bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–08–07
129 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Biopolymeric nanoparticles based effective delivery of bioactive compounds toward the sustainable development of anticancerous therapeutics.
  2. Nanomaterials-based photosensitizers and delivery systems for photodynamic cancer therapy.
  3. A reactive oxygen species-replenishing coordination polymer nanomedicine disrupts redox homeostasis and induces concurrent apoptosis-ferroptosis for combinational cancer therapy.
  4. Therapeutic Potential of Different Natural Products for the Treatment of Alzheimer's Disease.
  5. Metabolic intervention liposome for targeting glutamine-addiction of breast cancer.
  6. Targeting KRAS mutant cancers: from druggable therapy to drug resistance.
  7. Self-deliverable and self-immolative prodrug nanoassemblies as tumor targeted nanomedicine with triple cooperative anticancer actions.
  8. Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy.
  9. Fungal Mushrooms: A Natural Compound With Therapeutic Applications.
  10. Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor.
  11. Epigallocatechin gallate as a nutraceutical to potentially target the metabolic syndrome: novel insights into therapeutic effects beyond its antioxidant and anti-inflammatory properties.
  12. Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond.
  13. pH-responsive albumin-coated biopolymeric nanoparticles with lapatinab for targeted breast cancer therapy.
  14. Therapeutical and Nutraceutical Roles of Cyanobacterial Tetrapyrrole Chromophore: Recent Advances and Future Implications.
  15. Accurate programmed multifunctional nano-missiles for self-promoted deep delivery and synergistic cascade tumor therapy: Tactfully collaborating chemosynthesis with tumor microenvironment remodeling.
  16. Enzyme-loaded glycogen nanoparticles with tumor-targeting Activatable host-guest supramolecule for augmented chemodynamic therapy.
  17. Glucose deprivation reduces proliferation and motility, and enhances the anti-proliferative effects of paclitaxel and doxorubicin in breast cell lines in vitro.
  18. Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer.
  19. A review of the anti-diabetic potential of saffron.
  20. Microorganism-enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy.
  21. Nanoparticulate drugs and vaccines: Breakthroughs and bottlenecks of repurposing in breast cancer.
  22. Vitamin C Sensitizes Pancreatic Cancer Cells to Erastin-Induced Ferroptosis by Activating the AMPK/Nrf2/HMOX1 Pathway.
  23. Nanoparticles-based delivery system and its potentials in treating central nervous system disorders.
  24. Puzzling Out Iron Complications in Cancer Drug Resistance.
  25. Glycyrrhetinic acid-cyclodextrin grafted pullulan nanoparticles loaded doxorubicin as a liver targeted delivery carrier.
  26. Ferulic acid: An extraordinarily neuroprotective phenolic acid with anti-depressive properties.
  27. An update on nutritional profile, phytochemical compounds, health benefits, and potential applications in the food industry of pulses seed coats: A comprehensive review.
  28. Recent progress in the application of plant-based colloidal drug delivery systems in the pharmaceutical sciences.
  29. Multifunctional theranostic nanoplatform loaded with autophagy inhibitor for enhanced photothermal cancer therapy under mild near-infrared irradiation.
  30. Yolk-shell shaped Au-Bi2S3 heterostructure nanoparticles for controlled drug release and combined tumor therapy.
  31. Modified Bacterial Cellulose for Biomedical Applications.
  32. Glutamine metabolism modulates chondrocyte inflammatory response.
  33. Polyethylene Glycol-Stabilized Zein Nanoparticles Containing Gallic Acid.
  34. PEGylated SLN as a Promising Approach for Lymphatic Delivery of Gefitinib to Lung Cancer.
  35. Argininosuccinate synthase 1, arginine deprivation therapy and cancer management.
  36. A microfluidic approach to fabricate sucrose decorated liposomes with increased uptake in breast cancer cells.
  37. Selenium modulates cancer cell response to pharmacologic ascorbate.
  38. Tin-loaded mesoporous silica nanoparticles: Antineoplastic properties and genotoxicity assessment.
  39. Empagliflozin containing chitosan-alginate nanoparticles in orodispersible film: preparation, characterization, pharmacokinetic evaluation and its in-vitro anticancer activity.
  40. Recent advances in erythrocyte membrane-camouflaged nanoparticles for the delivery of anti-cancer therapeutics.
  41. Specific KRAS-Mutant Cancers Are Sensitive to Inhibition of V-type ATPases.
  42. CuS NP-based nanocomposite with photothermal and augmented-photodynamic activity for magnetic resonance imaging-guided tumor synergistic therapy.
  43. Photodynamic Effects of Thuja occidentalis on Lung Cancer Cells.
  44. Identifying the Antitumor Effects of Curcumin on Lung Adenocarcinoma Using Comprehensive Bioinformatics Analysis.
  45. Formulation, characterization and cellular toxicity assessment of a novel bee-venom microsphere in prostate cancer treatment.
  46. Fucoidan-based nanomaterial and its multifunctional role for pharmaceutical and biomedical applications.
  47. Nanoparticle-Based Inhalation Therapy for Pulmonary Diseases.
  48. The Updated Review on Plant Peptides and Their Applications in Human Health.
  49. Sustained delivery of gemcitabine via in situ injectable mussel-inspired hydrogels for the local therapy of pancreatic cancer.
  50. A novel carbon-nanodots-based theranostic nano-drug delivery system for mitochondria-targeted imaging and glutathione-activated delivering camptothecin.
  51. Polysaccharide-based nano-delivery systems for encapsulation, delivery, and pH-responsive release of bioactive ingredients.
  52. Chitosan reduces inflammation and protects against oxidative stress in a hyperlipidemic rat model: relevance to nonalcoholic fatty liver disease.
  53. Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors.
  54. Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma.
  55. Localized, on-demand, sustained drug delivery from biopolymer-based materials.
  56. Targeting microbiota-host interactions with resveratrol on cancer: Effects and potential mechanisms of action.
  57. [6]-Gingerol induces Caspase-Dependent Apoptosis in Bladder Cancer cells via MAPK and ROS Signaling.
  58. Targeted delivery of irinotecan to colon cancer cells using epidermal growth factor receptor-conjugated liposomes.
  59. Metabolic targeting of malignant tumors: a need for systemic approach.
  60. Aquasomes: Advanced vesicular-based nanocarrier systems.
  61. Kaempferol as a potential neuroprotector in Alzheimer's disease.
  62. Bioactive Flavonoids: A Comprehensive Review on Pharmacokinetics and Analytical Aspects.
  63. Biodegradable and removable implants for controlled drug delivery and release application.
  64. Development and optimization of a tamsulosin nanostructured lipid carrier loaded with saw palmetto oil and pumpkin seed oil for treatment of benign prostatic hyperplasia.
  65. Connecting Metabolic Rewiring With Phenotype Switching in Melanoma.
  66. Brown-fat-mediated tumour suppression by cold-altered global metabolism.
  67. Local Drug Delivery Strategies for Glioblastoma Treatment.
  68. The Mechanisms of Ferroptosis and the Applications in Tumor Treatment: Enemies or Friends?
  69. Review of phytochemical and nutritional characteristics and food applications of Citrus L. fruits.
  70. A dual-responsive "Yin-Yang" photothermal delivery system to accelerate Parthenolide anti-tumor efficacy.
  71. Research Progress Based on Regulation of Tumor Microenvironment Redox and Drug-Loaded Metal-Organic Frameworks.
  72. An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinations.
  73. Vitamin C-induced competitive binding of HIF-1α and p53 to ubiquitin E3 ligase CBL contributes to anti-breast cancer progression through p53 deacetylation.
  74. Natural Phenylethanoid Supplementation Alleviates Metabolic Syndrome in Female Mice Induced by High-Fructose Diet.
  75. Folic Acid-Modified Cyclodextrin Multivalent Supramolecular Assembly for Photodynamic Therapy.
  76. A review of recent progress in improving the bioavailability of nutraceutical-loaded emulsions after oral intake.
  77. Improving cellular uptake and bioavailability of periplocymarin-linoleic acid prodrug by combining PEGylated liposome.
  78. Metallo-alginate hydrogel can potentiate microwave tumor ablation for synergistic cancer treatment.
  79. Nanocrystals for controlled delivery: State of the art and approved drug products.
  80. Nanogels as Novel Nanocarrier Systems for Efficient Delivery of CNS Therapeutics.
  81. Cichorium intybus bio-callus synthesized silver nanoparticles: a promising antioxidant, antibacterial and anticancer compound.
  82. De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer.
  83. Nanoparticles in ocular applications and their potential toxicity.
  84. Amino-functionalized cross-linked cellulosic fabric with antibacterial, UV protection, and coloring effects using folic acid.
  85. A simple but efficient tumor-targeted nanoparticle delivery system constructed by oleic acid.
  86. Development and Characterization of Celecoxib Solid Self-nanoemulsifying Drug Delivery Systems (S-SNEDDS) Prepared Using Novel Cellulose-Based Microparticles as Adsorptive Carriers.
  87. Antiglycation, antioxidant and cytotoxicity activities of crude extract of Turnera ulmifolia L. before and after microencapsulation process.
  88. HXV2O5 Nanocatalysts Combined with Ultrasound for Triple Amplification of Oxidative Stress to Enhance Cancer Catalytic Therapy.
  89. Curcumin attenuates Cr (VI)-induced cell growth and migration by targeting autophagy-dependent reprogrammed metabolism.
  90. Preparation of graphene oxide/polydopamine-curcumin composite nanomaterials and its antibacterial effect against Staphylococcus aureus induced by white light.
  91. Cycloacceleration of Reactive Oxygen Species Generation Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for Tumor Ferroptosis Therapy.
  92. Two-Wave Variable Nanotheranostic Agents for Dual-Mode Imaging-Guided Photo-Induced Triple-Therapy for Cancer.
  93. Breast cancer vaccines: New insights into immunomodulatory and nano-therapeutic approaches.
  94. Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma.
  95. Ferroptosis: A Specific Vulnerability of RAS-Driven Cancers?
  96. Medicinal plants and their secondary metabolites in alleviating knee osteoarthritis: A systematic review.
  97. Metformin Inhibits HaCaT Cell Proliferation Under Hyperlipidemia Through Reducing Reactive Oxygen Species via FOXO3 Activation.
  98. Injectable Depot Forming Thermoresponsive Hydrogel for Sustained Intrascleral Delivery of Sunitinib Using Hollow Microneedles.
  99. Curcumin enhances p-cresyl sulfate-induced cytotoxic effects on renal tubular cells.
  100. Microencapsulation of Dandelion (Taraxacum officinale L.) Leaf Extract by Spray Drying.
  101. The fractal viewpoint of tumors and nanoparticles.
  102. Regulation of p53 and survivin by Curcuma longa extract to caspase-3 dependent apoptosis in triple negative breast cancer cells.
  103. Sorbitan Monolaurate-Containing Liposomes Enhance Skin Cancer Cell Cytotoxicity and in Association with Microneedling Increase the Skin Penetration of 5-Fluorouracil.
  104. HIF signaling: A new propellant in bone regeneration.
  105. Customizing nano-chitosan for sustainable drug delivery.
  106. Mitophagy and oral cancers.
  107. Amphiphilic Dendritic Nanomicelle-Mediated Delivery of Gemcitabine for Enhancing the Specificity and Effectiveness.
  108. Physiopathology of nonalcoholic fatty liver disease: from diet to nutrigenomics.
  109. Betalains: colours for human health.
  110. Bidirectional effects and mechanisms of traditional Chinese medicine.
  111. An anti-bacterial and anti-cancer fibrous membrane with multiple therapeutic effects for prevention of pancreatic cancer recurrence.
  112. Matrix metalloproteinase-responsive collagen-oxidized hyaluronic acid injectable hydrogels for osteoarthritic therapy.
  113. Antitumor Effects of a Solid Lipid Nanoparticle Loaded with Gemcitabine and Oxaliplatin on the Viability, Apoptosis, Autophagy and Hsp90 of Ovarian Cancer Cells.
  114. Effective dose/duration of natural flavonoid quercetin for treatment of diabetic nephropathy: A systematic review and meta-analysis of rodent data.
  115. Functional two-dimensional iron-based nanosheets for synergistic immunotherapy, phototherapy and chemotherapy of tumor.
  116. Reactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment.
  117. α-Fe2O3 based nanotherapeutics for near-infrared/dihydroartemisinin dual-augmented chemodynamic antibacterial therapy.
  118. Genetically engineered bacteria-mediated multi-functional nanoparticles for synergistic tumor-targeting therapy.
  119. Augmenting apoptosis-mediated anticancer activity of lactoperoxidase and lactoferrin by nanocombination with copper and iron hybrid nanometals.
  120. Biodegradable Polymer Matrix Composites Containing Graphene-Related Materials for Antibacterial Applications: A Critical Review.
  121. Anti-tumor immunity and ferroptosis of hepatocellular carcinoma are enhanced by combined therapy of sorafenib and delivering modified GO-based PD-L1 siRNAs.
  122. FDA-Approved Drugs to Treat Overweight and Obesity.
  123. MYC as a therapeutic target for the treatment of triple-negative breast cancer: preclinical investigations with the novel MYC inhibitor, MYCi975.
  124. Chemo-photothermal therapeutic effect of chitosan-gelatin hydrogels containing methotrexate and melanin on a collagen-induced arthritis mouse model.
  125. DNA Origami as a Nanomedicine for Targeted Rheumatoid Arthritis Therapy through Reactive Oxygen Species and Nitric Oxide Scavenging.
  126. Recent Advances on the Role of ATGL in Cancer.
  127. High endothelial venules as potential gateways for therapeutics.
  128. The Japanese Quail Chorioallantoic Membrane as a Model to Study an Amphiphilic Gradient copoly(2-Oxazoline)s- Based Drug Delivery System for Photodynamic Diagnosis and Therapy Research.
  129. Discovery of Novel Tyrosinase Inhibitors From Marine Cyanobacteria.
  1. Front Nutr. 2022 ;9 963413
    Biopolymeric nanoparticles based effective delivery of bioactive compounds toward the sustainable development of anticancerous therapeutics.
    Neelam Pathak, Pankaj Singh, Pradeep Kumar Singh, Swati Sharma, Rajat Pratap Singh, Anmol Gupta, Richa Mishra, Vivek Kumar Mishra, Manikant Tripathi.
      Nowadays, effective cancer therapy is a global concern, and recent advances in nanomedicine are crucial. Cancer is one of the major fatal diseases and a leading cause of death globally. Nanotechnology provides rapidly evolving delivery systems in science for treating diseases in a site-specific manner using natural bioactive compounds, which are gaining widespread attention. Nanotechnology combined with bioactives is a very appealing and relatively new area in cancer treatment. Natural bioactive compounds have the potential to be employed as a chemotherapeutic agent in the treatment of cancer, in addition to their nutritional benefits. Alginate, pullulan, cellulose, polylactic acid, chitosan, and other biopolymers have been effectively used in the delivery of therapeutics to a specific site. Because of their biodegradability, biopolymeric nanoparticles (BNPs) have received a lot of attention in the development of new anticancer drug delivery systems. Biopolymer-based nanoparticle systems can be made in a variety of ways. These systems have developed as a cost-effective and environmentally friendly solution to boost treatment efficacy. Effective drug delivery systems with improved availability, increased selectivity, and lower toxicity are needed. Recent research findings and current knowledge on the use of BNPs in the administration of bioactive chemicals in cancer therapy are summarized in this review.
    Keywords:  biopolymeric nanoparticles; cancer treatment; drug delivery; nanomedicines; natural bioactives
    DOI:  https://doi.org/10.3389/fnut.2022.963413
  2. Biomater Adv. 2022 Apr;pii: S2772-9508(22)00002-4. [Epub ahead of print]135 212725
    Nanomaterials-based photosensitizers and delivery systems for photodynamic cancer therapy.
    Xiao-Tong Yu, Shang-Yan Sui, Yu-Xuan He, Chen-Hao Yu, Qiang Peng.
      The increasing cancer morbidity and mortality requires the development of high-efficiency and low-toxicity anticancer approaches. In recent years, photodynamic therapy (PDT) has attracted much attention in cancer therapy due to its non-invasive features and low side effects. Photosensitizer (PS) is one of the key factors of PDT, and its successful delivery largely determines the outcome of PDT. Although a few PS molecules have been approved for clinical use, PDT is still limited by the low stability and poor tumor targeting capacity of PSs. Various nanomaterial systems have shown great potentials in improving PDT, such as metal nanoparticles, graphene-based nanomaterials, liposomes, ROS-sensitive nanocarriers and supramolecular nanomaterials. The small molecular PSs can be loaded in functional nanomaterials to enhance the PS stability and tumor targeted delivery, and some functionalized nanomaterials themselves can be directly used as PSs. Herein, we aim to provide a comprehensive understanding of PDT, and summarize the recent progress of nanomaterials-based PSs and delivery systems in anticancer PDT. In addition, the concerns of nanomaterials-based PDT including low tumor targeting capacity, limited light penetration, hypoxia and nonspecific protein corona formation are discussed. The possible solutions to these concerns are also discussed.
    Keywords:  Drug delivery; NIR; Nanotechnology; Phototherapy; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212725
  3. Acta Biomater. 2022 Aug 02. pii: S1742-7061(22)00459-7. [Epub ahead of print]
    A reactive oxygen species-replenishing coordination polymer nanomedicine disrupts redox homeostasis and induces concurrent apoptosis-ferroptosis for combinational cancer therapy.
    Zhuangzhuang Zhang, Yang Pan, Ju-E Cun, Junhua Li, Zhaoyuan Guo, Qingqing Pan, Wenxia Gao, Yuji Pu, Kui Luo, Bin He.
      Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapy such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo study revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity. STATEMENT OF SIGNIFICANCE: We develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular H2O2 and deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fe3+-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo study reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment.
    Keywords:  chemodynamic therapy; coordination polymer nanoparticle; ferroptosis; reactive oxygen species; redox dyshomeostasis
    DOI:  https://doi.org/10.1016/j.actbio.2022.07.055
  4. Oxid Med Cell Longev. 2022 ;2022 6873874
    Therapeutic Potential of Different Natural Products for the Treatment of Alzheimer's Disease.
    Biswajit Chakraborty, Nobendu Mukerjee, Swastika Maitra, Mehrukh Zehravi, Dattatreya Mukherjee, Arabinda Ghosh, Ehab El Sayed Massoud, Md Habibur Rahman.
      A high incidence of dementia (60-80%) and a high rate of memory loss are two of the most common symptoms of Alzheimer's disease (AD), which affects the elderly. Researchers have recommended that traditional Chinese medicine (TCM) and Indian medicines can be used to prevent and cure AD. Several studies have linked neuroinflammation linked to amyloid-β (Aβ) deposition in the brain to the pathophysiology of neurodegenerative disorders. As a result, more research is needed to determine the role of inflammation in neurodegeneration. Increased microglial activation, cytokine production, reactive oxygen species (ROS), and nuclear factor kappa B (NF-κB) all play a role in the inflammatory process of AD. This review focuses on the role of neuroinflammation in neuroprotection and the molecular processes used by diverse natural substances, phytochemicals, and herbal formulations in distinct signaling pathways. Currently, researchers are focusing on pharmacologically active natural compounds with the anti-neuroinflammatory potential, making them a possible contender for treating AD. Furthermore, the researchers investigated the limits of past studies on TCM, Indian Ayurveda, and AD. Numerous studies have been carried out to examine the effects of medicinal whole-plant extracts on AD. Clinical investigations have shown that lignans, flavonoids, tannins, polyphenols, triterpenoids, sterols, and alkaloids have anti-inflammatory, antiamyloidogenic, anticholinesterase, and antioxidant properties. This review summarizes information about numerous medicinal plants and isolated compounds used in the treatment of AD and a list of further references.
    DOI:  https://doi.org/10.1155/2022/6873874
  5. J Control Release. 2022 Jul 27. pii: S0168-3659(22)00453-9. [Epub ahead of print]
    Metabolic intervention liposome for targeting glutamine-addiction of breast cancer.
    Ming Wu, Qizhi Wang, Sai Chen, Zhanwei Zhou, Jing Li, Honghao Sun, Jiali Liu, Guangji Wang, Fang Zhou, Minjie Sun.
      The growth and rapid proliferation of tumor cells depend on both glycolysis and glutamine metabolism, leading to metabolic compensation. Here, dual inhibition on the metabolic plasticity by Glucose oxidase and Telaglenastat loaded liposome (Lip@GOx&Tel) were studied for intervening metabolic pathway on energy and material against breast cancer. Lip@GOx&Tel targeting inhibited the two nutrient supply mechanisms employed by tumor cells, reducing the supply of ATP production and biosynthesis precursors essential necessary for tumor, thereby eliciting anti-tumor and anti-metastasis effect. Meanwhile, Lip@GOx&Tel ingeniously amplify the therapeutic effect by up-regulating ROS and down-regulating GSH to disrupt redox homeostasis, thus resulting in inspiring 82% tumor suppression rate on 4 T1 tumor model. Moreover, our study solved the limitation of combination between protein drugs and small molecule drugs in vivo by using liposome nanoparticles with clinical translation value. In short, this work provides a unique perspective of nanomedicine for treating diseases from metabolic intervention.
    Keywords:  Breast cancer; Glutamine-addiction; Liposome nanomedicine; Metabolic intervention; Target delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.034
  6. Mol Cancer. 2022 Aug 04. 21(1): 159
    Targeting KRAS mutant cancers: from druggable therapy to drug resistance.
    Chunxiao Zhu, Xiaoqing Guan, Xinuo Zhang, Xin Luan, Zhengbo Song, Xiangdong Cheng, Weidong Zhang, Jiang-Jiang Qin.
      Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.
    Keywords:  Combination therapy; Druggable; KRAS mutations; Resistance
    DOI:  https://doi.org/10.1186/s12943-022-01629-2
  7. Biomaterials. 2022 Jul 18. pii: S0142-9612(22)00321-0. [Epub ahead of print]287 121681
    Self-deliverable and self-immolative prodrug nanoassemblies as tumor targeted nanomedicine with triple cooperative anticancer actions.
    Eunkyeong Jung, Seung Won Jeong, Yeongjong Lee, Chanhee Jeon, Hyunbin Shin, Nanhee Song, Yujin Lee, Dongwon Lee.
      Stimulus-responsive self-assembling prodrug-based nanomedicine has emerged as a novel paradigm in controlled drug delivery. All-trans retinoic acid (RA), one of vitamin A metabolites, induces apoptotic cancer cell death, but its clinical applications are limited by weak anticancer efficacy. To fully maximize the therapeutic potential of RA, we exploited the unique chemistry of arylboronic acid which undergoes hydrogen peroxide (H2O2)-triggered degradation to release quinone methide (QM) that alkylates glutathione (GSH) to disrupt redox homeostasis and is also converted into hydroxybenzyl alcohol (HBA) to suppress the expression of vascular endothelial growth factor (VEGF). Here, we report that boronated retinoic acid prodrug (RABA) can be formulated into self-deliverable nanoassemblies which release both RA and QM in a H2O2-triggered self-immolative manner to exert cooperative anticancer activities. RABA nanoassemblies exert anticancer effects by inducing reactive oxygen species (ROS)-mediated apoptosis, eliciting immunogenic cell death (ICD) and suppressing angiogenic VEGF expression. The excellent anticancer efficacy of RABA nanoassemblies can be explained by benefits of self-assembling prodrug-based drug self-delivery and cooperative anticancer actions. The design strategy of RABA would provide a new insight into the rational design of self-deliverable and self-immolative boronated prodrug nanoassemblies for targeted cancer therapy.
    Keywords:  Cancer; Drug self-delivery; Hybrid prodrug; Retinoic acid; Self-assembly
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121681
  8. Drug Deliv. 2022 Dec;29(1): 2513-2538
    Extracellular vesicles: emerging anti-cancer drugs and advanced functionalization platforms for cancer therapy.
    Manling Wu, Min Wang, Haoyuan Jia, Peipei Wu.
      Increasing evidences show that unmodified extracellular vesicles (EVs) derived from various cells can effectively inhibit the malignant progression of different types of tumors by delivering the bioactive molecules. Therefore, EVs are expected to be developed as emerging anticancer drugs. Meanwhile, unmodified EVs as an advanced and promising nanocarrier that is frequently used in targeted delivery therapeutic cargos and personalized reagents for the treatment and diagnosis of cancer. To improve the efficacy of EV-based treatments, researchers are trying to engineering EVs as an emerging nanomedicine translational therapy platform through biological, physical and chemical approaches, which can be broaden and altered to enhance their therapeutic capability. EVs loaded with therapeutic components such as tumor suppressor drugs, siRNAs, proteins, peptides, and conjugates exhibit significantly enhanced anti-tumor effects. Moreover, the design and preparation of tumor-targeted modified EVs greatly enhance the specificity and effectiveness of tumor therapy, and these strategies are expected to become novel ideas for tumor precision medicine. This review will focus on reviewing the latest research progress of functionalized EVs, clarifying the superior biological functions and powerful therapeutic potential of EVs, for researchers to explore new design concepts based on EVs and build next-generation nanomedicine therapeutic platforms.
    Keywords:  Engineered EVs; bioinspiration; cancer therapy; drug delivery; functionalization strategy
    DOI:  https://doi.org/10.1080/10717544.2022.2104404
  9. Front Pharmacol. 2022 ;13 925387
    Fungal Mushrooms: A Natural Compound With Therapeutic Applications.
    Rishi Man Chugh, Pooja Mittal, Namratha Mp, Tanu Arora, Tanima Bhattacharya, Hitesh Chopra, Simona Cavalu, Rupesh K Gautam.
      Fungi are extremely diverse in terms of morphology, ecology, metabolism, and phylogeny. Approximately, 130 medicinal activities like antitumor, immunomodulation, antioxidant, radical scavenging, cardioprotective and antiviral actions are assumed to be produced by the various varieties of medicinal mushrooms. The polysaccharides, present in mushrooms like β-glucans, micronutrients, antioxidants like glycoproteins, triterpenoids, flavonoids, and ergosterols can help establish natural resistance against infections and toxins.. Clinical trials have been performed on mushrooms like Agaricus blazei Murrill Kyowa for their anticancer effect, A. blazei Murrill for its antihypertensive and cardioprotective effects, and some other mushrooms had also been evaluated for their neurological effects. The human evaluation dose studies had been also performed and the toxicity dose was evaluated from the literature for number of mushrooms. All the mushrooms were found to be safe at a dose of 2000 mg/kg but some with mild side effects. The safety and therapeutic effectiveness of the fungal mushrooms had shifted the interest of biotechnologists toward fungal nanobiotechnology as the drug delivery system due to the vast advantages of nanotechnology systems. In complement to the vital nutritional significance of medicinal mushrooms, numerous species have been identified as sources of bioactive chemicals. Moreover, there are unanswered queries regarding its safety, efficacy, critical issues that affect the future mushroom medicine development, that could jeopardize its usage in the twenty-first century.
    Keywords:  Medicinal mushrooms; antiviral; cardioprotective; immune boosters; immunomodulation; radical scavenging
    DOI:  https://doi.org/10.3389/fphar.2022.925387
  10. Theranostics. 2022 ;12(12): 5272-5298
    Progress in advanced nanotherapeutics for enhanced photodynamic immunotherapy of tumor.
    Xiao Wei, Mingzhu Song, Guirong Jiang, Min Liang, Chunlan Chen, Zhiyong Yang, Liang Zou.
      Clinically, the conventional treatments of cancer are still often accompanied by tumor recurrence, metastasis and other poor prognosis. Nowadays, more attention has been paid to photodynamic therapy (PDT), which is regarded as an adjuvant antineoplastic strategy with superiorities in great spatiotemporal selectivity and minimal invasiveness. In addition to eliminating tumor cells via reactive oxygen species (ROS), more meaningfully, this phototherapy can trigger immunogenic cell death (ICD) that plays a vital role in photodynamic immunotherapy (PDIT). ICD-based PDIT holds some immunotherapeutic potential due to further enhanced antitumor efficacy by utilizing various combined therapies to increase ICD levels. To help the PDIT-related drugs improve pharmacokinetic properties, bioavailability and system toxicity, multifunctional nanocarriers can be reasonably designed for enhanced PDIT. In further consideration of severe hypoxia, low immunity and immune checkpoints in tumor microenvironment (TME), advanced nanotherapeutics-mediated PDIT has been extensively studied for boosting antitumor immunity by oxygen-augment, ICD-boosting, adjuvant stimulation and combined checkpoints blockade. Herein, this review will summarize different categories of nanocarriers consisting of their material type, targeting and stimuli-responsiveness. Moreover, we will focus on the latest progress of various strategies to enhance the antitumor immune effect for PDIT and elucidate their corresponding immune-activation mechanisms. Nevertheless, there are several thorny challenges in PDIT, including limited light penetration, tumor hypoxia, immune escape and the development of novel small-molecule compounds that replace immune checkpoint inhibitors (ICIs) for easy integration into nanosystems. It is hoped that these issues raised will be helpful to the preclinical study of nanotherapeutics-based PDIT, thus accelerating the transformation of PDIT to clinical practice.
    Keywords:  immunogenic cell death; nanotherapeutics; photodynamic therapy; tumor immunotherapy
    DOI:  https://doi.org/10.7150/thno.73566
  11. Crit Rev Food Sci Nutr. 2022 Aug 02. 1-23
    Epigallocatechin gallate as a nutraceutical to potentially target the metabolic syndrome: novel insights into therapeutic effects beyond its antioxidant and anti-inflammatory properties.
    Yonela Ntamo, Babalwa Jack, Khanyisani Ziqubu, Sithandiwe E Mazibuko-Mbeje, Bongani B Nkambule, Tawanda M Nyambuya, Sihle E Mabhida, Sidney Hanser, Patrick Orlando, Luca Tiano, Phiwayinkosi V Dludla.
      Epigallocatechin gallate (EGCG) is one of the most abundant and powerful flavonoids contained in green tea. Because of the global increase in green tea consumption, there has been a general interest in understanding its health benefits, including its bioactive compounds like EGCG. Indeed, preclinical evidence already indicates that EGCG demonstrated a strong antioxidant and anti-inflammatory properties that could be essential in protecting against metabolic syndrome. The current review explores clinical evidence reporting on the beneficial effects of EGCG supplementation in obese subjects or patients with diverse metabolic complications that include type 2 diabetes and cardiovascular disease. The discussion incorporates the impact of different formulations of EGCG, as well as the effective doses and treatment duration. Importantly, besides highlighting the potential use of EGCG as a nutraceutical, the current review also discusses crucial evidence related to its pharmaceutical development as an agent to hinder metabolic diseases, including its bioavailability and metabolism profile, as well as its well-known biological properties.
    Keywords:  Antioxidants; epigallocatechin gallate; green tea; inflammation; metabolic syndrome; nutraceuticals
    DOI:  https://doi.org/10.1080/10408398.2022.2104805
  12. Front Oncol. 2022 ;12 901951
    Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond.
    Abdellatif El Khayari, Najat Bouchmaa, Bouchra Taib, Zhiyun Wei, Ailiang Zeng, Rachid El Fatimy.
      Glioblastoma multiforme (GBM), a highly invasive and incurable tumor, is the humans' foremost, commonest, and deadliest brain cancer. As in other cancers, distinct combinations of genetic alterations (GA) in GBM induce a diversity of metabolic phenotypes resulting in enhanced malignancy and altered sensitivity to current therapies. Furthermore, GA as a hallmark of cancer, dysregulated cell metabolism in GBM has been recently linked to the acquired GA. Indeed, Numerous point mutations and copy number variations have been shown to drive glioma cells' metabolic state, affecting tumor growth and patient outcomes. Among the most common, IDH mutations, EGFR amplification, mutation, PTEN loss, and MGMT promoter mutation have emerged as key patterns associated with upregulated glycolysis and OXPHOS glutamine addiction and altered lipid metabolism in GBM. Therefore, current Advances in cancer genetic and metabolic profiling have yielded mechanistic insights into the metabolism rewiring of GBM and provided potential avenues for improved therapeutic modalities. Accordingly, actionable metabolic dependencies are currently used to design new treatments for patients with glioblastoma. Herein, we capture the current knowledge of genetic alterations in GBM, provide a detailed understanding of the alterations in metabolic pathways, and discuss their relevance in GBM therapy.
    Keywords:  GBM; genetic alteration; glioma therapy; glycolysis; metabolic genes
    DOI:  https://doi.org/10.3389/fonc.2022.901951
  13. Biomater Adv. 2022 Jul 21. pii: S2772-9508(22)00316-8. [Epub ahead of print]139 213039
    pH-responsive albumin-coated biopolymeric nanoparticles with lapatinab for targeted breast cancer therapy.
    Haroon Iqbal, Anam Razzaq, Naveed Ullah Khan, Saif Ur Rehman, Thomas J Webster, Run Xiao, Farid Menaa.
      One can enhance the therapeutic index of anti-cancer drugs using albumin as a tumor homing agent for targeted cancer therapy. Herein, we sought to load lapatinib (LAPA) into small albumin-coated biopolymeric (poly-lactic co-glycolic acid (PLGA)) nanoparticles (APL NPs) by an emulsification method to improve the anti-tumor efficacy of lapatinib. The prepared APL NPs exhibited a small spherical core with an average diameter of 120.5 ± 10.2 nm with a narrow particle size distribution, high drug loading capacity (LC of 9.65 ± 1.53 %), good entrapment efficiency (EE of 75.55 ± 3.25 %), enhanced colloidal stability and a pH-responsive controlled drug release profile. Their cell-uptake and cancer cell growth inhibition were significantly higher compared to free LAPA and uncoated PLGA-LAPA (UPL) NPs, most likely because aggressive breast tumor cells over-express albumin receptors and utilize albumin as nutrient source for their growth. In addition, APL NPs possessed enhanced tumor accumulation and prolonged blood residence time compared to free LAPA and UPL NPs, allowing for potent tumor growth inhibition while exhibiting excellent biosafety. In short, the current study exploited a new and simple strategy to concurrently improve the safety and efficacy of LAPA for breast cancer treatment.
    Keywords:  Albumin; Breast cancer; Encapsulation; Lapatinib; Nanoparticles; Therapy
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213039
  14. Front Microbiol. 2022 ;13 932459
    Therapeutical and Nutraceutical Roles of Cyanobacterial Tetrapyrrole Chromophore: Recent Advances and Future Implications.
    Kshetrimayum Birla Singh, Kaushalendra, Jay Prakash Rajan.
      Cyanobacteria have attracted the attention of researchers because of their promising role as primary and secondary metabolites in functional food and drug design. Due to an ever-increasing awareness of health and the use of natural products to avoid the onset of many chronic and lifestyle metabolic diseases, the global demand for the use of natural drugs and food additives has increased in the last few decades. There are several reports about the highly valuable cyanobacterial products such as carotenoids, vitamins, minerals, polysaccharides, and phycobiliproteins showing antioxidant, anti-cancerous, anti-inflammatory, hypoglycemic, and antimicrobial properties. Recently, it has been shown that allophycocyanin increases longevity and reduces the paralysis effect at least in Caenorhabditis elegans. Additionally, other pigments such as phycoerythrin and phycocyanin show antioxidative properties. Because of their high solubility in water and zero side effects, some of the cyanobacterial tetrapyrrole derivatives, i.e., pigments, facilitate an innovative and alternative way for the beverage and food industries in place of synthetic coloring agents at the commercial level. Thus, not only are the tetrapyrrole derivatives essential constituents for the synthesis of most of the basic physiological biomolecules, such as hemoglobin, chlorophyll, and cobalamin, but also have the potential to be used for the synthesis of synthetic compounds used in the pharmaceutical and nutraceutical industries. In the present review, we focused on the different aspects of tetrapyrrole rings in the drug design and food industries and addressed its remaining limitations to be used as natural nutrient supplements and therapeutic agents.
    Keywords:  antioxidants; phycobiliprotein; phycocyanin; tetrapyrrole; therapeutic agent
    DOI:  https://doi.org/10.3389/fmicb.2022.932459
  15. Theranostics. 2022 ;12(12): 5299-5316
    Accurate programmed multifunctional nano-missiles for self-promoted deep delivery and synergistic cascade tumor therapy: Tactfully collaborating chemosynthesis with tumor microenvironment remodeling.
    Runxin Lu, Siqi Wang, Zhongzhen Yang, Lin Zhou, Chunyan Yang, Yong Wu.
      Rationale: Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. The management of aggressive TNBC remains a formidable challenge. Tumor microenvironment (TME), with the unique features, which can serve as the "soil" for the growth and survival of tumor cells (the "seeds"), plays an important regulatory role in the occurrence, proliferation and metastasis of tumors. Catalytic tumor therapy, which can destroy the homeostasis of TME, affect the occurrence and progress of tumors in an all-round way and further magnify chemotherapy, is a quite potential tactic for TNBC-treatment. Methods: Herein, accurate programmed multifunctional cascade nano-missiles (GOx+L-Arg-NM/PTX-NM) composed of novel intelligent all-in-one "nano-rocket" (the drug delivery system) and "ammunitions" (the therapeutic agents) are innovatively constructed by mimicking the functionalities of military precision-guided missiles. Ammunitions can be precisely and effectively transported to the core region of TNBC (the "battlefield") by organic modification on the surface of nano-rocket via chemical means. Once successfully internalized by TNBC cells, the nano-missiles can automatically trigger relevant cascade reactions without external stimulation, prominently disrupt the homeostasis of TME, and produce a "bomb-like" attack on tumors, further promoting the chemotherapy. Results: Both in vitro and in vivo investigations indicated that the innovative nano-missiles could deliver ammunitions to the core area of TNBC to the utmost extent, dramatically ablate tumor and restrain tumor metastasis via orchestrated multimodal synergistic starvation/oxidation/gas/chemotherapy. Conclusion: The well-designed multifunctional nano-missiles may emerge as a new paradigm to suppress the malignant proliferation and metastasis of TNBC, offering a promising approach for the next generation cancer therapy.
    Keywords:  chemosynthesis; multimodal synergistic therapy; programmed nanodrug; self-promoted drug delivery; tumor microenvironment remodeling
    DOI:  https://doi.org/10.7150/thno.74550
  16. Int J Biol Macromol. 2022 Jul 28. pii: S0141-8130(22)01615-4. [Epub ahead of print]217 878-889
    Enzyme-loaded glycogen nanoparticles with tumor-targeting Activatable host-guest supramolecule for augmented chemodynamic therapy.
    Fuwei Yang, Wenjie Fang, Meiyang Yang, Weijun Chen, Jiamin Xu, Junze Wang, Wenhua Li, Bingke Zhao, Lipeng Qiu, Jinghua Chen.
      Chemodynamic therapy (CDT) has advantages in site-specific killing tumor and avoiding systemically side effect. Although numerous nano-systems have been developed to enhance the intracellular hydrogen peroxide (H2O2) for improving CDT effect, the biocompatibility of the materials limits their further biomedical applications. Herein glycogen, as a natural biological macromolecule, was used to construct a new targeted separable GOx@GF/HC nanoparticle system to deliver glucose oxidase (GOx) for CDT/starvation tumor therapy. Amination glycogen-ferrocene (GF) as a guest core and hyaluronic acid-β-cyclodextrin (HC) as a host shell were synthesized and self-assembled through host-guest interactions to deliver GOx. After being entered into tumor cells, GOx were released to catalyze glucose to produce gluconic acid and H2O2, which in turn cut off the nutrition of tumor cells for starvation therapy and enhanced the generation of OH with ferrous ion through Fenton reaction. Furthermore, GOx@GF/HC also exhibited remarkable tumor-targeting and tumor-suppression in vivo. Therefore, the GOx@GF/HC system can exert excellent synergistic effect of CDT and starvation therapy on cancer treatment through a cascade reaction, which have some potential application for the development of CDT tumor-treatment.
    Keywords:  Chemodynamic therapy; Glycogen; Tumor starvation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.183
  17. PLoS One. 2022 ;17(8): e0272449
    Glucose deprivation reduces proliferation and motility, and enhances the anti-proliferative effects of paclitaxel and doxorubicin in breast cell lines in vitro.
    Maitham A Khajah, Sarah Khushaish, Yunus A Luqmani.
       BACKGROUND: Breast cancer chemotherapy with high dose alkylating agents is severely limited by their collateral toxicity to crucial normal tissues such as immune and gut cells. Taking advantage of the selective dependence of cancer cells on high glucose and combining glucose deprivation with these agents could produce therapeutic synergy.
    METHODS: In this study we examined the effect of glucose as well as its deprivation, and antagonism using the non-metabolized analogue 2-deoxy glucose, on the proliferation of several breast cancer cell lines MCF7, MDA-MB-231, YS1.2 and pII and one normal breast cell line, using the MTT assay. Motility was quantitatively assessed using the wound healing assay. Lactate, as the end product of anaerobic glucose metabolism, secreted into culture medium was measured by a biochemical assay. The effect of paclitaxel and doxorubicin on cell proliferation was tested in the absence and presence of low concentrations of glucose using MTT assay.
    RESULTS: In all cell lines, glucose supplementation enhanced while glucose deprivation reduced both their proliferation and motility. Lactate added to the medium could substitute for glucose. The inhibitory effects of paclitaxel and doxorubicin were significantly enhanced when glucose concentration was decreased in the culture medium, requiring 1000-fold lesser concentration to achieve a similar degree of inhibition to that seen in glucose-containing medium.
    CONCLUSION: Our data show that a synergy was obtained by combining paclitaxel and doxorubicin with glucose reduction to inhibit cancer cell growth, which in vivo, might be achieved by applying a carbohydrate-restricted diet during the limited phase of application of chemotherapy; this could permit a dose reduction of the cytotoxic agents, resulting in greater tolerance and lesser side effects.
    DOI:  https://doi.org/10.1371/journal.pone.0272449
  18. Front Oncol. 2022 ;12 908487
    Capsaicin: A Two-Decade Systematic Review of Global Research Output and Recent Advances Against Human Cancer.
    Tomi Lois Adetunji, Femi Olawale, Chijioke Olisah, Ademola Emmanuel Adetunji, Adeyemi Oladapo Aremu.
      Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is one of the most important natural products in the genus Capsicum. Due to its numerous biological effects, there has been extensive and increasing research interest in capsaicin, resulting in increased scientific publications in recent years. Therefore, an in-depth bibliometric analysis of published literature on capsaicin from 2001 to 2021 was performed to assess the global research status, thematic and emerging areas, and potential insights into future research. Furthermore, recent research advances of capsaicin and its combination therapy on human cancer as well as their potential mechanisms of action were described. In the last two decades, research outputs on capsaicin have increased by an estimated 18% per year and were dominated by research articles at 93% of the 3753 assessed literature. In addition, anti-cancer/pharmacokinetics, cytotoxicity, in vivo neurological and pain research studies were the keyword clusters generated and designated as thematic domains for capsaicin research. It was evident that the United States, China, and Japan accounted for about 42% of 3753 publications that met the inclusion criteria. Also, visibly dominant collaboration nodes and networks with most of the other identified countries were established. Assessment of the eligible literature revealed that the potential of capsaicin for mitigating cancer mainly entailed its chemo-preventive effects, which were often linked to its ability to exert multi-biological effects such as anti-mutagenic, antioxidant and anti-inflammatory activities. However, clinical studies were limited, which may be related to some of the inherent challenges associated with capsaicin in the limited clinical trials. This review presents a novel approach to visualizing information about capsaicin research and a comprehensive perspective on the therapeutic significance and applications of capsaicin in the treatment of human cancer.
    Keywords:  TRPV 1; anticancer; bibliometrics; cytotoxicity; vanilloid
    DOI:  https://doi.org/10.3389/fonc.2022.908487
  19. Nutr Metab Insights. 2022 ;15 11786388221095223
    A review of the anti-diabetic potential of saffron.
    Anis Sani, Ali Tajik, Seiied Sina Seiiedi, Razieh Khadem, Haniye Tootooni, Mohammadhossein Taherynejad, Nasim Sabet Eqlidi, Seyyed Mohammad Matin Alavi Dana, Niloofar Deravi.
      Diabetes mellitus is one of the most prevalent metabolic disorders that affect people of all genders, ages, and races. Medicinal herbs have gained attention from researchers and have been widely investigated for their antidiabetic potential. Saffron (Crocus sativus L.) and its main constituents, that is, crocin and crocetin, are natural carotenoid compounds, widely known to possess a wide spectrum of properties and induce pleiotropic anti-inflammatory, anti-oxidative, and neuro-protective effects. An increasing number of experimental, animal and human studies have investigated the effects and mechanism of action of these compounds and their potential therapeutic use in the treatment of diabetes. This narrative review presents the key findings of published clinical studies that examined the effects of saffron and/or its constituents in the context of diabetes mellitus. Moreover, an overview of the proposed underlying mechanisms mediating these effects, the medicinal applications of saffron, and the new findings regarding its effect on diabetes and various cellular and molecular mechanisms of action will be debated.
    Keywords:  Crocus sativus L.; Saffron; antioxidant; crocetin; crocin; diabetes mellitus
    DOI:  https://doi.org/10.1177/11786388221095223
  20. Biomaterials. 2022 Jul 21. pii: S0142-9612(22)00328-3. [Epub ahead of print]287 121688
    Microorganism-enabled photosynthetic oxygeneration and ferroptosis induction reshape tumor microenvironment for augmented nanodynamic therapy.
    Shuting Lu, Wei Feng, Xijuan Yao, Xinran Song, Jinhe Guo, Yu Chen, Zhongqian Hu.
      Nanodynamic therapy (NDT) based on reactive oxygen species (ROS) generation has been envisioned as a distinct modality for efficient cancer treatment. However, insufficient ROS generation and partial ROS consumption frequently limit the theraputic effect and outcome of NDT owing to the low oxygen (O2) tension and high glutathione (GSH) level in tumor microenvironment (TME). To circumvent these critical issues, we herein proposed and engineered the biodegradable GSH-depletion Mn(III)-riched manganese oxide nanospikes (MnOx NSs) with the photosynthetic bacterial cyanobacteria (Cyan) as a high-efficient and synergistic platform to reshape TME by simultaneously increasing oxygen content and decreasing GSH level. Specifically, under the trigger of acidity, MnOx NSs reacted with photosynthetic oxygen can generate toxic singlet oxygen (1O2). Moreover, MnOx NSs significantly reduced intracellular GSH, resulting in decreased GPX4 activity, which induced tumor cell non-apoptotic ferroptosis. Consequently, this combined strategy based on coadministration with Cyan and MnOx NSs demonstrated the superior antitumor efficacy via amplification of oxidative stress in 4T1 tumor-bearing mice for the synergetic oxygen-augmented nanodynamic/ferroptosis therapy. This work highlights a facile synergistic micro-/nano-system with the specific capability of reshaping TME to augment the sensitivity and therapeutic efficacy of NDT in solid hypoxic tumor therapy.
    Keywords:  Cyanobacteria; Ferroptosis; Manganese oxide nanospikes; Nanodynamic therapy; Photosynthesis
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121688
  21. J Control Release. 2022 Jul 29. pii: S0168-3659(22)00474-6. [Epub ahead of print]
    Nanoparticulate drugs and vaccines: Breakthroughs and bottlenecks of repurposing in breast cancer.
    Popat Kumbhar, Kapil Kole, Varsha Khadake, Pradnya Marale, Arehalli Manjappa, Sameer Nadaf, Rajendra Jadhav, Ajit Patil, Sachin Kumar Singh, Kamal Dua, Niraj Kumar Jha, John Disouza, Vandana Patravale.
      Breast cancer (BC) is a highly diagnosed and topmost cause of death in females worldwide. Drug repurposing (DR) has shown great potential against BC by overcoming major shortcomings of approved anticancer therapeutics. However, poor physicochemical properties, pharmacokinetic performance, stability, non-selectivity to tumors, and side effects are severe hurdles in repurposed drug delivery against BC. The variety of nanocarriers (NCs) has shown great promise in delivering repurposed therapeutics for effective treatment of BC via improving solubility, stability, tumor selectivity and reducing toxicity. Besides, delivering repurposed cargos via theranostic NCs can be helpful in the quick diagnosis and treatment of BC. Localized delivery of repurposed candidates through apt NCs can diminish the systemic side effects and improve anti-tumor effectiveness. However, breast tumor variability and tumor microenvironment have created several challenges to nanoparticulate delivery of repurposed cargos. This review focuses on DR as an ingenious strategy to treat BC and circumvent the drawbacks of approved anticancer therapeutics. Various nanoparticulate avenues delivering repurposed therapeutics, including non-oncology cargos and vaccines to target BC effectively, are discussed along with case studies. Moreover, clinical trial information on repurposed medications and vaccines for the treatment of BC is covered along with various obstacles in nanoparticulate drug delivery against cancer that have been so far identified. In a nutshell, DR and drug delivery of repurposed drugs via NCs appears to be a propitious approach in devastating BC.
    Keywords:  Breast cancer; Clinical trials; Drug repurposing; Nano-vaccines; Nanocarriers; Vaccines
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.039
  22. Oxid Med Cell Longev. 2022 ;2022 5361241
    Vitamin C Sensitizes Pancreatic Cancer Cells to Erastin-Induced Ferroptosis by Activating the AMPK/Nrf2/HMOX1 Pathway.
    Yawen Liu, Pu Huang, Zheng Li, Chunhui Xu, Huizhi Wang, Baoqing Jia, Aihua Gong, Min Xu.
      Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc- inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.
    DOI:  https://doi.org/10.1155/2022/5361241
  23. Nanotechnology. 2022 Aug 02.
    Nanoparticles-based delivery system and its potentials in treating central nervous system disorders.
    Tianyou Liu, Qinglian Xie, Zaiquan Dong, Qiang Peng.
      Central nervous system (CNS) disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), have become severe health concern worldwide. The treatment of the CNS diseases is of great challenges due largely to the presence of the blood-brain barrier (BBB). On the one hand, BBB protects brain from the harmful exogenous molecules via inhibiting their entry into the brain. On the other hand, it also hampers the transport of therapeutic drugs into the brain, resulting in the difficulties in treating the CNS diseases. In the past decades, nanoparticles-based drug delivery systems have shown great potentials in overcoming the BBB owing to their unique physicochemical properties, such as small size and specific morphology. In addition, functionalization of nanomaterials confers these nanocarriers controlled drug release features and targeting capacities. These properties make nanocarriers the potent delivery systems for treating the CNS disorders. Herein, we summarize the recent progress in nanoparticles-based systems for the CNS delivery, including the conventional and innovative systems. The prerequisites, drawbacks and challenges of nanocarriers (such as protein corona formation) in the CNS delivery are also discussed.
    Keywords:  Nanomedicine; blood brain barrier; central nervous system; drug delivery; nanomaterials
    DOI:  https://doi.org/10.1088/1361-6528/ac85f3
  24. Crit Rev Oncol Hematol. 2022 Jul 29. pii: S1040-8428(22)00196-2. [Epub ahead of print] 103772
    Puzzling Out Iron Complications in Cancer Drug Resistance.
    Marjan Abedi, Soheila Rahgozar.
      Iron metabolism are frequently disrupted in cancer. Patients with cancer are prone to anemia and receive transfusions frequently; the condition which results in iron overload, contributing to serious therapeutic complications. Iron is introduced as a carcinogen that may increase tumor growth. However, investigations regarding its impact on response to chemotherapy, particularly the induction of drug resistance are still limited. Here, iron contribution to cell signaling and various molecular mechanisms underlying iron-mediated drug resistance are described. A dual role of this vital element in cancer treatment is also addressed. On one hand, the need to administer iron chelators to surmount iron overload and improve the sensitivity of tumor cells to chemotherapy is discussed. On the other hand, the necessary application of iron as a therapeutic option by iron-oxide nanoparticles or ferroptosis inducers is explained. Authors hope that this paper can help unravel the clinical complications related to iron in cancer therapy.
    Keywords:  Cancer; Chelators; Chemotherapy; Drug resistance; Ferroptosis; Iron
    DOI:  https://doi.org/10.1016/j.critrevonc.2022.103772
  25. Int J Biol Macromol. 2022 Jul 29. pii: S0141-8130(22)01614-2. [Epub ahead of print]216 789-798
    Glycyrrhetinic acid-cyclodextrin grafted pullulan nanoparticles loaded doxorubicin as a liver targeted delivery carrier.
    Wenzhi Yang, Yi Zhang, Jiajia Wang, Haiying Li, Hu Yang.
      In this work, glycyrrhetinic acid (GA)-β-cyclodextrin grafted pullulan (GCDPu) was synthesized and used to form nanoparticles for liver-specific drug delivery. GCDPu was characterized by Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR). The self-aggregated nanoparticles (GCDPu NPs) with a spherical dimension of about 200 nm were prepared and analyzed by dynamic light scattering (DLS), zeta potential, and transmission electron microscopy (TEM). Doxorubicin (DOX) was selected as an anti-cancer model drug, and the drug-loaded GCDPu NPs were prepared by the emulsion solvent evaporation method. Moreover, the drug loading efficiency (LE%) and loading content (LC%) were determined. Slow DOX release from DOX/GCDPu NPs was confirmed. GCDPu NPs were cytocompatible with Bel-7404 cells and showed high cellular uptake according to the MTT assay, confocal laser scanning microscope (CLSM) and flow cytometry (FCM) results. Compared with free DOX, DOX/GCDPu NPs have exhibited a longer half-life time (t1/2) and a larger area-under-the-curve (AUC). GCDPu NPs significantly increased DOX contents in the liver and decreased in heart and kidney. Furthermore, DOX/GCDPu NPs exhibited a better anticancer therapeutic effect on tumor-bearing mice. These findings suggest that GCDPu can serve a liver-specific drug delivery system.
    Keywords:  Glycyrrhetinic acid-modified β-cyclodextrin pullulan; Liver cancer; Self-aggregated nanoparticle; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.182
  26. Phytomedicine. 2022 Jul 22. pii: S0944-7113(22)00434-2. [Epub ahead of print]105 154355
    Ferulic acid: An extraordinarily neuroprotective phenolic acid with anti-depressive properties.
    Xiaoyu Dong, Rui Huang.
       BACKGROUND: Depression, one of the most common mental illnesses and mood disorder syndromes, can seriously harm physical and mental health. As the pathophysiology of depression remains unclear, there is a need to find novel therapeutic agents. Ferulic acid (FA), a phenolic compound found in various Chinese herbal medicines, has anti-inflammatory and free radical scavenging properties as well as a wide range of therapeutic effects against depression.
    PURPOSE: In this review, we appraised preclinical research to fully discuss the anti-depression capacity of FA and discussed FAs' holistic characteristics that can contribute to better management of depression.
    STUDY DESIGN: We reviewed the results of in vitro and in vivo experiments using FA to treat depression and explored the possible antidepressant pharmacological mechanisms of FA for the clinical treatment of depression.
    METHODS: Electronic databases, including PubMed, Google Scholar, and China National Knowledge Infrastructure, were searched from the beginning of the database creation to December 2021.
    RESULTS: Studies on the antidepressant effects of FA show that it may exert such effects through various mechanisms. These include the following: the regulation of monoamine and non-monoamine neurotransmitter levels, inhibition of hypothalamic-pituitary-adrenal axis hyperfunction and neuroinflammation, promotion of hippocampal neurogenesis and upregulation brain-derived neurotrophic factor level, neuroprotection (inhibition of neuroinflammation, oxidative stress, mitochondrial dysfunction, and apoptosis), and downregulation of oxidative stress.
    CONCLUSION: Preclinical studies on the antidepressant effects of FA were reviewed in this study, and research on the antidepressant mechanisms of FA was summarized, confirming that FA can exert antidepressant effects through various pharmacological mechanisms. However, more multicenter clinical case-control studies are needed to confirm the clinical efficacy of FA.
    Keywords:  Depression; Ferulic acid; Pharmacological mechanism; Therapy; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.phymed.2022.154355
  27. Crit Rev Food Sci Nutr. 2022 Aug 05. 1-23
    An update on nutritional profile, phytochemical compounds, health benefits, and potential applications in the food industry of pulses seed coats: A comprehensive review.
    Dianzhi Hou, Qiqian Feng, Jian Tang, Qun Shen, Sumei Zhou.
      Pulses, as a sustainable source of nutrients, are an important choice for human diets, but vast quantities of seed coats generated in pulses processing are usually discarded or used as low-value ruminant feed. It has been demonstrated that pulses seed coats are excellent sources of dietary nutrients and phytochemicals with potential health benefits. With growing interest in the sustainable use of resources and the circular economy, utilization of pulses seed coats to recover these valuable components is a core objective for their valorization and an important step toward agricultural sustainability. This review comprehensively provides a comprehensive insight on the nutritional and phytochemical profiles presented in pulses seed coats and their health benefits obtained from the findings of in vitro and in vivo studies. Furthermore, in the food industry, pulses seed coats can be acted as potential food ingredients with nutritional, antioxidant and antimicrobial characteristics or as the matrix or active components of films for food packaging and edible coatings. A better understanding of pulses seed coats may provide a reference for increasing the overall added value and realizing the pulses' sustainable diets.
    Keywords:  Sustainable diet; food industry; health benefits; phytochemicals; pulses seed coats
    DOI:  https://doi.org/10.1080/10408398.2022.2105303
  28. Adv Colloid Interface Sci. 2022 Jul 18. pii: S0001-8686(22)00136-1. [Epub ahead of print]307 102734
    Recent progress in the application of plant-based colloidal drug delivery systems in the pharmaceutical sciences.
    Keyhan Mohammadi, Mahmood Alizadeh Sani, Maryam Azizi-Lalabadi, David Julian McClements.
      The potential for utilizing plant-derived components, such as plant proteins, polysaccharides, lipids, and phospholipids, to create targeted drug delivery systems has been demonstrated in recent years. These colloidal delivery systems can encapsulate, protect, and release pharmaceuticals, vitamins, and nutraceuticals, thereby improving their bioavailability and efficacy. Moreover, they have the potential to reduce the side effects associated with some conventional drug formulations, while still achieving controlled or targeted delivery of pharmaceutical agents by various administration routes, including oral, nasal, dermal and inhalation. The pharmacokinetic and pharmacodynamic profiles of drugs can be modulated by altering the composition, dimensions, and structure of drug formulations created using plant-based colloidal delivery systems. The utilization of plant-derived ingredients may also reduce the environmental impact and improve the sustainability of drug formulations. Initially, we provide an overview of the general characteristics and requirements of drug delivery systems. The opportunities and challenges of using plant-derived components to fabricate colloidal particles for drug delivery applications is then discussed. Finally, potential clinical applications of plant-based delivery drug systems are reviewed.
    Keywords:  Controlled release; Drug-therapy; Natural-based particles; Plant ingredients; Sustainability; Targeted drug-delivery systems
    DOI:  https://doi.org/10.1016/j.cis.2022.102734
  29. Biomater Adv. 2022 Jul;pii: S2772-9508(22)00196-0. [Epub ahead of print]138 212919
    Multifunctional theranostic nanoplatform loaded with autophagy inhibitor for enhanced photothermal cancer therapy under mild near-infrared irradiation.
    Meilin Shi, Yawen Liu, Jie Huang, Zhian Chen, Chen Ni, Jiahui Lu, Yingying Zhang, Zhenbao Liu, Jin Bai.
      Photothermal therapy (PTT) usually causes hyperthermia and damages healthy tissues. Developing a PTT platform with enhanced therapeutic effects and reduced side effects to normal tissues attracts increasing attention. Herein, we developed a multifunctional theranostic nanoplatform using poly(lactic-co-glycolic acid) (PLGA) loaded with near-infrared (NIR) photothermal agent (new indocyanine green IR820), fluorescence imaging agent (ZnCdSe/ZnS quantum dots, QDs) and autophagy inhibitor (chloroquine, CQ). These PLGA/IR820/Fluorescence imaging agent/CQ co-loading nanoparticles (termed PIFC NPs) displayed photothermal effects, enhanced the stability of IR820 in vivo, and enabled QDs to have stable fluorescent signals in vitro and in vivo. The PIFC NPs with particle size around 240 nm aggregated to tumor sites through the high permeability and retention effects of solid tumors. The intracellular delivery of CQ molecules through PIFC NPs significantly attenuated the degradation of autophagic lysosomes in tumor cells and effectively inhibited the autophagy mediated repair of photothermal damaged cells. Under milder NIR irradiation conditions, PIFC NPs exhibited high antitumor effect. By regulating autophagy, PTT can be effectively sensitized, which will provide a new idea for future cancer treatment research.
    Keywords:  Autophagy inhibitor; Near-infrared photothermal agent; Photothermal therapy; Quantum dot; Theranostic nanoplatform
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212919
  30. Nanotechnology. 2022 Aug 01.
    Yolk-shell shaped Au-Bi2S3 heterostructure nanoparticles for controlled drug release and combined tumor therapy.
    Tingting Zhao, Qin Zhang, Feng Cang, Shilong Wu, Yu Jiang, Qiyao Zhao, Yifan Zhou, Xiaomeng Qu, Xuesong Zhang, Yushen Jin, Yanyan Li, Yujie Fu.
      To fabricate a novel stimuli-responsive system enabling controlled drug release and synergistic therapy, yolk-shell shaped bismuth sulfide modified with Au nanoparticles (Au-Bi2S3) was prepared. The Au-Bi2S3 nanomaterial with heterojunction structure exhibited excellent photothermal conversion efficiency and considerable free radicals yield under laser irradiation. The drug delivery capacity was confirmed by co-loading Berberine hydrochloride (BBR) and a phase change material 1-tetradecanol (PCM), which could be responsible for NIR-light induced thermal controlled drug release. In vitro investigation demonstrated that Au-Bi2S3 has cell selectivity, and with the assistance of the properties of Au-Bi2S3, the loaded drug could give full play to their cancer cell inhibition ability. Our work highlights the great potential of this nanoplatform which could deliver and control Berberine hydrochloride release as well as realize the synergistic anti-tumor strategy of photothermal therapy, photodynamic therapy and chemotherapy for tumor therapy.
    Keywords:  bismuth sulfide nanomaterials; drug delivery; phase change materials; synergistic therapy
    DOI:  https://doi.org/10.1088/1361-6528/ac85c2
  31. Chem Asian J. 2022 Aug 01.
    Modified Bacterial Cellulose for Biomedical Applications.
    Karen Yuanting Tang, Jerry Zhi Xiong Heng, Casandra Hui Teng Chai, Chui Yu Chan, Beverly Qian Ling Low, Serene Ming En Chong, Hong Yi Loh, Zibiao Li, Enyi Ye, Xian Jun Loh.
      Bacterial cellulose, or microbial cellulose, had gained tremendous interest as a hydrogel material for biomedical purposes in the recent years. It has many intrinsic physiological properties like fibrous nature, ultrafine 3D nanostructure network, high water holding capacity, excellent mechanical properties, biocompatibility and biodegradability that allow for the use of such purposes, and the lacking properties can be easily supplemented or enhanced by modifications. In this review, some of the biomedical applications that uses bacterial cellulose are discussed. These include wound healing, drug delivery, tissue engineering and tumor cell and cancer therapy. In each section, different modifications of BC are showcased and examined on how they benefit the application. Finally, key takeaways on these modifications are also deliberated.
    Keywords:  cellulose-based hydrogel; drug delivery; modified bacterial cellulose; tissue engineering and therapy; wound healing
    DOI:  https://doi.org/10.1002/asia.202200598
  32. Elife. 2022 Aug 02. pii: e80725. [Epub ahead of print]11
    Glutamine metabolism modulates chondrocyte inflammatory response.
    Manoj Arra, Gaurav Swarnkar, Naga Suresh Adapala, Syeda-Kanwal Batool Naqvi, Lei Cai, Muhammad Farooq Rai, Srikanth Singamaneni, Gabriel Mbalaviele, Robert Brophy, Yousef Abu-Amer.
      Osteoarthritis is the most common joint disease in the world with significant societal consequences, but lacks effective disease modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that mouse chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.80725
  33. Food Technol Biotechnol. 2022 Jun;60(2): 145-154
    Polyethylene Glycol-Stabilized Zein Nanoparticles Containing Gallic Acid.
    Heliton Augusto Wiggers, Margani Taise Fin, Najeh Maissar Khalil, Rubiana Mara Mainardes.
       Research background: Gallic acid is a polyphenol with antioxidant and antitumor activities; however, its use as a nutraceutical or drug is hindered by its low bioavailability. Zein is a natural protein found in corn and has been applied as nanoparticle drug carrier. In this study, zein nanoparticles were obtained and stabilized with polyethylene glycol (PEG) as gallic acid carriers.
    Experimental approach: Nanoparticles were obtained by the liquid-liquid method and characterized in terms of mean size, polydispersity index, zeta potential, morphology, solid-state interactions and encapsulation efficiency/drug loading. The stability of nanoparticles was evaluated in simulated gastrointestinal fluids and food simulants, and the antioxidant activity was determined by the scavenging of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical.
    Results and conclusions: Zein nanoparticles containing gallic acid were obtained and stabilized only in the presence of PEG. Under optimal conditions, nanoparticles with mean size <200 nm, low polydispersity index (<0.25) and negative zeta potential (-20 mV) were obtained. The gallic acid encapsulation efficiency was about 40%, loading about 5%, and it was encapsulated in an amorphous state. Fourier transform infrared spectroscopy (FTIR) did not identify chemical interactions after gallic acid nanoencapsulation. Zein nanoparticles were more prone to release the gallic acid in gastric than intestinal simulated medium; however, more than 50% of drug content was protected from premature release. In food simulants, the gallic acid release from nanoparticles was prolonged and sustained. Moreover, the nanoencapsulation did not reduce the antioxidant activity of gallic acid.
    Novelty and scientific contribution: The results show the importance of PEG in the formation and its effect on the properties of zein nanoparticles obtained by the liquid-liquid dispersion method. This study indicates that PEG-stabilized zein nanoparticles are potential carriers for oral intake of gallic acid, preserving its antioxidant properties and enabling its use in the pharmaceutical and food industries.
    Keywords:  DPPH scavenging; food simulants; gallic acid release; polyethylene glycol; zein nanoparticles
    DOI:  https://doi.org/10.17113/ftb.60.02.22.6981
  34. Int J Nanomedicine. 2022 ;17 3287-3311
    PEGylated SLN as a Promising Approach for Lymphatic Delivery of Gefitinib to Lung Cancer.
    Abdelrahman Y Sherif, Gamaleldin I Harisa, Fars K Alanazi, Fahd A Nasr, Ali S Alqahtani.
       Purpose: The present study aimed to develop gefitinib-loaded solid lipid nanoparticles (GEF-SLN), and GEF-loaded PEGylated SLN (GEF-P-SLN) for targeting metastatic lung cancer through the lymphatic system.
    Methods: The prepared SLNs were characterized in terms of physicochemical properties, entrapment efficiency, and in-vitro release. Furthermore, ex-vivo permeability was investigated using the rabbit intestine. Cytotoxicity and apoptotic effects were studied against A549 cell lines as a model for lung cancer.
    Results: The present results revealed that the particle size and polydispersity index of the prepared formulations range from 114 to 310 nm and 0.066 to 0.350, respectively, with negative zeta-potential (-14 to -27.6). Additionally, SLN and P-SLN showed remarkable entrapment efficiency above 89% and exhibited sustained-release profiles. The permeability study showed that GEF-SLN and GEF-P-SLN enhanced the permeability of GEF by 1.71 and 2.64-fold, respectively, compared with GEF suspension. Cytotoxicity showed that IC50 of pure GEF was 3.5 μg/mL, which decreased to 1.95 and 1.8 μg/mL for GEF-SLN and GEF-P-SLN, respectively. Finally, the apoptotic study revealed that GEF-P-SLN decreased the number of living cells from 49.47 to 3.43 when compared with pure GEF.
    Conclusion: These results concluded that GEF-P-SLN is a promising approach to improving the therapeutic outcomes of GEF in the treatment of metastatic lung cancer.
    Keywords:  PEGylated SLN; apoptosis; cytotoxicity; gefitinib; intestinal permeability; solid lipid nanoparticles
    DOI:  https://doi.org/10.2147/IJN.S365974
  35. Front Pharmacol. 2022 ;13 935553
    Argininosuccinate synthase 1, arginine deprivation therapy and cancer management.
    Naihui Sun, Xing Zhao.
      Metabolic reprogramming is an emerging hallmark of tumor cells. In order to survive in the nutrient-deprived environment, tumor cells rewire their metabolic phenotype to provide sufficient energy and build biomass to sustain their transformed state and promote malignant behaviors. Amino acids are the main compositions of protein, which provide key intermediate substrates for the activation of signaling pathways. Considering that cells can synthesize arginine via argininosuccinate synthase 1 (ASS1), arginine is regarded as a non-essential amino acid, making arginine depletion as a promising therapeutic strategy for ASS1-silencing tumors. In this review, we summarize the current knowledge of expression pattern of ASS1 and related signaling pathways in cancer and its potential role as a novel therapeutic target in cancer. Besides, we outline how ASS1 affects metabolic regulation and tumor progression and further discuss the role of ASS1 in arginine deprivation therapy. Finally, we review approaches to target ASS1 for cancer therapies.
    Keywords:  amino acid; arginine; metabolic reprogramming; prognosis; resistance
    DOI:  https://doi.org/10.3389/fphar.2022.935553
  36. Eur J Pharm Biopharm. 2022 Jul 30. pii: S0939-6411(22)00153-9. [Epub ahead of print]
    A microfluidic approach to fabricate sucrose decorated liposomes with increased uptake in breast cancer cells.
    Shiva Khorshid, Mariele Montanari, Serena Benedetti, Sofia Moroni, Annalisa Aluigi, Barbara Canonico, Stefano Papa, Mattia Tiboni, Luca Casettari.
      Developing targeted drug delivery systems is an urgent need to decrease the side effects and increase the drug's efficiency. Most cancer cells show an increased sugar consumption compared to healthy cells due to the deregulation of sugar transporters. Consequently, liposomes, as a biocompatible nanocarrier, could be surface decorated by sugars to enhance drug targeting into cancer cells. Our work outlines a new strategy to easily manufacture sucrose decorated liposomes using sucrose stearate, a biocompatible and biodegradable non-ionic surfactant, with a scalable microfluidic approach. Sucrose decorated liposomes were loaded with berberine hydrochloride, a well-known phytochemical compound to investigate its effects on triple-negative breast cancer cells (MDA-MB-231). Using the microfluidic manufacturing system, we prepared berberine-loaded liposomes using a mixture of phosphatidylcholine and cholesterol with and without sucrose stearate with a size up to 140 nm and narrow polydispersity. Stability was confirmed for 90 days, and the in vitro release profile was evaluated. The formulations showed acceptable in vitro biocompatibility and significantly higher anti-proliferative effect on MDA-MB-231 cell line. These results have been confirmed by an increased uptake evaluated by flow cytometry and confocal microscopy. Taken together, our findings represent an innovative, easy, and scalable approach to obtain sugar decorated liposomal formulations without any surface-chemistry reactions. They can be potentially used as an anticancer targeted drug delivery system.
    Keywords:  3D printed microfluidic chips; Additive manufacturing; Surface modification; nanomedicine; sucrose esters
    DOI:  https://doi.org/10.1016/j.ejpb.2022.07.015
  37. Cancer Res. 2022 Aug 02. pii: CAN-22-0408. [Epub ahead of print]
    Selenium modulates cancer cell response to pharmacologic ascorbate.
    Connor S R Jankowski, Joshua D Rabinowitz.
      High-dose ascorbate (vitamin C) has shown promising anti-cancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0408
  38. Biomater Adv. 2022 Jun;pii: S2772-9508(22)00096-6. [Epub ahead of print]137 212819
    Tin-loaded mesoporous silica nanoparticles: Antineoplastic properties and genotoxicity assessment.
    Pallavi C Choudante, Susheel Kumar Nethi, Diana Díaz-García, Sanjiv Prashar, Sunil Misra, Santiago Gómez-Ruiz, Chitta Ranjan Patra.
      Nanotechnology has immensely advanced the field of cancer diagnostics and treatment by introducing potential delivery vehicles as carriers for drugs or therapeutic agents. In due course, mesoporous silica nanoparticles (MSNs) have emerged as excellent vehicles for delivering drugs, biomolecules, and biomaterials, attributed to their solid framework and porosity providing a higher surface area for decorating with various functional ligands. Recently, the metal tin (Sn) has gained huge importance in cancer research owing to its excellent cytotoxicity and ability to kill cancer cells. In the present work, we synthesized MSNs, conjugated them with organotin compounds, and characterized them using various physicochemical techniques. Subsequently, the biological evaluation of MSN (S1), MSN-MP (S2) and tin-conjugated MSNs (S3: MSN-MP-SnPh3) (MP = 3-mercaptopropyltriethoxysilane) revealed that these nanoconjugates induced cytotoxicity, necrosis, and apoptosis in MCF-7 cells. Moreover, these nanoconjugates exhibited anti-angiogenic properties as demonstrated in the chick embryo model. The increase of reactive oxygen species (ROS) was found as a one of the plausible mechanisms underlying cancer cell cytotoxicity induced by these nanoconjugates, encouraging their application for the treatment of cancer. The tin-conjugated MSNs demonstrated less toxicity to normal cells compared to cancer cells. Furthermore, the genotoxicity studies revealed the clastogenic and aneugenic effects of these nanoconjugates in CHO cells mostly at high concentrations. These interesting observations are behind the idea of developing tin-conjugated MSNs as prospective candidates for anticancer therapy.
    Keywords:  Anti-angiogenesis; Anticancer activity; Genotoxicity; Mesoporous silica nanoparticles; Organotin
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212819
  39. Drug Dev Ind Pharm. 2022 Aug 01. 1-41
    Empagliflozin containing chitosan-alginate nanoparticles in orodispersible film: preparation, characterization, pharmacokinetic evaluation and its in-vitro anticancer activity.
    Suhani Sinha, Sonali, Vandana Garg, Sonia Thapa, Shashank Singh, Mahima Chauhan, Rohit Dutt, Rahul Pratap Singh.
       OBJECTIVE: The main objective of the this study was to develop orodispersity film using chitosan-alginate to improve dissolution profile, therapeutic effect with improvedbioavailability of empagliflozin through oral route non-invasively for further cytotoxicity study.
    METHODS: The nanoparticles were developed through two-step mechanisms ionotropic pre-gelation and polyelectrolyte complexation methods. The prepared nanoparticles were added to a polymer matrix containinghypromellose, polyvinyl alcohol, and maltodextrin and casted to rapidly dissolving thin film by solvent casting method.
    RESULTS: The physicochemical characteristics of empagliflozin in orodispersible film was most favourable for further studies. This formulation have acheived a higher permeability (7.2-fold) as compared to the reference drug product (Jardiance®) after 45 min.In-vivo pharmacokinetic studies in Wistar ratshaverevealed that chitosan-alginate empagliflozin nanoparticles in the orodispersible film were 1.18-fold more bioavailable in comparison to empagliflozin in orodispersible film. The Cmax observed for the empagliflozin-loaded orodispersible film was 15.42 ± 5.13 μg/ml in comparison to 18.21 ± 5.53 μg/ml for empagliflozin nanoparticle-containing orodispersible film and 12.19 ± 6.71 μg/ml for freedrug suspension. The t1/2and AUC0-t values for chitosan-alginate nanoparticles of empagliflozin in the orodispersible film was found1.4-fold more than empagliflozin loaded orodispersible film(without nanoparticles). The cytotoxicity study have shownthat chitosan-alginate nanoparticles of empagliflozin in orodispersible film achieved a 2.5-fold higher cytotoxic effect than free empagliflozin in orodispersible film in A549lung cancer cells.
    CONCLUSIONS: This study provides evidence that chitosan-alginate nanoparticles of empagliflozin in orodispersible film can be an effective drug carrier system to improve sustained effect with better bioavailability of poorly water soluble drug.
    Keywords:  Anticancer agent; lung cancer; nanomedicine; oral bioavailability; orodispersible film; physicochemical characterization; stability study
    DOI:  https://doi.org/10.1080/03639045.2022.2108829
  40. Expert Opin Drug Deliv. 2022 Aug 02.
    Recent advances in erythrocyte membrane-camouflaged nanoparticles for the delivery of anti-cancer therapeutics.
    Siyu Wang, Yiwei Wang, Kai Jin, Bo Zhang, Shaojun Peng, Amit Kumar Nayak, Zhiqing Pang.
       INTRODUCTION: Red blood cell (or erythrocyte) membrane-camouflaged nanoparticles (RBC-NPs) not only have a superior circulation life and do not induce accelerated blood clearance, but also possess special functions, which offers great potential in cancer therapy.
    AREAS COVERED: This review focuses on the recent advances of RBC-NPs for delivering various agents to treat cancers in light of their vital role in improving drug delivery. Meanwhile, the construction and in vivo behavior of RBC-NPs are discussed to provide an in-depth understanding of the basis of RBC-NPs for improved cancer drug delivery.
    EXPERT OPINION: Although RBC-NPs are quite prospective in delivering anti-cancer therapeutics, they are still in their infancy stage and many challenges need to be overcome for successful translation into the clinic. The preparation and modification of RBC membranes, the optimization of coating methods, the scale-up production and the quality control of RBC-NPs, and the drug loading and release should be carefully considered in the clinical translation of RBC-NPs for cancer therapy.
    Keywords:  biomimetic nanoparticles; cancer therapy; erythrocyte membrane-camouflaged nanoparticles; pharmacokinetics; targeting drug delivery
    DOI:  https://doi.org/10.1080/17425247.2022.2108786
  41. Cancer Discov. 2022 Aug 05. OF1
    Specific KRAS-Mutant Cancers Are Sensitive to Inhibition of V-type ATPases.
      249C was identified as a selective Ras-mutant cytotoxic agent that binds to and inhibits V-ATPase.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-142
  42. J Inorg Biochem. 2022 Jul 23. pii: S0162-0134(22)00229-X. [Epub ahead of print]235 111940
    CuS NP-based nanocomposite with photothermal and augmented-photodynamic activity for magnetic resonance imaging-guided tumor synergistic therapy.
    Bichong Luo, Xiujie Huang, Yaojiang Ye, Jihai Cai, Youzhen Feng, Xiangran Cai, Xiaoying Wang.
      Although many treatments have been developed for oncotherapy, the lack of effective imaging guidance in the therapeutic process is still an urgent problem to be solved. In this study, magnetic resonance contrast agent (Gd) chelated on CuS nanoparticles and glucose oxidase (GOx) were coloaded into mesoporous silica nanoparticles (MSNs) to form GOx-Gd-CuS@MSNs, in which the Gd provided magnetic resonance imaging (MRI) for therapeutic process monitor while GOx could catalyze the generation of H2O2 to enhance the photodynamic therapy (PDT). The in vitro results show that under near-infrared (NIR) laser irradiation (2 W·cm-2, 5 min), temperature rapidly increased by approximately 30 °C for the accumulation of heat. At the same time, GOx on GOx-Gd-CuS@MSNs effectively consumed glucose to produce a large amount of H2O2, which was used to augment PDT through producing highly toxic hydroxyl radicals (·OH) and singlet oxygen (1O2). The photothermal and augmented-photodynamic could induce apoptosis and death of tumor cells. More importantly, the study found that GOx-Gd-CuS@MSNs had MRI performance, which provided imaging guidance during the treatment process, and it can monitor the diffusion of water molecules in the tumor tissue during the treatment and microcirculation perfusion of capillary network. These results indicate that the nanomaterial produced significant synergistic therapeutic effects through photothermal and photodynamic forces, meanwhile showed excellent spatial resolution and deep tissue penetration in imaging.
    Keywords:  Copper sulfide; Glucose oxidase; Magnetic resonance imaging; Photothermal and photodynamic therapy; Tumor treatment
    DOI:  https://doi.org/10.1016/j.jinorgbio.2022.111940
  43. Front Pharmacol. 2022 ;13 928135
    Photodynamic Effects of Thuja occidentalis on Lung Cancer Cells.
    Ayesha Loonat, Rahul Chandran, Janice Pellow, Heidi Abrahamse.
      The global incidence and mortality rates resulting from lung cancer encapsulate a need to identify more effective treatment protocols. Photodynamic therapy (PDT) and homeopathy offer possible anticancer therapies as part of a multi-disciplinary approach. Studies have identified the anticancer effects of Thuja occidentalis L. plant extracts. The aim of this study was to investigate the effects of Thuja occidentalis (TO) homeopathic mother tincture and TO mediated PDT (TO-PDT) on A549 lung cancer cells. Commercially available A549 cells were pre-treated with TO, or laser irradiation at 660 nm, or the combined treatment (TO-PDT). Cells were analyzed morphologically by inverted light microscopy and Hoechst stain; and biochemically by lactate dehydrogenase (LDH), adenosine triphosphate (ATP), and trypan blue assays. Cells treated with TO and TO-PDT demonstrated morphological changes in the cell and cell nuclei indicative of cell death. These groups exhibited a dose dependent increase in LDH release and a decrease in ATP levels and cell viability indicating its cytotoxic and antiproliferative potential. Furthermore, at the same doses, TO when photoactivated in PDT induced enhanced anticancer responses thereby surpassing the effects of treatment with the tincture alone. Results demonstrate how the direct cytotoxic effects of TO can be improved when administered as a photosensitizer in PDT to promote cancer cell death.
    Keywords:  cytotoxicity; homeopathy; lung cancer; photodynamic therapy; photosensitizer
    DOI:  https://doi.org/10.3389/fphar.2022.928135
  44. Drug Des Devel Ther. 2022 ;16 2365-2382
    Identifying the Antitumor Effects of Curcumin on Lung Adenocarcinoma Using Comprehensive Bioinformatics Analysis.
    Fei-Ran Yang, Si-Yi Li, Xi-Wen Hu, Xiu-Rong Li, Hui-Jie Li.
       Background: As the main component of turmeric (Curcuma longa L.), curcumin is widely used in the treatment of various diseases. Previous studies have demonstrated that curcumin has great potential as a therapeutic agent, but the lack of understanding of the functional mechanism of the drug has hindered the widespread use of the natural product. In the present study, we used comprehensive bioinformatics analysis and in vitro experiments to explore the anti-tumor mechanism of curcumin.
    Materials and Methods: LUAD mRNA expression data were obtained from TCGA database and differentially expressed genes (DEGs) were identified using R software. Functional enrichment analysis was conducted to further clarify its biological properties and hub genes were identified by a protein-protein interaction (PPI) network analysis. Survival analysis and molecular docking were used to analyze the effectiveness of the hub genes. By an in vitro study, we evaluated whether curcumin could influence the proliferation, migration, and invasion activities of LUAD cells.
    Results: In this study, 1783 DEGs from LUAD tissue samples compared to normal samples were evaluated. Functional enrichment analysis and the PPI network revealed the characteristics of the DEGs. We performed a topological analysis and identified 10 hub genes. Of these, six genes (INS, GCG, SST, F2, AHSG, and NPY) were identified as potentially effective biomarkers of LUAD. The molecular docking results indicated that curcumin targets in regulating lung cancer may be INS and GCG. We found that curcumin significantly inhibited the proliferation, migration, and invasion of LUAD cells and significantly decreased the expression of the INS and GCG genes.
    Conclusion: The results of this study suggest that the therapeutic effects of curcumin on LUAD may be achieved through the intervention of INS and GCG, which may act as potential biomarkers for LUAD prevention and treatment.
    Keywords:  TCGA; antitumor effect; bioinformatics analysis; curcumin; lung adenocarcinoma
    DOI:  https://doi.org/10.2147/DDDT.S371420
  45. Sci Rep. 2022 Aug 02. 12(1): 13213
    Formulation, characterization and cellular toxicity assessment of a novel bee-venom microsphere in prostate cancer treatment.
    Samia E El-Didamony, Reham I Amer, Ghada H El-Osaily.
      Bee venom (B.V.) is a toxin produced naturally by honey bees with several toxic and therapeutic efficacies. It is used in the treatment of different cancer kinds like renal, hepatic, and prostate cancer. Due to its protein nature, it is degraded in the upper gastrointestinal tract. Colon-targeted drug delivery systems represent a useful tool to protect B.V. from degradation and can be administered orally instead of I.V. infusion and traditional bee stinging. In the present study, B.V. loaded enteric-coated cross-linked microspheres were prepared by emulsion cross-linking method. Percentage yield, entrapment efficiency %, swelling degree, and in-vitro release are evaluated for prepared microspheres. Free B.V., optimized microspheres formula (F3), and doxorubicin cytotoxic effects were tested by MTT assay. Results concluded that free B.V. was more effective against the growth of human prostate adenocarcinoma (PC3) cells followed by optimized microspheres than doxorubicin. But both free B.V. and doxorubicin have a cytotoxic effect on normal oral epithelial cells (OEC). According to flow cytometric analysis, the optimized microsphere formula induced apoptosis and reduced necrosis percent at IC50 concentration. Furthermore, microspheres did not affect the viability of OEC. These results revealed that microspheres have a degree of specificity for malignant cells. Therefore, it seems that this targeted formulation could be a good candidate for future clinical trials for cancer therapy.
    DOI:  https://doi.org/10.1038/s41598-022-17391-w
  46. Crit Rev Food Sci Nutr. 2022 Aug 05. 1-27
    Fucoidan-based nanomaterial and its multifunctional role for pharmaceutical and biomedical applications.
    Muhammad Waheed Iqbal, Tahreem Riaz, Shahid Mahmood, Muhammad Bilal, Muhammad Faisal Manzoor, Sarmad Ahmad Qamar, Xianghui Qi.
      Fucoidans are promising sulfated polysaccharides isolated from marine sources that have piqued the interest of scientists in recent years due to their widespread use as a bioactive substance. Bioactive coatings and films, unsurprisingly, have seized these substances to create novel, culinary, therapeutic, and diagnostic bioactive nanomaterials. The applications of fucoidan and its composite nanomaterials have a wide variety of food as well as pharmacological properties, including anti-oxidative, anti-inflammatory, anti-cancer, anti-thrombic, anti-coagulant, immunoregulatory, and anti-viral properties. Blends of fucoidan with other biopolymers such as chitosan, alginate, curdlan, starch, etc., have shown promising coating and film-forming capabilities. A blending of biopolymers is a recommended approach to improve their anticipated properties. This review focuses on the fundamental knowledge and current development of fucoidan, fucoidan-based composite material for bioactive coatings and films, and their biological properties. In this article, fucoidan-based edible bioactive coatings and films expressed excellent mechanical strength that can prolong the shelf-life of food products and maintain their biodegradability. Additionally, these coatings and films showed numerous applications in the biomedical field and contribute to the economy. We hope this review can deliver the theoretical basis for the development of fucoidan-based bioactive material and films.
    Keywords:  Fucoidan; bioactive coatings; composite films; seaweed polysaccharides
    DOI:  https://doi.org/10.1080/10408398.2022.2106182
  47. Curr Drug Metab. 2022 Aug 03.
    Nanoparticle-Based Inhalation Therapy for Pulmonary Diseases.
    Dhananjay Yadav, Pallavi Singh Chauhan, Peninah M Wairagu, Minseok Kwak, Jun-O Jin.
      The lung is exposed to various pollutants and is the primary site for the onset of various diseases, including infections, allergies, and cancers. One possible treatment approach for such pulmonary diseases involves direct administration of therapeutics to the lung so as to maintain the topical concentration of the drug. Particles with nanoscale diameters tend to reach the pulmonary region. Nanoparticles (NPs) have garnered significant interest for applications in biomedical and pharmaceutical industries because of their unique physicochemical properties and biological activities. In this article, we describe the biological and pharmacological activities of NPs as well as summarize their potential in the formulation of drugs employed to treat pulmonary diseases. Recent advances in the use of NPs in inhalation chemotherapy for the treatment of lung diseases have also been highlighted.
    Keywords:  Biomedical applications; Nanoparticle; Natural polymer; Respiratory disease
    DOI:  https://doi.org/10.2174/1389200223666220803103039
  48. Int J Pept Res Ther. 2022 ;28(5): 135
    The Updated Review on Plant Peptides and Their Applications in Human Health.
    Saiprahalad Mani, Smruti B Bhatt, Vinduja Vasudevan, Dhamodharan Prabhu, Sundararaj Rajamanikandan, Palaniyandi Velusamy, Palaniappan Ramasamy, Pachaiappan Raman.
      Biologically active plant peptides, consisting of secondary metabolites, are compounds (amino acids) utilized by plants in their defense arsenal. Enzymatic processes and metabolic pathways secrete these plant peptides. They are also known for their medicinal value and have been incorporated in therapeutics of major human diseases. Nevertheless, its limitations (low bioavailability, high cytotoxicity, poor absorption, low abundance, improper metabolism, etc.) have demanded a need to explore further and discover other new plant compounds that overcome these limitations. Keeping this in mind, therapeutic plant proteins can be excellent remedial substitutes for bodily affliction. A multitude of these peptides demonstrates anti-carcinogenic, anti-microbial, anti-HIV, and neuro-regulating properties. This article's main aim is to list out and report the status of various therapeutic plant peptides and their prospective status as peptide-based drugs for multiple diseases (infectious and non-infectious). The feasibility of these compounds in the imminent future has also been discussed.
    Keywords:  Anti-HIV; Anti-carcinogenic; Antifungal; Peptide-based drugs; Ribosomal-Inactivating Proteins (RIPs); Therapeutic plant peptides
    DOI:  https://doi.org/10.1007/s10989-022-10437-7
  49. J Mater Chem B. 2022 Aug 05.
    Sustained delivery of gemcitabine via in situ injectable mussel-inspired hydrogels for the local therapy of pancreatic cancer.
    Li Xu, Shengnan Tang, Huiquan Yang, Min Liang, Pengfei Ren, Dandan Wei, Jian He, Weiwei Kong, Peidang Liu, Tianzhu Zhang.
      The issue of pervasively enhanced drug resistance of pancreatic cancer is fundamental to a better understanding of gemcitabine-based chemotherapy. Currently available treatment plans involving injectable therapeutics are mainly engineered to improve the performance and broaden their applications in the domain of biomedicine. Fixed-dose-rate infusion of free gemcitabine (Gem) has drawn appropriate attention for its potent anti-tumor efficacy against various solid tumors, whereas it remains a considerable challenge to extend its application and achieve better treatment. Here, we have prepared and demonstrated a long-acting delivery system using gemcitabine and injectable in situ hydrogel for the localized treatment of pancreatic cancer. The hydrogel was prepared using polysaccharide derivatives, oxidized-carboxymethylcellulose (OCMC) and carboxymethylchitosan (CMCS) at optimal ratios by a dopamine-functionalized method for the controlled release of Gem. In vitro drug release behaviors for up to a week indicated sustained drug release of the Gem delivery system. Moreover, desirable apoptosis promotion and apparent cellular proliferation inhibition associated with the drug depot have been found in vitro against BxPC-3 pancreatic cancer cells, bringing minimized side effects to systemic normal tissues. The current findings manifested that the release out of the localized delivery platform in a sustained pattern afforded a durable gemcitabine-based chemotherapy effect and inhibited tumor metastasis more persistently after intratumoral injection of the Gem@Gel system, thereby advancing the development of novel drug-loaded materials with properties not accessed previously.
    DOI:  https://doi.org/10.1039/d1tb02858h
  50. Colloids Surf B Biointerfaces. 2022 Jul 20. pii: S0927-7765(22)00395-2. [Epub ahead of print]218 112712
    A novel carbon-nanodots-based theranostic nano-drug delivery system for mitochondria-targeted imaging and glutathione-activated delivering camptothecin.
    Xiaojuan Gong, Zihan Wang, Li Zhang, Wenjuan Dong, Ruiping Wang, Yang Liu, Shengmei Song, Qin Hu, Fangfang Du, Shaomin Shuang, Chuan Dong.
      Chemotherapy is severely limited by continuously decreased therapeutic efficacy and uncontrolled side effects on normal tissue, which can be improved by constructing a nanoparticle-based drug delivery system (DDS). Nevertheless, no studies have reported on DDS-based on carbon-nanodots (CNDs), combining subcellular organelle-targeted imaging/drug delivery, high drug loading content, and glutathione (GSH)-sensitive drug release into one system. Herein, the as-fabricated CNDs can be covalently conjugated with a mitochondria-targeting ligand (triphenylphosphine, TPP), a smart GSH-responsive disulfide linker (S-S), and the anticancer drug (camptothecin, CPT) to initially prepare a theranostic nano-DDS (TPP-CNDs-S-CPT) with the drug loading efficiency of 64.6 wt%. Owing to excellent water dispersibility, superior fluorescence properties, satisfactory cell permeability, and favorable biocompatibility, TPP-CNDs-S-CPT was successfully used for intracellular mitochondrial-targeted imaging in vitro. High intracellular GSH concentrations in tumor cells caused the cleavage of S-S, resulting in concomitant activation and release of CPT, as well as significant fluorescence enhancement. In vivo, TPP-CNDs-S-CPT exhibited lower biological toxicity and even higher tumor-activatable performance than free CPT, as well as specific cancer therapy with few side effects. The mitochondria-targeted ability and the precise drug-release in tumor make TPP-CNDs-S-CPT a hopeful chemotherapy prodrug, providing significant theoretical basis and data support for in-depth understanding and exploration of chemotherapeutic DDS-based on CNDs.
    Keywords:  Camptothecin; Carbon-nanodots; GSH-activation; Mitochondria-targeted imaging; Theranostic nano-drug delivery system
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112712
  51. Crit Rev Food Sci Nutr. 2022 Aug 05. 1-15
    Polysaccharide-based nano-delivery systems for encapsulation, delivery, and pH-responsive release of bioactive ingredients.
    Yaxu Meng, Chao Qiu, Xiaojing Li, David Julian McClements, Shangyuan Sang, Aiquan Jiao, Zhengyu Jin.
      Polysaccharides are natural polymers isolated from plants, microorganisms, algae, and some animals they are composed of aldoses or ketoses linked by glycosidic bonds. Due to the affordability, abundance, safety, and functionality, polysaccharides are widely used in the foods and medicines to construct oral delivery systems for sensitive bioactive ingredients. In this article, the characteristics and applications of nanoscale polysaccharide-based delivery carriers are reviewed, including their ability to encapsulate, protect, and deliver bioactive ingredients. This review discusses the sources, characteristics, and functional properties of common food polysaccharides, including starch, pectin, chitosan, xanthan gum, and alginate. It also highlights the potential advantages of using polysaccharides for the construction of nano-delivery systems, such as nanoparticles, nanogels, nanoemulsions, nanocapsules, and nanofibers. Moreover, the application of delivery systems assembled from polysaccharides is summarized, with a focus on pH-responsive delivery of bioactives. There are some key findings and conclusions: Nanoscale polysaccharide delivery systems provide several advantages, including improved water-dispersibility, flavor masking, stability enhancement, reduced volatility, and controlled release; Polysaccharide nanocarriers can be used to construct pH-responsive delivery vehicles to achieve intestinal-targeted delivery and controlled release of bioactive ingredients; Polysaccharides can be used in combination with other biopolymers to form composite delivery systems with enhanced functional attributes.
    Keywords:  Polysaccharides; bioactive ingredients; bioavailability; controlled release; nanotechnology
    DOI:  https://doi.org/10.1080/10408398.2022.2105800
  52. Mol Biol Rep. 2022 Aug 04.
    Chitosan reduces inflammation and protects against oxidative stress in a hyperlipidemic rat model: relevance to nonalcoholic fatty liver disease.
    Raushan Kumar, Jitendra Kumar Arya, Syed Ibrahim Rizvi.
       BACKGROUND: An altered lipid profile may lead to the development of inflammation and NAFLD (Non-alcoholic fatty liver disease). Although statins have a positive effect on blood lipid levels their long-term use is known to cause adverse effects, in this backdrop there is an interest in natural compounds which may affect lipid metabolism and prevent NAFLD. We have examined the effect of Chitosan on rats subjected to a high-fat diet.
    METHODS AND RESULTS: Male Wistar middle aged rats (12-16 months) were treated with high-fat diet orally for two months for creating a NAFLD model. Rats were also supplemented with Chitosan (2% chitosan daily) for 2 months. We assessed the activity of antioxidant enzymes, the histopathological profile of the liver. Inflammatory cytokines and adiponectin levels were also measured in serum. HFD induced significant changes in liver tissue and inflammatory markers (Il-6, TNF- alpha, NF-KB). Chitosan treatment protected rats from HFD induced alterations.
    CONCLUSIONS: The findings suggest that Chitosan can effectively improve liver lipid metabolism by normalizing cholesterol, triglyceride, lowering NF-KB expression, and protecting the liver from oxidative stress by improving hepatic function. Chitosan also regulates genes related to lipidemic stress i,e leptin and adiponectin.
    Keywords:  Chitosan; High-fat diet; Liver; Non-alcoholic fatty liver disease; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-022-07810-6
  53. J Pharm Investig. 2022 Jul 24. 1-34
    Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors.
    Seung-Hyun Jeong, Ji-Hun Jang, Yong-Bok Lee.
       Background: Cranial nerve-related diseases such as brain tumors, Alzheimer's disease, and epilepsy are serious diseases that continue to threaten human. Brain-related diseases are increasing worldwide, including in the United States and Korea, and these increases are closely related to the exposure to harmful substances and excessive stress caused by rapid industrialization and environmental pollution. Drug delivery to the brain is very important for the effective prevention and treatment of brain-related diseases. However, due to the presence of the blood-brain barrier and the extensive first-pass metabolism effect, the general routes of administration such as oral and intravenous routes have limitations in drug delivery to the brain. Therefore, as an alternative, the nasal-brain drug delivery route is attracting attention as a route for effective drug delivery to the brain.
    Areas covered: This review includes physiological factors, advantages, limitations, current application status, especially in clinical applications, and the necessary factors for consideration in formulation development related to nasal-brain drug delivery.
    Expert opinion: The nasal-brain drug delivery route has the advantage of enhancing drug delivery to the brain locally, mainly through the olfactory route rather than the systemic circulation. The nasal-brain lymphatic system has recently attracted attention, and it has been implied that the delivery of anticancer drugs to the brain nervous system is possible effectively. However, there are limitations such as low drug permeability, as well as nasal mucosa and the mucociliary system, as obstacles in nasal-brain drug delivery. Therefore, to overcome the limitations of nasal-brain drug delivery, the use of nanocarriers and mucoadhesive agents is being attempted. However, very few drugs have been officially approved for clinical application via the nasal-brain drug delivery route. This is probably because the understanding of and related studies on nasal-brain drug delivery are limited. In this review, we tried to explore the major considerations and target factors in drug delivery through the nasal-brain route based on physiological knowledge and formulation research information. This will help to provide a mechanistic understanding of drug delivery through the nasal-brain route and bring us one step closer to developing effective formulations and drugs in consideration of the key factors for nasal-brain drug delivery.
    Keywords:  Brain disease; Drug delivery; Lymphatic system; Nanocarrier; Nasal-brain; Olfactory route
    DOI:  https://doi.org/10.1007/s40005-022-00589-5
  54. Chin Med. 2022 Jul 30. 17(1): 90
    Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma.
    Lai Wei, Zeyu Wang, Niancai Jing, Yi Lu, Jili Yang, Hongyu Xiao, Huanyu Guo, Shoukun Sun, Mingjing Li, Daqing Zhao, Xiangyan Li, Wenxiu Qi, Yue Zhang.
      Hepatocellular carcinoma (HCC, accounting for 90% of primary liver cancer) was the sixth most common cancer in the world and the third leading cause of cancer death in 2020. The number of new HCC patients in China accounted for nearly half of that in the world. HCC was of occult and complex onset, with poor prognosis. Clinically, at least 15% of patients with HCC had strong side effects of interventional therapy (IT) and have poor sensitivity to chemotherapy and targeted therapy. Traditional Chinese medicine (TCM), as a multi-target adjuvant therapy, had been shown to play an active anti-tumor role in many previous studies. This review systematically summarized the role of TCM combined with clinically commonly used drugs for the treatment of HCC (including mitomycin C, cyclophosphamide, doxorubicin, 5-fluorouracil, sorafenib, etc.) in the past basic research, and summarized the efficacy of TCM combined with surgery, IT and conventional therapy (CT) in clinical research. It was found that TCM, as an adjuvant treatment, played many roles in the treatment of HCC, including enhancing the tumor inhibition, reducing toxic and side effects, improving chemosensitivity and prolonging survival time of patients. This review summarized the advantages of integrated traditional Chinese and modern medicine in the treatment of HCC and provides a theoretical basis for clinical research.
    Keywords:  Adjuvant therapy; Antitumor; Apoptosis; Chemotherapy; Combination therapy; Hepatocellular carcinoma; Molecular targeted therapy; Multidrug resistance; Overall survival; Traditional Chinese medicine
    DOI:  https://doi.org/10.1186/s13020-022-00645-0
  55. Expert Opin Drug Deliv. 2022 Aug 05.
    Localized, on-demand, sustained drug delivery from biopolymer-based materials.
    Junqi Wu, Sawnaz Shaidani, Sophia K Theodossiou, Emily J Hartzell, David L Kaplan.
       INTRODUCTION: Local drug delivery supports high concentrations of drug molecules at or near the treatment site to enhance treatment efficiency and reduce drug toxicity and other systemic side effects. However, local drug delivery systems face challenges in terms of encapsulation, delivery, and controlled release of therapeutics.
    AREAS COVERED: We provide an overview of naturally derived biopolymer-based drug delivery systems for localized, sustained, and on-demand treatment. We introduce the advantages and limitations of these systems for drug encapsulation, delivery, and local release, as well as recent applications.
    EXPERT OPINION: Naturally derived biopolymers like cellulose, silk fibroin, chitosan, alginate, hyaluronic acid, and gelatin are good candidates for localized drug delivery because they are readily chemically modified, biocompatible, biodegradable with the generation of metabolically compatible degradation products, non-toxic, and can be processed in aqueous and ambient environments to maintain the bioactivity of peptides, proteins, and other therapeutics. The drug release mechanisms can be diffusion-based, degradation-controlled, and on-demand, triggered release. The tradeoff between the effective treatment dosage and the response by local healthy tissue should be balanced during the design of these delivery systems. Future directions will be focused on strategies to design tunable and controlled biodegradation rates, as well as to explore commercial utility in substituting biopolymer-based systems for currently utilized synthetic polymers for implants for drug delivery.
    Keywords:  biodegradation; biopolymer; hydrogel; localized drug delivery; medical implant; on-demand release; sustained release
    DOI:  https://doi.org/10.1080/17425247.2022.2110582
  56. Crit Rev Food Sci Nutr. 2022 Aug 02. 1-23
    Targeting microbiota-host interactions with resveratrol on cancer: Effects and potential mechanisms of action.
    Pan Wang, Runze Shang, Yue Ma, Dan Wang, Wenting Zhao, Fang Chen, Xiaosong Hu, Xiaoyan Zhao.
      Resveratrol (RSV) is a natural polyphenolic compound detected in grapes, berries, and red wine. The anticancer activities of RSV have been observed in vivo and in vitro studies. However, the pharmacology mechanism of RSV is confusing due to its low bioavailability. According to studies of the metabolic characteristics of RSV, the gut intestine is a crucial site of its health benefits. Dietary RSV exhibits a profound effect on the gut microbiota structure and metabolic function. In addition, emerging evidence demonstrates a protective effect of RSV metabolites against carcinogenesis. Therefore, to better understand the anticancer mechanisms of dietary RSV, it is vital to evaluate the role of RSV-microbiota-host interactions in cancer therapy. In this review, we summarized significant findings on the anticancer activities of RSV based on epidemiological, experimental and clinical studies involved in investigating the metabolic characteristics and the traditional anticancer mechanisms of RSV. Special attention is given to the putative mechanisms involving microbiota-host interactions, such as the modulation of gut microecology and the anticancer effects of RSV metabolites. The changes in microbiota-host interactions after RSV supplementation play vital roles in cancer prevention and thus offering a new perspective on nutritional interventions to treat cancer.
    Keywords:  Resveratrol; anticancer activity; gut microbiota; metabolism characterization; metabolites
    DOI:  https://doi.org/10.1080/10408398.2022.2106180
  57. Int J Med Sci. 2022 ;19(7): 1093-1102
    [6]-Gingerol induces Caspase-Dependent Apoptosis in Bladder Cancer cells via MAPK and ROS Signaling.
    Na Ri Choi, Woo-Gyun Choi, Min Ji Kwon, Joo Han Woo, Byung Joo Kim.
      The anti-cancer effects of [6]-gingerol ([6]-GIN), the main active polyphenol of ginger (Zingiber officinale), were investigated in the human bladder cancer cell line 5637. [6]-GIN inhibited cell proliferation, increased sub‑G1 phase ratios, and depolarized mitochondrial membrane potential. [6]-GIN-induced cell death was associated with the downregulation of B‑cell lymphoma 2 (BCL‑2) and survivin and the upregulation of Bcl‑2‑associated X protein (Bax). [6]-GIN activated caspase‑3 and caspase-9 and regulated the activation of mitogen-activated protein kinases (MAPKs). Further, [6]-GIN also increased the intracellular reactive oxygen species (ROS) levels and TG100-115 or tranilast increased [6]-GIN‑induced cell death. These results suggest that [6]-GIN induced apoptosis in the bladder cancer cell line 5637 and therefore has the potential to be used in the development of new drugs for bladder cancer treatment.
    Keywords:  5637; [6]-gingerol; apoptosis; bladder cancer; cell proliferation
    DOI:  https://doi.org/10.7150/ijms.73077
  58. Biomed Eng Online. 2022 Aug 02. 21(1): 53
    Targeted delivery of irinotecan to colon cancer cells using epidermal growth factor receptor-conjugated liposomes.
    Yongwei Liu, Xinghui Li, Renqun Pen, Wei Zuo, Ya Chen, Xiuying Sun, Juhua Gou, Qianwen Guo, Maoling Wen, Wuqi Li, Shuangjiang Yu, Hao Liu, Min Huang.
       BACKGROUND: CPT-11 (irinotecan) is one of the most efficient agents used for colorectal cancer chemotherapy. However, as for many other chemotherapeutic drugs, how to minimize the side effects of CPT-11 still needs to be thoroughly described.
    OBJECTIVES: This study aimed to develop the CPT-11-loaded DSPE-PEG 2000 targeting EGFR liposomal delivery system and characterize its targeting specificity and therapeutic effect on colorectal cancer (CRC) cells in vitro and in vivo.
    RESULTS: The synthesized liposome exhibited spherical shapes (84.6 ± 1.2 nm to 150.4 nm ± 0.8 nm of estimated average sizes), good stability, sustained release, and enough drug loading (55.19%). For in vitro experiments, SW620 cells treated with CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome showed lower survival extended level of intracellular ROS production. In addition, it generated an enhanced apoptotic cell rate by upregulating the protein expression of both cleaved-caspase-3 and cleaved-caspase-9 compared with those of SW620 cells treated with free CPT-11. Importantly, the xenograft model showed that both the non-target and EGFR-targeted liposomes significantly inhibited tumor growth compared to free CPT-11.
    CONCLUSIONS: Compared with the non-target CPT-11-loaded DSPE-PEG2000 liposome, CPT-11-loaded DSPE-PEG2000 targeting EGFR liposome treatment showed much better antitumor activity in vitro in vivo. Thus, our findings provide new assets and expectations for CRC targeting therapy.
    Keywords:  Colorectal cancer; DSPE-PEG2000; EGFR; Irinotecan (CPT-11); SW620 cell
    DOI:  https://doi.org/10.1186/s12938-022-01012-8
  59. J Cancer Res Clin Oncol. 2022 Aug 04.
    Metabolic targeting of malignant tumors: a need for systemic approach.
    Aggelos T Margetis.
       PURPOSE: Dysregulated metabolism is now recognized as a fundamental hallmark of carcinogenesis inducing aggressive features and additional hallmarks. In this review, well-established metabolic changes displayed by tumors are highlighted in a comprehensive manner and corresponding therapeutical targets are discussed to set up a framework for integrating basic research findings with clinical translation in oncology setting.
    METHODS: Recent manuscripts of high research impact and relevant to the field from PubMed (2000-2021) have been reviewed for this article.
    RESULTS: Metabolic pathway disruption during tumor evolution is a dynamic process potentiating cell survival, dormancy, proliferation and invasion even under dismal conditions. Apart from cancer cells, though, tumor microenvironment has an acting role as extracellular metabolites, pH alterations and stromal cells reciprocally interact with malignant cells, ultimately dictating tumor-promoting responses, disabling anti-tumor immunity and promoting resistance to treatments.
    CONCLUSION: In the field of cancer metabolism, there are several emerging prognostic and therapeutic targets either in the form of gene expression, enzyme activity or metabolites which could be exploited for clinical purposes; both standard-of-care and novel treatments may be evaluated in the context of metabolism rewiring and indeed, synergistic effects between metabolism-targeting and other therapies would be an attractive perspective for further research.
    Keywords:  Cancer; Metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00432-022-04212-w
  60. Curr Pharm Des. 2022 Jul 28.
    Aquasomes: Advanced vesicular-based nanocarrier systems.
    Samruddhi Kulkarni, Bala Prabhakar, Pravin Shende.
       BACKGROUND: Aquasomes are novel trilayered non-lipoidal vesicular nanocarriers that demonstrate structural similarity to ceramic nanoparticles with theranostic activity for diseases like ovarian cancer and antigen delivery.
    OBJECTIVE: The objective of the present article is to highlight the multifaceted potential of aquasomes over other nanocarriers for the treatment of various treatments like hemophilia A, cancer, and hepatitis.
    METHODS: Aquasomes enter the target cell by modifying the surface chemistry, extending drug release. The solid core of aquasomes provides structural stability whereas their oligomeric coatings protect drugs from dehydration. This vesicular delivery system was successfully utilized for the delivery of acid-labile enzymes, antigens, vaccines, etc. The aquasomes nanocarrier exhibits a larger surface area, volume and mass ratio that allows drug to penetrate inside the cells and a prolonged drug release profile. Moreover, aquasomes consist of a high mechanical strength, reduced or no biodegradability during storage and a good body response that facilitates deeper penetration into capillaries this makes them more special and interesting.
    RESULTS: Aquasomes is a potential alternative over other nanocarriers for insulin, antigen, and oxygen delivery.
    CONCLUSION: In the near future, aquasomes based nano-drug delivery systems can be a fascinating field for research in nanotechnology.
    Keywords:  Aquasomes; biodegradation; drug delivery; lipid vesicles; nanocarriers; vesicular carriers.
    DOI:  https://doi.org/10.2174/1381612828666220728112741
  61. J Food Biochem. 2022 Aug 05.
    Kaempferol as a potential neuroprotector in Alzheimer's disease.
    Hamid Reza Nejabati, Leila Roshangar.
      Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is largely associated with cognitive disability, amnesia, and abnormal behavior, which accounts for about two third of people with dementia worldwide. A growing body of research demonstrates that AD is connected to several factors, such as aberrant accumulation of amyloid-beta (Aβ), increase in the hyperphosphorylation of Tau protein, and the formation of neurofibrillary tangles, mitochondrial dysfunction, and inordinate production of reactive oxygen species (ROS). Despite remarkable efforts to realize the etiology and pathophysiology of AD, until now, scientists have not developed and introduced medications that can permanently cease the progression of AD. Thus, nowadays, research on the role of natural products in the treatment and prevention of AD has attracted great attention. Kaempferol (KMP), one of the prominent members of flavonols, exerts its ameliorative actions via attenuating oxidative stress and inflammation, reducing Aβ-induced neurotoxicity, and regulating the cholinergic system. Therefore, in this review article, we outlined the possible effects of KMP in the prevention and treatment of AD. PRACTICAL APPLICATIONS: Kaempferol (KMP) exerts its ameliorative actions against AD via attenuating oxidative stress and inflammation, reducing Aβ-induced neurotoxicity, and regulating the cholinergic system. The beneficial effects of KMP were addressed in both in vitro and in vivo studies; however, conducting further research can warrant its long-term effects as a safe agent. Therefore, after confirming its favorable functions in the prevention and treatment of AD, it could be used as a safe and effective agent.
    Keywords:  Alzheimer's disease; kaempferol; reactive oxygen species
    DOI:  https://doi.org/10.1111/jfbc.14375
  62. Crit Rev Anal Chem. 2022 Aug 05. 1-15
    Bioactive Flavonoids: A Comprehensive Review on Pharmacokinetics and Analytical Aspects.
    Koushal Billowria, Rouchan Ali, Naresh Kumar Rangra, Ram Kumar, Pooja A Chawla.
      Flavonoids are a diversified group of natural substances which were discovered to provide a variety of health benefits in human beings. Vegetables, fruits, wine and tea are the primary flavonoid dietary sources for humans and as the flavonoids are so closely connected to human dietary items and health, it is vital to explore the structural-activity connection. The arrangement, replacement of functional groups, and total number of hydroxyl groups around flavonoid's nucleus structure affect their biological activity, metabolism, and bioavailability. Various flavonoids have been proven to have hepatoprotective properties, that help in the prevention of coronary heart disease. Similarly, these flavonoids also possess anticancer, and anti-inflammatory activities. Flavonoids have been found to have a functional and structural link with their enzyme inhibitory action, that appears to have antiviral effect through acting as antioxidants, damaging cell membranes, blocking enzymes, activating mechanisms of host self-defense, and limiting virus penetration and attaching to cells. Identification, characterization, isolation, and biological role of flavonoids, as well as their uses on health advantages, are all major topics in research and development currently. This review represents a summary of various sources of flavonoids, class, subclass, their chemical structures, biological activities, the pharmacokinetics of flavonoids and various analytical, bioanalytical and electrochemical methods for determination of flavonoids from different matrices.
    Keywords:  Flavonoids; analytical methods; bioanalytical methods; biological activity; pharmacokinetics
    DOI:  https://doi.org/10.1080/10408347.2022.2105641
  63. Expert Opin Drug Deliv. 2022 Aug 05.
    Biodegradable and removable implants for controlled drug delivery and release application.
    Vivek P Chavda, Gargi Jogi, Ana Cláudia Paiva-Santos, Ajeet Kaushik.
      Conventional drug delivery route has several limitations such as hepatic first-pass metabolism, gastric issues, hypersensitivity reactions, etc. Additionally, such approaches are not found to be patient compliant, especially for chronic diseases. Conversely, implantable, polymeric drug delivery systems provide prolonged as well as controlled release of drug from the device implanted in the body. This editorial summarizes various types of implantable drug delivery systems along with their associated advantages and challenges. Additionally, recent advances in this field such as shape memory-based polymeric implants and 3-D printed implants are also discussed carefully and critically.
    Keywords:  Implantable drug delivery system; Polymeric implants; biodegradable implants; removable implants; sustainable health wellness
    DOI:  https://doi.org/10.1080/17425247.2022.2110065
  64. Drug Deliv. 2022 Dec;29(1): 2579-2591
    Development and optimization of a tamsulosin nanostructured lipid carrier loaded with saw palmetto oil and pumpkin seed oil for treatment of benign prostatic hyperplasia.
    Rana B Bakhaidar, Khaled M Hosny, Imman M Mahier, Waleed Y Rizq, Awaji Y Safhi, Deena M Bukhary, Muhammad H Sultan, Haitham A Bukhary, Osama A Madkhali, Fahad Y Sabei.
      Benign prostatic hyperplasia (BPH) is a nonmalignant growth of the prostate tissue and causes urinary tract symptoms. To provide effective treatment, tamsulosin (TM), saw palmetto oil (SP), and pumpkin seed oil (PSO) were combined and fabricated a nanostructured lipid carrier (NLC) as TM-S/P-NLC using experimental design. The purpose was to enhance the permeation and therapeutic activity of TM; combining TM with SP and PSO in an NLC generates a synergistic activity. An optimized TM-S/P-NLC was obtained after statistical analysis, and it had a particle size, percentage of entrapment efficiency, and steady-state flux of 102 nm, 65%, and 4.5 μg/cm2.min, respectively. Additionally, the optimized TM-S/P-NLC had spherical particles with a more or less uniform size and a stability score of 95%, indicating a high level of stability. The in vitro release studies exhibited the optimized TM-S/P-NLC had the maximum release profile for TM (81 ± 4%) as compared to the TM-NLCs prepared without the addition of S/P oil (59 ± 3%) or the TM aqueous suspension (30 ± 5%). The plasma TM concentration-time profile for the TM-S/P-NLC and the marketed TM tablets indicated that when TM was supplied in a TM-S/P-NLC, the pharmacokinetic profile of the drug was improved. Simultaneously, in vivo therapeutic efficacy studies also showed favorable results for the TM-S/P-NLC in terms of the prostate weight and prostate index following treatment of BPH. Based on the findings of present study, we suggest that in the future, the TM-S/P-NLC could be a novel drug delivery system for treating BPH.
    Keywords:  Tamsulosin; drug delivery system; experimental design; nanoparticle; prostate index
    DOI:  https://doi.org/10.1080/10717544.2022.2105448
  65. Front Cell Dev Biol. 2022 ;10 930250
    Connecting Metabolic Rewiring With Phenotype Switching in Melanoma.
    Paola Falletta, Colin R Goding, Yurena Vivas-García.
      Melanoma is a complex and aggressive cancer type that contains different cell subpopulations displaying distinct phenotypes within the same tumor. Metabolic reprogramming, a hallmark of cell transformation, is essential for melanoma cells to adopt different phenotypic states necessary for adaptation to changes arising from a dynamic milieu and oncogenic mutations. Increasing evidence demonstrates how melanoma cells can exhibit distinct metabolic profiles depending on their specific phenotype, allowing adaptation to hostile microenvironmental conditions, such as hypoxia or nutrient depletion. For instance, increased glucose consumption and lipid anabolism are associated with proliferation, while a dependency on exogenous fatty acids and an oxidative state are linked to invasion and metastatic dissemination. How these different metabolic dependencies are integrated with specific cell phenotypes is poorly understood and little is known about metabolic changes underpinning melanoma metastasis. Recent evidence suggests that metabolic rewiring engaging transitions to invasion and metastatic progression may be dependent on several factors, such as specific oncogenic programs or lineage-restricted mechanisms controlling cell metabolism, intra-tumor microenvironmental cues and anatomical location of metastasis. In this review we highlight how the main molecular events supporting melanoma metabolic rewiring and phenotype-switching are parallel and interconnected events that dictate tumor progression and metastatic dissemination through interplay with the tumor microenvironment.
    Keywords:  MITF; drug resisitance; fatty acids; heterogeneity; melanoma; metabolic plasticity; mitochondria
    DOI:  https://doi.org/10.3389/fcell.2022.930250
  66. Nature. 2022 Aug 03.
    Brown-fat-mediated tumour suppression by cold-altered global metabolism.
    Takahiro Seki, Yunlong Yang, Xiaoting Sun, Sharon Lim, Sisi Xie, Ziheng Guo, Wenjing Xiong, Masashi Kuroda, Hiroshi Sakaue, Kayoko Hosaka, Xu Jing, Masahito Yoshihara, Lili Qu, Xin Li, Yuguo Chen, Yihai Cao.
      Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1-the key mediator for BAT-thermogenesis-ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
    DOI:  https://doi.org/10.1038/s41586-022-05030-3
  67. Brain Tumor Res Treat. 2022 Jul;10(3): 151-157
    Local Drug Delivery Strategies for Glioblastoma Treatment.
    Gi Doo Cha, Sonwoo Jung, Seung Hong Choi, Dae-Hyeong Kim.
      Glioblastoma multiforme (GBM) is a brain tumor notorious for its malignancy. The key reason for the limited efficacy of standard treatment is the high recurrence rate of GBM, even after surgical resection. Hence, intensive postsurgical chemical therapies, such as the systemic delivery of various drugs and/or drug combinations, are typically followed after surgery. However, overcoming the blood-brain barrier by systemic administration to efficiently deliver drugs to the brain tumor remains a daunting goal. Therefore, various local drug delivery methods showing potential for improved therapeutic efficacy have been proposed. In particular, the recent application of electronic devices for the controlled delivery of chemotherapy drugs to GBM tissue has attracted attention. We herein review the recent progress of local drug delivery strategies, including electronics-assisted strategies, at the research and commercial level. We also present a brief discussion of the unsolved challenges and future research direction of localized chemotherapy methods for GBM.
    Keywords:  Absorbable implants; Blood-brain barrier; Brain tumor; Chemotherapy; Drug administration routes; Drug delivery systems
    DOI:  https://doi.org/10.14791/btrt.2022.0017
  68. Front Mol Biosci. 2022 ;9 938677
    The Mechanisms of Ferroptosis and the Applications in Tumor Treatment: Enemies or Friends?
    Shuzheng Tan, Ying Kong, Yongtong Xian, Pengbo Gao, Yue Xu, Chuzhong Wei, Peixu Lin, Weilong Ye, Zesong Li, Xiao Zhu.
      Ferroptosis, as a newly discovered non-apoptotic cell death mode, is beginning to be explored in different cancer. The particularity of ferroptosis lies in the accumulation of iron dependence and lipid peroxides, and it is different from the classical cell death modes such as apoptosis and necrosis in terms of action mode, biochemical characteristics, and genetics. The mechanism of ferroptosis can be divided into many different pathways, so it is particularly important to identify the key sites of ferroptosis in the disease. Herein, based on ferroptosis, we analyze the main pathways in detail. More importantly, ferroptosis is linked to the development of different systems of the tumor, providing personalized plans for the examination, treatment, and prognosis of cancer patients. Although some mechanisms and side effects of ferroptosis still need to be studied, it is still a promising method for cancer treatment.
    Keywords:  ferroptosis; immunotherapy; iron overload; lipid peroxidation; mitochondria
    DOI:  https://doi.org/10.3389/fmolb.2022.938677
  69. Front Nutr. 2022 ;9 968604
    Review of phytochemical and nutritional characteristics and food applications of Citrus L. fruits.
    Shuxun Liu, Ying Lou, Yixian Li, Jiaojiao Zhang, Ping Li, Baoru Yang, Qing Gu.
      Since the dietary regimen rich in fruits is being widely recognized and encouraged, Citrus L. fruits have been growing in popularity worldwide due to their high amounts of health-promoting phytonutrients and bioactive compounds, such as flavonoids, phenolic acids, vitamins, carotenoids, pectins, and fatty acids. The diverse physicochemical properties and multiple utilization of citrus fruits in food industry are associated with their unique chemical compositions. Throughout the world, citrus has been used for producing various value-added and nutritionally enhanced products, including juices, wines, jams, canned citrus, and dried citrus. However, the current studies regarding the phytochemical and nutritional characteristics and food applications of citrus are scattered. This review systematically summarizes the existing bibliography on the chemical characteristics, functional and nutraceutical benefits, processing, and potential applications of citrus. A thorough understanding of this information may provide scientific guidance for better utilizing citrus as a functional fruit and benefit the extension of citrus value chain.
    Keywords:  citrus; food applications; health benefits; nutrients; phytochemicals
    DOI:  https://doi.org/10.3389/fnut.2022.968604
  70. Biomater Adv. 2022 Jul;pii: S2772-9508(22)00212-6. [Epub ahead of print]138 212935
    A dual-responsive "Yin-Yang" photothermal delivery system to accelerate Parthenolide anti-tumor efficacy.
    Anshuo Li, Wenbin Gao, Xuwu Zhang, Yuwei Deng, Yuhui Zhu, Hao Gu, Jin Wen, Xinquan Jiang.
      Parthenolide (PTL), a germacrane sesquiterpene lactone extracted from the "Yin" Chinese traditional herb feverfew, has gained interest due to its lethal effects on tumor cells and its pharmacological effects within traditional Chinese medicine theory. To overcome low, non-targeted accumulation and uncontrolled release of PTL administration, a dual-responsive PTL-liposomes@chitosan@gold nanoshells (PTL-Lips@CS@GNS) system was fabricated. Hyperthermia generated under light irradiation in the near-infrared region via local surface plasmon resonance of gold nanoshells induced photothermal therapy, which also stimulated PTL release due to the liposomes gel-to-liquid crystalline phase transition. Additionally, PTL-Lips@CS@GNS exhibited a pH-responsive release in the acidic tumor microenvironment. Collectively, this study provides a realistic strategy for an effective combination of traditional Chinese medicine and current nanotechnology for tumor therapy.
    Keywords:  Dual-responsive release; Nano-drug delivery system; Parthenolide; Photothermal therapy; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212935
  71. Oxid Med Cell Longev. 2022 ;2022 7302883
    Research Progress Based on Regulation of Tumor Microenvironment Redox and Drug-Loaded Metal-Organic Frameworks.
    Tong Xu.
      The process of tumor growth and deterioration is accompanied by increased oxygen free radicals, high glutathione concentration, hypoxia, and poor drug targeting during treatment, limiting the treatment of tumors. Metal-organic framework (MOF) preparations are continuously being developed and applied in tumor therapy. In this paper, the design and application of reactive oxygen species (ROS) and redox drug-loaded MOF preparations are reviewed. Moreover, the research challenges and application prospects of MOFs in tumor therapy are also discussed.
    DOI:  https://doi.org/10.1155/2022/7302883
  72. Cancer Res. 2022 Aug 05. pii: CAN-22-0325. [Epub ahead of print]
    An immunogenic model of KRAS-mutant lung cancer enables evaluation of targeted therapy and immunotherapy combinations.
    Jesse Boumelha, Sophie de Carné Trécesson, Emily K Law, Pablo Romero-Clavijo, Matthew Coelho, Kevin Ng, Edurne Mugarza, Christopher Moore, Sareena Rana, Deborah R Caswell, Miguel Murillo, David C Hancock, Prokopios P Argyris, William L Brown, Cameron Durfee, Lindsay K Larson, Rachel I Vogel, Alejandro Suarez-Bonnet, Simon L Priestnall, Philip East, Sarah J Ross, George Kassiotis, Miriam Molina-Arcas, Charles Swanton, Reuben Harris, Julian Downward.
      Mutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumor regression but ultimately fail to elicit cures. As a result, there is an intense interest in how to best combine targeted therapies with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumors with the host immune system are inadequate, in part due to the low tumor mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumor mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumor mutational burden and autochthonous tumors remained refractory to immunotherapy. However, establishing clonal cell lines from these tumors enabled the generation of an immunogenic syngeneic transplantation model of KRAS-mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, anti-tumor immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12C inhibitors to cause regression of KRASG12C-expressing tumors was markedly potentiated by the adaptive immune system, highlighting the importance of using immunocompetent models for evaluating targeted therapies. Overall, this model provides a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0325
  73. Food Chem Toxicol. 2022 Aug 02. pii: S0278-6915(22)00519-1. [Epub ahead of print] 113321
    Vitamin C-induced competitive binding of HIF-1α and p53 to ubiquitin E3 ligase CBL contributes to anti-breast cancer progression through p53 deacetylation.
    Yan Xiong, Shiyao Xu, Beibei Fu, Wanyan Tang, Mohamed Y Zaky, Rong Tian, Rui Yao, Shanfu Zhang, Qingting Zhao, Weiqi Nian, Xiaoyuan Lin, Haibo Wu.
      Vitamin C (VC), in regard to its effectiveness against tumors, has had a controversial history in cancer treatment. However, the anticancer mechanisms of VC are not fully understood. Here, we reported that VC exerted an anticancer effect on cancer cell and xenograft models via inhibiting HIF-1α-dependent cell proliferation and promoting p53-dependent cell apoptosis. To be specific, VC modulated the competitive binding of HIF-1α and p53 to their common E3 ubiquitin ligase CBL, thereby inhibiting tumorigenesis. Moreover, VC treatment activated SIRT1, resulting in p53 deacetylation and CBL-p53 complex dissociation, which in turn facilitated CBL recruitment of HIF-1α for ubiquitination in a proteasome-dependent manner. Altogether, our results provided a mechanistic rationale for exploring the therapeutic use of VC in cancer therapy.
    Keywords:  Acetylation; HIF-1α; SIRT1; Vitamin C; p53
    DOI:  https://doi.org/10.1016/j.fct.2022.113321
  74. Front Pharmacol. 2022 ;13 850777
    Natural Phenylethanoid Supplementation Alleviates Metabolic Syndrome in Female Mice Induced by High-Fructose Diet.
    Xiujun Zhan, Mingshuai He, Jierong Pei, Wenjing Fan, Charity Ngina Mwangi, Peng Zhang, Xin Chai, Miaomiao Jiang.
      Tyrosol (T), hydroxytyrosol (H), and salidroside (S) are typical phenylethanoids and also powerful dietary antioxidants. This study aimed at evaluating the influence of three natural phenylethanoids, which are dietary phenylethanoids of natural origins, on reversing gut dysbiosis and attenuating nonalcoholic fatty liver features of the liver induced by metabolic syndrome (MetS) mice. C57BL/6J female mice induced with high-fructose diet were established and administrated with salidroside, tyrosol, and hydroxytyrosol for 12 weeks, respectively. Biochemical analysis showed that S, T, and H significantly improved glucose metabolism and lipid metabolism, including reduced levels of total cholesterol insulin (INS), uric acid, low-density lipoprotein cholesterol (LDL-C), and aspartate aminotransferase (ALT). Histopathological observation of the liver confirmed the protective effects of S, T, and H against hepatic steatosis, which were demonstrated by the results of metabolomic analysis, such as the improvement in glycolysis, purine metabolism, bile acid, fatty acid metabolism, and choline metabolism. Additionally, 16S rRNA gene sequence data revealed that S, T, and H could enhance the diversity of gut microbiota. These findings suggested that S, T, and H probably suppress lipid accumulation and have hepatoprotective effects and improve intestinal microflora disorders to attenuate metabolic syndromes.
    Keywords:  fructose; gut microbiota; hepatic protection; metabolic syndrome; salidroside
    DOI:  https://doi.org/10.3389/fphar.2022.850777
  75. Biomacromolecules. 2022 Aug 03.
    Folic Acid-Modified Cyclodextrin Multivalent Supramolecular Assembly for Photodynamic Therapy.
    Xianyin Dai, Man Huo, Bing Zhang, Zhixue Liu, Yu Liu.
      The construction of supramolecular multivalent assemblies with unique photoluminescence behaviors and biological functions has become a research hot spot recently in the biomaterial field. Herein, we report an adaptive supramolecular assembly via a multivalent co-assembly strategy prepared in two stages by using an adamantane-connected pyrenyl pyridinium derivative (APA2), sulfonated aluminum phthalocyanine (PcS), and folic acid-modified β-cyclodextrin (FA-CD) for efficient dual-organelle targeted photodynamic cancer cell ablation. Benefiting from π-π and electrostatic interactions, APA2 and PcS could first assemble into non-fluorescent irregular nanoaggregates because of the heterodimer aggregation-induced quenching and then secondarily assemble with FA-CD to afford targeted spherical nanoparticles (NPs) with an average diameter of around 50 nm, which could be specifically taken up by HeLa cancer cells through endocytosis in comparison with 293T normal cells. Intriguingly, such multivalent NPs could adaptively disaggregate in an intracellular physiological environment of cancer cells and further respectively and selectively accumulate in mitochondria and lysosomes, which not only displayed near-infrared two-organelle localization in situ but also aroused efficient singlet oxygen generation under light irradiation to effectively eliminate cancer cells up to 99%. This supramolecular multivalent assembly with an adaptive feature in a specific cancer cell environment provides a feasible strategy for precise organelle-targeted imaging and an efficiently synergetic photodynamic effect in situ for cancer cell ablation.
    DOI:  https://doi.org/10.1021/acs.biomac.2c00276
  76. Compr Rev Food Sci Food Saf. 2022 Aug 01.
    A review of recent progress in improving the bioavailability of nutraceutical-loaded emulsions after oral intake.
    Xing Chen, Yan Chen, Yikun Liu, Liqiang Zou, David Julian McClements, Wei Liu.
      Increasing awareness of the health benefits of specific constituents in fruits, vegetables, cereals, and other whole foods has sparked a broader interest in the potential health benefits of nutraceuticals. Many nutraceuticals are hydrophobic substances, which means they must be encapsulated in colloidal delivery systems. Oil-in-water emulsions are one of the most widely used delivery systems for improving the bioavailability and bioactivity of these nutraceuticals. The composition and structure of emulsions can be designed to improve the water dispersibility, physicochemical stability, and bioavailability of the encapsulated nutraceuticals. The nature of the emulsion used influences the interfacial area and properties of the nutraceutical-loaded oil droplets in the gastrointestinal tract, which influences their digestion, as well as the bioaccessibility, metabolism, and absorption of the nutraceuticals. In this article, we review recent in vitro and in vivo studies on the utilization of emulsions to improve the bioavailability of nutraceuticals. The findings from this review should facilitate the design of more efficacious nutraceutical-loaded emulsions with increased bioactivity.
    Keywords:  emulsions; gastrointestinal fate; metabolic elimination; micellization; nutraceuticals; oral bioavailability; transcellular transport
    DOI:  https://doi.org/10.1111/1541-4337.13017
  77. Drug Deliv. 2022 Dec;29(1): 2491-2497
    Improving cellular uptake and bioavailability of periplocymarin-linoleic acid prodrug by combining PEGylated liposome.
    Huiyun Zhang, Shunru Wei, Yu Zhang, Anran Pan, Michael Adu-Frimpong, Congyong Sun, Gang Qi.
      Periplocymarin (PPM), a cardiac glycoside isolated from Cortex periplocae, has a strong anti-tumor effect against various cancer cells. However, cardiotoxicity and rapid metabolism hinder its clinical applications. In this study, small molecule prodrug was integrated into PEGylated liposome to improve the efficiency of periplocymarin in vivo. The periplocymarin-linoleic acid (PL) prodrug was constructed by conjugating the linoleic acid with PPM via esterification, which was further facilitated to form PEGylated liposome (PL-Lip) through film dispersion. Compared with PL self-assembling nano-prodrug (PL-SNP), PL-Lip showed better colloid stability, sustained drug release kinetics, and enhanced cellular uptake by tumor cells. Notably, PL-Lip performed better than PPM and PL-SNP in terms of tumor distribution and pharmacokinetics, which include bioavailability and half-life. Altogether, the prodrug PEGylated liposome represents a good strategy and method for long-circulating and tumor-targeting delivery of periplocymarin with enhanced clinical application prospect.
    Keywords:  PEGylated liposome; Periplocymarin; small molecule prodrug
    DOI:  https://doi.org/10.1080/10717544.2022.2104406
  78. Sci Adv. 2022 Aug 05. 8(31): eabo5285
    Metallo-alginate hydrogel can potentiate microwave tumor ablation for synergistic cancer treatment.
    Yujie Zhu, Zhijuan Yang, Zijian Pan, Yu Hao, Chunjie Wang, Ziliang Dong, Quguang Li, Yikai Han, Longlong Tian, Liangzhu Feng, Zhuang Liu.
      Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca2+ fixed by alginate as Ca2+-surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca2+ homeostasis. Resultantly, Ca2+-surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn2+, an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ-formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.
    DOI:  https://doi.org/10.1126/sciadv.abo5285
  79. Expert Opin Drug Deliv. 2022 Aug 05.
    Nanocrystals for controlled delivery: State of the art and approved drug products.
    Rahul S Kalhapure, Siddhant Palekar, Ketan Patel, Jasmin Monpara.
       INTRODUCTION: Controlled/extended-release formulations offer numerous benefits over conventional especially reduced side effects, improved therapeutic outcomes and high patient compliance. Controlled release nanocrystal is extremely versatile technology with several advantages such as very high drug loading, ease of manufacturing, avoidance of dose dumping, reproducible drug release. Usually, nanonization of drug is performed to improve dissolution rate, intrinsic solubility and thereby bioavailability. Most of the times, this is done for immediate release dosage forms where objective is quick onset of action. However, nanocrystals can also provide a sustained, reproducible plasma concentration profile for weeks to months based on tissue microenvironment, surface coating administration route.
    AREAS COVERED: This review briefly describes the methods for producing nanocrystals, summarizes preclinical research and commercial products demonstrating tremendous potential of controlled release nanocrystals.
    EXPERT OPINION: Lipophilic drugs are attractive candidates for the development of nanocrystal based controlled release formulations. However, constraint should be practiced while generalizing the technology for the controlled release purpose. Not all drugs fit in the requirement from the perspectives of physicochemical properties or pharmacokinetic requirements. Additionally, technologies should be explored which can convert the nanocrystal into its final dosage form for administration yet preserves the benefits of small particle size and controlled release.
    Keywords:  controlled release; extended release; nanocrystals; nanosuspension; size reduction
    DOI:  https://doi.org/10.1080/17425247.2022.2110579
  80. Front Bioeng Biotechnol. 2022 ;10 954470
    Nanogels as Novel Nanocarrier Systems for Efficient Delivery of CNS Therapeutics.
    Yunhan Zhang, Zhulin Zou, Shuang Liu, Shengjie Miao, Haiyan Liu.
      Nanogels have come out as a great potential drug delivery platform due to its prominently high colloidal stability, high drug loading, core-shell structure, good permeation property and can be responsive to environmental stimuli. Such nanoscopic drug carriers have more excellent abilities over conventional nanomaterials for permeating to brain parenchyma in vitro and in vivo. Nanogel-based system can be nanoengineered to bypass physiological barriers via non-invasive treatment, rendering it a most suitable platform for the management of neurological conditions such as neurodegenerative disorders, brain tumors, epilepsy and ischemic stroke, etc. Therapeutics of central nervous system (CNS) diseases have shown marked limited site-specific delivery of CNS by the poor access of various drugs into the brain, due to the presences of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB). Hence, the availability of therapeutics delivery strategies is considered as one of the most major challenges facing the treatment of CNS diseases. The primary objective of this review is to elaborate the newer advances of nanogel for CNS drugs delivery, discuss the early preclinical success in the field of nanogel technology and highlight different insights on its potential neurotoxicity.
    Keywords:  CNS diseases; blood-brain barrier; nanogel; nanotechnology; smart drug release
    DOI:  https://doi.org/10.3389/fbioe.2022.954470
  81. Int J Pharm. 2022 Jul 30. pii: S0378-5173(22)00616-0. [Epub ahead of print] 122062
    Cichorium intybus bio-callus synthesized silver nanoparticles: a promising antioxidant, antibacterial and anticancer compound.
    Zahra Gharari, Parichehr Hanachi, Hanie Sadeghinia, Tony R Walker.
      Cichorium intybus, commonly called chicory, has been widely used as a coffee substitute. It display a wide range of natural compounds and medicinally uses in treatment of gastrointestinal disorders. This study synthesized silver nanoparticles (Ci-AgNPs) using C. intybus leaf-derived callus extract to evaluate phytochemical content, antibacterial, antioxidant and anti-proliferative activities against human breast cancer cells (MDA-MB231). The optimal shape, size and stability of Ci-AgNPs was confirmed using UV-visible spectrophotometry, FESEM, EDX, XRD, DLS, Zeta potential, FTIR and sp-ICP-MS studies. The antibacterial activity of Ci-AgNPs was assessed using disk diffusion method against Staphylococcus aureus and Escherichia coli, and they displayed distinct zones of inhibition. Colorimetric phytochemical analysis of Ci-AgNPs revealed their higher total phenolic (TP) and total flavonoid (TF) content. Ci-AgNPs also indicated a high level of antioxidant activity using FRAP and DPPH assays. The Ci-AgNPs were investigated for their anticancer activities on the cancerous MDA-MB231 cells viability and apoptosis using MTT and flow cytometry, respectively. Ci-AgNPs showed dose dependent cytotoxicity against MDA-MB231 cells with IC50 value of 187.6 μg/mL at 48h through induction of apoptosis. The biocompatibility test showed that Ci-AgNPs induced neglectable cytotoxicity (lower than 3%) toward human erythrocytes. This is the first study that reports the bio-callus mediated synthesis of silver nanoparticle using C. intybus callus extract which provided a promising anticancer activity against human breast cancer MDA-MB231 cells and therefore could be used as an alternative and interesting benign strategy for biosynthesis of silver nanoparticles useful in cancer therapy.
    Keywords:  Anti-bacterial; Breast cancer; Callus; Cichorium intybus; Selective cytotoxicity; Silver nanoparticles
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122062
  82. Cancer Lett. 2022 Jul 31. pii: S0304-3835(22)00321-4. [Epub ahead of print] 215837
    De novo pyrimidine synthesis fuels glycolysis and confers chemoresistance in gastric cancer.
    Daochuan He, Mengqian Chen, Lei Chang, Jianxin Gu, Fenglin Liu, Xiaodong Gao, Yuanyuan Ruan.
      Metabolic reprogramming is a hallmark in multiple types of malignancies. Fast-growing cancer cells require facilitated synthesis of essential metabolites and excessive energy production. However, whether they are internally coordinated remains largely unknown. Herein, we found that de novo pyrimidine synthesis enhanced aerobic glycolysis in cancer cells. Mechanistically, pyrimidine biosynthesis augmented Notch signaling and transcriptionally increased c-Myc expression, leading to up-regulation of critical glycolytic enzymes. Further studies revealed that pyrimidine synthesis could stabilize γ-secretase subunit Nicastrin at post-translational N-linked glycosylation level, thereby inducing the cleavage and activation of Notch. Besides, we found that up-regulation of the key enzymes for de novo pyrimidine synthesis CAD and DHODH conferred the chemotherapeutic resistance of gastric cancer via accelerating glycolysis, and pharmacologic inhibition of pyrimidine biosynthetic pathway sensitized cancer cells to chemotherapy in vitro and in vivo. Collectively, our findings provide more insights into the regulation of aerobic glycolysis and a metabolic vulnerability that can be exploited to enhance chemotherapy efficacy in gastric cancer.
    Keywords:  C-Myc; Chemotherapy; N-linked glycosylation; Nicastrin; Notch1
    DOI:  https://doi.org/10.1016/j.canlet.2022.215837
  83. Front Mol Biosci. 2022 ;9 931759
    Nanoparticles in ocular applications and their potential toxicity.
    Cao Yang, Junling Yang, Ao Lu, Jing Gong, Yuanxing Yang, Xi Lin, Minghui Li, Haiwei Xu.
      Nanotechnology has been developed rapidly in recent decades and widely applied in ocular disease therapy. Nano-drug delivery systems overcome the bottlenecks of current ophthalmic drug delivery and are characterized with strong biocompatibility, stability, efficiency, sustainability, controllability, and few side effects. Nanoparticles have been identified as a promising and generally safe ophthalmic drug-delivery system based on the toxicity assessment in animals. Previous studies have found that common nanoparticles can be toxic to the cornea, conjunctiva, and retina under certain conditions. Because of the species differences between humans and animals, advanced in vitro cell culture techniques, such as human organoids, can mimic the human organism to a certain extent, bringing nanoparticle toxicity assessment to a new stage. This review summarizes the advanced application of nanoparticles in ocular drug delivery and the potential toxicity, as well as some of the current challenges and future opportunities in nanotoxicological evaluation.
    Keywords:  assessment; challenges; nanoparticles; ocular drug delivery; toxicity
    DOI:  https://doi.org/10.3389/fmolb.2022.931759
  84. Int J Biol Macromol. 2022 Jul 29. pii: S0141-8130(22)01652-X. [Epub ahead of print]
    Amino-functionalized cross-linked cellulosic fabric with antibacterial, UV protection, and coloring effects using folic acid.
    Mojgan Razaghpour, Reza Mohammad Ali Malek, Majid Montazer, Shadpour Mallakpour.
      The amino-functionalized cellulose with folic acid, via an esterification reaction between carboxylic acid of folic acid and hydroxyl groups of cellulose, can develop multifunctional products with new chemical and physical properties. Folic acid contains two carboxylic groups as well as an amine group that can be used as a coupling agent and provide suitable conditions for coupling hydroxyl-based compounds to cellulose. Also; the multi-functionalized cellulose with folic acid has no effects on the physical and mechanical properties and also has benefits such as antibacterial, UV protection, and wrinkle resistance. The FTIR-ATR and Raman analysis confirmed the amino functionalized-cellulosic fabric via an esterification reaction between cellulose and folic acid. The cell viability of L929 fibroblast (NCBI C161) and MCF-7 (NCBI C135) cancer cells indicated more effectiveness on MCF-7 cancer cells. Therefore; folic acid can be used as a biocompatible natural cross-linker to modify cellulose fabrics for apparel and medical applications.
    Keywords:  Amino-functionalized; Antimicrobial properties; Cell viability; Cross-linking; Folic acid; UV protection
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.214
  85. Drug Deliv. 2022 Dec;29(1): 2539-2548
    A simple but efficient tumor-targeted nanoparticle delivery system constructed by oleic acid.
    Jingxin Fu, Yian Wang, Haowen Li, Likang Lu, Meihua Han, Yifei Guo, Xiangtao Wang.
      Oleic acid (OA) is a kind of monounsaturated omega-3 fatty acid that abounds in plants and animals which can induce apoptosis and has broad-spectrum inhibitory activity against a variety of tumor cell lines. However, OA is quite insoluble and thus inconvenient to be efficiently delivered in vivo. In this work, OA was fabricated into nanoparticles to generate OA elastic nanoparticles (OA-ENPs) with a particle size of 185.6 nm and good stability in various physiological media. OA-ENPs alone achieved a high tumor inhibition rate of 60.3% without significant side effect. More surprisingly, the resultant OA-ENPs displayed dose-dependent tumor targetability. Low dose of OA-ENPs (10 mg/kg) mainly distributed in the liver after intravenous injection, while high dose of OA-ENPs mainly distributed in tumor. At the high dose of 90 mg/kg, OA-ENPs accumulation in tumor reached nearly twice as that in the liver. Here we provide a simple but effective way to achieve excellent tumor targetability without the need of any surface modification of nanoparticles.
    Keywords:  Oleic acid; elastic; nanoparticles; tumor-targeted
    DOI:  https://doi.org/10.1080/10717544.2022.2105447
  86. AAPS PharmSciTech. 2022 Aug 03. 23(6): 213
    Development and Characterization of Celecoxib Solid Self-nanoemulsifying Drug Delivery Systems (S-SNEDDS) Prepared Using Novel Cellulose-Based Microparticles as Adsorptive Carriers.
    Fabian-Pascal Schmied, Alexander Bernhardt, Victor Baudron, Birte Beine, Sandra Klein.
      Self-nanoemulsifying drug delivery systems (SNEDDS) represent an interesting platform for improving the oral bioavailability of poorly soluble lipophilic drugs. While Liquid-SNEDDS (L-SNEDDS) effectively solubilize the drug in vivo, they have several drawbacks, including poor storage stability. Solid-SNEDDS (S-SNEDDS) combine the advantages of L-SNEDDS with those of solid dosage forms, particularly stability. The aim of the present study was to convert celecoxib L-SNEDDS into S-SNEDDS without altering their release behavior. Various commercially available adsorptive carrier materials were investigated, as well as novel cellulose-based microparticles prepared by spray drying from an aqueous dispersion containing Diacel® 10 and methyl cellulose or gum arabic as a binder prior to their use. Particle size and morphology of the carrier materials were screened by scanning electron microscopy and their effects on the loading capacity for L-SNEDDS were investigated, and comparative in vitro dissolution studies of celecoxib L-SNEDDS and the different S-SNEDDS were performed immediately after preparation and after 3 months of storage. Among the adsorptive carrier materials, the novel cellulose-based microparticles were found to be the most suitable for the preparation of celecoxib S-SNEDDS from L-SNEDDS, enabling the preparation of a solid, stable formulation while preserving the in vitro release performance of the L-SNEDDS formulation.
    Keywords:  Cellulose; Drug release; L-SNEDDS; Poorly soluble drugs; Scanning electron microscopy
    DOI:  https://doi.org/10.1208/s12249-022-02347-0
  87. J Pharm Biomed Anal. 2022 Jul 29. pii: S0731-7085(22)00396-X. [Epub ahead of print]219 114975
    Antiglycation, antioxidant and cytotoxicity activities of crude extract of Turnera ulmifolia L. before and after microencapsulation process.
    Amanda Martins Viel, Célia Cristina Malaguti Figueiredo, Filipe Oliveira Granero, Luciana Pereira Silva, Valdecir Farias Ximenes, Thais Miranda Godoy, Luis Eduardo Menezes Quintas, Regildo Márcio Gonçalves da Silva.
      Turnera ulmifolia L. is used in folk medicine and it is known to have anti-hyperglycemic effect on the organism in order to reduce complications in diabetic patients. Glycation process is directly related to oxidative stress, acting as an important endogenous source, inducing the production of free radicals, and thus increasing the production of reactive oxygen species. The encapsulation technology on natural compounds can minimize and even mitigate the risk of loss of biological activity in order to maintain their activities against oxidative stress and glycation. The present study aimed to evaluate the antiglycation and antioxidant activities of T. ulmifolia extract before and after encapsulation and cytotoxicity of the crude extract. This study presents important information about the biological activities, highlighting antioxidant and antiglycation potential and no cytotoxicity of Turnera ulmifolia crude extract, a species of genus Turnera that has been poorly studied. T. ulmifolia crude extract presented flavonoids as main active compounds. The results showed a promising activity in scavenging free and peroxyl radicals, chelating iron ions and inhibiting BSA glycation. In addition, this study showed the possible encapsulation of bioactive compounds using maltodextrin as wall material.
    Keywords:  Flavonoids; Microcapsules; Oxidative stress; Protein glycation; Turnera ulmifolia L
    DOI:  https://doi.org/10.1016/j.jpba.2022.114975
  88. Angew Chem Int Ed Engl. 2022 Aug 05.
    HXV2O5 Nanocatalysts Combined with Ultrasound for Triple Amplification of Oxidative Stress to Enhance Cancer Catalytic Therapy.
    Linqian Hou, Fei Gong, Zhihui Han, Yuanjie Wang, Yuqi Yang, Shuning Cheng, Nailin Yang, Zhuang Liu, Liang Cheng.
      Multiple amplification of tumor oxidative stress has been demonstrated as efficient strategy to enhance the reactive oxygen species (ROS)-mediated cancer therapy. Herein, vanadium-based nanocatalysts, hydrogen vanadium bronzes (HXV2O5 , for short HVO), were constructed and employed as novel biocatalysts for amplifying tumor oxidative stress and enhancing cancer catalytic therapy. Such HVO nanocatalysts harboring multivalent V element possessed multi-functional catalytic activity in decomposing H2O2 into •OH and depleting endogenous glutathione (GSH) to dually amplify tumor oxidative stress. Meanwhile, HVO nanocatalysts could also be activated by ultrasound to further triply amplify oxidative stress. The massive intracellular ROS caused mitochondrial dysfunction, DNA damage, cell cycle arrest, and cell proliferation inhibition, further realizing cancer cell death and tumor growth inhibition. Collectively, HVO nanocatalysts highlight the remarkable value of ROS-mediated cancer therapies.
    Keywords:  HVO nanocatalysts, ROS amplification, catalytic therapy, sonodynamic therapy, oxidative stress
    DOI:  https://doi.org/10.1002/anie.202208849
  89. J Biochem Mol Toxicol. 2022 Aug 04. e23193
    Curcumin attenuates Cr (VI)-induced cell growth and migration by targeting autophagy-dependent reprogrammed metabolism.
    Mongameli B Dlamini, Shibo Bao, Zeyun Gao, Junjie Mei, Hong Ge, Liping Jiang, Chengyan Geng, Qiujuan Li, Xiaoxia Shi, Yong Liu, Jun Cao.
      Hexavalent chromium [Cr (VI)] is a well-established carcinogen. Cr (VI)-treated cells are phenotypically characterized by aberrant levels of growth and migration. Curcumin, a polyphenolic compound from the plant turmeric, has been found to possess antiproliferation, anti-inflammation, and antioxidant properties. In this study, the effect of curcumin on Cr (VI)-induced cell survival and migration and the underlying mechanism were investigated. Cell viability assay on A549 and human embryonic lung fibroblast cells showed that curcumin at the concentration of 10 µM could significantly attenuate Cr (VI)-induced viability in both cell lines. Following Western blot assay and metabolomics assays, cotreatment with curcumin and Cr (VI) resulted in the suppression of Cr (VI)-induced glycolysis-, autophagy-, and migration-related proteins. Meanwhile, curcumin increased Cr (VI)-reduced oxidative phosphorylation (OXPHOS)-related proteins, COXIV and ND1. Moreover, curcumin suppressed Cr (VI)-induced mitochondrial dysfunction, mitochondrial mass decrease, and mitochondrial membrane potential loss. Treatment with curcumin for 24 h significantly attenuated pcATG4B-induced autophagy and the subsequent expression of glucose transporter 1, hexokinase II, and pyruvate kinase M2. Wound healing and transwell assay demonstrated that curcumin reduced Cr (VI)-induced cell migration. Taken together, these results showed that curcumin was able to attenuate Cr (VI)-induced cell viability and migration by targeting autophagy-dependent reprogrammed metabolism from OXPHOS to glycolysis.
    Keywords:  cell migration; curcumin; glycolysis; hexavalent chromium; reprogrammed metabolism
    DOI:  https://doi.org/10.1002/jbt.23193
  90. Biomater Adv. 2022 Jul 25. pii: S2772-9508(22)00317-X. [Epub ahead of print]139 213040
    Preparation of graphene oxide/polydopamine-curcumin composite nanomaterials and its antibacterial effect against Staphylococcus aureus induced by white light.
    Hongjun Yan, Peiyuan Li, Xiantao Jiang, Xiaoxun Wang, Yuting Hu, Ying Zhang, Rixiang Su, Wei Su.
      Curcumin (Cur) plays a key role in photodynamic antibacterial activity as a photosensitizer. On the other hand, the antimicrobial potential of graphene oxide (GO) has been reported controversially, and how to improve its antimicrobial ability has become an meaningful study. In this study, we prepared polydopamine-curcumin (PDA-Cur) by pi-pi stacking and loaded it onto the GO surface to obtain GO/PDA-Cur composite nanomaterials. GO/PDA-Cur was characterized by physical and optical means, and GO/PDA-Cur possessed good dispersion and stability in water. In vitro antibacterial results showed that GO/PDA-Cur mediated photodynamic therapy significantly reduced Gram-positive Staphylococcus aureus (S. aureus) by 4 orders of magnitude with a bactericidal rate of 99.99 %. The antibacterial mechanism stems from the fact that GO/PDA-Cur can generate reactive oxygen species (ROS) under white light irradiation (405-780 nm), which causes bacterial outer membrane breakage and cellular deformation. In addition, GO/PDA-Cur has good biocompatibility. The antibacterial ability of graphene oxide was significantly improved by combining it with PDA-Cur, which allows it to be used as a photodynamic antibacterial material.
    Keywords:  Antibacterial; Curcumin; Graphene oxide; Nanocomposite; Photodynamic therapy; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bioadv.2022.213040
  91. Small. 2022 Aug 03. e2202705
    Cycloacceleration of Reactive Oxygen Species Generation Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for Tumor Ferroptosis Therapy.
    Huimin Zhou, Xuanyi Lu, Chao Du, Zijian Zhou, Jie Feng, Zhiyu Liang, Yikai Xu, Xiaozhong Qiu, Zheyu Shen.
      Because of the insufficiency of hydrogen peroxide, the relatively low rate of Fenton reaction, and the active glutathione (GSH) peroxidase 4 (GPX4) in tumor cells, it is difficult to achieve a desirable efficacy of ferroptosis therapy (FT) for tumors based on nanomaterials. Inspired by the concept of "cyclotron" in physics, in this study, a new concept of cycloacceleration of reactive oxygen species (ROS) generation in tumor cells to realize high-performance FT of tumors is proposed. Typically, a magnetic resonance imaging (MRI) contrast agent of dotted core-shell Fe3 O4 /Gd2 O3 hybrid nanoparticles (FGNPs) is prepared based on exceedingly small magnetic iron oxide nanoparticles (ES-MIONs). Sorafenib (SFN) is loaded and poly(ethylene glycol) methyl ether-poly(propylene sulfide)-NH2 (mPEG-PPS-NH2 ) is grafted on the surface of FGNP to generate SA-SFN-FGNP via self-assembly. The results of in vitro and in vivo demonstrate SA-SFN-FGNP can work with the acidic tumor microenvironment and endosomal conditions, Fenton reaction and system XC - , and generate cyclic reactions in tumor cells, resulting in specific cycloacceleration of ROS generation for high-performance FT of tumors. The very high longitudinal relaxivity (r1 , 33.43 mM-1 s-1 , 3.0 T) makes sure that the SA-SFN-FGNP can be used for MRI-guided FT of tumors.
    Keywords:  Fenton reaction; cycloacceleration; ferroptosis therapy (FT); magnetic resonance imaging (MRI) contrast agents; reactive oxygen species (ROS) generation
    DOI:  https://doi.org/10.1002/smll.202202705
  92. Adv Sci (Weinh). 2022 Aug 02. e2201834
    Two-Wave Variable Nanotheranostic Agents for Dual-Mode Imaging-Guided Photo-Induced Triple-Therapy for Cancer.
    Xiao Sang, Tong Gao, Xiaoqing Liu, Yelong Shen, Lili Chang, Shunli Fu, Han Yang, Huizhen Yang, Weiwei Mu, Shuang Liang, Zipeng Zhang, Na Zhang, Yongjun Liu.
      Photothermal therapy (PTT) is a promising strategy for cancer treatment, but its clinical application relies heavily on accurate tumor positioning and effective combination. Nanotheranostics has shown superior application in precise tumor positioning and treatment, bringing potential opportunities for developing novel PTT-based therapies. Here, a nanotheranostic agent is proposed to enhance magnetic resonance imaging (MRI)/ near-infrared fluorescence imaging (NIRFI) imaging-guided photo-induced triple-therapy for cancer. Thermosensitive liposomes co-loaded with SPIONs/IR780 and Abemaciclib (SIA-TSLs), peptide ACKFRGD, and click group 2-cyano-6-amino-benzothiazole (CABT) are co-modified on the surface of SIA-TSLs to form SIA-αTSLs. ACKFRGD can be hydrolyzed to expose the 1, 2-thiolamino groups in the presence of cathepsin B in tumors, which click cycloaddition with the cyano group on CABT, resulting in the formation of SIA-αTSLs aggregates. The aggregation of SIA-αTSLs in tumors enhances the MRI/NIRFI imaging capability and enables precise PTT. Photo-induced triple-therapy enhances precision cancer therapy. First, PTT ablates specific tumors and induces ICD via localized photothermal. Second, local tumor heating promotes the rupture of SIA-αTSLs, which release Abemaciclib to block the tumor cell cycle and inhibit Tregs proliferation. Third, injecting GM-CSF into tumor tissue leads to recruitment of dendritic cells and initiation of antitumor immunity. Collectively, these results present a promising nanotheranostic strategy for future cancer therapy.
    Keywords:  antitumor immune response; dual-mode imaging; imaging-guided triple-therapy; magnetic resonance imaging; nanotheranostics; near-infrared fluorescence imaging; photothermal therapy
    DOI:  https://doi.org/10.1002/advs.202201834
  93. J Control Release. 2022 Jul 28. pii: S0168-3659(22)00463-1. [Epub ahead of print]
    Breast cancer vaccines: New insights into immunomodulatory and nano-therapeutic approaches.
    Fatemeh Davodabadi, Mohammad Sarhadi, Javad Arabpour, Saman Sargazi, Abbas Rahdar, Ana M Díez-Pascual.
      Breast cancer (BC) is known to be a highly heterogeneous disease that is clinically subdivided into four primary molecular subtypes, each having distinct morphology and clinical implications. These subtypes are principally defined by hormone receptors and other proteins involved (or not involved) in BC development. BC therapeutic vaccines [including peptide-based vaccines, protein-based vaccines, nucleic acid-based vaccines (DNA/RNA vaccines), bacterial/viral-based vaccines, and different immune cell-based vaccines] have emerged as an appealing class of cancer immunotherapeutics when used alone or combined with other immunotherapies. Employing the immune system to eliminate BC cells is a novel therapeutic modality. The benefit of active immunotherapies is that they develop protection against neoplastic tissue and readjust the immune system to an anti-tumor monitoring state. Such immunovaccines have not yet shown effectiveness for BC treatment in clinical trials. In recent years, nanomedicines have opened new windows to increase the effectiveness of vaccinations to treat BC. In this context, some nanoplatforms have been designed to efficiently deliver molecular, cellular, or subcellular vaccines to BC cells, increasing the efficacy and persistence of anti-tumor immunity while minimizing undesirable side effects. Immunostimulatory nano-adjuvants, liposomal-based vaccines, polymeric vaccines, virus-like particles, lipid/calcium/phosphate nanoparticles, chitosan-derived nanostructures, porous silicon microparticles, and selenium nanoparticles are among the newly designed nanostructures that have been used to facilitate antigen internalization and presentation by antigen-presenting cells, increase antigen stability, enhance vaccine antigenicity and remedial effectivity, promote antigen escape from the endosome, improve cytotoxic T lymphocyte responses, and produce humoral immune responses in BC cells. Here, we summarized the existing subtypes of BC and shed light on immunomodulatory and nano-therapeutic strategies for BC vaccination. Finally, we reviewed ongoing clinical trials on BC vaccination and highlighted near-term opportunities for moving forward.
    Keywords:  Breast cancer; Clinical trial; Immunomodulation; Nanotechnology; Vaccine
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.036
  94. Front Oncol. 2022 ;12 906014
    Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma.
    Andrea Katharina Lindner, Gennadi Tulchiner, Andreas Seeber, Peter J Siska, Martin Thurnher, Renate Pichler.
      Fumarate hydratase (FH) - deficient renal cell carcinoma (FHdRCC) is a rare aggressive subtype of RCC caused by a germline or sporadic loss-of-function mutation in the FH gene. Here, we summarize how FH deficiency results in the accumulation of fumarate, which in turn leads to activation of hypoxia-inducible factor (HIF) through inhibition of prolyl hydroxylases. HIF promotes tumorigenesis by orchestrating a metabolic switch to glycolysis even under normoxia, a phenomenon well-known as the Warburg effect. HIF activates the transcription of many genes, including vascular endothelial growth factor (VEGF). Crosstalk between HIF and epidermal growth factor receptor (EGFR) has also been described as a tumor-promoting mechanism. In this review we discuss therapeutic options for FHdRCC with a focus on anti-angiogenesis and EGFR-blockade. We also address potential targets that arise within the metabolic escape routes taken by FH-deficient cells for cell growth and survival.
    Keywords:  bevacizumab; erlotinib; fumarate hydratase; fumarate hydratase deficient renal cell carcinoma; glucose; hereditary leiomyomatosis and renal cell cancer; metabolism; renal cell carcinoma (RCC)
    DOI:  https://doi.org/10.3389/fonc.2022.906014
  95. Front Oncol. 2022 ;12 923915
    Ferroptosis: A Specific Vulnerability of RAS-Driven Cancers?
    Cristina Andreani, Caterina Bartolacci, Pier Paolo Scaglioni.
      Ferroptosis has emerged as a new type of programmed cell death that can be harnessed for cancer therapy. The concept of ferroptosis was for the first time proposed in in the early 2000s, as an iron-dependent mode of regulated cell death caused by unrestricted lipid peroxidation (LPO) and subsequent plasma membrane rupture. Since the discovery and characterization of ferroptosis, a wealth of research has improved our understanding of the main pathways regulating this process, leading to both the repurposing and the development of small molecules. However, ferroptosis is still little understood and several aspects remain to be investigated. For instance, it is unclear whether specific oncogenes, cells of origin or tumor niches impose specific susceptibility/resistance to ferroptosis or if there are some ferroptosis-related genes that may be used as bona fide pan-cancer targetable dependencies. In this context, even though RAS-driven cancer cell lines seemed to be selectively sensitive to ferroptosis inducers, subsequent studies have questioned these results, indicating that in some cases mutant RAS is necessary, but not sufficient to induce ferroptosis. In this perspective, based on publicly available genomic screening data and the literature, we discuss the relationship between RAS-mutation and ferroptosis susceptibility in cancer.
    Keywords:  CRISPR screening; RAS-driven cancer; cancer dependency map; cell death; ferroptosis
    DOI:  https://doi.org/10.3389/fonc.2022.923915
  96. Phytomedicine. 2022 Jul 18. pii: S0944-7113(22)00426-3. [Epub ahead of print]105 154347
    Medicinal plants and their secondary metabolites in alleviating knee osteoarthritis: A systematic review.
    Zhuo Wang, Thomas Efferth, Xin Hua, Xin-An Zhang.
       BACKGROUND: With the increasing ages of the general population, the incidence of knee osteoarthritis (KOA) is also rising, and KOA has become a major health problem worldwide. Recently, medicinal plants and their secondary metabolites have gained interest due to their activity in treating KOA. In this paper, a comprehensive systematic review of the literature was performed concerning the effects of medicinal plant extracts and natural compounds against KOA in recent years. The related molecular pathways of natural compounds against KOA were summarized, and the possible crosstalk among components in chondrocytes was discussed to propose possible solutions for the current situation of treating KOA.
    PURPOSE: This review focused on the molecular mechanisms by which medicinal plants and their secondary metabolites act against KOA.
    METHODS: Literature searches were performed in the PUBMED, Embase, Science Direct, and Web of Science databases for a 10-year period from 2011 to 2022 with the search terms "medicinal plants," "bioactive compounds," "natural products," "phytochemical," "knee osteoarthritis," "knee joint osteoarthritis," "knee osteoarthritis," "osteoarthritis of the knee," and "osteoarthritis of knee joint."
    RESULTS: According to the results, substantial plant extracts and secondary metabolites show a positive effect in fighting KOA. Plant extracts and their secondary metabolites can affect the diagnostic and prognostic biomarkers of KOA. Natural products inhibit the expression of MMP1, MMP3, MMP19, syndecan IV, ADAMTS-4, ADAMTS-5, iNOS, COX-2, collagenases, IL-6, IL-1β, and TNF-α in vitro and in vivo and . Cytokines also upregulate the expression of collagen II and aggrecan. The main signaling pathways affected by the extracts and isolated compounds include AMPK, SIRT, NLRP3, MAPKs, PI3K/AKT, mTOR, NF-κB, WNT/β-catenin, JAK/STAT3, and NRF2, as well as the cell death modes apoptosis, autophagy, pyroptosis, and ferroptosis.
    CONCLUSION: The role of secondary metabolites in different signaling pathways supplies a better understanding of their potential to develop further curative options for KOA.
    Keywords:  Knee osteoarthritis; Medicinal plants; Molecular pharmacology; Phytotherapy; Secondary metabolites
    DOI:  https://doi.org/10.1016/j.phymed.2022.154347
  97. Clin Cosmet Investig Dermatol. 2022 ;15 1403-1413
    Metformin Inhibits HaCaT Cell Proliferation Under Hyperlipidemia Through Reducing Reactive Oxygen Species via FOXO3 Activation.
    Li Zhang, Xiaoling Liu, Min Huang, Rui Wang, Wenwei Zhu, Yu Li, Lin Shen, Chengxin Li.
       Purpose: Metformin (MET) has been proved to be effective for the treatment of psoriasis. The mechanisms of its action under the hyperlipidemia have yet to be fully elucidated. Here, we investigated the effect of metformin on the cell proliferation induced by hyperlipidemia and the underlying mechanism in immortalized human keratinocyte cell line (HaCat).
    Methods: Wild-type or FOXO3 knockdown HaCat cells were treated with free fatty acids (FFA) for 10 days and then co-treated with metformin for another 4 days. Triglyceride (TG) level, cell viability, proliferation, apoptosis, antioxidant enzymes, reactive oxygen species (ROS) levels, as well as the transcription activity of FOXO3 were analyzed.
    Results: Metformin decreased HaCaT cell proliferation and induced cell apoptosis after FFA treatment. Metformin was found to significantly increase the expressions and the activities of superoxide dismutase (SOD) as well as catalase (CAT), and reduced the reactive oxygen species (ROS) level. Metformin significantly promoted the autophagy and increase FOXO3 protein level in the nucleus under hyperlipidemia. However, all of the effects from metformin were partially blocked by FOXO3 knockdown.
    Conclusion: This study demonstrated that under the hyperlipidemia, metformin has significant antiproliferation and proapoptosis effects by reducing ROS level as well as increasing autophagy. All of these effects from metformin were through FOXO3-dependent pathway.
    Keywords:  FOXO3; ROS; apoptosis; autophagy; forkhead box O3; reactive oxygen species
    DOI:  https://doi.org/10.2147/CCID.S368845
  98. J Ocul Pharmacol Ther. 2022 Jul-Aug;38(6):38(6): 433-448
    Injectable Depot Forming Thermoresponsive Hydrogel for Sustained Intrascleral Delivery of Sunitinib Using Hollow Microneedles.
    Shilpkala Shankar Gade, Sreekanth Pentlavalli, Deepakkumar Mishra, Lalitkumar K Vora, David Waite, Carmen Isabel Alvarez-Lorenzo, Maria Roccio Herrero Vanrell, Garry Laverty, Eneko Larraneta, Ryan F Donnelly, Raghu Raj Singh Thakur.
      Purpose: Age-related macular degeneration is a vision-threatening disorder affecting the posterior segment of the eye. Drug delivery to the posterior segment is challenging owing to the complex anatomical and physiological structure, necessitating monthly injections of antivascular endothelial growth factors. Thermoresponsive hydrogels provide sustained drug delivery and ease of injection, due to their sol-gel transition. Poly (N-isopropyl acrylamide) (PNIPAAm) is a widely researched thermoresponsive hydrogel; however, insufficient wet strength and a wide mesh network make it inept for the entrapment of small molecules. Methods: A novel approach of grafting PNIPAAm with chitosan is exploited. A chitosan concentration altered in 10%, 30%, and 50% compared to PNIPAAm is investigated for entrapment of a small-molecular weight, hydrophilic drug, sunitinib (SUN), a multiple tyrosine kinase receptor inhibitor. Furthermore, these hydrogels were characterized using 1H-NMR, FTIR, differential scanning calorimetry (DSC), and thermogravimetric analysis for chemical characterization and viscosity, swellability, syringeability, degradation, and In-vitro permeation using Franz-diffusion cell. Results: In-vitro drug release kinetics suggested that the release of SUN could be controlled with the percentage of chitosan grafting; however, gel strength (3%-5% w/v) of 30% Cs-g-PNIPAAm did not significantly affect percentage drug release. Sustained release of SUN was observed for 1 month. In-vitro permeation studies on porcine sclera suggested that a thermoresponsive gel of chitosan grafted PNIPAAm (Cs-g-PNIPAAm) was able to sustain the drug release by 40%, compared to SUN solution. Conclusions: The study indicates that the synthesized Cs-g-NIPAAm hydrogel has the potential to serve as a tailorable injectable platform for intrascleral drug delivery applications.
    Keywords:  age-related macular degeneration; chitosan; grafting; poly(n-isopropylacrylamide); sunitinib; thermoresponsive hydrogel
    DOI:  https://doi.org/10.1089/jop.2022.0016
  99. Int J Med Sci. 2022 ;19(7): 1138-1146
    Curcumin enhances p-cresyl sulfate-induced cytotoxic effects on renal tubular cells.
    Chyou-Wei Wei, Tsai-Kun Wu, Shu-Cing Wu, Yi-Lin Chen, Ying-Ru Pan, Yi-Chung Chien, Jia-Yan Wu, Yung-Lung Yu, Giou-Teng Yiang.
      Indoxyl sulfate (IS) and p-cresyl sulfate (PCS), protein-bound uremic toxins, can induce oxidative stress and cause renal disease progression. However, the different cytotoxic effects on renal cells between IS and PCS are not stated. Due to uremic toxins are generally found in CKD patients, the mechanisms of uremic toxins-induced renal injury are required to study. Curcumin has anti-oxidant, anti-inflammatory and anti-apoptotic effects which may be potential used to protect against renal damage. In contrast, curcumin also exert cytotoxic effects on various cells. In addition, curcumin may reduce or enhance cytotoxicity combined with different chemicals treatments. However, whether curcumin may influence uremic toxins-induced renal injury is unclear. The goal of this study is to compare the different cytotoxic effects on renal cells between IS and PCS treatment, as well as the synergistic or antagonistic effects by combination treatments with curcumin and PCS. Our experimental result shows the PCS exerts a stronger antiproliferative effect on renal tubular cells than IS treatment. In addition, our study firstly demonstrates that curcumin enhances PCS-induced cell cytotoxicity through caspase-dependent apoptotic pathway and cell cycle alteration.
    Keywords:  Curcumin; Indoxyl sulfate; p-cresyl sulfate
    DOI:  https://doi.org/10.7150/ijms.72646
  100. Food Technol Biotechnol. 2022 Jun;60(2): 237-252
    Microencapsulation of Dandelion (Taraxacum officinale L.) Leaf Extract by Spray Drying.
    Arijana Martinić, Ana Kalušević, Steva Lević, Viktor Nedović, Aleksandra Vojvodić Cebin, Sven Karlović, Igor Špoljarić, Gordan Mršić, Krunoslav Žižek, Draženka Komes.
       Research background: Due to numerous health-promoting properties, dandelion has been used in traditional medicine as a herbal remedy, but also as a food product. Dandelion health benefits are ascribed to the presence of different bioactive compounds in its tissues, among which polyphenols play a significant role. However, the low stability of polyphenols is a critical parameter for their successful implementation into products. Thus, their encapsulation using appropriate carrier vehicles is highlighted as an effective technique for their stabilization and protection. The aim of this study is to microencapsulate dandelion leaf extract using spray drying and different carrier materials for the first time.
    Experimental approach: In spray drying, low inlet temperature of 130 °C was employed to preserve sensitive dandelion polyphenols, while guar gum, gum arabic, inulin, maltodextrin, pectin and alginate were used as carriers. The influence of different carriers and their content on physicochemical, morphological and colour properties, polyphenolic content and encapsulation efficiency of polyphenols in dandelion powders was examined. Specific polyphenols were determined using HPLC-PAD analysis. Their release profiles and antioxidant capacity in simulated gastrointestinal conditions were also evaluated.
    Results and conclusions: Compared to plain dandelion powder, carrier-containing dandelion powders have favourably increased solubility, enhanced flow and cohesive properties, reduced particle size and prolonged release of polyphenols under simulated gastrointestinal conditions. Powders were characterized by low moisture content (~2-8%) and high solubility (~92-97%). Chicoric acid was the most abundant compound in dandelion powders. Pectin-dandelion powder showed to be the most effective for microencapsulation of polyphenols, especially for chicoric acid entrapment (74.4%). Alginate-dandelion powder enabled the slowest gradual release of polyphenols.
    Novelty and scientific contribution: Spray drying at 130 °C and the applied carriers proved to be effective for microencapsulation of dandelion extract, where polyphenolic-rich dandelion powders, due to good physicochemical and encapsulation properties, could serve for the enrichment/production of different functional food products. Also, due to the lack of data on dandelion encapsulation, the obtained results could be of great interest for researchers in the encapsulation field, but also for food industry, especially in the field of instant powders.
    Keywords:  carriers; dandelion; encapsulation efficiency; physicochemical properties; polyphenols; spray drying
    DOI:  https://doi.org/10.17113/ftb.60.02.22.7384
  101. Curr Med Chem. 2022 Aug 01.
    The fractal viewpoint of tumors and nanoparticles.
    Athanasios Alexiou, Christos Tsagkaris, Stylianos Chatzichronis, Andreas Koulouris, Ioannis Haranas, Ioannis Gkigkitzis, Georgios Zouganelis, Nobendu Mukerjee, Swastika Maitra, Niraj Kumar Jha, Gaber El-Saber Batiha, Mohammad Amjad Kamal, Michail Nikolaou, Ghulam Md Ashraf.
      Even though the promising therapies against cancer are rapidly improved, the oncology patients population has seen exponential growth, placing cancer in 5th place among the ten deadliest diseases. Efficient drug delivery systems must overcome multiple barriers and maximize drug delivery to the target tumors, limiting the side effects simultaneously. Since the first observation of the quantum tunneling phenomenon, many multidisciplinary studies have offered quantum-inspired solutions to optimized tumor mapping and efficient nanodrug design. The property of a wave function to propagate through a potential barrier offer the capability of obtaining 3D surface profiles using imaging of individual atoms on the surface of a material. The application of quantum tunneling on a scanning tunneling microscope offers an exact surface roughness mapping of tumors and pharmaceutical particles. Critical elements to cancer nanotherapeutics apply the fractal theory and calculate the fractal dimension for efficient tumor surface imaging at the atomic level. This review study presents the latest biological approaches to cancer management based on fractal geometry.
    Keywords:  Box-Counting Algorithm; Cancer; Chaos Theory; Drug Delivery; Fractal Dimension; Fractality; Imaging Data; Lacunarity; Nanoparticles; Pharmacokinetics; Quantum Tunneling; Scanning Tunneling Microscope; Succolarity
    DOI:  https://doi.org/10.2174/0929867329666220801152347
  102. Med Glas (Zenica). 2022 Aug 01. 19(2):
    Regulation of p53 and survivin by Curcuma longa extract to caspase-3 dependent apoptosis in triple negative breast cancer cells.
    Deryne Anggia Paramita, Dedy Hermansyah, Desiree Anggia Paramita, Nur Dina Amalina.
      Aim Triple negative breast cancer cells (TNBC) are the population of breast cancer cells that are responsible for cancer recurrence and apoptosis resistance. Unfortunately, current therapies have limited efficacy to TNBC population due to apoptosis resistance and chemoresistance. Tumour suppressor p53 and survivin are primary targets for TNBC therapy. Consequently, a search for a natural compound which targets p53 and survivin is needed to further advance TNBC treatment. Curcuma longa extract (CL), a natural compound induces apoptosis in several cancer cells by targeting various molecules and possess fewer side effects. However, a possible potential of CL as p53- and survivin modulating agent in TNBC cells has not been investigated. Methods MDAMB-231 cells were treated with several concentration of CL, after which, viability, p53 gene expression, surviving protein expression, and caspase-3 protein expression were evaluated. Results After 24-h treatment, CL possessed cytotoxic effect with IC50 value of 13 μg/mL. Treatment with 1.625, 3.25, 6.5, and 13 μg/mL of CL resulted in 2.70-25.80% increase in caspase-3 expression levels followed by 94.60 - 21.60% decrease in survivin protein levels. CL induced remarkably p53 gene expression ratio up to 5-fold at 13 μg/mL. Survivin protein levels were inversely proportional to p53 accumulation levels. Low survivin protein levels combined with high levels of p53 accumulation were correlated to higher apoptotic rates. Conclusion p53 and survivin as molecular targets of CL contribute to caspase-3-dependent apoptosis in TNBC cells and this compound represents an attractive p53- and survivin modulating agent in TNBC.
    Keywords:  Caspase-3; Curcuma longa extract; TNBC; p53; survivin
    DOI:  https://doi.org/10.17392/1453-22
  103. AAPS PharmSciTech. 2022 Aug 02. 23(6): 212
    Sorbitan Monolaurate-Containing Liposomes Enhance Skin Cancer Cell Cytotoxicity and in Association with Microneedling Increase the Skin Penetration of 5-Fluorouracil.
    Luiziana Cavalcante Costa Fernandes Crisóstomo, Genuína Stephanie Guimarães Carvalho, Luzia Kalyne Almeida Moreira Leal, Tamara Gonçalves de Araújo, Karina Alexandre Barros Nogueira, Durcilene Alves da Silva, Fábio de Oliveira Silva Ribeiro, Raquel Petrilli, Josimar O Eloy.
      Squamous cell carcinoma (SCC) represents 20% of cases of non-melanoma skin cancer, and the most common treatment is the removal of the tumor, which can leave large scars. 5-Fluorouracil (5FU) is a drug used in the treatment of SCC, but it is highly hydrophilic, resulting in poor skin penetration in topical treatment. Some strategies can be used to increase the cutaneous penetration of the drug, such as the combination of liposomes containing penetration enhancers, for instance, surfactants, associated with the use of microneedling. Thus, the present work addresses the development of liposomes with penetration enhancers, such as sorbtitan monolaurate, span 20, for topical application of 5-FU and associated or not with the use of microneedling for skin delivery. Liposomes were developed using the lipid film hydration, resulting in particle size, polydispersity index, zeta potential, and 5-FU encapsulation efficiency of 88.08 nm, 0.169, -12.3 mV, and 50.20%, respectively. The presence of span 20 in liposomes potentiated the in vitro release of 5-FU. MTT assay was employed for cytotoxicity evaluation and the IC50 values were 0.62, 30.52, and 24.65 μM for liposomes with and without span 20 and 5-FU solution, respectively after 72-h treatment. Flow cytometry and confocal microscopy analysis evidenced high cell uptake for the formulations. In skin penetration studies, a higher concentration of 5-FU was observed in the epidermis + dermis, corresponding to 1997.71, 1842.20, and 2585.49 ng/cm2 in the passive penetration and 3214.07, 2342.84, and 5018.05 ng/cm2 after pretreatment with microneedles, for solution, liposome without and with span 20, respectively. Therefore, herein, we developed a nanoformulation for 5-FU delivery, with suitable physicochemical characteristics, potent skin cancer cytotoxicity, and cellular uptake. Span 20-based liposomes increased the skin penetration of 5-FU in association of microneedling. Altogether, the results shown herein evidenced the potential of the liposome containing span 20 for topical delivery of 5-FU.
    Keywords:  5-Fluorouracil; Liposome; Microneedling; Nanotechnology; Penetration enhancers
    DOI:  https://doi.org/10.1208/s12249-022-02356-z
  104. Biomater Adv. 2022 Jul;pii: S2772-9508(22)00151-0. [Epub ahead of print]138 212874
    HIF signaling: A new propellant in bone regeneration.
    Hetian Bai, Yue Wang, Yi Zhao, Xin Chen, Yu Xiao, Chongyun Bao.
      Bone tissue destruction leads to severe pain, physical flaws, and loss of motility. Bone repair using biocompatible and osteo-inductive scaffolds is regarded as a viable and potential therapeutic approach. However, for large-scale bone regeneration, oxygen and nutrient supply have become limiting factors. Further, a considerable need exists for recruited cell activities and blood vessel growth. Hypoxia-inducible factor (HIF) signaling pathways induced by hypoxia are involved in angiogenesis and osteogenesis. As an important transcription factor, HIF-1 functions by modulating vital genes, such as VEGF, PDK1, and EPO, and is a crucial regulator that influences the final fate of bone regeneration. Collectively, to achieve better osteogenesis results, the in-depth molecular mechanisms that underpin the links between materials, cells, and HIF signaling pathways must be determined. This review aimed to provide an in-depth insight into recent progress in HIF-regulated bone regeneration. Hypoxia and cellular oxygen-sensing mechanisms and their correlations with osteogenesis were determined, and recent studies on hypoxia-inducing and hypoxia-mimicking strategies were briefly described. Finally, the potential applications of HIF signaling in bone regeneration were highlighted. This review provides theoretical support for establishing a novel and viable bone repair strategy in the clinic by harnessing HIF signaling.
    Keywords:  Bone tissue engineering; Hypoxia manipulating strategies; Hypoxia-inducible factor; Osteogenesis
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212874
  105. J Control Release. 2022 Jul 29. pii: S0168-3659(22)00473-4. [Epub ahead of print]
    Customizing nano-chitosan for sustainable drug delivery.
    Mostafa Saeedi, Omid Vahidi, Mohammadreza Moghbeli, Sepideh Ahmadi, Mohsen Asadnia, Omid Akhavan, Farzad Seidi, Mohammad Rabiee, Mohammad Reza Saeb, Thomas J Webster, Rajender S Varma, Esmaeel Sharifi, Ali Zarrabi, Navid Rabiee.
      Chitosan is a natural polymer with acceptable biocompatibility, biodegradability, and mechanical stability; hence, it has been widely appraised for drug and gene delivery applications. However, there has been no comprehensive assessment to tailor-make chitosan cross-linkers of various types and functionalities as well as complex chitosan-based semi- and full-interpenetrating networks for drug delivery systems (DDSs). Herein, the various fabrication methods developed for chitosan hydrogels are deliberated, including chitosan crosslinking with and without diverse cross-linkers. Tripolyphosphate, genipin and multi-functional aldehydes, carboxylic acids, and epoxides are common cross-linkers used in developing biomedical chitosan for DDSs. Methods deployed for modifying the properties and performance of chitosan hydrogels, via their composite production (semi- and full-interpenetrating networks), are also cogitated here. In addition, recent advances in the fabrication of advanced chitosan hydrogels for drug delivery applications such as oral drug delivery, transdermal drug delivery, and cancer therapy are discussed. Lastly, thoughts on what is needed for the chitosan field to continue to grow is also debated in this comprehensive review article.
    Keywords:  Chitosan polymer; Composite hydrogels; Cross-linkers; Drug delivery; Hydrogels
    DOI:  https://doi.org/10.1016/j.jconrel.2022.07.038
  106. Natl J Maxillofac Surg. 2022 Jan-Apr;13(1):13(1): 11-19
    Mitophagy and oral cancers.
    Ripon Md Chowdhury.
      Mitophagy is a progressive process that selectively targets weakened, old and damaged mitochondria, by an autophagic pathway, causing its destruction. Mitophagy maintains normal cellular physiology and tissue development, thereby controlling the cohesiveness of the mitochondrial pool. The mechanisms of mitophagy, tumorogenesis, and cell death are usually interrelated with each other and could be initiated by definite stressful conditions like hypoxia and nutrient starvation, which leads to the overall reduction in mitochondrial mass. This impedes the production of reactive oxygen species, and conserves nutrition, leading to cell survival in such extreme conditions. The inability to harmonize and regulate mitochondrial outcome in response to oncogenic stress can either stimulate or suppress tumorogenesis. Therefore, the relationship between mitophagy, tumorogenesis, and cell death plays an important role in the identification of potential targets of cell death and selective wiping out of cancer cells. This review portrays the mechanism of mitophagy, along with its role in cancers especially on oral cancers, and its importance in cancer therapeutics.
    Keywords:  Autophagy; cell death; mitophagy; oral cancers; treatment; tumorogenesis
    DOI:  https://doi.org/10.4103/njms.NJMS_123_20
  107. Int J Nanomedicine. 2022 ;17 3239-3249
    Amphiphilic Dendritic Nanomicelle-Mediated Delivery of Gemcitabine for Enhancing the Specificity and Effectiveness.
    Weidong Zhao, Shaoyou Yang, Chunxiao Li, Feifei Li, Houjun Pang, Guangling Xu, Yuxin Wang, Mei Cong.
       Purpose: Gemcitabine is the first line and the gold standard drug for pancreatic cancer. However, the anticancer efficacy is severely limited by its instability and poor cellular uptake. To enhance the clinical efficacy of gemcitabine, we constructed a novel nanodrug delivery system based on amphiphilic dendrimers and aliphatic gemcitabine prodrug.
    Methods: An aliphatic gemcitabine prodrug and a small amphiphilic dendrimer were synthesized and characterized by high resolution mass spectrometry (HRMS) as well as nuclear magnetic resonance (NMR). Then the aliphatic gemcitabine prodrug was encapsulated into the small amphiphilic dendrimer by film dispersion method, resulting in a novel nanodrug delivery system. Subsequently, the size, morphology, drug loading, stability, drug release profiles, cell uptake, toxicity, the anticancer activity and in vivo distribution of the new developed gemcitabine delivery system were systematically evaluated by different technical methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), ultraviolet spectrophotometer, flow cytometry, in vivo imaging system etc.
    Results: We developed a novel nanodrug delivery system of gemcitabine using amphiphilic dendrimer. This dendrimer-based gemcitabine nanoformulation reported here possess a high drug loading of 33%. With the features of small size, stable formulation and pH-responsive drug release, the obtained gemcitabine nanoformulation could effectively accumulate in tumor site and rapid uptake in cells. Finally, the gemcitabine nanoformulation displayed more potent anticancer activity compared to free gemcitabine both in vitro and in vivo. Moreover, the nanodrug displayed greatly reduced adverse effects and satisfactory biocompatibility.
    Conclusion: Benefiting the advantageous features of both amphiphilic dendrimers and nanotechnology-based drug delivery, this gemcitabine nanosystem constitutes a promising therapeutic candidate for pancreatic cancer treatment. This study also underlines the potential use of self-assembling amphiphilic dendrimer-based nanotechnology for improving drug efficacy as well as reducing drug toxicity.
    Keywords:  amphiphilic dendrimer; anticancer candidate; gemcitabine; pancreatic cancer; self-assembling
    DOI:  https://doi.org/10.2147/IJN.S371775
  108. Curr Opin Clin Nutr Metab Care. 2022 Sep 01. 25(5): 329-333
    Physiopathology of nonalcoholic fatty liver disease: from diet to nutrigenomics.
    Paola Meneghel, Elisa Pinto, Francesco Paolo Russo.
       PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is strongly associated with metabolic disorders, such as obesity, type 2 diabetes mellitus, and metabolic syndrome, to the extent that a new definition of metabolic associated fatty liver disease has been proposed.
    RECENT FINDINGS: Insulin resistance, worsened by a high-fat and high-carbohydrate diet, is the key to the physiopathology of hepatic steatosis. This is driven by several mechanisms that are mostly activated at a genetic level, such as de-novo lipogenesis and triglyceride synthesis. Therefore, many diet regimens have been studied, although significant controversies remain regarding their metabolic effects and long-term sustainability.
    SUMMARY: In this review, we summarized the role and effects of the main macronutrients on the development of NAFLD and discussed the molecular mechanisms involved. We also discussed the importance of genetic polymorphisms, epigenetic alterations, and dysbiosis to determine if lifestyle modification and a specific dietary regimen could be an essential part of NAFLD treatment.
    DOI:  https://doi.org/10.1097/MCO.0000000000000859
  109. Nat Prod Res. 2022 Aug 03. 1-20
    Betalains: colours for human health.
    Pasquale Calvi, Simona Terzo, Antonella Amato.
      In the last years, the use of natural phytochemical compounds as protective agents in the prevention and treatment of obesity and the related-metabolic syndrome has gained much attention worldwide. Different studies have shown health benefits for many vegetables such Opuntia ficus-indica and Beta vulgaris and their pigments collectively referred as betalains. Betalains exert antioxidative, anti-inflammation, lipid lowering, antidiabetic and anti-obesity effects. This review summarizes findings in the literature and highlights the therapeutic potential of betalains and their natural source as valid alternative for supplementation in obesity-related disorders treatment. Further research is needed to establish the mechanisms through which these natural pigments exert their beneficial effects and to translate the promising findings from animal models to humans.
    Keywords:  Betalains; Opuntia ficus indica; metabolic syndrome; obesity
    DOI:  https://doi.org/10.1080/14786419.2022.2106481
  110. J Ethnopharmacol. 2022 Jul 30. pii: S0378-8741(22)00617-1. [Epub ahead of print] 115578
    Bidirectional effects and mechanisms of traditional Chinese medicine.
    Xiaonian Peng, Fang Tang, Yong Yang, Tiandan Li, Xiaochao Hu, Sha Li, Weihua Wu, Kai He.
       ETHNOPHARMACOLOGICAL RELEVANCE: The bidirectional property of traditional Chinese medicines (TCMs) was recorded in the classic work Medicine Origin (Yi Xue Qi Yuan) as early as the Jin and Yuan dynasties of ancient China. Since then, this imperative theory has been applied to guide the clinical application of TCMs. Studies have been performed to investigate this phenomenon only over the last three decades. A limited number of reviews on the bidirectional role of TCMs have been published, and almost all current studies are published in the Chinese language.
    AIM OF THE REVIEW: The aim of this review is to provide the first comprehensive evidence regarding the bidirectional effects and the underlying mechanisms of TCMs and their active compounds.
    MATERIALS AND METHODS: Information relevant to opposing pharmacological activities or opposing properties exerted by TCM prescriptions, herbal medicines, and their active compound, as well as their mechanisms was summarized by searching Chinese and English databases, including the Chinese National Knowledge Infrastructure (CNKI), Wan Fang Data, Chinese Scientific Journal Database (VIP), Google Scholar, PubMed, Web of Science, Science Direct, and Wiley Online Library.
    RESULTS: Although the bidirectional regulation of TCMs has been applied in the clinic since ancient times in China, only limited reviews have been published in Chinese. The existing data showed that bidirectional effects can be found in TCM prescriptions, herbal medicines, and pure active compounds. Additionally, the bidirectional role of TCMs was primarily reported in the modulation of immune function, blood circulation and hemostasis, gastrointestinal motility, the central nervous system and blood pressure. This may because the therapeutic outcomes of these disorders are more obvious than those of other complicated diseases. Intriguingly, some herbal medicines have multiple bidirectional activities; for instance, Panax ginseng C. A. Meyer showed bidirectional regulation of immune function and the central nervous system; Astragalus membranaceus can bidirectionally regulate blood pressure and immune function; and Rheum officinale Baill exerts bidirectional effects on blood circulation and hemostasis, gastrointestinal motility and immune function. The mechanisms underlying the bidirectional effects of TCMs are largely attributed to the complexity of herbal constituents, dosage differences, the processing of herbal medicine, and compatibility of medicines, the physiological conditions of patients and adaptogenic effects.
    CONCLUSION: Uncovering the bidirectional effects and mechanisms of TCMs is of great importance for both scientific research and clinical applications. This review may help to facilitate the recognition of the bidirectional role of TCMs, to explain some seemingly-opposite phenomena in the pharmacological study of herbal medicines and to provide guidance for TCM practitioners.
    Keywords:  Bidirectional effects; Blood circulation; Central nervous system; Gastrointestinal motility; Immune function; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jep.2022.115578
  111. Biomater Adv. 2022 Jun;pii: S2772-9508(22)00108-X. [Epub ahead of print]137 212831
    An anti-bacterial and anti-cancer fibrous membrane with multiple therapeutic effects for prevention of pancreatic cancer recurrence.
    Qiang Zhang, Yang Luo, Bo Liang, Di Suo, Shang Lyu, Yi Wang, Xin Zhao.
      Adjuvant systemic chemotherapy with gemcitabine (GEM) is recognized as the standard of care to improve the prognosis of patients with resected pancreatic cancer (PC); however, it is greatly limited by poor absorption of chemotherapy agents. Moreover, surgical site infection and Gammaproteobacteria-induced GEM resistance further decrease the chemotherapy efficacy and increase the risk of recurrence and even mortality. Here, we develop an implantable anti-bacterial and anti-cancer fibrous membrane (AAFM) to inhibit PC recurrence in a well-coordinated manner. Our AAFM can be readily prepared via simple co-electrospinning of GEM and poly-L-lactic acid (PLLA) and subsequent tannic acid (TA)-mediated in-situ generation of silver nanoparticles (AgNPs). The resultant membrane presents highly porous fibrous morphology and appropriate mechanical performance. Most importantly, we find the surface-deposited TA/AgNP complexes can exert multiple therapeutic effects: (1) they can act as a fence to extend GEM diffusion route, achieving a sustained drug release; (2) they can fight the pathogenic microorganisms in the local microenvironment and prevent infectious complications and alleviate Gammaproteobacteria-induced chemotherapy resistance; (3) they can combat residual cancer cells to synchronously strengthen the effectiveness of GEM-based chemotherapy. Altogether, our AAFM provides a proof-of-concept demonstration of the integrated anti-cancer and anti-bacterial strategy for enhanced therapeutic efficacy and will inspire the design of other high-performance implants for prevention of tumor relapse.
    Keywords:  Anti-bacterial activity; Anti-cancer activity; Electrospun fibers; Pancreatic cancer recurrence
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212831
  112. Biomater Adv. 2022 Jun;pii: S2772-9508(22)00081-4. [Epub ahead of print]137 212804
    Matrix metalloproteinase-responsive collagen-oxidized hyaluronic acid injectable hydrogels for osteoarthritic therapy.
    Xueling Yi, Zhilang Xu, Qisong Liu, Hongmei Zhou, Lun Yuan, Defu Li, Lei Zhao, Changdao Mu, Liming Ge.
      Drug delivery system and intra-articular injection have been clinically applied to prolong drug residence time and reduce side effects in the treatment of osteoarthrosis. Herein, injectable hydrogels with sustained-dexamethasone sodium phosphate (DSP) release behavior in response to matrix metalloproteinase (MMP) were developed for osteoarthritic therapy. Hyaluronic acid undergoes specific oxidation in the present of sodium periodate to prepare oxidized hyaluronic acid (OHA). Then the DSP-loaded collagen-based hydrogels (Col-OHA) were developed by the Schiff's base crosslinking between OHA and Type I collagen besides the self-assembly of collagen induced by OHA. The results indicate that the collagen self-assembly into collagen fibrils makes great contribution for shortening gelation time of Col-OHA hydrogels. Col-OHA hydrogels possess interconnected porous microstructure, good injectability, excellent self-healing performance, strong mechanical property, low swelling ability, good blood compatibility and no cytotoxicity. Significantly, Col-OHA hydrogels show highly sensitive and significantly substantially sustained release of DSP in response to MMP. DSP-loaded Col-OHA hydrogel possesses significant inhibition for the production of inflammatory cytokines in the joint synovium, which can effectively relieve the symptoms of osteoarthritis continuously. Col-OHA hydrogel has no obvious effect on liver and kidney functions. Overall, the Col-OHA hydrogels with excellent biocompatibility are the promising drug-loading system for the intra-articular injection therapy of osteoarthrosis.
    Keywords:  Drug delivery; Injectable hydrogel; Osteoarthrosis; Self-healing performance; Sustained release
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212804
  113. J Microencapsul. 2022 Aug 02. 1-17
    Antitumor Effects of a Solid Lipid Nanoparticle Loaded with Gemcitabine and Oxaliplatin on the Viability, Apoptosis, Autophagy and Hsp90 of Ovarian Cancer Cells.
    Ashwaq A Al-Mutairi, Mayson H Alkhatib.
      Aim: The present study aimed to explore the sensitizing capability of the anticancer agents, gemcitabine (GEM) and oxaliplatin (OXA), encapsulated in a novel SLN (GEM:OXA-SLN) against the ovarian cancer cell lines.
    METHODS: A novel SLN, prepared using hot homogenization by mixing phosphatidylcholine, cholesterol, tween 80 and oleic acid, was characterized using Transmission Electron Microscope and zetasizer. The anticancer activities and the underlying molecular mechanisms of GEM:OXA-SLN were investigated.
    RESULTS: The average z-diameter of the homogeneous spherical GEM:OXA-SLN was (70.33 ± 0.70) nm with zeta potential (-7.69 ± 0.61) mV. GEM:OXA-SLN significantly inhibited the viability of ovarian cancer cells in a dose-dependent manner within 24 h. It also triggered the induction of autophagy cellular death, suppression of multidrug resistance efflux pump and inhibition of heat shock protein (Hsp90).
    CONCLUSION: The encapsulation of GEM and OXA in SLN improved the efficacy of the drugs and diminished the ovarian cancer cell's resistance.
    Keywords:  Caspase-3; Chemotherapeutics; Dynamic light scattering; Heat shock protein; Multidrug resistance
    DOI:  https://doi.org/10.1080/02652048.2022.2109218
  114. Phytomedicine. 2022 Jul 19. pii: S0944-7113(22)00427-5. [Epub ahead of print]105 154348
    Effective dose/duration of natural flavonoid quercetin for treatment of diabetic nephropathy: A systematic review and meta-analysis of rodent data.
    Ziyu Li, Haichuan Deng, Xiaochuan Guo, Sining Yan, Chaorui Lu, Zewei Zhao, Xinyu Feng, Qihong Li, Jiayi Wang, Jinhao Zeng, Xiao Ma.
       BACKGROUND: Given the challenges on diabetic nephropathy (DN) treatment, research has been carried out progressively focusing on dietary nutrition and natural products as a novel option with the objective of enhancing curative effect and avoiding adverse reactions. As a representative, Quercetin (Qu) has proved to be of great value in current data.
    PURPOSE: We aimed to synthetize the evidence regarding the therapeutic effect and specific mechanism of quercetin on DN via systematically reviewing and performing meta-analysis.
    METHODS: Preclinical literature published prior to August 2021, was systematical retrieval and manually filtrated across four major databases including PubMed, Web of Science, EMBASE and Cochrane library. Pooled overall effect sizes of results were generated by STATA 16.0, and underlying mechanisms were summarized. Three-dimensional dose/time-effect analyses and radar maps were conducted to examine the dosage/time-response relations between Qu and DN.
    RESULTS: This paper pools all current available evidence in a comprehensive way, and shows the therapeutic benefits as well as potential action mechanisms of Qu in protecting the kidney against damage. A total of 304 potentially relevant citations were identified, of which 18 studies were enrolled into analysis. Methodological quality was calculated, resulting in an average score of 7.06/10. This paper provided the preliminary evidence that consumption of Qu could induce a statistical reduction in mesangial index, Scr, BUN, 24-h urinary protein, serum urea, BG, kidney index, TC, TG, LDL-C, AST, MDA, AGE, TNF-α, TGF-β1, TGF-β1 mRNA, CTGF and IL-1β, whereas HDL-C, SOD, GSH, GSH-Px, CAT and smad-7 were significantly increased. Furthermore, Qu could remarkably improve the renal pathology. In terms of the mechanisms underlying therapy of DN, Qu exerts anti-diabetic nephropathy properties possibly through PI3K/PKB, AMPK-P38 MAPK, SCAP/SREBP2/LDLr, mtROS-TRX/TXNIP/NLRP3/IL-1β, TGF-β1/Smad, Nrf2/HO-1, Hippo, mTORC1/p70S6K and SHH pathways. Dose/time-response images predicted a modest association between Qu dosage consumption/administration length and therapeutic efficacy, with the optimal dosage at 90-150 mg/kg/d and administration length ranging from 8 weeks to 12 weeks.
    CONCLUSIONS: Quercetin exhibit highly pleiotropic actions, which simultaneously contributes to prevent fundamental progression of DN, such as hyperglycemia, dyslipidemia, inflammation, fibrotic lesions and oxidative stress. The therapeutic effect becomes stronger when Qu administration at higher dosages lasts for longer durations. Taken together, quercetin could be used in patients with DN as a promising agent, which has well-established safety profiles and nontoxicity according to existing literature.
    Keywords:  Diabetic nephropathy; Meta-analysis; Natural products; Quercetin; Systematic review
    DOI:  https://doi.org/10.1016/j.phymed.2022.154348
  115. Adv Healthc Mater. 2022 Aug 01. e2200776
    Functional two-dimensional iron-based nanosheets for synergistic immunotherapy, phototherapy and chemotherapy of tumor.
    Xingbo Wang, Yan Cheng, Xiaoqing Han, Jiao Yan, Yunyun Wu, Panpan Song, Yanjing Wang, Xi Li, Haiyuan Zhang.
      Immunotherapy efficacy has been limited by tumor-associated macrophages (TAMs), which are the most abundant immune regulatory cells infiltrating around tumor tissues. The repolarization of pro-tumor M2 TAMs to anti-tumor M1 TAMs is a very promising immunotherapeutic strategy for cancer therapy. In this manuscript, multifunctional two-dimensional (2D) iron-based nanosheets (FeNSs) were synthesized via a simple hydrothermal method for the first time, which not only possess photothermal and photodynamic properties, but also can repolarize TAMs from M2 to M1. After modified with polyethylene glycol (PEG) and loaded with bioreductive prodrug banoxantrone (AQ4N), abbreviated as AP FeNSs, it could effectively repolarize TAMs from M2 to M1 and delivery AQ4N to tumor microenvironment (TME). Moreover, the repolarized M1 TAMs overexpress inducible nitric oxide synthase (iNOS), which can convert nontoxic AQ4N to cytotoxic AQ4 under hypoxic TME, enabling immunomodulation-activated chemotherapy. A series of in vitro and in vivo results corroborated that AP FeNSs could effectively exert photothermal and photodynamic effects and repolarize M2 TAMs to M1 TAMs, releasing inflammatory factors and activating the chemotherapeutic effect, thereby realizing synergistic tumor therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Immunomodulation; Iron-based nanosheets; Repolarization; Synergistic tumor therapy; Tumor-associated macrophages
    DOI:  https://doi.org/10.1002/adhm.202200776
  116. Nat Commun. 2022 Aug 05. 13(1): 4553
    Reactive oxygen species-responsive and Raman-traceable hydrogel combining photodynamic and immune therapy for postsurgical cancer treatment.
    Yiyi Zhang, Sidan Tian, Liping Huang, Yanan Li, Yuan Lu, Hongyu Li, Guiping Chen, Fanling Meng, Gang L Liu, Xiangliang Yang, Jiasheng Tu, Chunmeng Sun, Liang Luo.
      Combining immune checkpoint blockade (ICB) therapy with photodynamic therapy (PDT) holds great potential in treating immunologically "cold" tumors, but photo-generated reactive oxygen species (ROS) can inevitably damage co-administered ICB antibodies, hence hampering the therapeutic outcome. Here we create a ROS-responsive hydrogel to realize the sustained co-delivery of photosensitizers and ICB antibodies. During PDT, the hydrogel skeleton poly(deca-4,6-diynedioic acid) (PDDA) protects ICB antibodies by scavenging the harmful ROS, and at the same time, triggers the gradual degradation of the hydrogel to release the drugs in a controlled manner. More interestingly, we can visualize the ROS-responsive hydrogel degradation by Raman imaging, given the ultrastrong and degradation-correlative Raman signal of PDDA in the cellular silent window. A single administration of the hydrogel not only completely inhibits the long-term postoperative recurrence and metastasis of 4T1-tumor-bearing mice, but also effectively restrains the growth of re-challenged tumors. The PDDA-based ROS-responsive hydrogel herein paves a promising way for the durable synergy of PDT and ICB therapy.
    DOI:  https://doi.org/10.1038/s41467-022-32160-z
  117. Acta Biomater. 2022 Jul 30. pii: S1742-7061(22)00448-2. [Epub ahead of print]
    α-Fe2O3 based nanotherapeutics for near-infrared/dihydroartemisinin dual-augmented chemodynamic antibacterial therapy.
    Yueying Xu, Le Xiao, Jia Chen, Quanxin Wu, Wenhua Yu, Weishen Zeng, Yaxin Shi, Yingnian Lu, Yun Liu.
      Due to the negligible bacterial resistance, chemodynamic therapy (CDT) is a promising treatment for bacterial infection. However, it is severely impeded by the constant body temperature, shortage of Fe(Ⅱ) ions and insufficient H2O2 level in infected tissue. To enhance the therapeutic efficiency of CDT, improved strategies are urgently needed to tackle these problems. Herein, we exploited an infection microenvironment-responsive nanotherapeutics for near-infrared (NIR)/dihydroartemisinin (DHA) dual-augmented antibacterial CDT. The convenient encapsulation of DHA-loaded α-Fe2O3 nanorods with metal-polyphenol networks (MPN) led to the generation of an antibacterial nanoagent Fe2O3@DHA@MPN (FDM). Afterwards, its photothermal and peroxidase-like activities were intensively studied. Furthermore, the bactericidal efficacy of FDM was evaluated through both in vitro and in vivo antibacterial assays. Firstly, FDM showed both satisfactory photothermal and NIR/DHA dual-augmented peroxidase-like activities. Besides, it exhibited a pH-responsive release behavior of both Fe(Ⅱ) ions and DHA. Moreover, it presented tannic acid-mediated bacterial adhesion effect. In vitro experiments demonstrated that FDM could achieve a satisfactory efficiency against both planktonic bacteria and biofilms. In vivo assays illustrated both the extraordinary synergistic antibacterial effect and efficient anti-inflammatory ability of FDM. The outcomes indicated that the exploited antibacterial agent could offer new insight on developing intelligent nanotherapeutics for clinical use in the future. STATEMENT OF SIGNIFICANCE: : The antibacterial efficiency of chemodynamic therapy (CDT) is seriously limited by the constant body temperature, shortage of Fe(Ⅱ) ions and insufficient H2O2 level at the mildly acidic inflammatory microenvironment. To address these issues, we have developed a pH-responsive nanoagent (Fe2O3@DHA@MPN) for near-infrared (NIR)/dihydroartemisinin (DHA) dual-augmented CDT. Through the NIR-induced photothermal effect of exterior Fe(Ⅲ)/tannic acid complex, the increased local temperature led to a photothermal enhanced CDT. Besides, a continuous supply of Fe(Ⅱ) ions could be achieved by tannic acid-mediated Fe(Ⅲ) reduction. Moreover, DHA was adopted as a substitute for H2O2 to initiate DHA-mediated CDT. Both in vitro and in vivo assays demonstrated its outstanding bactericidal efficiency. Therefore, the developed nanotherapeutics could be a promising candidate for clinical trials.
    Keywords:  Antibacterial therapy; Chemodynamic therapy; Dihydroartemisinin; Photothermal effect; α-Fe(2)O(3) nanorods
    DOI:  https://doi.org/10.1016/j.actbio.2022.07.047
  118. Acta Biomater. 2022 Aug 02. pii: S1742-7061(22)00456-1. [Epub ahead of print]
    Genetically engineered bacteria-mediated multi-functional nanoparticles for synergistic tumor-targeting therapy.
    Yaotai Wang, Yu Tang, Yan Du, Li Lin, Zhong Zhang, Xia Ou, Sheng Chen, Qi Wang, Jianzhong Zou.
      Focused ultrasonic ablation surgery (FUAS) for tumor treatment has emerged as an effective non-invasive therapeutic approach, but its widespread clinical utilization is limited by its low therapeutic efficiency caused by inadequate tumor targeting, single imaging modality, and possible tumor recurrence following surgery. Therefore, this study aimed to develop a biological targeting synergistic system consisting of genetically engineered bacteria and multi-functional nanoparticles to overcome these limitations. Escherichia coli was genetically modified to carry an acoustic reporter gene encoding the formation of gas vesicles (GVs) and then target the tumor hypoxic environment in mice. After E. coli producing GVs (GVs-E. coli) colonized the tumor target area, ultrasound imaging and collaborative FUAS were performed; multi-functional nanoparticles were then enriched in the tumor target area through electrostatic adsorption. Multi-functional cationic lipid nanoparticles containing IR780, perfluorohexane, and banoxantrone dihydrochloride (AQ4N) were coloaded in the tumor to realize targeted multimodal imaging and enhance the curative effect of FUAS. AQ4N was stimulated by the tumor hypoxic environment and synergistically cooperated with FUAS to kill tumor cells. In sum, synergistic tumor therapy involving multi-functional nanoparticles mediated by genetically engineered bacteria overcomes the limitations and improves the curative effect of existing FUAS. STATEMENT OF SIGNIFICANCE: Inadequate tumor targeting, single image monitoring mode, and prone tumor recurrence following surgery remain significant challenges yet critical for tumor therapy. This study proposes a strategy for genetically engineered bacteria-mediated multifunctional nanoparticles for synergistic tumor therapy. The multifunctional genetically engineered biological targeting synergistic agent can accomplish tumor-targeting therapy, synergistic FUAS ablation, hypoxia-activated chemotherapy combined with FUAS ablation, and multiple-imaging guidance and monitoring all at the same time, thereby compensating for the shortcomings of FUAS treatment. This strategy could pave the way for the progress of tumor therapy.
    Keywords:  bacteriotherapy; focused ultrasound ablation surgery; hypoxic activation; multimodal imaging; tumor therapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.07.056
  119. Sci Rep. 2022 Aug 01. 12(1): 13153
    Augmenting apoptosis-mediated anticancer activity of lactoperoxidase and lactoferrin by nanocombination with copper and iron hybrid nanometals.
    Esmail M El-Fakharany, Marwa M Abu-Serie, Noha H Habashy, Marwa Eltarahony.
      There is an urgent need in the medicinal fields to discover biocompatible nanoformulations with low cytotoxicity, which provide new strategies for promising therapies for several types of tumors. Bovine lactoperoxidase (LP) and lactoferrin (LF) have recently attracted attention in medicine for their antitumor activities with recognized safety pattern. Both LP and LF are suitable proteins to be coated or adsorbed to Cu and Fe nanometals for developing stable nanoformulations that boost immunity and strong anticancer effects. New nanometals of Cu and Fe NPs embedded in LP and LF forming novel nanocombinations of LP-CNPs and LF-FNPs had a spherical shape with an average nanosize of about 21 nm. The combination of LP-CNPs and LF-FNPs significantly exhibited the highest growth inhibitory efficacy, in terms of effectively lowering the half-maximal inhibitory concentration (IC50) values, against Caco-2, HepG2 and MCF7 cells comparing to nanometals, LP, LF and individual nanoproteins (LP-CNPs or LF-FNPs). The highest apoptotic effect of this nanocombination (LP-CNPs and LF-FNPs) was confirmed by the highest percentages of annexin-stained apoptotic cells and G0 population with the strongest alteration in the expression of two well-characterized apoptosis guards (p53 and Bcl-2) and the maximum suppression in the proliferation marker (Ki-67). Also, the in silico analysis predicted that LP-CNPs and LF-FNPs enhanced AMP-activated protein kinase (AMPK, p53 activator) activity and inhibited cancer migration-related proteases (cathepsin B and matrix metalloproteinase (MMP)-9). Our results offer for the first time that these novel nanocombinations of LP and LF were superior in their selectivity and apoptosis-mediating anticancer activity to Cu and Fe nanometals as well as the free form of these proteins or their individual nanoforms.
    DOI:  https://doi.org/10.1038/s41598-022-17357-y
  120. Acta Biomater. 2022 Jul 31. pii: S1742-7061(22)00450-0. [Epub ahead of print]
    Biodegradable Polymer Matrix Composites Containing Graphene-Related Materials for Antibacterial Applications: A Critical Review.
    Egemen Avcu, Fatih E Bastan, Mert Guney, Yasemin Yildiran Avcu, Muhammad A Ur Rehman, Aldo R Boccaccini.
      For the first time, the present review critically evaluates biodegradable polymer matrix composites containing graphene-related materials (GRMs) for antibacterial applications while discussing their development, processing routes, mechanical properties, and antibacterial activity. Due to its suitable biological properties and processability, chitosan has been the most widely used biodegradable polymer for the fabrication of GRM-containing composites with antibacterial properties. The majority of biodegradable polymers (including cellulose-, gelatine-, PVA-, PCL-, and PHA-based polymers) exhibit little to no antibacterial effect alone; however, they show significant antibacterial activity (>70%) when combined with GRMs. In vitro and in vivo studies indicate that GRMs functionalization with biodegradable polymers also reduces potential GRM cytotoxicity. Overall, GRMs in biodegradable polymer matrices provide attractive antibacterial activity against a broad spectrum of bacteria (>30 different bacteria) along with improved mechanical properties over pristine polymers, where the type and the degree of improvement provided by GRMs depend on the specific matrix. For example, the addition of GRMs into chitosan, PVA, and PCL matrices increases their tensile strength by 80%, 180%, and 40%, respectively. Challenges remain in understanding the effects of processing routes and post-processing methods on the antibacterial activity and biocompatibility of biodegradable polymer/GRM composites. Given their promising properties and functionality, research on these composites is expected to further increase along with the implementation of new composite systems. These would include a wide range of applications, e.g., wound dressings, tissue engineering, drug delivery, biosensing, and photo-thermal therapy, as well as non-medical use, e.g., antibacterial food packaging, water treatment, and antibacterial fabrics. STATEMENT OF SIGNIFICANCE: : Graphene-related materials (GRMs) in polymer matrices can provide excellent antibacterial activity against a broad spectrum of bacteria together with improved mechanical properties (e.g., tensile strength and elastic modulus) over pristine polymers; thus, research efforts and applications of biodegradable polymer matrix composites containing GRMs have increased notably in the last ten years. For the first time, the present review critically evaluates biodegradable polymer matrix composites containing GRMs for antibacterial applications while discussing their development, processing routes, mechanical properties, and antibacterial activity. Future research directions for each composite system are proposed to shed light on overcoming the existing challenges in composite performance (e.g., mechanical properties, toxicity) reported in the literature.
    Keywords:  Bactericide; Cellulose; Chitosan; GO (Graphene oxide); PVA (Polyvinyl alcohol)
    DOI:  https://doi.org/10.1016/j.actbio.2022.07.048
  121. Biomater Adv. 2022 May;pii: S2772-9508(22)00038-3. [Epub ahead of print]136 212761
    Anti-tumor immunity and ferroptosis of hepatocellular carcinoma are enhanced by combined therapy of sorafenib and delivering modified GO-based PD-L1 siRNAs.
    Zhiwei Li, Jiaqi Bu, Xinyu Zhu, Hao Zhou, Kaiqun Ren, Paul K Chu, Limin Li, Xiang Hu, Xiaofeng Ding.
      Programmed cell death receptor ligand 1 (PD-L1)/PD-1 signaling has been exploited to design inhibitors that deliver promising clinical outcome albeit with limited efficacy. Herein, we prepare graphene oxide (GO)-PEI-PEG with low cytotoxicity and long stability and GO-PEI-PEG delivers PD-L1 siRNAs to hepatocellular carcinoma (HCC) cells by the endocytosis-lysosome pathway. The functional GO-PEI-PEG/PD-L1 siRNAs decrease PD-L1 and PD-1 abundance, increase pro-inflammation cytokine IFN-γ and TNF-α release, and improve the proliferation activity of Jurkat T cells. Since GO-PEI-PEG targets the mouse liver effectively, the intrahepatic tumors in C57BL/6 mice are treated with GO-PEI-PEG/Pd-l1 siRNAs via the tail vein, resulting in shrinkage of the HCC tumors and boosting the anti-tumor efficacy in combination with oral sorafenib. A single treatment improves the total CD3+ and cytotoxic CD8+ T cell infiltration in the HCC tumor tissues and even spleen and upregulates the expression of Perforin, Gzmb, Ifng, Il-1b and Tnfa in the tumors after the combined treatment. Both the single and combined treatments enhance reactive oxygen species (ROS) accumulation, and improved HCC ferroptosis. The results suggest that GO-PEI-PEG delivered PD-L1 siRNAs combined with oral sorafenib can activate the adaptive immunity and tumor ferroptosis and reveal an effective therapy to treat advanced HCC patients.
    Keywords:  Anti-tumor immunity; GO-PEI-PEG; HCC ferroptosis; PD-L1 siRNA
    DOI:  https://doi.org/10.1016/j.bioadv.2022.212761
  122. J Psychosoc Nurs Ment Health Serv. 2022 08;60(8): 7-8
    FDA-Approved Drugs to Treat Overweight and Obesity.
      
    DOI:  https://doi.org/10.3928/02793695-20220615-79
  123. Breast Cancer Res Treat. 2022 Jul 30.
    MYC as a therapeutic target for the treatment of triple-negative breast cancer: preclinical investigations with the novel MYC inhibitor, MYCi975.
    Minhong Tang, Shane O'Grady, John Crown, Michael J Duffy.
       BACKGROUND: MYC is one of the most frequently altered driver genes in triple-negative breast cancer (TNBC). The aim of this study was to evaluate targeting MYC for the treatment of TNBC.
    METHODS: The anti-proliferative and apoptosis-inducing effects of the recently discovered MYC inhibitor, MYCi975 were investigated in a panel of 14 breast cancer cell lines representing the main molecular forms of breast cancer.
    RESULTS: IC50 values for growth inhibition by MYCi975 varied from 2.49 to 7.73 µM. Response was inversely related to endogenous MYC levels as measured by western blotting (p = 0.047, r = - 0.5385) or ELISA (p = 0.001, r = - 0.767), i.e., response to MYCi975 decreased as endogenous MYC levels increased. MYCi975 also induced variable levels of apoptosis across the panel of cell lines, ranging from no detectable induction to 80% induction. Inhibition of proliferation and induction of apoptosis were greater in TNBC than in non-TNBC cell lines (p = 0.041 and p = 0.001, respectively). Finally, combined treatment with MYCi975 and either paclitaxel or doxorubicin resulted in enhanced cell growth inhibition.
    DISCUSSION: Our findings open the possibility of targeting MYC for the treatment of TNBC. Based on our results, we suggest that trials use a combination of MYCi975 and either docetaxel or doxorubicin and include MYC as a putative therapy predictive biomarker.
    Keywords:  Breast cancer; Inhibitor; MYC; MYCi975; Treatment; Triple-negative
    DOI:  https://doi.org/10.1007/s10549-022-06673-6
  124. Int J Biol Macromol. 2022 Aug 01. pii: S0141-8130(22)01667-1. [Epub ahead of print]
    Chemo-photothermal therapeutic effect of chitosan-gelatin hydrogels containing methotrexate and melanin on a collagen-induced arthritis mouse model.
    Min Ah Kim, So Ryung Shin, Hyeon Jin Kim, Jung Sick Lee, Chang-Moon Lee.
      Heat stimulation can promote osteoblast differentiation and bone formation. Combining photothermal therapy and chemotherapy is an effective strategy for treating rheumatoid arthritis (RA). Herein, we prepared chitosan/gelatin/β-glycerophosphate-melanin-methotrexate (CMM) hydrogel that could be used to perform simultaneous chemotherapy and photothermal therapy for patients with RA. The CMM solution was successfully converted to a gel state at body temperature. Due to intrinsic photothermal properties of melanin, CMM hydrogel exhibited effective temperature increase both in vitro and in vivo with increasing time of near-infrared (NIR) laser irradiation. After NIR laser irradiation, 50 % of methotrexate was rapidly released from the hydrogel within 3 h. Its release rate showed an instantaneous increase with additional NIR laser irradiation. After CMM hydrogel was injected directly into the paw joint of each collagen-induced arthritis (CIA) mouse followed by irradiation with a NIR laser (808 nm, 0.5 W/cm2, 3 min), swelling and redness at the inflamed area were significantly alleviated at 14 days after treatment. Micro-CT analysis confirmed that treated joints of mice were similar to normal joints. Hence, CMM hydrogel could be used as an attractive RA therapeutic agent for simultaneous chemo-photothermal therapy.
    Keywords:  Chemo-photothermal therapy; In situ hydrogel; Near-infrared laser; Rheumatoid arthritis; Therapeutic agents
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.227
  125. ACS Nano. 2022 Aug 02.
    DNA Origami as a Nanomedicine for Targeted Rheumatoid Arthritis Therapy through Reactive Oxygen Species and Nitric Oxide Scavenging.
    Yuxuan Ma, Zhangwei Lu, Bin Jia, Ye Shi, Jun Dong, Shuoxing Jiang, Zhe Li.
      Rheumatoid arthritis (RA) severely threatens human health by causing inflammation, swelling, and pain in the joints and resulting in persistent synovitis and irreversible joint disability. In the development of RA, pro-inflammatory M1 macrophages, which express high levels of reactive oxygen species (ROS) and nitric oxide (NO), induce synovial inflammation and bone erosion. Eliminating ROS and NO in the inflamed joints is a potential RA therapeutic approach, which can drive the transition of pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype. Taking advantage of the intrinsic ROS- and NO-scavenging capability of DNA molecules, herein, we report the development of folic acid-modified triangular DNA origami nanostructures (FA-tDONs) for targeted RA treatment. FA-tDONs could efficiently scavenge ROS and NO and actively target M1 macrophages, facilitating the M1-to-M2 transition and the recovery of associated cytokines and biomarkers to the normal level. The therapeutic efficacy of FA-tDONs was examined in the RA mouse model. As validated by appearance, histological, and serum examinations, FA-tDONs treatment effectively alleviated synovial infiltration and cartilage damage, attenuating disease progression. This study demonstrated the usage of DNA origami for RA treatment and suggested its potential in other antioxidant therapies.
    Keywords:  DNA origami; macrophages; nitric oxide; reactive oxygen species; rheumatoid arthritis
    DOI:  https://doi.org/10.1021/acsnano.2c03991
  126. Front Oncol. 2022 ;12 944025
    Recent Advances on the Role of ATGL in Cancer.
    Renshuai Zhang, Jingsen Meng, Shanbo Yang, Wenjing Liu, Lingyu Shi, Jun Zeng, Jing Chang, Bing Liang, Ning Liu, Dongming Xing.
      The hypoxic state of the tumor microenvironment leads to reprogramming lipid metabolism in tumor cells. Adipose triglyceride lipase, also known as patatin-like phospholipase= domain-containing protein 2 and Adipose triglyceride lipase (ATGL), as an essential lipid metabolism-regulating enzyme in cells, is regulated accordingly under hypoxia induction. However, studies revealed that ATGL exhibits both tumor-promoting and tumor-suppressing effects, which depend on the cancer cell type and the site of tumorigenesis. For example, elevated ATGL expression in breast cancer is accompanied by enhanced fatty acid oxidation (FAO), enhancing cancer cells' metastatic ability. In prostate cancer, on the other hand, tumor activity tends to be negatively correlated with ATGL expression. This review outlined the regulation of ATGL-mediated lipid metabolism pathways in tumor cells, emphasizing the Hypoxia-inducible factors 1 (HIF-1)/Hypoxia-inducible lipid droplet-associated (HIG-2)/ATGL axis, peroxisome proliferator-activated receptor (PPAR)/G0/G1 switch gene 2 (G0S2)/ATGL axis, and fat-specific protein 27 (FSP-27)/Early growth response protein 1 (EGR-1)/ATGL axis. In the light of recent research on different cancer types, the role of ATGL on tumorigenesis, tumor proliferation, and tumor metastasis was systemically reviewed.
    Keywords:  Adipose triglyceride lipase (ATGL); HIF-1; cancer; hypoxia; lipid metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.944025
  127. Trends Immunol. 2022 Aug 03. pii: S1471-4906(22)00139-9. [Epub ahead of print]
    High endothelial venules as potential gateways for therapeutics.
    Bilal Hussain, Vivek Kasinath, Gabriel P Ashton-Rickardt, Thomas Clancy, Kenji Uchimura, George Tsokos, Reza Abdi.
      High endothelial venules (HEVs) are specialized blood vessels that support the migration of lymphocytes from the bloodstream into lymph nodes (LNs). They are also formed ectopically in mammalian organs affected by chronic inflammation and cancer. The recent arrival of immunotherapy at the forefront of many cancer treatment regimens could boost a crucial role for HEVs as gateways for the treatment of cancer. In this review, we describe the microanatomical and biochemical characteristics of HEVs, mechanisms of formation of newly made HEVs, immunotherapies potentially dependent on HEV-mediated T cell homing to tumors, and finally, how HEV-targeted therapies might be used as a complementary approach to potentially shape the therapeutic landscape for the treatment of cancer and immune-mediated diseases.
    Keywords:  cancer immunology; high endothelial venule; lymph node; nanomedicine; nanoparticles; transplantation
    DOI:  https://doi.org/10.1016/j.it.2022.07.002
  128. Photodiagnosis Photodyn Ther. 2022 Jul 30. pii: S1572-1000(22)00332-5. [Epub ahead of print] 103046
    The Japanese Quail Chorioallantoic Membrane as a Model to Study an Amphiphilic Gradient copoly(2-Oxazoline)s- Based Drug Delivery System for Photodynamic Diagnosis and Therapy Research.
    Barbora Kundeková, Mariana Máčajová, Majlinda Meta, Ivan Čavarga, Veronika Huntošová, Shubhashis Datta, Pavol Miškovský, Juraj Kronek, Boris Bilčík.
      Amphiphilic gradient copoly(2-oxazoline)s are widely researched in the field of drug delivery. They could be used as a transport system for hydrophobic drugs such as hypericin (HYP). We prepared six gradient copolymers (EtOx)-grad-(ROPhOx) by living cationic ring-opening polymerization of a hydrophilic comonomer 2-ethyl-2-oxazoline (EtOx) and a hydrophobic comonomer 2-(4-alkyloxyphenyl)-2-oxazoline (ROPhOx), with different composition ratio (88:12 and 85:15) and three different alkyl chain lengths of alkyl (R) substituents. As an experimental model, Japanese quail chorioallantoic membrane (CAM) was used. The effect of nanoparticles loaded with HYP was evaluated by the changes of fluorescence intensity during photodynamic diagnosis (PDD) monitored under 405 nm LED light before administration, and 0,1,3 and 24 h after topical administration. The effectiveness of photodynamic therapy (PDT) (405 nm, 285 mW/cm2) applied 1h after the administration of HYP-loaded nanoparticles was evaluated using vascular damage score and histological sections. Molecular analysis was done by measuring angiogenesis-related gene expression by qPCR. The application of nanoparticles unloaded or loaded with HYP proved to be biocompatible, non-toxic, and undamaging to the CAM tissue, while they successfully altered the HYP fluorescence. We observed a possible anti-angiogenic potential of prepared nanoparticles, which could present an advantage for PDT used for tumour treatment.
    Keywords:  biodegradable polymers; chorioallantoic membrane; drug delivery; nanoparticles; photodynamic therapy
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.103046
  129. Front Microbiol. 2022 ;13 912621
    Discovery of Novel Tyrosinase Inhibitors From Marine Cyanobacteria.
    Yifan He, Takashi L Suyama, Hyunwoo Kim, Evgenia Glukhov, William H Gerwick.
      Tyrosinase, an important oxidase involved in the primary immune response in humans, can sometimes become problematic as it can catalyze undesirable oxidation reactions. Therefore, for decades there has been a strong pharmaceutical interest in the discovery of novel inhibitors of this enzyme. Recent studies have also indicated that tyrosinase inhibitors can potentially be used in the treatment of melanoma cancer. Over the years, many new tyrosinase inhibitors have been discovered from various natural sources; however, marine natural products (MNPs) have contributed only a small number of promising candidates. Therefore, in this study we focused on the discovery of new MNP tyrosinase inhibitors of marine cyanobacterial and algal origins. A colorimetric tyrosinase inhibitory assay was used to screen over 4,500 marine extracts against mushroom tyrosinase (A. bisporus). Our results revealed that scytonemin monomer (ScyM), a pure compound from our compound library and also the monomeric last-step precursor in the biosynthesis of the well-known cyanobacterial sunscreen pigment "scytonemin," consistently showed the highest tyrosinase inhibitory score. Determination of the half maximal inhibitory concentration (IC50) further indicated that ScyM is more potent than the commonly used commercial inhibitor standard "kojic acid" (KA; IC50 of ScyM: 4.90 μM vs. IC50 of KA: 11.31 μM). After a scaled-up chemical synthesis of ScyM as well as its O-methyl analog (ScyM-OMe), we conducted a series of follow-up studies on their structures, inhibitory properties, and mode of inhibition. Our results supported ScyM as the second case ever of a novel tyrosinase inhibitory compound based on a marine cyanobacterial natural product. The excellent in vitro performance of ScyM makes it a promising candidate for applications such as a skin-whitening agent or an adjuvant therapy for melanoma cancer treatment.
    Keywords:  kinetic study; marine cyanobacteria and algae; molecular docking; mushroom tyrosinase inhibition; scytonemin; scytonemin monomer synthesis; skin whitening; synergistic effect
    DOI:  https://doi.org/10.3389/fmicb.2022.912621
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