels in the testes of tramadol-treated rabbits which could be due to the downregulation of CYPs proteins, induction of oxidative stress, and inhibition of antioxidant enzyme activities. In addition, the present data showed that such toxic effects of tramadol were attenuated and restored to their normal levels after pretreatment of rabbits with garlic, selenium, and/or their combination. This finding may pave the way for a new approach to reducing the toxicity of tramadol.
    DOI:  https://doi.org/10.1038/s41598-022-16862-4
  121. MicroPubl Biol. 2022 ;2022
    Curcumin, but not its degradation products, in combination with silibinin is primarily responsible for the inhibition of colon cancer cell proliferation.
    Alhan Sayyed, Rita Heuertz, Uthayashanker R Ezekiel.
      Colorectal cancer (CRC) is the third leading cause of cancer death globally and the most-commonly diagnosed cancer in men and women in the United States. We have previously shown that the phytochemicals curcumin, derived from turmeric, and silibinin from milk thistle exhibit synergistically enhanced anticancer activity against colorectal cancer cells. In the present study, the combination of curcumin, a major component of turmeric, and its degraded products trans-ferulic acid, ferulic aldehyde, and vanillin in combination with silibinin were assessed for their action against cancer cell proliferation. Our results indicate that only curcumin plus silibinin has significant antiproliferative effects on colon cancer cells.
    DOI:  https://doi.org/10.17912/micropub.biology.000617
  122. Curr Drug Deliv. 2022 Aug 17.
    Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake.
    Arshad Ali Khan, Safia Akhtar, Yogesh Yadav, Atiya Akhtar, Walla Alelwani, Azzah M Bannunah, Syed Mahmood.
      Background - The antiretroviral protease inhibitor drug lopinavir (LPV) is used to treat HIV-1 infection. LPV is known to have limited oral bioavailability, which may be attributed to its poor aqueous solubility, low efficacy and high first-pass metabolism. Self-nanoemulsifying drug delivery systems (SNEDDS) for LPV have been developed and optimised to counter the current issues. Methods- The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and % transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS. Results-The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension). Conclusion- The LPV-SNEDDS could be a potential carrier for LPV oral delivery.
    Keywords:  Caco-2 cells; Lopinavir; Pseudo-ternary phase diagrams; SNEDDS; titration method
    DOI:  https://doi.org/10.2174/1567201819666220817111054
  123. Biomater Adv. 2022 Aug 09. pii: S2772-9508(22)00350-8. [Epub ahead of print]140 213073
    Metronidazole nanosuspension loaded dissolving microarray patches: An engineered composite pharmaceutical system for the treatment of skin and soft tissue infection.
    Qonita Kurnia Anjani, Akmal Hidayat Bin Sabri, Juan Domínguez-Robles, Natalia Moreno-Castellanos, Emilia Utomo, Luki Ahmadi Hari Wardoyo, Eneko Larrañeta, Ryan F Donnelly.
      Bacteroides fragilis is one of the most common causative group of microorganisms that is associated with skin and soft tissue infections (SSTI). Metronidazole (MTZ) is the drug of choice used in the treatment of SSTI caused by the bacterium. However, owing to its physiochemical properties, MTZ have limited skin permeation, which render the drug unsuitable for the treatment of deep-rooted SSTIs. One strategy to overcome this limitation is to reformulate MTZ into nanosuspension which will then be loaded into dissolving microarray patches (MAPs) for the treatment of SSTIs caused by B. fragilis. Herein, we report for the first time on the preparation and optimisation of MAP loaded with MTZ nanosuspension (MTZ-NS). After screening a range of polymeric surfactants, we identified that Soluplus® resulted in the formation of MTZ-NS with the smallest particle size (115 nm) and a narrow PDI of 0.27. Next, the MTZ-NS was further optimised using a design of experiments (DoE) approach. The optimised MTZ-NS was then loaded into dissolving MAPs with varying MTZ-NS content. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell proliferation assays along with LIVE/DEAD™ staining on the 3T3L1 cell line showed that the MTZ-NS loaded dissolving MAPs displayed minimal toxicity and acceptable biocompatibility. In vitro dermatokinetic studies showed that the MTZ-NS loaded MAPs were able to deliver the nitroimidazole antibiotic across all strata of the skin resulting in a delivery efficiency of 95 % after a 24-hour permeation study. Lastly, agar plating assay using bacterial cultures of B. fragilis demonstrated that MTZ-NS loaded MAP resulted in complete bacterial inhibition in the entire plate relative to the control group. Should this formulation be translated into clinical practice, this pharmaceutical approach may provide a minimally invasive strategy to treat SSTIs caused by B. fragilis.
    Keywords:  Dissolving microarray patches; Metronidazole; Skin and soft tissue infections; Soluplus®
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213073
  124. Cell Death Dis. 2022 Aug 16. 13(8): 708
    Glycosylated modification of MUC1 maybe a new target to promote drug sensitivity and efficacy for breast cancer chemotherapy.
    Xiaomin Xi, Jiting Wang, Yue Qin, Weidong Huang, Yilin You, Jicheng Zhan.
      Breast cancer, the most common cancer in women, usually exhibits intrinsic insensitivity to drugs, even without drug resistance. MUC1 is a highly glycosylated transmembrane protein, overexpressed in breast cancer, contributing to tumorigenesis and worse prognosis. However, the molecular mechanism between MUC1 and drug sensitivity still remains unclear. Here, natural flavonoid apigenin was used as objective due to the antitumor activity and wide availability. MUC1 knockout (KO) markedly sensitized breast cancer cells to apigenin cytotoxicity in vitro and in vivo. Both genetical and pharmacological inhibition significantly enhanced the chemosensitivity to apigenin and clinical drugs whereas MUC1 overexpression conversely aggravated such drug resistance. Constitutively re-expressing wild type MUC1 in KO cells restored the drug resistance; however, the transmembrane domain deletant could not rescue the phenotype. Notably, further investigation discovered that membrane-dependent drug resistance relied on the extracellular glycosylated modification since removing O-glycosylation via inhibitor, enzyme digestion, or GCNT3 (MUC1 related O-glycosyltransferase) knockout markedly reinvigorated the chemosensitivity in WT cells, but had no effect on KO cells. Conversely, inserting O-glycosylated sites to MUC1-N increased the drug tolerance whereas the O-glycosylated deletant (Ser/Thr to Ala) maintained high susceptibility to drugs. Importantly, the intracellular concentration of apigenin measured by UPLC and fluorescence distribution firmly revealed the increased drug permeation in MUC1 KO and BAG-pretreated cells. Multiple clinical chemotherapeutics with small molecular were tested and obtained the similar conclusion. Our findings uncover a critical role of the extracellular O-glycosylation of MUC1-N in weakening drug sensitivity through acting as a barrier, highlighting a new perspective that targeting MUC1 O-glycosylation has great potential to promote drug sensitivity and efficacy.
    DOI:  https://doi.org/10.1038/s41419-022-05110-2
  125. Front Nutr. 2022 ;9 957321
    Regular exercise combined with ferulic acid exhibits antiobesity effect and regulates metabolic profiles in high-fat diet-induced mice.
    Ou Wang, Nanhai Zhang, Chao Han, Jian Huang.
      Exercise (Ex) has been recognized as an effective way of obesity prevention, but it shows a dual effect on the body's antioxidant system. Ferulic acid (FA) is a kind of phenolic acid with well-known antioxidant capacity and numerous health benefits. Therefore, the aim of the study was to compare the antiobesity effect of Ex, FA, and Ex combined with FA (Ex-FA) in vivo and to illustrate the potential mechanisms. Mice were fed a high-fat diet (HFD) with or without administration of Ex, FA, and Ex-FA for 13 weeks. The body weight, antioxidant ability, Ex performance, and lipid profiles in the serum, liver, and skeletal muscle were compared among the groups, and serum metabolomics analysis was conducted. The results showed that Ex, FA, and Ex-FA exhibited a similar effect on body weight management. Ex had a more beneficial function by alleviating HFD-induced dyslipidemia than FA, while FA exerted a more efficient effect in mitigating lipid deposition in the liver and skeletal muscle. Ex-FA showed comprehensive effects in the regulation of the lipid contents in serum, liver, and skeletal muscle, and provoked enhancement effects on antioxidant ability and Ex capacity. Mice administered with Ex, FA, and Ex-FA showed different metabolic profiles, which might be achieved through different metabolic pathways. The findings of this research implied that Ex coupled with FA could become an effective and safe remedy for the management of dietary-induced obesity.
    Keywords:  exercise; ferulic acid; lipid metabolism; metabolic profiles; obesity; oxidative stress
    DOI:  https://doi.org/10.3389/fnut.2022.957321
  126. J Pharm Pharm Sci. 2022 ;25 253-265
    Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy.
    Sanaa Bardaweel, Ahmad Issa.
       PURPOSE: To evaluate the effects of SGLT2 inhibitors on the proliferation, tumorigenesis, migration, colony formation, apoptosis, selected gene expression pattern, and combination with known chemotherapeutic drugs in different human cancer cell lines.
    METHODS:  The antiproliferative and combined effects of SGLT2 inhibitors were evaluated by MTT assay. Cell migration was assessed using wound-healing and colony formation assays. Apoptosis assay was conducted using annexin V-FITC/ propidium iodide staining. SGLT2 gene expression was determined using real-time PCR.
    RESULTS: Canagliflozin, dapagliflozin, and ipragliflozin significantly inhibited the growth of different cancer cell lines in a dose and time-dependent manner. IC50 values after 48 hours of treatment with canagliflozin, ipragliflozin, and dapagliflozin ranged from 41.97 µM to 69.49 µM, 63.67 µM to 255.80 µM, and 167.7 µM to 435.70 µM in the examined cancer cell lines, respectively. The combined treatment of SGLT2 with doxorubicin and raloxifene separately resulted in a synergistic effect in Caco-2 and A-549 cell lines. On the other hand, the combination of SGLT2 inhibitors with cisplatin resulted in an antagonistic effect in A-549, Du-145, and Panc-1 cell lines. Canagliflozin and ipragliflozin inhibited cell migration and colony formation ability at IC50 and Sub-IC50 in the examined cancer cell lines. Canagliflozin and ipragliflozin significantly induced apoptosis at IC50 and Double-IC50 in the Du-145 cell line compared to the control. Real-time PCR showed that the treatment with 0.1 IC50 and 0.2 IC50 of both canagliflozin and ipragliflozin resulted in diminished RNA expression of SGLT2, VEGF, and Bcl-2 genes in the Du-145 cell line.
    CONCLUSION: SGLT2 inhibitors have antiproliferation, anti-tumorigenesis, and anti-migration effects and may induce apoptosis in cancer cells. In addition, treatment with SGLT2 inhibitors resulted in the downregulation of selected genes in the Du-145 cell line.
    DOI:  https://doi.org/10.18433/jpps32879
  127. Free Radic Biol Med. 2022 Aug 16. pii: S0891-5849(22)00518-4. [Epub ahead of print]
    Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection.
    Junmin Xi, Zhijun Zhang, Zuo Wang, Qingfeng Wu, Ying He, Yanyi Xu, Zhenjiang Ding, Huanhuan Zhao, Honghong Da, Fang Zhang, Haiyu Zhao, Jianguo Fang.
      The intrinsic link of ferroptosis to neurodegeneration, such as Parkinson's disease and Alzheimer's disease, has set promises to apply ferroptosis inhibitors for treatment of neurodegenerative disorders. Herein, we report that the natural small molecule hinokitiol (Hino) functions as a potent ferroptosis inhibitor to rescue neuronal damages in vitro and in vivo. The action mechanisms of Hino involve chelating irons and activating cytoprotective transcription factor Nrf2 to upregulate the antioxidant genes including solute carrier family 7 member 11, glutathione peroxidase 4 and Heme oxygenase-1. In vivo studies demonstrate that Hino rescues the deficits of locomotor activity and neurodevelopment in zebrafishes. In addition, Hino shows the efficient blood-brain barrier permeability in mice, supporting the application of Hino for brain disorders. Paclitaxel is one of the most widely used broad-spectrum antineoplastic agents. However, its neurotoxic side effect is a severe concern. We demonstrate that the neurotoxicity of paclitaxel is ferroptosis-related and Hino also alleviates the paclitaxel-induced neurotoxicity without compromising its cytotoxicity to cancer cells. Hino also salvages the neurobehavioral impairment by paclitaxel in zebrafishes. Collectively, the discovery of Hino as a novel ferroptosis inhibitor and disclosure of its action mechanisms establish a foundation for the further development of Hino as a neuroprotective agent.
    Keywords:  6-Hydroxydopamine; Ferroptosis; Hinokitiol; Nrf2; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.08.011
  128. Diabetes Metab Syndr Obes. 2022 ;15 2427-2442
    Lingguizhugan Decoction Targets Intestinal Microbiota and Metabolites to Reduce Insulin Resistance in High-Fat Diet Rats.
    Ying Ning, Yanju Gong, Tianyan Zheng, Ya Xie, Shiqing Yuan, Weijun Ding.
       Background: The increasing incidence of obesity and its complications has become a global public health problem. Lingguizhugan decoction (LGZGD) is a representative compound of traditional Chinese medicine (TCM) for metabolic diseases, such as nonalcoholic fatty liver disease, but its role in insulin resistance (IR) treatment is still less known. This study aims to evaluate the therapeutic properties of LGZGD on obesity-induced IR and explore the potential mechanism of LGZGD on gut microbiota and its metabolites in the treatment of IR.
    Methods: In this study, we induced an IR model in the form of high-fat diet (HFD) rats gavaged with LGZGD (1.64 g/kg BW) for three weeks. The IR status was measured by biochemical assays and oral glucose tolerance tests. The degrees of damage to liver function and the intestinal barrier were observed by hematoxylin and eosin (H&E) staining and immunohistochemistry. Alterations in intestinal microbiota and metabolites were assessed by 16S rRNA and an untargeted metabolomics platform.
    Results: Our results showed that after LGZGD treatment, the body weight, plasma insulin concentration and blood lipids were significantly decreased, and glucose tolerance and hepatic steatosis were ameliorated. In addition, small intestinal villi were restored, and the expression of Occludin was upregulated. The relative abundance of Akkermansia, Faecalibacterium and Phascolarctobacterium in the HFD-LGZG group was upregulated. Obesity-related metabolic pathways, such as bile secretion, biosynthesis of amino acids, phenylalanine metabolism, serotonergic synapse, protein digestion and absorption, taurine and hypotaurine metabolism, and primary bile acid biosynthesis, were changed. After LGZGD intervention, metabolites developed toward the healthy control group. In addition, the expression of bile acid metabolism related genes was also regulated in IR rats.
    Conclusion: We showed that LGZGD relieved IR, possibly by regulating the composition of the fecal microbiota and its metabolites. The above studies provide a basis for further study of LGZGD in the treatment of IR and its clinical application.
    Keywords:  HFD; IR; LGZGD; high-fat diet; insulin resistance; intestinal microbiota; lingguizhugan decoction; nontargeted metabolomics
    DOI:  https://doi.org/10.2147/DMSO.S370492
  129. Biomater Sci. 2022 Aug 17.
    Sustained release of chlorogenic acid-loaded nanomicelles alleviates bone loss in mouse periodontitis.
    Han Li, Jiming Xu, Jun-Feng Hu, Qing-Yun Hu, Xiaolin Fang, Zhi-Jun Sun, Zhigang Xu, Lu Zhang.
      Periodontitis is a prevalent chronic inflammatory disease that destroys the periodontal supporting tissues, impinges on oral health, and is correlated with an increased risk of systemic disease. Currently, the main drug treatment is antibiotic therapy; however, systemic antibiotic therapy still has various drawbacks such as bacterial resistance, low bioavailability and burst release. It is noteworthy that the local use of non-antibiotic drugs with sustained release characteristics can effectively overcome these problems. It has been documented that chlorogenic acid (CGA) has good anti-inflammatory and antioxidant properties. To achieve the sustained release of CGA, we synthesized CGA-PLGA@PVP nanomicelles by loading CGA onto poly(D,L-lactide-co-glycolide) (PLGA) and modified them with polyvinylpyrrolidone (PVP) for better dispersion. The results demonstrated that CGA-PLGA@PVP nanomicelles could prolong the release time of CGA, and could not only effectively remove reactive oxygen species (ROS) but also downregulate the overexpression of proinflammatory cytokines in lipopolysaccharide (LPS)-treated RAW264.7 cells. Moreover, CGA-PLGA@PVP nanomicelles could remain in gingival tissue for more than 24 hours after local injection, inhibit alveolar bone resorption and prevent the progression of periodontitis in a mouse model, showing good biocompatibility. Therefore, CGA-PLGA@PVP nanomicelles have great properties and are expected to be a novel therapeutic strategy for periodontitis.
    DOI:  https://doi.org/10.1039/d2bm01099b
  130. J Pharm Pharmacol. 2022 Aug 16. pii: rgac051. [Epub ahead of print]
    Glycation-induced age-related illnesses, antiglycation and drug delivery strategies.
    Hamdy Abdelkader, Wesam W Mustafa, Ali M Alqahtani, Sultan Alsharani, Adel Al Fatease, Raid G Alany.
       OBJECTIVES: Ageing is a major cause of multiple age-related diseases. Several mechanisms have been reported to contribute to these abnormalities including glycation, oxidative stress, the polyol pathway and osmotic stress. Glycation, unlike glycosylation, is an irregular biochemical reaction to the formation of active advanced glycation end-products (AGEs), which are considered to be one of the causes of these chronic diseases. This study provides a recent and comprehensive review on the possible causes, mechanisms, types, analytical techniques, diseases and treatments of the toxic glycation end products.
    KEY FINDINGS: Several mechanisms have been found to play a role in generating hyperglycaemia-induced oxidative stress including an increase in the levels of reactive oxygen species (ROS), increase in the levels of AGEs, binding of AGEs and their receptors (RAGE) and the polyol pathway and thus have been investigated as promising novel targets.
    SUMMARY: This review focuses on the key mechanisms attributed to cumulative increases of glycation and pathological RAGE expression as a significant cause of multiple age-related diseases, and reporting on different aspects of antiglycation therapy as a novel approach to managing/treating age-related diseases. Additionally, historical, current and possible future antiglycation approaches will be presented focussing on novel drug delivery methods.
    Keywords:  Maillard reaction; drug repurposing; flavonoids; glycation; nanotechnology; polyphenols
    DOI:  https://doi.org/10.1093/jpp/rgac051
  131. ACS Appl Mater Interfaces. 2022 Aug 15.
    Nanotrains of DNA Copper Nanoclusters That Triggered a Cascade Fenton-Like Reaction and Glutathione Depletion to Doubly Enhance Chemodynamic Therapy.
    Qianqian Li, Fei Wang, Lu Shi, Qiaorong Tang, Baoxin Li, Xiaobing Wang, Yan Jin.
      Many current chemodynamic therapy (CDT) strategies suffer from either low therapeutic efficiency or the deficiency of poor targeting. The low therapeutic efficiency is mainly ascribed to the intracellular antioxidant system and the inefficient Fenton reaction in the weakly acidic tumor microenvironment (TME). Herein, by exploitation of the diverse function and programmability of functional nucleic acid, aptamer-tethered nanotrains of DNA copper nanoclusters (aptNTDNA-CuNCs) were assembled to simultaneously achieve targeted recognition, loading, and delivery of CDT reagents into tumor cells without an external carrier. The intracellular hydrogen peroxide (H2O2) oxidized nanotrains of DNA-CuNCs to produce a lot of Cu2+ and Cu+ ions, which can generate reactive oxygen species (ROS) in the weakly acidic TME based on the pH-independent Fenton-like reaction of Cu+/H2O2. Meanwhile, the redox reaction between intracellular glutathione (GSH) and Cu2+ depleted GSH and generated Cu+ ions, which weakened the antioxidant ability of cancer cells and further enhanced the Fenton-like reaction of Cu+/H2O2, respectively. Thus, the cascade Fenton-like reaction and GSH depletion doubly improved the efficacy of CDT. The in vivo and in vitro study solidly confirmed that aptNTDNA-CuNCs have excellent antitumor efficacy and no cytotoxicity to healthy cells. Therefore, aptNTDNA-CuNCs can act as CDT reagents to achieve highly efficient, biocompatible, and targeted CDT.
    Keywords:  Fenton-like reaction; aptamer; chemodynamic therapy; nanotrains of DNA-CuNCs; targeted recognition
    DOI:  https://doi.org/10.1021/acsami.2c05944
  132. Curr Mol Pharmacol. 2022 Aug 19.
    Genetics of Dravet Syndrome and its Targeted Therapy by Nanomedicine: A Roadmap for Future Treatment of Drug Resistant Seizures.
    Muhammad Ikram, Sufian Rasheed.
      According to the World Health Organization (WHO), epilepsy is the 4th most prevalent neurological disorder after migraine, stroke, and Alzheimer's disease. There are numerous types of epileptic syndrome that are reported in children; one of them is Dravet syndrome. It is a neurological disorder of infants' outset during the first year of life. Dravet syndrome is a genetically determined syndrome and the most studied form of genetic epilepsy. Nearly 70-80% of its cases are due to genetic alterations in the SCN1A gene, and almost 16% of cases are due to variations in the PCDH19 gene. Besides that, mutations in SCN1B, SCN2A, and GABRG2, including some novel genes, STXBP1, HCN1, and CDH2 have been observed in DS patients. It is a drug-resistant epileptic syndrome and its complete removal is still challenging. So, novel therapeutic techniques are being used to treat drug-resistant seizures. Recently, new strategies have been made to improve the neuron-specific targeting of AEDs encapsulated by nanocarriers. The nanocarriers will have a major contribution to nano-neuro medicines such as drug delivery, neuroimaging, neuroprotection, neurosurgery, and neuroregeneration. The nanotechnology-mediated techniques also have a fantastic success rate in gene therapy, as reported in recent years. The anti-epileptic drug delivery with the help of nanoparticles, at the targeted position, makes them applicable for the possible treatment of drug-resistant seizures and gives new hope to patients affected with it.
    Keywords:  Dravet syndrome (DS); Epilepsy; drug-resistant; genetics; nanoparticles; treatment
    DOI:  https://doi.org/10.2174/1874467215666220819143105
  133. Acta Biomater. 2022 Aug 12. pii: S1742-7061(22)00491-3. [Epub ahead of print]
    Enzyme-manipulated hydrogelation of small molecules for biomedical applications.
    ChengCheng, Qingyun Sun, Xiuping Wang, Bingfang He, Tianyue Jiang.
      Enzyme-manipulated hydrogelation based on self-assembly of small molecules is an attractive methodology for development of functional biomaterials. Upon the catalysis of enzymes, small-molecule precursors are converted into assemblable building blocks, which arrange into high-ordered nanofibers via non-covalent interactions at the molecular level, and further trap water to form hydrogels at the macroscopic level. Such approach has numerous advantages of region- and enantioselectivity, and mild reaction conditions for encapsulation of biomedications or cells that are fragile to environmental change. In addition to the common applications as drug reservoirs or cell scaffolds, the utilization of endogenous enzymes as stimuli to initiate self-assembly in the living cells and tissue is considered as an intelligent spatiotemporally controllable hydrogelation strategy for biomedical applications. The enzyme-instructed in situ self-assembly and hydrogelation can modulate the cell behavior, and even present therapeutic bioactivities, which provides a new perspective in the field of disease treatment. In this review, we categorize distinct enzymatic stimuli and elaborate substrate design, catalytic characteristics, and mechanisms of self-assembly and hydrogelation. The biomedical applications in drug delivery, tissue engineering, bioimaging, and in situ gelation-produced bioactivity are outlined. Advantages and limitations regarding the state-of-the-art enzyme-driven hydrogelation technologies and future perspectives are also discussed. STATEMENT OF SIGNIFICANCE: : Hydrogel is a semi-solid soft material containing a large amount of water. Due to the features of adjustable flexibility, extremely porous architecture, and the high similarity of structure to natural extracellular matrices, the hydrogel has broad application prospects in biomedicine. In recent 20 years, enzyme-manipulated hydrogelation based on self-assembly of small molecules has developed rapidly as an attractive methodology for the construction of functional biomaterials. Upon the catalysis of enzymes, small-molecule precursors are converted into assemblable building blocks, which arrange into high-ordered nanofibers via non-covalent interactions at the molecular level, and further trap water to form hydrogels at the macroscopic level. This review summarized the characteristics of enzymatic hydrogel, as well as the traditional application and emerging prospect of enzyme-instructed self-assembly and hydrogelation.
    Keywords:  drug delivery; enzyme-catalysis; hydrogel; self-assembly; tissue engineering
    DOI:  https://doi.org/10.1016/j.actbio.2022.08.016
  134. Front Med (Lausanne). 2022 ;9 810189
    Systemic immune effects of anesthetics and their intracellular targets in tumors.
    Ting Luan, Yi Li, Lihui Sun, Siqi Xu, Haifeng Wang, Jiansong Wang, Chong Li.
      According to the result released by the World Health Organization (WHO), non-communicable diseases have occupied four of the top 10 current causes for death in the world. Cancer is one of the significant factors that trigger complications and deaths; more than 80% cancer patients require surgical or palliative treatment. In this case, anesthetic treatment is indispensable. Since cancer is a heterogeneous disease, various types of interventions can activate oncogenes or mutate tumor suppressor genes. More and more researchers believe that anesthetics have a certain effect on the long-term recurrence and metastasis of tumors, but it is still controversial whether they promote or inhibit the progression of cancer. On this basis, a series of retrospective or prospective randomized clinical trials have been conducted, but it seems to be difficult to reach a conclusion within 5 years or longer. This article focuses on the effects of anesthetic drugs on immune function and cancer and reviews their latest targets on the tumor cells, in order to provide a theoretical basis for optimizing the selection of anesthetic drugs, exploring therapeutic targets, and improving the prognosis of cancer patients.
    Keywords:  immune effect; intravenous; local anesthetics; opioids; tumor-associated signal pathway; tumor-targeting gene; volatile anesthetics
    DOI:  https://doi.org/10.3389/fmed.2022.810189
  135. Adv Sci (Weinh). 2022 Aug 17. e2103677
    Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies.
    Santiago Correa, Emily L Meany, Emily C Gale, John H Klich, Olivia M Saouaf, Aaron T Mayer, Zunyu Xiao, Celine S Liong, Ryanne A Brown, Caitlin L Maikawa, Abigail K Grosskopf, Joseph L Mann, Juliana Idoyaga, Eric A Appel.
      When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long-lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, this study explored the ability of a slow-releasing injectable hydrogel depot to reduce dose-limiting toxicities of immunostimulatory CD40 agonist (CD40a) while maintaining its potent anticancer efficacy. A previously described polymer-nanoparticle (PNP) hydrogel system is leveraged that exhibits shear-thinning and yield-stress properties that are hypothesized to improve locoregional delivery of CD40a immunotherapy. Using positron emission tomography, it is demonstrated that prolonged hydrogel-based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a-loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10 melanoma model. PNP hydrogels, therefore, represent a facile, drug-agnostic method to ameliorate immune-related adverse effects and explore locoregional delivery of immunostimulatory drugs.
    Keywords:  biomaterials; cancer; drug delivery; immunotherapy; pharmacokinetics
    DOI:  https://doi.org/10.1002/advs.202103677
  136. J Photochem Photobiol B. 2022 Aug 08. pii: S1011-1344(22)00153-1. [Epub ahead of print]234 112539
    Photobiomodulation and photodynamic therapy-induced switching of autophagy and apoptosis in human dermal fibroblasts.
    Viktoria Pevna, Denis Horvath, Georges Wagnieres, Veronika Huntosova.
      Nowadays, photobiomodulation (PBM) in combination with chemotherapy or other therapeutic approaches is an attractive adjuvant modality for cancer treatment. Targeted destruction of cancer cells is one of the main advantages of photodynamic therapy (PDT). We have shown in previous studies that the combination of PBM at 808 nm and hypericin-mediated PDT increases PDT efficacy in human glioblastoma cells U87 MG. The study presented here shows significant differences between U87 MG and non-cancerous human dermal fibroblasts (HDF) cells treated by PBM and PDT. This study focuses on mitochondria because PBM mainly affects these organelles. We demonstrated that an interplay between mitochondrial and autophagic proteins plays a crucial role in the response of HDF cells to PBM and PDT. Fluorescence microscopy, flow cytometry, and Western blot analysis were used to examine the autophagic profile of HDF cells after these treatments. An increase in ubiquitin, SQSTM1, LC3BII, and cytochrome c was accompanied by a decrease in M6PR, ATG16L1, and Opa1 in HDF cells exposed to PBM and PDT. Overall, we observed that the switching of autophagy and apoptosis is dose-dependent and also occurs independently of PBM in HDF cells after hypericin-mediated PDT. However, PBM might preferentially induce autophagy in noncancer cells, which might escape apoptosis under certain conditions.
    Keywords:  Apoptosis; Autophagy; Human dermal fibroblast; Hypericin; Mitochondria; Photobiomodulation; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jphotobiol.2022.112539
  137. Front Oncol. 2022 ;12 972718
    Editorial: Metabolism of anti-cancer drugs: Interplay involving pharmacology and pharmacokinetics.
    Tashinga E Bapiro, Rose Hayeshi, Collet Dandara.
      
    Keywords:  anticancer drugs; cytochrome P450; drug metabolism; drug-drug interactions; pharmacodynamics; pharmacokinetics
    DOI:  https://doi.org/10.3389/fonc.2022.972718
  138. Nat Prod Rep. 2022 Aug 16.
    Recent ring distortion reactions for diversifying complex natural products.
    Yu Li, Shihao Cheng, Yun Tian, Yanan Zhang, Yu Zhao.
      Covering: 2013-2022.Chemical diversification of natural products is an efficient way to generate natural product-like compounds for modern drug discovery programs. Utilizing ring-distortion reactions for diversifying natural products would directly alter the core ring systems of small molecules and lead to the production of structurally complex and diverse compounds for high-throughput screening. We review the ring distortion reactions recently used in complexity-to-diversity (CtD) and pseudo natural products (pseudo-NPs) strategies for diversifying complex natural products. The core ring structures of natural products are altered via ring expansion, ring cleavage, ring edge-fusion, ring spiro-fusion, ring rearrangement, and ring contraction. These reactions can rapidly provide natural product-like collections with properties suitable for a wide variety of biological and medicinal applications. The challenges and limitations of current ring distortion reactions are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We also provide a toolbox for chemists for the application of ring distortion reactions to access natural product-like molecules.
    DOI:  https://doi.org/10.1039/d2np00027j
  139. Eur J Pharmacol. 2022 Aug 15. pii: S0014-2999(22)00469-1. [Epub ahead of print] 175208
    Aspirin blocks AMPK/SIRT3-mediated glycolysis to inhibit NSCLC cell proliferation.
    Guanghui Ren, Yan Ma, Xingjie Wang, Zhaodi Zheng, Guorong Li.
      Non-small cell lung cancer (NSCLC) has the highest incidence and mortality in the world. Aspirin has been reported to promote apoptosis, inhibit proliferation, stemness, angiogenesis, cancer-associated inflammation and migration in NSCLC. But the effect of aspirin on aerobic glycolysis in NSCLC is less reported. In the present study, we investigated whether aspirin blocked aerobic glycolysis of NSCLC cell to inhibit proliferation. Our results showed that aspirin inhibited viability, PCNA expression, ability of colony formation, and reduced level of two glycolysis products, pyruvic acid and lactic acid, accompanied with reduced mitochondrial membrane potential (MMP), PGC-1α expression and ROS production to induce mitochondrial dysfunction in NSCLC cells. AMPK and mitochondrial-localized deacetylase sirtuin3 (SIRT3) were identified as the relevant molecular targets in glycolysis, but function mechanism and relationship between AMPK and SIRT3 for aspirin induced glycolysis inhibition remain unknown in cancer cells. The investigation of underlying mechanisms here indicated that aspirin activated AMPK pathway in dose- and time-dependent manners to inhibit aerobic glycolysis and proliferation by upregulating SIRT3 after application of compound C (CC), an inhibitor of AMPK activity or SIRT3 siRNA. Upon activation of SIRT3, aspirin promoted the release of hexokinase-II (HK-II) from mitochondria outer membrane to cytosol by deacetylating cyclophilin D (CypD). Consistently, aspirin significantly inhibited the growth of NSCLC xenografts and exhibited antitumor activity probably through AMPK/SIRT3/HK-II pathway in vivo. Collectively, AMPK/SIRT3/HK-II pathway plays a critical role in anticancer effects of aspirin, and our findings might serve as potential target for clinical practice and chemoprevention of aspirin in NSCLC.
    Keywords:  AMPK; Aerobic glycolysis; Aspirin; Non-small cell lung cancer; Proliferation; SIRT3
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175208
  140. Drug Deliv. 2022 Dec;29(1): 2705-2712
    Prostate-specific membrane antigen targeted, glutathione-sensitive nanoparticles loaded with docetaxel and enzalutamide for the delivery to prostate cancer.
    Yang Chen, Zhenyu Xu, Tingxun Lu, Jia Luo, Hua Xue.
      Prostate cancer (PCa) is the most common malignant tumor in men. Chemotherapy with docetaxel (DTX) and novel hormonal agents such as enzalutamide (EZL) and abiraterone are the preferred first-line therapeutic regimens. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of PCa cells. This study aimed to prepare a PSMA targeted (Glutamate-Urea-Lysine, GUL ligand modified), glutathione (GSH)-sensitive (Cystamine, SS), DTX and EZL co-loaded nanoparticles (GUL-SS DTX/EZL-NPs) to treat PCa. Polyethylene glycol (PEG) was conjugated with oleic acid (OA) using a GSH-sensitive ligand: cystamine (PEG-SS-OA). GUL was covalently coupled to PEG-SS-OA to achieve GUL-PEG-SS-OA. GUL-PEG-SS-OA was used to prepare GUL-SS DTX/EZL-NPs. To evaluate the in vitro and in vivo efficiency of the system, human prostate cancer cell lines and PCa cells bearing mice were applied. Single drug-loaded nanoparticle and free drugs systems were utilized for the comparison of the anticancer ability. GUL-SS DTX/EZL-NPs showed a size of 143.7 ± 4.1 nm, with a PDI of 0.162 ± 0.037 and a zeta potential of +29.1 ± 2.4 mV. GUL-SS DTX/EZL-NPs showed high cancer cell uptake of about 70%, as well as higher cell growth inhibition efficiency (a maximum 79% of cells were inhibited after treatment) than single drug-loaded NPs and free drugs. GUL-SS DTX/EZL-NPs showed the most prominent tumor inhibition ability and less systemic toxicity. The novel GUL-SS DTX/EZL-NPs could be used as a promising system for PCa therapy.
    Keywords:  Prostate cancer; docetaxel; enzalutamide; glutathione responsive; nanoparticles; prostate-specific membrane antigen
    DOI:  https://doi.org/10.1080/10717544.2022.2110998
  141. RSC Adv. 2022 Aug 04. 12(34): 21690-21703
    Mitochondria-targeted alginate/triphenylphosphonium-grafted-chitosan for treatment of hepatocellular carcinoma.
    Kholoud K Arafa, Mohamed A Hamzawy, Shaker A Mousa, Ibrahim M El-Sherbiny.
      Mitochondrial targeting of anticancer drugs can effectively eradicate chemotherapy-refractory cells through different mechanisms. This work presents the rational designing of mitochondria-targeted core-shell polymeric nanoparticles (NPs) for efficient delivery of doxorubicin (DOX) to the hepatic carcinoma mitochondria. DOX was electrostatically nano-complexed with sodium alginate (SAL) then coated with mitotropic triphenylphosphonium-grafted chitosan (TPP+-g-CS) nanoshell. Polyvinyl alcohol (PVA) was co-solubilized into the TPP+-g-CS solution to enhance the stability of the developed NPs. The optimum NPs formula is composed of TPP+-g-CS (0.05% w/v) coating a DOX-SAL core complex (0.05% w/v), with 0.2% PVA relative to CS (w/w). The optimum NPs attained an entrapment efficiency of 63.33 ± 10.18%; exhibited a spherical shape with particle size of 70-110 nm and a positive surface charge which enhances mitochondrial uptake. FTIR and DSC studies results were indicative of an efficacious poly-complexation. In vitro biological experiments proved that the developed mitotropic NPs exhibited a significantly lower IC50, effectively induced apoptotic cell death and cell cycle arrest. Moreover, the in vivo studies demonstrated an enhanced antitumor bioactivity for the mitotropic NPs along with a reduced biological toxicity profile. In conclusion, this study proposes a promising nanocarrier system for the efficient targeting of DOX to the mitochondria of hepatic tumors.
    DOI:  https://doi.org/10.1039/d2ra03240f
  142. Endocrinol Metab Clin North Am. 2022 Sep;pii: S0889-8529(22)00023-8. [Epub ahead of print]51(3): 437-458
    Lipid and Lipoprotein Metabolism.
    Kenneth R Feingold.
      The exogenous lipoprotein pathway starts with the incorporation of dietary lipids into chylomicrons in the intestine. Chylomicron triglycerides are metabolized in muscle and adipose tissue and chylomicron remnants are formed, which are removed by the liver. The endogenous lipoprotein pathway begins in the liver with the formation of very low-density lipoprotein particles (VLDL). VLDL triglycerides are metabolized in muscle and adipose tissue forming intermediate-density lipoprotein (IDL), which may be taken up by the liver or further metabolized to low-density lipoprotein (LDL). Reverse cholesterol transport begins with the formation of nascent high-density lipoprotein (HDL) by the liver and intestine that acquire cholesterol from cells resulting in mature HDL. The HDL then transports the cholesterol to the liver either directly or indirectly by transferring the cholesterol to VLDL or LDL.
    Keywords:  Apolipoproteins; Chylomicrons; HDL; LDL; Lipoprotein (a); Reverse cholesterol transport; VLDL
    DOI:  https://doi.org/10.1016/j.ecl.2022.02.008
  143. J Cancer Res Clin Oncol. 2022 Aug 16.
    The benefits of vitamin A as a complementary treatment for oncology patients: a systematic review.
    Theresa Retzlaff, Jennifer Dörfler, Sabine Kutschan, Maren Freuding, Jutta Hübner.
       PURPOSE: Vitamin A and its derivatives positively influence the differentiation of epithelia and other tissues and prevent the proliferation of preneoplastic and neoplastic cells. Vitamin A is therefore taken into account as a potential supporting factor in cancer therapy.
    METHODS: In November 2020, a systematic search was conducted searching five electronic databases (EMBASE, Cochrane, PsycINFO, CINAHL and Medline) to find studies looking at the effects of using vitamin A as a complementary therapy for cancer patients. From all 12,823 search results, 9 publications referring to 9 studies with 4296 patients were included in this systematic review.
    RESULTS: The patients treated with vitamin A were diagnosed with various cancers and stages. Outcome variables were overall survival of cancer, progression-free survival, occurrence of second primary tumours and recurrences, improvement of chronic radiation-induced proctopathy and side effects of vitamin A. For the most part, the studies had a limited methodological quality. In summary, it can be said that due to the methodological deficiencies of the studies, no concrete statement can be made regarding the prolongation of overall survival and progression-free survival. There is also no evidence of the benefit of vitamin A in the treatment of chronic radiation-induced proctopathy, which can be attributed to methodological deficiencies in the study, as well. In the studies that report on side effects, it becomes clear that side effects, such as mucocutaneous symptoms, temporary increase in liver enzymes and gastrointestinal side effects occur more frequently in the group with vitamin A intervention.
    CONCLUSION: The limited interpretability of the results due to the methodological deficiencies of the included studies does not allow a final statement on the benefits of vitamin A as a complementary treatment for cancer patients.
    Keywords:  Beta-carotene; Cancer treatment; Drug side effects; Retinyl palmitate; Vitamin A
    DOI:  https://doi.org/10.1007/s00432-022-04224-6
  144. PLoS One. 2022 ;17(8): e0271634
    High fat diets induce early changes in gut microbiota that may serve as markers of ulterior altered physiological and biochemical parameters related to metabolic syndrome. Effect of virgin olive oil in comparison to butter.
    Natalia Andújar-Tenorio, Isabel Prieto, Antonio Cobo, Ana M Martínez-Rodríguez, Marina Hidalgo, Ana Belén Segarra, Manuel Ramírez, Antonio Gálvez, Magdalena Martínez-Cañamero.
      Butter and virgin olive oil (EVOO) are two fats differing in their degree of saturation and insaponifiable fraction. EVOO, enriched in polyphenols and other minority components, exerts a distinct effect on health. Using next generation sequencing, we have studied early and long-term effects of both types of fats on the intestinal microbiota of mice, finding significant differences between the two diets in the percentage of certain bacterial taxa, correlating with hormonal, physiological and metabolic parameters in the host. These correlations are not only concomitant, but most noticeably some of the changes detected in the microbial percentages at six weeks are correlating with changes in physiological values detected later, at twelve weeks. Desulfovibrionaceae/Desulfovibrio/D. sulfuricans stand out by presenting at six weeks a statistically significant higher percentage in the butter-fed mice with respect to the EVOO group, correlating with systolic blood pressure, food intake, water intake and insulin at twelve weeks. This not only suggests an early implication in the probability of developing altered physiological and biochemical responses later on in the host lifespan, but also opens the possibility of using this genus as a marker in the risk of suffering different pathologies in the future.
    DOI:  https://doi.org/10.1371/journal.pone.0271634
  145. J Ovarian Res. 2022 Aug 13. 15(1): 93
    Targeting purine metabolism in ovarian cancer.
    Jingchun Liu, Shasha Hong, Jiang Yang, Xiaoyi Zhang, Ying Wang, Haoyu Wang, Jiaxin Peng, Li Hong.
      Purine, an abundant substrate in organisms, is a critical raw material for cell proliferation and an important factor for immune regulation. The purine de novo pathway and salvage pathway are tightly regulated by multiple enzymes, and dysfunction in these enzymes leads to excessive cell proliferation and immune imbalance that result in tumor progression. Maintaining the homeostasis of purine pools is an effective way to control cell growth and tumor evolution, and exploiting purine metabolism to suppress tumors suggests interesting directions for future research. In this review, we describe the process of purine metabolism and summarize the role and potential therapeutic effects of the major purine-metabolizing enzymes in ovarian cancer, including CD39, CD73, adenosine deaminase, adenylate kinase, hypoxanthine guanine phosphoribosyltransferase, inosine monophosphate dehydrogenase, purine nucleoside phosphorylase, dihydrofolate reductase and 5,10-methylenetetrahydrofolate reductase. Purinergic signaling is also described. We then provide an overview of the application of purine antimetabolites, comprising 6-thioguanine, 6-mercaptopurine, methotrexate, fludarabine and clopidogrel. Finally, we discuss the current challenges and future opportunities for targeting purine metabolism in the treatment-relevant cellular mechanisms of ovarian cancer.
    Keywords:  Antimetabolites; Metabolizing enzyme; Ovarian cancer; Purine metabolism; Purinergic signaling
    DOI:  https://doi.org/10.1186/s13048-022-01022-z
  146. Mol Cell Biochem. 2022 Aug 13.
    Anti-cancer effect of in vivo inhibition of nitric oxide synthase in a rat model of breast cancer.
    Nikolay Avtandilyan, Hayarpi Javrushyan, Mikayel Ginovyan, Anna Karapetyan, Armen Trchounian.
      Increased expression of nitric oxide synthase (NOS) is associated with different cancers such as cervical, breast, lung, brain, and spinal cord. Inhibition of NOS activity has been suggested as potential tool to prevent breast cancer. The anti-tumor therapeutic effect of L-nitro arginine methyl ester (L-NAME), NOS inhibitor, using in vivo models is currently under investigation. We hypothesized that L-NAME will show an anti-tumor effect by delaying a progression of breast cancer via a modulation of cell death and proliferation, and angiogenesis. We used a novel model of anti-cancer treatment by the administration of L-NAME (30 mg/kg in a day, intraperitoneal) injected every third day for five weeks to rat model of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumor. Concentrations of nitrite anions, polyamines, malondialdehyde, NH4+ levels, and arginase activity in the blood were decreased in DMBA + L-NAME-treated rats compared with DMBA rats. The mortality rates, tumor number, weight, and volume, as well as the histopathological grade of breast cancer were also significantly reduced. In addition, L-NAME treatment showed a delay in tumor formation, and in body weight compared with rats administrated only with DMBA. In conclusion, our data show that L-NAME is a promising anti-cancer agent to treat breast cancer, which can lead to development of anti-tumor therapeutic tools in future.
    Keywords:  7,12-dimethylbenz[a]anthracene; Arginase; L-NAME; Nitric oxide; Polyamine; Tumor prevention
    DOI:  https://doi.org/10.1007/s11010-022-04489-y
  147. Prostate. 2022 Aug 18.
    Prostate cancer cells demonstrate unique metabolism and substrate adaptability acutely after androgen deprivation therapy.
    Mikolaj J Filon, Amani A Gillette, Bing Yang, Tariq A Khemees, Melissa C Skala, David F Jarrard.
       BACKGROUND: Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone-sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate-resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment.
    METHODS: A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4-2 and DU145.
    RESULTS: Mass spectrometry analysis of LNCaP pre- and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2-Deoxy- d-glucose(2-DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2-DG results in synergistic cell death, a result not seen with simultaneous administration.
    CONCLUSIONS: Hormone-sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2-DG) as a sequential treatment after ADT may be promising.
    Keywords:  androgen deprivation therapy; mass spectrometry; metabolism; optical metabolic imaging; prostate cancer
    DOI:  https://doi.org/10.1002/pros.24428
  148. Talanta. 2022 Aug 02. pii: S0039-9140(22)00560-4. [Epub ahead of print]252 123764
    A pH-sensitive field-effect transistor for monitoring of cancer cell external acid environment.
    Ling Xiao, Kun Li, Binzhu Liu, Jiyuan Tu, Tingxian Li, Yu-Tao Li, Guo-Jun Zhang.
      The external acid environment of cancer cells is different from that of normal cells, making a profound impact on cancer progression. Here we report a simple poly-l-lysine-modified graphene field-effect transistor (PLL@G-FET) for in situ monitoring of extracellular acidosis around cancer cells. PLL is a well-known material with good biocompatibility and is rich in amino groups that are sensitive to hydrogen ions. After a simple drop-casting of PLL on the reduced graphene oxide (RGO) FET surface, the PLL@G-FET was able to realize the real-time monitoring of the localized pH change of cancer cells after the cancer cells were grown on the device. The PLL@G-FET sensor achieved a Nernstian value of 52.9 mV/pH in phosphate buffer saline from pH 4.0 to 8.0. In addition, the sensor exhibited excellent biocompatibility as well as good anti-interference ability in the cell culture medium. Furthermore, the device was used to real-time monitor the extracellular pH changes of MCF-7 cells under the intervention of different concentrations of drugs. This developed pH-sensitive FET provides a new method to study the extracellular acid environment in situ and helps us to enhance our understanding of cancer cell metabolism.
    Keywords:  External acid environment; Field-effect transistor; Monitoring; Poly-l-lysine; pH
    DOI:  https://doi.org/10.1016/j.talanta.2022.123764
  149. Small. 2022 Aug 20. e2203325
    A Supramolecular Self-Assembling Nanoagent by Inducing Intracellular Aggregation of PSMA for Prostate Cancer Molecularly Targeted Theranostics.
    Weijie Zhang, He Wang, Tianjiao Wang, Dan Ding, Jianquan Hou, Yang Shi, Yuhua Huang.
      Prostate cancer (PCa) with prostate-specific membrane antigen (PSMA)-specific high expression is well suited for molecularly targeted theranostics. PSMA expression correlates with the malignancy of PCa, and its dimeric form can promote tumor progression by exerting enzymatic activity to activate downstream signal transduction. However, almost no studies have shown that arresting the procancer signaling of the PSMA receptors themselves can cause tumor cell death. Meanwhile, supramolecular self-assembling peptides are widely used to design anticancer agents due to their unique and excellent properties. Here, a PSMA-targeting supramolecular self-assembling nanotheranostic agent, DBT-2FFGACUPA, which actively targets PSMA receptors on PCa cell membranes and induces them to enter the cell and form large aggregates, is developed. This process not only selectively images PSMA-positive tumor cells but also suppresses the downstream procancer signals of PSMA, causing tumor cell death. This work provides an alternative approach and an advanced agent for molecularly targeted theranostics options in PCa that can induce tumor cell death without relying on any reported anticancer drugs.
    Keywords:  intracellular aggregation; molecularly targeted theranostics; prostate cancer; prostate-specific membrane antigen (PSMA); supramolecular self-assembling peptides
    DOI:  https://doi.org/10.1002/smll.202203325
  150. Am J Cancer Res. 2022 ;12(7): 2920-2949
    Breast cancer: molecular mechanisms of underlying resistance and therapeutic approaches.
    Muhammad Tufail, Jia Cui, Changxin Wu.
      Breast cancer (BC) affects over 250,000 women in the US each year. Drug-resistant cancer cells are responsible for most breast cancer fatalities. Scientists are developing novel chemotherapeutic drugs and targeted therapy combinations to overcome cancer cell resistance. Combining drugs can reduce the chances of a tumor developing resistance to treatment. Clinical research has shown that combination chemotherapy enhances or improves survival, depending on the patient's response to treatment. Combination therapy is a highly successful supplemental cancer treatment. This review sheds light on intrinsic resistance to BC drugs and the importance of combination therapy for BC treatment. In addition to recurrence and metastasis of BC, the article discussed biomarkers for BC.
    Keywords:  Breast cancer; breast cancer biomarkers; breast cancer metastasis; breast cancer recurrence; combination therapies; intrinsic/acquired resistance
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