bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–02–27
131 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Synergistic H2O2 self-supplying and NIR-responsive drug delivery nanoplatform for chemodynamic-photothermal-chemotherapy.
  2. Light-Decomposable Polymeric Micelles with Hypoxia-Enhanced Phototherapeutic Efficacy for Combating Metastatic Breast Cancer.
  3. Some Natural Photosensitizers and Their Medicinal Properties for Use in Photodynamic Therapy.
  4. Skin-safe nanophotosensitizers with highly-controlled synthesized polydopamine shell for synergetic chemo-photodynamic therapy.
  5. Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer.
  6. Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer.
  7. Development of Novel Tetrapyrrole Structure Photosensitizers for Cancer Photodynamic Therapy.
  8. Artemisinin-Type Drugs in Tumor Cell Death: Mechanisms, Combination Treatment with Biologics and Nanoparticle Delivery.
  9. Cell-Specific Metabolic Reprogramming of Tumors for Bioactivatable Ferroptosis Therapy.
  10. Development and Optimization of Hybrid Polymeric Nanoparticles of Apigenin: Physicochemical Characterization, Antioxidant Activity and Cytotoxicity Evaluation.
  11. Near-Infrared Light Irradiation of Porphyrin-Modified Gold Nanoparticles Promotes Cancer-Cell-Specific Cytotoxicity.
  12. PI3K-AKT Pathway Modulation by Thymoquinone Limits Tumor Growth and Glycolytic Metabolism in Colorectal Cancer.
  13. ATP-responsive near-infrared fluorescent nanoparticles for synergistic chemotherapy and starvation therapy.
  14. An Overview of Nanotechnologies for Drug Delivery to the Brain.
  15. Antiangiogenic Phytochemicals Constituent of Diet as Promising Candidates for Chemoprevention of Cancer.
  16. Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet.
  17. Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review.
  18. Ultra-small bimetallic phosphides for dual-modal MRI imaging guided photothermal ablation of tumors.
  19. A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy.
  20. Lipid Metabolism and Epigenetics Crosstalk in Prostate Cancer.
  21. N-Doped Graphene Quantum Dots/Titanium Dioxide Nanocomposites: A Study of ROS-Forming Mechanisms, Cytotoxicity and Photodynamic Therapy.
  22. Synergic Antitumor Effect of Photodynamic Therapy and Chemotherapy Mediated by Nano Drug Delivery Systems.
  23. Anticancer mechanisms of Berberine: a good choice for glioblastoma multiforme therapy.
  24. Glutathione-sensitive IPI-549 nanoparticles synergized with photodynamic Chlorin e6 for the treatment of breast cancer.
  25. Photo-Reduction with NIR Light of Nucleus Targeting Pt(IV) Nanoparticles for Combined Tumor-Targeted Chemotherapy and Photodynamic Immunotherapy.
  26. Effects of Metformin Combined With Antifolates on HepG2 Cell Metabolism and Cellular Proliferation.
  27. Metabolic Biomarkers in B-Cell Lymphomas for Early Diagnosis and Prediction, as Well as Their Influence on Prognosis and Treatment.
  28. Anticancer Biosurfactant-Loaded PLA-PEG Nanoparticles Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cells.
  29. Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy.
  30. Gold nanodoughnut as an outstanding nanoheater for photothermal applications.
  31. PEGylated Chitosan Nanoparticles Encapsulating Ascorbic Acid and Oxaliplatin Exhibit Dramatic Apoptotic Effects against Breast Cancer Cells.
  32. A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer.
  33. Obesity and breast cancer: Preventive and therapeutic possibilities for bariatric surgery.
  34. Synergism of ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment.
  35. Fruit peel bioactives, valorisation into nanoparticles and potential applications: A review.
  36. A review on enzymatic acylation as a promising opportunity to stabilizing anthocyanins.
  37. Oxygen Self-Supply Engineering-Ferritin for the Relief of Hypoxia in Tumors and the Enhancement of Photodynamic Therapy Efficacy.
  38. Aspirin Repurposing in Folate-Decorated Nanoparticles: Another Way to Target Breast Cancer.
  39. Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy.
  40. Tumor redox microenvironment modulating composite hydrogels for enhanced sonodynamic therapy of colorectal cancer.
  41. Application of engineered extracellular vesicles for targeted tumor therapy.
  42. Photosensitive EGFR-Targeted Nanocarriers for Combined Photodynamic and Local Chemotherapy.
  43. A Facile and Universal Method for Preparing Polyethylene glycol-Metal Hybrid Nanoparticles and Their Application in Tumor Theranostics.
  44. Role of Vitamin C in Selected Malignant Neoplasms in Women.
  45. A light-driven dual-nanotransformer with deep tumor penetration for efficient chemo-immunotherapy.
  46. Design and preparation of a Theranostic Peptideticle for targeted Cancer therapy: Peptide-based Codelivery of doxorubicin/curcumin and graphene quantum dots.
  47. Natural products in the treatment of pulmonary emphysema: Therapeutic effects and mechanisms of action.
  48. Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine Biosynthetic Pathway.
  49. Fabrication of pH/Redox Dual-Responsive Mixed Polyprodrug Micelles for Improving Cancer Chemotherapy.
  50. HSA-Binding Prodrugs-Based Nanoparticles Endowed with Chemo and Photo-Toxicity against Breast Cancer.
  51. Lactate-Loaded Nanoparticles Induce Glioma Cytotoxicity and Increase the Survival of Rats Bearing Malignant Glioma Brain Tumor.
  52. Applications of the ROS-Responsive Thioketal Linker for the Production of Smart Nanomedicines.
  53. An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment.
  54. Enhancing the Bioavailability and Efficacy of Vismodegib for the Control of Skin Cancer: In Vitro and In Vivo Studies.
  55. Single and Multiple Stimuli-Responsive Polymer Particles for Controlled Drug Delivery.
  56. Folic Acid-Adorned Curcumin-Loaded Iron Oxide Nanoparticles for Cervical Cancer.
  57. Redox-Based Strategy for Selectively Inducing Energy Crisis Inside Cancer Cells: An Example of Modifying Dietary Curcumin to Target Mitochondria.
  58. 3D printed tablets containing oxaliplatin loaded alginate nanoparticles for colon cancer targeted delivery. An in vitro/in vivo study.
  59. Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics.
  60. Biofunctionalized Chrysin-conjugated gold nanoparticles neutralize Leishmania parasites with high efficacy.
  61. Photolytic Controlled Release Formulation of Methotrexate Loaded in Chitosan/TiO2 Nanoparticles for Breast Cancer.
  62. An Overview of Potential Seaweed-Derived Bioactive Compounds for Pharmaceutical Applications.
  63. Pre-Exposure to Stress-Inducing Agents Increase the Anticancer Efficacy of Focused Ultrasound against Aggressive Prostate Cancer Cells.
  64. Chitosan-Crosslinked Low Molecular Weight PEI-Conjugated Iron Oxide Nanoparticle for Safe and Effective DNA Delivery to Breast Cancer Cells.
  65. Correlation between Chemical Characterization and Biological Activity: An Urgent Need for Human Studies Using Extra Virgin Olive Oil.
  66. Engineered nanomaterials for synergistic photo-immunotherapy.
  67. Targeted Polymeric Nanoparticles Based on Mangiferin for Enhanced Protection of Pancreatic β-Cells and Type 1 Diabetes Mellitus Efficacy.
  68. Metal nanoparticles as a promising technology in targeted cancer treatment.
  69. Strategies to Overcome Biological Barriers Associated with Pulmonary Drug Delivery.
  70. Engineering Robust Ag-Decorated Polydopamine Nano-Photothermal Platforms to Combat Bacterial Infection and Prompt Wound Healing.
  71. Nontoxic Metal-Free Visible Light-Responsive Carbon Nitride Quantum Dots Cause Oxidative Stress and Cancer-Specific Membrane Damage.
  72. Effects of Olive Oil and Its Components on Intestinal Inflammation and Inflammatory Bowel Disease.
  73. Tumor-derived extracellular vesicles as messengers of natural products in cancer treatment.
  74. Dietary Natural Compounds and Vitamins as Potential Cofactors in Uterine Fibroids Growth and Development.
  75. Enhanced antimicrobial activity through the combination of antimicrobial photodynamic therapy and low-frequency ultrasonic irradiation.
  76. Recent Advances in Drumstick (Moringa oleifera) Leaves Bioactive Compounds: Composition, Health Benefits, Bioaccessibility, and Dietary Applications.
  77. Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors.
  78. An Insight to Brain Targeting Utilizing Polymeric Nanoparticles: Effective Treatment Modalities for Neurological Disorders and Brain Tumor.
  79. Re-engineering the inner surface of ferritin nanocage enables dual drug payloads for synergistic tumor therapy.
  80. Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications.
  81. Nanotechnological approaches for pentamidine delivery.
  82. Fabrication and characterization of chitosan nanoparticles using the coffee-ring effect for photodynamic therapy.
  83. Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.
  84. A critical review on the extraction and pharmacotherapeutic activity of piperine.
  85. Health Benefits and Applications of Goji Berries in Functional Food Products Development: A Review.
  86. Cannabidiol (CBD) in Cancer Management.
  87. Interplay Between m6A RNA Methylation and Regulation of Metabolism in Cancer.
  88. Vine Cane Compounds to Prevent Skin Cells Aging through Solid Lipid Nanoparticles.
  89. Nutraceutical potential of high-latitude and high-altitude berries rich in ellagitannins.
  90. Advancement of nanomedicines in chronic inflammatory disorders.
  91. Formulation Development and Evaluation of Pravastatin-Loaded Nanogel for Hyperlipidemia Management.
  92. The Pharmacological Activities of Crocus sativus L.: A Review Based on the Mechanisms and Therapeutic Opportunities of its Phytoconstituents.
  93. Cannabis sativa Extract Induces Apoptosis in Human Pancreatic 3D Cancer Models: Importance of Major Antioxidant Molecules Present Therein.
  94. Natural compounds as safe therapeutic options for ulcerative colitis.
  95. Alpinetin: A Review of Its Pharmacology and Pharmacokinetics.
  96. Glycans as Targets for Drug Delivery in Cancer.
  97. Hesperidin-Loaded Lipid Polymer Hybrid Nanoparticles for Topical Delivery of Bioactive Drugs.
  98. Transferrin Receptor-Targeted Nanocarriers: Overcoming Barriers to Treat Glioblastoma.
  99. Teaching an old dog new tricks: Drug discovery by repositioning natural products and their derivatives.
  100. Tacrolimus-Loaded Solid Lipid Nanoparticle Gel: Formulation Development and In Vitro Assessment for Topical Applications.
  101. A Review on the Main Phytoconstituents, Traditional Uses, Inventions, and Patent Literature of Gum Arabic Emphasizing Acacia seyal.
  102. Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment.
  103. Towards principled design of cancer nanomedicine to accelerate clinical translation.
  104. NIR-regulated dual-functional silica nanoplatform for infected-wound therapy via synergistic sterilization and anti-oxidation.
  105. The Interplay of Ascorbic Acid with Quinones-Chelators-Influence on Lipid Peroxidation: Insight into Anticancer Activity.
  106. Polydatin: A Critical Promising Natural Agent for Liver Protection via Antioxidative Stress.
  107. Radiosensitization and Radioprotection by Curcumin in Glioblastoma and Other Cancers.
  108. Anti-Cancer Properties of Stevia rebaudiana; More than a Sweetener.
  109. Lycopene: A Natural Arsenal in the War against Oxidative Stress and Cardiovascular Diseases.
  110. HOXA7 promotes the metastasis of KRAS mutant colorectal cancer by regulating myeloid-derived suppressor cells.
  111. Investigating the Impact of Optimized Trans-Cinnamic Acid-Loaded PLGA Nanoparticles on Epithelial to Mesenchymal Transition in Breast Cancer.
  112. A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives.
  113. EGFR-Targeted Photodynamic Therapy.
  114. Synthesis and characterization of silver nanoparticles using curcumin: cytotoxic, apoptotic, and necrotic effects on various cell lines.
  115. Adherence to Low-Carbohydrate Diets in Patients with Diabetes: A Narrative Review.
  116. Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia.
  117. Microneedle-Based Natural Polysaccharide for Drug Delivery Systems (DDS): Progress and Challenges.
  118. Emerging photodynamic nanotherapeutics for inducing immunogenic cell death and potentiating cancer immunotherapy.
  119. Natural Products as Novel Neuroprotective Agents; Computational Predictions of the Molecular Targets, ADME Properties, and Safety Profile.
  120. The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects.
  121. Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation.
  122. Medicinal Components in Edible Mushrooms on Diabetes Mellitus Treatment.
  123. Treatment of Liver Cancer: Role of the Traditional Mongolian Medicine.
  124. Tumor-permeable smart liposomes by modulating the tumor microenvironment to improve the chemotherapy.
  125. Chitosan Nanoparticles Containing Lipoic Acid with Antioxidant Properties as a Potential Nutritional Supplement.
  126. Mitochondrial ROS-Mediated Metabolic and Cytotoxic Effects of Isoproterenol on Cardiomyocytes Are p53-Dependent and Reversed by Curcumin.
  127. Liposomal-Based Formulations: A Path from Basic Research to Temozolomide Delivery Inside Glioblastoma Tissue.
  128. Research progress on self-assembled nanodrug delivery systems.
  129. Concentrically Encapsulated Dual-Enzyme Capsules for Synergistic Metabolic Disorder Redressing and Cytotoxic Intermediates Scavenging.
  130. Targeting KRAS Regulation with PolyPurine Reverse Hoogsteen Oligonucleotides.
  131. Paclitaxel Drug Delivery Systems: Focus on Nanocrystals' Surface Modifications.
  1. Colloids Surf B Biointerfaces. 2022 Feb 12. pii: S0927-7765(22)00095-9. [Epub ahead of print]213 112412
    Synergistic H2O2 self-supplying and NIR-responsive drug delivery nanoplatform for chemodynamic-photothermal-chemotherapy.
    Mi Wang, Lina Zhang, Han Hao, Xiaoxiao Hu, Zhichuan Xin, Yanyan Zhu, Yanting Shen, Jing Wang.
      Developing effectively synergistic multi-mode drug delivery nanoplatform for cancer treatment is of great significance but still challenging. Here, we construct core-shell (CaO2@Au nanoshells) nanoparticles coated with doxorubicin-loaded hyaluronic acid. The developed platform can be used as synergistic H2O2 self-supplying and near-infrared-enhanced reactive oxygen species producer for chemodynamic-photothermal-chemotherapy multi-mode drug delivery. In this platform, the CaO2 possesses a high capacity of self-supplying H2O2 in acidic conditions, while retains desired stability under physiological conditions. The in-situ deposited Au nanoshells not only provide a remarkable photothermal therapy, but function as peroxidase mimics to catalyze H2O2 to produce hydroxyl radical to afford highly efficient chemodynamic therapy. Furthermore, the outer layer hyaluronic acid can load doxorubicin and target overexpressed receptor CD44 of cancer cell, meanwhile, trigger release of DOX in photothermal condition and acidic tumor microenvironment. The results of in vitro cell viability and in vivo tumor inhibition indicate that the developed synergistic nanoplatform hold the potential as an efficient strategy for chemodynamic-photothermal-chemotherapy combination therapy of cancer.
    Keywords:  Au nanoshells; Chemodynamic therapy; H(2)O(2) self-supplying; Multimodal therapy; Photothermal therapy
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112412
  2. Pharmaceutics. 2022 Jan 21. pii: 253. [Epub ahead of print]14(2):
    Light-Decomposable Polymeric Micelles with Hypoxia-Enhanced Phototherapeutic Efficacy for Combating Metastatic Breast Cancer.
    Yuanyuan Li, Aiyang Tong, Peiyuan Niu, Wenjing Guo, Yangye Jin, Yi Hu, Pei Tao, Wenjun Miao.
      Oxygen dependence and anabatic hypoxia are the major factors responsible for the poor outcome of photodynamic therapy (PDT) against cancer. Combining of PDT and hypoxia-activatable bioreductive therapy has achieved remarkably improved antitumor efficacy compared to single PDT modality. However, controllable release and activation of prodrug and safety profiles of nanocarrier are still challenging in the combined PDT/hypoxia-triggered bioreductive therapy. Herein, we developed a near infrared (NIR) light-decomposable nanomicelle, consisting of PEGylated cypate (pCy) and mPEG-polylactic acid (mPEG2k-PLA2k) for controllable delivery of hypoxia-activated bioreductive prodrug (tirapazamine, TPZ) (designated TPZ@pCy), for combating metastatic breast cancer via hypoxia-enhanced phototherapies. TPZ@pCy was prepared by facile nanoprecipitation method, with good colloidal stability, excellent photodynamic and photothermal potency, favorable light-decomposability and subsequent release and activation of TPZ under irradiation. In vitro experiments demonstrated that TPZ@pCy could be quickly internalized by breast cancer cells, leading to remarkable synergistic tumor cell-killing potential. Additionally, metastatic breast tumor-xenografted mice with systematic administration of TPZ@pCy showed notable tumor accumulation, promoting tumor ablation and lung metastasis inhibition with negligible toxicity upon NIR light illumination. Collectively, our study demonstrates that this versatile light-decomposable polymeric micelle with simultaneous delivery of photosensitizer and bioreductive agent could inhibit tumor growth as well as lung metastasis, representing a promising strategy for potent hypoxia-enhanced phototherapies for combating metastatic breast cancer.
    Keywords:  antitumor; bioreductive prodrug; hypoxia; micelles; phototherapy
    DOI:  https://doi.org/10.3390/pharmaceutics14020253
  3. Molecules. 2022 Feb 10. pii: 1192. [Epub ahead of print]27(4):
    Some Natural Photosensitizers and Their Medicinal Properties for Use in Photodynamic Therapy.
    Tomasz Piotr Kubrak, Przemysław Kołodziej, Jan Sawicki, Anna Mazur, Katarzyna Koziorowska, David Aebisher.
      Despite significant advances in early diagnosis and treatment, cancer is one of the leading causes of death. Photodynamic therapy (PDT) is a therapy for the treatment of many diseases, including cancer. This therapy uses a combination of a photosensitizer (PS), light irradiation of appropriate length and molecular oxygen. The photodynamic effect kills cancer cells through apoptosis, necrosis, or autophagy of tumor cells. PDT is a promising approach for eliminating various cancers but is not yet as widely applied in therapy as conventional chemotherapy. Currently, natural compounds with photosensitizing properties are being discovered and identified. A reduced toxicity to healthy tissues and a lower incidence of side effects inspires scientists to seek natural PS for PDT. In this review, several groups of compounds with photoactive properties are presented. The use of natural products has been shown to be a fruitful approach in the discovery of novel pharmaceuticals. This review focused on the anticancer activity of furanocoumarins, polyacetylenes, thiophenes, tolyporphins, curcumins, alkaloid and anthraquinones in relation to the light-absorbing properties. Attention will be paid to their phototoxic and anti-cancer effects on various types of cancer.
    Keywords:  alkaloids; anthraquinones; curcumins; furanocoumarins; photodynamic therapy (PDT); polyacetylenes; thiophenes; tolyporphin
    DOI:  https://doi.org/10.3390/molecules27041192
  4. J Colloid Interface Sci. 2022 Feb 14. pii: S0021-9797(22)00272-7. [Epub ahead of print]616 81-92
    Skin-safe nanophotosensitizers with highly-controlled synthesized polydopamine shell for synergetic chemo-photodynamic therapy.
    Lan-Ying Guo, Qi-Sheng Xia, Jing-Lei Qin, Mu Yang, Ting-Yu Yang, Fang-Tian You, Zhi-Hua Chen, Bei Liu, Hong-Shang Peng.
      Although photodynamic therapy (PDT) has been extensively studied as an established modality of cancer treatment, it still suffers from a few clinical limitations, such as skin phototoxicity and tumor hypoxia. To circumvent these hurdles, hollow silica mesoporous nanoparticles (HMSNs) loaded with photosensitizers were employed as the nanoplatform to construct multifunctional nanoparticles (NPs). Specifically, an ultra-uniform polydopamine (PDA) shell was highly controlled grown around HMSNs by photogenerated outwards-diffused 1O2, followed by conjugation of folic acid-poly(ethylene glycol) and chelation of Fe2+ ions. Thanks to the optimal thickness of light-absorbing PDA shell, the multifunctional NPs exhibited not only negligible skin phototoxicity but also efficient 1O2 generation and photothermal (PT)-enhanced •OH generation upon respective photoirradiation. Anti-tumor therapy was then performed on both 4 T1 tumor cells and tumor-bearing mice by the combination of 638 nm PDT and 808 nm PT-enhanced chemodynamic therapy (CDT). As a result, high therapeutic efficacy was achieved compared to single-modality therapy, with a cell inhibitory rate of 86% and tumor growth inhibition of 70.4% respectively. More interestingly, tumor metastasis was effectively inhibited by the synergetic treatment. These results convincingly demonstrate that our multifunctional NPs are very promising skin-safe PDT agents combined with CDT for efficient tumor therapy.
    Keywords:  Chemodynamic therapy; Hollow silica mesoporous nanoparticle; Photodynamic therapy; Polydopamine; Skin phototoxicity
    DOI:  https://doi.org/10.1016/j.jcis.2022.02.046
  5. J Control Release. 2022 Feb 21. pii: S0168-3659(22)00100-6. [Epub ahead of print]
    Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer.
    Young Seok Cho, Gui Chul Kim, Hye Min Lee, Byoungmo Kim, Ha Rin Kim, Seung Woo Chung, Hyo Won Chang, Yoon Gun Ko, Yoon Se Lee, Seong Who Kim, Youngro Byun, Sang Yoon Kim.
      Despite recent breakthroughs in the development of direct KRAS inhibitors and modulators, no drugs targeting pan-KRAS mutant cancers are clinically available. Here, we report a novel strategy to treat pan-KRAS cancers using a caspase-3 cleavable peptide-drug conjugate that exploits enhanced albumin metabolism in KRAS altered cancers to deliver a cytotoxic agent that can induce a widespread bystander killing effect in tumor cells. Increased albumin metabolism in KRAS mutant cancer cells induced apoptosis via the intracellular uptake of albumin-bound MPD1. This allowed caspase-3 upregulation activated MPD1 to release the payload and exert the non-selective killing of neighboring cancer cells. MPD1 exhibited potent and durable antitumor efficacy in mouse xenograft models with different KRAS genotypes. An augmentation of anti-cancer efficacy was achieved by the bystander killing effect derived from the caspase-3 mediated activation of MPD1. In summary, albumin metabolism-induced apoptosis, together with the bystander killing effect of MPD1 boosted by caspase-3 mediated activation, intensified the efficacy of MPD1 in KRAS mutant cancers. These findings suggest that this novel peptide-drug conjugate could be a promising breakthrough for the treatment in the targeting of pan-KRAS mutant cancers.
    Keywords:  Albumin metabolism; Bystander killing effect; Caspase-3; KRAS mutant cancer; Peptide-drug conjugate; Prodrug
    DOI:  https://doi.org/10.1016/j.jconrel.2022.02.026
  6. Int J Mol Sci. 2022 Feb 15. pii: 2144. [Epub ahead of print]23(4):
    Curcumin as an Enhancer of Therapeutic Efficiency of Chemotherapy Drugs in Breast Cancer.
    Reyhaneh Farghadani, Rakesh Naidu.
      Female breast cancer is the world's most prevalent cancer in 2020. Chemotherapy still remains a backbone in breast cancer therapy and is crucial in advanced and metastatic breast cancer treatment. The clinical efficiency of chemotherapy regimens is limited due to tumor heterogeneity, chemoresistance, and side effects. Chemotherapeutic drug combinations with natural products hold great promise for enhancing their anticancer efficacy. Curcumin is an ideal chemopreventive and chemotherapy agent owning to its multitargeting function on various regulatory molecules, key signaling pathways, and pharmacological safety. This review aimed to elucidate the potential role of curcumin in enhancing the efficacy of doxorubicin, paclitaxel, 5-fluorouracil, and cisplatin via combinational therapy. Additionally, the molecular mechanisms underlying the chemosensitizing activity of these combinations have been addressed. Overall, based on the promising therapeutic potential of curcumin in combination with conventional chemotherapy drugs, curcumin is of considerable value to develop as an adjunct for combination chemotherapy with current drugs to treat breast cancer. Furthermore, this topic may provide the frameworks for the future research direction of curcumin-chemotherapy combination studies and may benefit in the development of a novel therapeutic strategy to maximize the clinical efficacy of anticancer drugs while minimizing their side effects in the future breast cancer treatment.
    Keywords:  anticancer agent; cancer drug discovery; chemosensitizer; clinical trial; combination therapy; curcumin; drug resistance; signaling pathway
    DOI:  https://doi.org/10.3390/ijms23042144
  7. Bioengineering (Basel). 2022 Feb 19. pii: 82. [Epub ahead of print]9(2):
    Development of Novel Tetrapyrrole Structure Photosensitizers for Cancer Photodynamic Therapy.
    Natalia Plekhova, Olga Shevchenko, Oksana Korshunova, Aleksandra Stepanyugina, Ivan Tananaev, Vladimir Apanasevich.
      The effectiveness of photodynamic therapy (PDT) is based on the triad effects of photosensitizer (PS), molecular oxygen and visible light on malignant tumors. Such complex induces a multifactorial manner including reactive-oxygen-species-mediated damage and the killing of cells, vasculature damage of the tumor, and activation of the organism immunity. The effectiveness of PDT depends on the properties of photosensitizing drugs, their selectivity, enhanced photoproduction of reactive particles, absorption in the near infrared spectrum, and drug delivery strategies. Photosensitizers of the tetrapyrrole structure (porphyrins) are widely used in PDT because of their unique diagnostic and therapeutic functions. Nevertheless, the clinical use of the first-generation PS (sodium porfimer and hematoporphyrins) revealed difficulties, such as long-term skin photosensitivity, insufficient penetration into deep-seated tumors and incorrect localization to it. The second generation is based on different approaches of the synthesis and conjugation of porphyrin PS with biomolecules, which made it possible to approach the targeted PDT of tumors. Despite the fact that the development of the second-generation PS started about 30 years ago, these technologies are still in demand and are in intensive development, especially in the direction of improving the process of optimization split linkers responsive to input. Bioconjugation and encapsulation by targeting molecules are among the main strategies for developing of the PS synthesis. A targeted drug delivery system with the effect of increased permeability and retention by tumor cells is one of the ultimate goals of the synthesis of second-generation PS. This review presents porphyrin PS of various generations, discusses factors affecting cellular biodistribution and uptake, and indicates their role as diagnostic and therapeutic (theranostic) agents. New complexes based on porphyrin PS for photoimmunotherapy are presented, where specific antibodies are used that are chemically bound to PS, absorbing light from the near infrared part of the spectrum. Additionally, a two-photon photodynamic approach using third-generation photosensitizers for the treatment of tumors is discussed, which indicates the prospects for the further development of a promising method antitumor PDT.
    Keywords:  cancer; photodynamic therapy; photosensitizers; porphyrins; properties; tetrapyrrole structure
    DOI:  https://doi.org/10.3390/bioengineering9020082
  8. Pharmaceutics. 2022 Feb 10. pii: 395. [Epub ahead of print]14(2):
    Artemisinin-Type Drugs in Tumor Cell Death: Mechanisms, Combination Treatment with Biologics and Nanoparticle Delivery.
    Xinyu Zhou, Fengzhi Suo, Kristina Haslinger, Wim J Quax.
      Artemisinin, the most famous anti-malaria drug initially extracted from Artemisia annua L., also exhibits anti-tumor properties in vivo and in vitro. To improve its solubility and bioavailability, multiple derivatives have been synthesized. However, to reveal the anti-tumor mechanism and improve the efficacy of these artemisinin-type drugs, studies have been conducted in recent years. In this review, we first provide an overview of the effect of artemisinin-type drugs on the regulated cell death pathways, which may uncover novel therapeutic approaches. Then, to overcome the shortcomings of artemisinin-type drugs, we summarize the recent advances in two different therapeutic approaches, namely the combination therapy with biologics influencing regulated cell death, and the use of nanocarriers as drug delivery systems. For the former approach, we discuss the superiority of combination treatments compared to monotherapy in tumor cells based on their effects on regulated cell death. For the latter approach, we give a systematic overview of nanocarrier design principles used to deliver artemisinin-type drugs, including inorganic-based nanoparticles, liposomes, micelles, polymer-based nanoparticles, carbon-based nanoparticles, nanostructured lipid carriers and niosomes. Both approaches have yielded promising findings in vitro and in vivo, providing a strong scientific basis for further study and upcoming clinical trials.
    Keywords:  artemisinin; combination treatment; nanoparticle delivery; regulated cell death
    DOI:  https://doi.org/10.3390/pharmaceutics14020395
  9. ACS Nano. 2022 Feb 24.
    Cell-Specific Metabolic Reprogramming of Tumors for Bioactivatable Ferroptosis Therapy.
    Yanan Li, Menghuan Li, Li Liu, Chencheng Xue, Yang Fei, Xuan Wang, Yuchen Zhang, Kaiyong Cai, Yanli Zhao, Zhong Luo.
      Ferroptosis is a nonapoptotic iron-dependent cell death pathway with a significant clinical potential, but its translation is impeded by lack of tumor-specific ferroptosis regulators and aberrant tumor iron metabolism. Herein, we report a combinational strategy based on clinically tested constituents to selectively induce ferroptosis in metabolically reprogrammed tumor cells through cooperative GPX4-inhibition and ferritinophagy-enabled Fe2+ reinforcement. Azido groups were first introduced on tumor cells using biocompatible long-circulating self-assemblies based on polyethylene glycol-disulfide-N-azidoacetyl-d-mannosamine via metabolic glycoengineering. The azido-expressing tumor cells could specifically react with dibenzocyclooctyne-modified disulfide-bridged nanoassemblies via bioorthogonal click reactions, where the nanoassemblies were loaded with ferroptosis inducer RSL3 and ferritinophagy initiator dihydroartemisinin (DHA) and could release them in a bioresponsive manner. DHA-initiated ferritinophagy could degrade intracellular ferritin to liberate stored iron species and cooperate with the RSL3-mediated GPX4-inhibition for enhanced ferroptosis therapy. This tumor-specific ferroptosis induction strategy provides a generally applicable therapy with enhanced translatability, especially for tumors lacking targetable endogenous receptors.
    Keywords:  bioorthogonal tumor targeting; cancer therapy; ferritinophagy; ferroptosis; metabolic labeling
    DOI:  https://doi.org/10.1021/acsnano.1c09480
  10. Sensors (Basel). 2022 Feb 10. pii: 1364. [Epub ahead of print]22(4):
    Development and Optimization of Hybrid Polymeric Nanoparticles of Apigenin: Physicochemical Characterization, Antioxidant Activity and Cytotoxicity Evaluation.
    Ameeduzzafar Zafar, Nabil K Alruwaili, Syed Sarim Imam, Omar Awad Alsaidan, Mohammed Muqtader Ahmed, Mohd Yasir, Musarrat Husain Warsi, Ali Alquraini, Mohammed M Ghoneim, Sultan Alshehri.
      Breast cancer is the most common cancer in females and ranked second after skin cancer. The use of natural compounds is a good alternative for the treatment of breast cancer with less toxicity than synthetic drugs. The aim of the present study is to develop and characterize hybrid Apigenin (AN) Nanoparticles (NPs) for oral delivery (AN-NPs). The hybrid AN-NPs were prepared by the self-assembly method using lecithin, chitosan and TPGS. Further, the NPs were optimized by Box-Behnken design (3-factor, 3-level). The hybrid NPs were evaluated for particle size (PS), entrapment efficiency (EE), zeta potential (ZP), and drug release. The optimized hybrid NPs (ON2), were further evaluated for solid state characterization, permeation, antioxidant, cytotoxicity and antimicrobial study. The formulation (ON2) exhibited small PS of 192.6 ± 4.2 nm, high EE 69.35 ± 1.1%, zeta potential of +36.54 mV, and sustained drug release (61.5 ± 2.5% in 24 h), as well as significantly (p < 0.05) enhanced drug permeation and antioxidant activity. The IC50 of pure AN was found to be significantly (p < 0.05) lower than the formulation (ON2). It also showed significantly greater (p < 0.05) antibacterial activity than pure AN against Bacillus subtilis and Salmonella typhimurium. From these findings, it revealed that a hybrid AN polymeric nanoparticle is a good carrier for the treatment of breast cancer.
    Keywords:  antimicrobial activity; apigenin; breast cancer; cytotoxic activity; hybrid nanoparticle
    DOI:  https://doi.org/10.3390/s22041364
  11. Molecules. 2022 Feb 12. pii: 1238. [Epub ahead of print]27(4):
    Near-Infrared Light Irradiation of Porphyrin-Modified Gold Nanoparticles Promotes Cancer-Cell-Specific Cytotoxicity.
    Hiromi Kurokawa, Atsushi Taninaka, Toru Yoshitomi, Hidemi Shigekawa, Hirofumi Matsui.
      The use of nanoparticles has been investigated as a new cancer treatment. These can induce specific cytotoxicity in cancer cells. In particular, Au nanoparticles (AuNPs) have unique characteristics. The maximum absorption spectrum of AuNPs can be adjusted to modify their size or shape to absorb near-infrared light that can penetrate into tissue without photodamage. Thus, the combination of AuNPs and near-infrared light can be used to treat cancer in deep-seated organs. To obtain effective cancer-specific accumulation of AuNPs, we focused on porphyrin and synthesized a porphyrin-attached Au compound: Au-HpD. In this study, we investigated whether Au-HpD possesses cancer-specific accumulation and cytotoxicity. Intracellular Au-HpD accumulation was higher in cancer cells than in normal cells. In order to analyze the cytotoxicity induced by Au-HpD, cancer cells and normal cells were co-cultured in the presence of Au-HpD; then, they were subjected to 870 nm laser irradiation. We observed that, after laser irradiation, cancer cells showed significant morphological changes, such as chromatin condensation and nuclear fragmentation indicative of cell apoptosis. This strong effect was not observed when normal cells were irradiated. Moreover, cancer cells underwent cell apoptosis with combination therapy.
    Keywords:  Au-HpD; nearinfrared; photodynamic therapy; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules27041238
  12. Int J Mol Sci. 2022 Feb 19. pii: 2305. [Epub ahead of print]23(4):
    PI3K-AKT Pathway Modulation by Thymoquinone Limits Tumor Growth and Glycolytic Metabolism in Colorectal Cancer.
    Shahid Karim, Abdulhadi S Burzangi, Aftab Ahmad, Nasir Ali Siddiqui, Ibrahim M Ibrahim, Priyanka Sharma, Walaa A Abualsunun, Gamal A Gabr.
      Colorectal cancer (CRC) is the third leading cause of death in men and the fourth in women worldwide and is characterized by deranged cellular energetics. Thymoquinone, an active component from Nigella sativa, has been extensively studied against cancer, however, its role in affecting deregulated cancer metabolism is largely unknown. Further, the phosphoinositide 3-kinase (PI3K) pathway is one of the most activated pathways in cancer and its activation is central to most deregulated metabolic pathways for supporting the anabolic needs of growing cancer cells. Herein, we provide evidence that thymoquinone inhibits glycolytic metabolism (Warburg effect) in colorectal cancer cell lines. Further, we show that such an abrogation of deranged cell metabolism was due, at least in part, to the inhibition of the rate-limiting glycolytic enzyme, Hexokinase 2 (HK2), via modulating the PI3/AKT axis. While overexpression of HK2 showed that it is essential for fueling glycolytic metabolism as well as sustaining tumorigenicity, its pharmacologic and/or genetic inhibition led to a reduction in the observed effects. The results decipher HK2 mediated inhibitory effects of thymoquinone in modulating its glycolytic metabolism and antitumor effects. In conclusion, we provide evidence of metabolic perturbation by thymoquinone in CRC cells, highlighting its potential to be used/repurposed as an antimetabolite drug, though the latter needs further validation utilizing other suitable cell and/or preclinical animal models.
    Keywords:  Warburg effect; antimetabolite; colorectal cancer; thymoquinone
    DOI:  https://doi.org/10.3390/ijms23042305
  13. Nanoscale. 2022 Feb 22.
    ATP-responsive near-infrared fluorescent nanoparticles for synergistic chemotherapy and starvation therapy.
    Xi-Xi Chen, Mei-Jia Hou, Wen-Xin Wang, Min Tan, Zhi-Ke Tan, Guo-Jiang Mao, Bin Yang, Yongfei Li, Chun-Yan Li.
      Cancer is a major public health problem worldwide, and traditional chemotherapy or a single therapeutic strategy often fails to achieve expected results in cancer treatment. Thus, the development of a method to realize controlled drug delivery and synergistic therapy is required. Herein, MOF-based nanoparticles named RhI-DOX-GOD@ZIF-90 are synthesized using RhI (a near-infrared fluorescent dye), DOX (an anti-cancer drug) and GOD (glucose oxidase). RhI and DOX are encapsulated inside the ZIF-90 framework and GOD is loaded on the surface of ZIF-90. Owing to the fact that the ATP level in cancer cells is abnormally higher than that in normal cells, RhI-DOX-GOD@ZIF-90 nanoparticles are destructed only in cancer cells. RhI is released to give outstanding NIR emission and realize controlled drug delivery. DOX is released and cancer cells are killed by chemotherapy. Also, GOD is released to consume glucose and achieve the purpose of starving the cancer cells. By making full use of the advantages of near-infrared emission, RhI-DOX-GOD@ZIF-90 nanoparticles can be used to image ATP in tumor-bearing mice. At the same time, DOX and GOD can be released accurately at tumor sites of mice and excellent anti-tumor efficiency by synergistic chemotherapy and starvation therapy is achieved.
    DOI:  https://doi.org/10.1039/d1nr07233a
  14. Pharmaceutics. 2022 Jan 19. pii: 224. [Epub ahead of print]14(2):
    An Overview of Nanotechnologies for Drug Delivery to the Brain.
    Ahsan Ayub, Shawn Wettig.
      Drug delivery to the brain has been one of the toughest challenges researchers have faced to develop effective treatments for brain diseases. Owing to the blood-brain barrier (BBB), only a small portion of administered drug can reach the brain. A consequence of that is the need to administer a higher dose of the drug, which, expectedly, leads to a variety of unwanted side effects. Research in a variety of different fields has been underway for the past couple of decades to address this very serious and frequently lethal problem. One area of research that has produced optimistic results in recent years is nanomedicine. Nanomedicine is the science birthed by fusing the fields of nanotechnology, chemistry and medicine into one. Many different types of nanomedicine-based drug-delivery systems are currently being studied for the sole purpose of improved drug delivery to the brain. This review puts together and briefly summarizes some of the major breakthroughs in this crusade. Inorganic nanoparticle-based drug-delivery systems, such as gold nanoparticles and magnetic nanoparticles, are discussed, as well as some organic nanoparticulate systems. Amongst the organic drug-delivery nanosystems, polymeric micelles and dendrimers are discussed briefly and solid polymeric nanoparticles are explored in detail.
    Keywords:  brain; brain tumours; cancer; dendrimer; drug delivery; micelle; nanomedicine; nanoparticle; polymer; targeting
    DOI:  https://doi.org/10.3390/pharmaceutics14020224
  15. Antioxidants (Basel). 2022 Jan 31. pii: 302. [Epub ahead of print]11(2):
    Antiangiogenic Phytochemicals Constituent of Diet as Promising Candidates for Chemoprevention of Cancer.
    Ana Dácil Marrero, Ana R Quesada, Beatriz Martínez-Poveda, Miguel Ángel Medina.
      Despite the extensive knowledge on cancer nature acquired over the last years, the high incidence of this disease evidences a need for new approaches that complement the clinical intervention of tumors. Interestingly, many types of cancer are closely related to dietary habits associated with the Western lifestyle, such as low fruit and vegetable intake. Recent advances around the old-conceived term of chemoprevention highlight the important role of phytochemicals as good candidates for the prevention or treatment of cancer. The potential to inhibit angiogenesis exhibited by many natural compounds constituent of plant foods makes them especially interesting for their use as chemopreventive agents. Here, we review the antitumoral potential, with a focus on the antiangiogenic effects, of phenolic and polyphenolic compounds, such as quercetin or myricetin; terpenoids, such as ursolic acid or kahweol; and anthraquinones from Aloe vera, in different in vitro and in vivo assays, and the available clinical data. Although clinical trials have failed to assess the preventive role of many of these compounds, encouraging preclinical data support the efficacy of phytochemicals constituent of diet in the prevention and treatment of cancer, but a deeper understanding of their mechanisms of action and better designed clinical trials are urgently needed.
    Keywords:  angiogenesis; bioactive compounds; cancer prevention; chemoprevention; phytochemicals
    DOI:  https://doi.org/10.3390/antiox11020302
  16. Nutrients. 2022 Feb 13. pii: 782. [Epub ahead of print]14(4):
    Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet.
    Mari Murakami, Paola Tognini.
      The consumption of a high-fat, low-carbohydrate diet (ketogenic diet) has diverse effects on health and is expected to have therapeutic value in neurological disorders, metabolic syndrome, and cancer. Recent studies have shown that a ketogenic diet not only pronouncedly shifts the cellular metabolism to pseudo-starvation, but also exerts a variety of physiological functions on various organs through metabolites that act as energy substrates, signaling molecules, and epigenetic modifiers. In this review, we highlight the latest findings on the molecular mechanisms of a ketogenic diet and speculate on the significance of these functions in the context of the epigenome and microbiome. Unraveling the molecular basis of the bioactive effects of a ketogenic diet should provide solid evidence for its clinical application in a variety of diseases including cancer.
    Keywords:  circadian clock; epigenetics; ketogenic diet; microbiome; neurological disorder; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/nu14040782
  17. Polymers (Basel). 2022 Feb 12. pii: 712. [Epub ahead of print]14(4):
    Angiopep-2-Modified Nanoparticles for Brain-Directed Delivery of Therapeutics: A Review.
    Saffiya Habib, Moganavelli Singh.
      Nanotechnology has opened up a world of possibilities for the treatment of brain disorders. Nanosystems can be designed to encapsulate, carry, and deliver a variety of therapeutic agents, including drugs and nucleic acids. Nanoparticles may also be formulated to contain photosensitizers or, on their own, serve as photothermal conversion agents for phototherapy. Furthermore, nano-delivery agents can enhance the efficacy of contrast agents for improved brain imaging and diagnostics. However, effective nano-delivery to the brain is seriously hampered by the formidable blood-brain barrier (BBB). Advances in understanding natural transport routes across the BBB have led to receptor-mediated transcytosis being exploited as a possible means of nanoparticle uptake. In this regard, the oligopeptide Angiopep-2, which has high BBB transcytosis capacity, has been utilized as a targeting ligand. Various organic and inorganic nanostructures have been functionalized with Angiopep-2 to direct therapeutic and diagnostic agents to the brain. Not only have these shown great promise in the treatment and diagnosis of brain cancer but they have also been investigated for the treatment of brain injury, stroke, epilepsy, Parkinson's disease, and Alzheimer's disease. This review focuses on studies conducted from 2010 to 2021 with Angiopep-2-modified nanoparticles aimed at the treatment and diagnosis of brain disorders.
    Keywords:  Angiopep-2; brain; drug delivery; nanoparticles; targeting; transcytosis
    DOI:  https://doi.org/10.3390/polym14040712
  18. Dalton Trans. 2022 Feb 23.
    Ultra-small bimetallic phosphides for dual-modal MRI imaging guided photothermal ablation of tumors.
    Yu Lu, Peng Zhang, Lihao Lin, Xuan Gao, Yifei Zhou, Jing Feng, Hongjie Zhang.
      Metal phosphides have been proved to be potential theranostic agents of tumors. However, the limitations of single-modal imaging or the treatment effect of such materials need to be further improved. Here, we successfully prepared polyvinylpyrrolidone-modified bimetallic nickel cobalt phosphide (NiCoP/PVP) nanoparticles as a theranostic agent of tumors. Owing to the different types of magnetic properties of Ni and Co components, T1- and T2-weighted magnetic resonance imaging (MRI) could be simultaneously achieved to compensate the low accuracy brought about by single-modal MRI. In addition, NiCoP/PVP possesses excellent photothermal properties owing to its obvious absorption in the near-infrared (NIR) region, which endows NiCoP/PVP with high photothermal conversion efficiency (PCE) to serve as a photothermal agent for tumor ablation. Therefore, NiCoP/PVP is a promising theranostic agent for accurate diagnosis and effective treatment of tumors.
    DOI:  https://doi.org/10.1039/d1dt03898b
  19. ACS Nano. 2022 Feb 25.
    A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy.
    Ying Huang, Si Wu, Lu Zhang, Qingqing Deng, Jinsong Ren, Xiaogang Qu.
      The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.
    Keywords:  glutathione; glycolysis; metabolic; reactive oxygen species; tumor-specific
    DOI:  https://doi.org/10.1021/acsnano.1c10231
  20. Nutrients. 2022 Feb 18. pii: 851. [Epub ahead of print]14(4):
    Lipid Metabolism and Epigenetics Crosstalk in Prostate Cancer.
    Juan C Pardo, Vicenç Ruiz de Porras, Joan Gil, Albert Font, Manel Puig-Domingo, Mireia Jordà.
      Prostate cancer (PCa) is the most commonly diagnosed malignant neoplasm in men in the Western world. Localized low-risk PCa has an excellent prognosis thanks to effective local treatments; however, despite the incorporation of new therapeutic strategies, metastatic PCa remains incurable mainly due to disease heterogeneity and the development of resistance to therapy. The mechanisms underlying PCa progression and therapy resistance are multiple and include metabolic reprogramming, especially in relation to lipid metabolism, as well as epigenetic remodelling, both of which enable cancer cells to adapt to dynamic changes in the tumour. Interestingly, metabolism and epigenetics are interconnected. Metabolism can regulate epigenetics through the direct influence of metabolites on epigenetic processes, while epigenetics can control metabolism by directly or indirectly regulating the expression of metabolic genes. Moreover, epidemiological studies suggest an association between a high-fat diet, which can alter the availability of metabolites, and PCa progression. Here, we review the alterations of lipid metabolism and epigenetics in PCa, before focusing on the mechanisms that connect them. We also discuss the influence of diet in this scenario. This information may help to identify prognostic and predictive biomarkers as well as targetable vulnerabilities.
    Keywords:  DNA methylation; cholesterol; diet; epigenetics; fatty acid; histone modifications; lipid metabolism; predictive biomarkers; prostate cancer; therapeutic vulnerabilities
    DOI:  https://doi.org/10.3390/nu14040851
  21. Biomedicines. 2022 Feb 10. pii: 421. [Epub ahead of print]10(2):
    N-Doped Graphene Quantum Dots/Titanium Dioxide Nanocomposites: A Study of ROS-Forming Mechanisms, Cytotoxicity and Photodynamic Therapy.
    Pravena Ramachandran, Boon-Keat Khor, Chong Yew Lee, Ruey-An Doong, Chern Ein Oon, Nguyen Thi Kim Thanh, Hooi Ling Lee.
      Titanium dioxide nanoparticles (TiO2 NPs) have been proven to be potential candidates in cancer therapy, particularly photodynamic therapy (PDT). However, the application of TiO2 NPs is limited due to the fast recombination rate of the electron (e-)/hole (h+) pairs attributed to their broader bandgap energy. Thus, surface modification has been explored to shift the absorption edge to a longer wavelength with lower e-/h+ recombination rates, thereby allowing penetration into deep-seated tumors. In this study, TiO2 NPs and N-doped graphene quantum dots (QDs)/titanium dioxide nanocomposites (N-GQDs/TiO2 NCs) were synthesized via microwave-assisted synthesis and the two-pot hydrothermal method, respectively. The synthesized anatase TiO2 NPs were self-doped TiO2 (Ti3+ ions), have a small crystallite size (12.2 nm) and low bandgap energy (2.93 eV). As for the N-GQDs/TiO2 NCs, the shift to a bandgap energy of 1.53 eV was prominent as the titanium (IV) tetraisopropoxide (TTIP) loading increased, while maintaining the anatase tetragonal crystal structure with a crystallite size of 11.2 nm. Besides, the cytotoxicity assay showed that the safe concentrations of the nanomaterials were from 0.01 to 0.5 mg mL-1. Upon the photo-activation of N-GQDs/TiO2 NCs with near-infrared (NIR) light, the nanocomposites generated reactive oxygen species (ROS), mainly singlet oxygen (1O2), which caused more significant cell death in MDA-MB-231 (an epithelial, human breast cancer cells) than in HS27 (human foreskin fibroblast). An increase in the N-GQDs/TiO2 NCs concentrations elevates ROS levels, which triggered mitochondria-associated apoptotic cell death in MDA-MB-231 cells. As such, titanium dioxide-based nanocomposite upon photoactivation has a good potential as a photosensitizer in PDT for breast cancer treatment.
    Keywords:  N-doped graphene quantum dots; apoptosis; near-infrared light; photodynamic therapy; reactive oxygen species; titanium dioxide
    DOI:  https://doi.org/10.3390/biomedicines10020421
  22. Pharmaceutics. 2022 Jan 29. pii: 322. [Epub ahead of print]14(2):
    Synergic Antitumor Effect of Photodynamic Therapy and Chemotherapy Mediated by Nano Drug Delivery Systems.
    Mozhgan Aghajanzadeh, Mostafa Zamani, Fereshteh Rajabi Kouchi, Josh Eixenberger, Dorsa Shirini, David Estrada, Farhad Shirini.
      This review provides a summary of recent progress in the development of different nano-platforms for the efficient synergistic effect between photodynamic therapy and chemotherapy. In particular, this review focuses on various methods in which photosensitizers and chemotherapeutic agents are co-delivered to the targeted tumor site. In many cases, the photosensitizers act as drug carriers, but this review, also covers different types of appropriate nanocarriers that aid in the delivery of photosensitizers to the tumor site. These nanocarriers include transition metal, silica and graphene-based materials, liposomes, dendrimers, polymers, metal-organic frameworks, nano emulsions, and biologically derived nanocarriers. Many studies have demonstrated various benefits from using these nanocarriers including enhanced water solubility, stability, longer circulation times, and higher accumulation of therapeutic agents/photosensitizers at tumor sites. This review also describes novel approaches from different research groups that utilize various targeting strategies to increase treatment efficacy through simultaneous photodynamic therapy and chemotherapy.
    Keywords:  cancer; combination of photodynamic therapy/chemotherapy; drug delivery systems; nano photosensitizers; nano-platforms; synergistic effect
    DOI:  https://doi.org/10.3390/pharmaceutics14020322
  23. Curr Med Chem. 2022 Feb 24.
    Anticancer mechanisms of Berberine: a good choice for glioblastoma multiforme therapy.
    Bahram Bibak, Farzaneh Shakeri, Zakieh Keshavarzi, Hamid Mollazadeh, Hossein Javid, Mohammad Jalili-Nik, Thozhukat Sathyapalan, Amir R Afshari, Amirhossein Sahebkar.
      The most typical malignant brain tumor, glioblastoma multiforme (GBM), seems to have a grim outcome, despite the intensive multi-modality interventions. Literature suggests that biologically active phytomolecules may exert anticancer properties by regulating several signaling pathways. Berberine, an isoquinoline alkaloid, has various pharmacological applications to combat severe diseases like cancer. Mechanistically, Berberine inhibits cell proliferation and invasion, suppresses tumor angiogenesis, and induces cell apoptosis. The effect of the antitumoral effect of Berberine in GBM is increasingly recognized. This review sheds new light on the regulatory signaling mechanisms of Berberine in various cancer, proposing its potential role as a therapeutic agent for GBM. ‎.
    Keywords:  Apoptosis; Autophagy; Berberine; Glioblastoma multiforme; Phytomolecules
    DOI:  https://doi.org/10.2174/0929867329666220224112811
  24. Nanotechnology. 2022 Feb 22.
    Glutathione-sensitive IPI-549 nanoparticles synergized with photodynamic Chlorin e6 for the treatment of breast cancer.
    Mengjia Yang, Xiaojun Lv, Siwen Zhan, Mengli Lu, Xueqiong Zhang, Tong Qiu.
      We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2 μM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.
    Keywords:  Breast cancer; Carboxymethyl chitosan; Chlorin e6; IPI-549; Nanoparticles
    DOI:  https://doi.org/10.1088/1361-6528/ac57ac
  25. Angew Chem Int Ed Engl. 2022 Feb 25.
    Photo-Reduction with NIR Light of Nucleus Targeting Pt(IV) Nanoparticles for Combined Tumor-Targeted Chemotherapy and Photodynamic Immunotherapy.
    Dengshuai Wei, Yun Huang, Bin Wang, Lili Ma, Johannes Karges, Haihua Xiao.
      The development of Pt(IV) prodrugs which are selectively reduced within cancerous cells into their Pt(II) therapeutically active species has received increasing attention within the last decade. Despite recent research progress, the majority of investigated compounds are excited using ultraviolet or blue light. As the light penetration depth is low at these wavelengths, the treatment of deep-seated or large tumors is limited. To overcome this limitation, herein, the first example of Pt(IV) functionalized nanoparticles that could be excited within the NIR region at 808 nm is reported. The polymer backbone which can self-assemble into nanoparticles was functionalized with Pt(IV) complexes for chemotherapy, photosensitizers for photodynamic immunotherapy, and nucleus/cancer-targeting peptides. Upon irradiation, the Pt(IV) center is reduced to Pt(II) and the axially coordinated ligands are released, presenting a multimodal treatment. While selectively accumulating in tumorous tissue, the nanoparticles demonstrated to eradicate a triple-negative breast cancer tumor inside a mouse model.
    Keywords:  Bioinorganic Chemistry; Chemotherapy; Medicinal Inorganic Chemistry; Metals in Medicine; Photodynamic Therapy
    DOI:  https://doi.org/10.1002/anie.202201486
  26. Front Oncol. 2022 ;12 828988
    Effects of Metformin Combined With Antifolates on HepG2 Cell Metabolism and Cellular Proliferation.
    Sherouk M Tawfik, Maha R A Abdollah, Mohey M Elmazar, Hassan A N El-Fawal, Anwar Abdelnaser.
      Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Furthermore, a growing body of evidence shows that cancer metabolic changes are a key feature of many types of human malignancies. Metabolic reprogramming refers to cancer cells' ability to change their metabolism in order to meet the increased energy demand caused by continuous growth, rapid proliferation, and other neoplastic cell characteristics. For these reasons, metabolic pathways may become new therapeutic and chemopreventive targets. The aim of this study was to investigate the metabolic alterations associated with metformin (MET), an anti-diabetic agent when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate (MTX), and how metabolic changes within the cancer cell may be used to increase cellular death. In this study, single drugs and combinations were investigated using in vitro assays including cytotoxicity assay (MTT), RT-qPCR, annexin V/PI apoptosis assay, scratch wound assay and Seahorse XF analysis, on a human HCC cell line, HepG2. The cytotoxicity assay showed that the IC50 of MET as single therapy was 44.08 mM that was reduced to 22.73 mM and 29.29 mM when combined with TMP and MTX, respectively. The co-treatment of both drugs increased p53 and Bax apoptotic markers, while decreased the anti-apoptotic marker; Bcl-2. Both combinations increased the percentage of apoptotic cells and halted cancer cell migration when compared to MET alone. Furthermore, both combinations decreased the MET-induced increase in glycolysis, while also inducing mitochondrial damage, altering cancer cell bioenergetics. These findings provide an exciting insight into the anti-proliferative and apoptotic effects of MET and anti-folates on HepG2 cells, and how in combination, may potentially combat the aggressiveness of HCC.
    Keywords:  antifolates; glycolysis; hepatocellular carcinoma; metformin; methotrexate; oxidative phosphorylation; seahorse; trimethoprim
    DOI:  https://doi.org/10.3389/fonc.2022.828988
  27. Diagnostics (Basel). 2022 Feb 03. pii: 394. [Epub ahead of print]12(2):
    Metabolic Biomarkers in B-Cell Lymphomas for Early Diagnosis and Prediction, as Well as Their Influence on Prognosis and Treatment.
    Abdullah Alfaifi, Salem Bahashwan, Mohammed Alsaadi, Hafiz Malhan, Aqeel Aqeel, Waiel Al-Kahiry, Hussein Almehdar, Ishtiaq Qadri.
      B-cell lymphomas exhibit a vast variety of clinical and histological characteristics that might complicate the diagnosis. Timely diagnosis is crucial, as treatments for aggressive subtypes are considered successful and frequently curative, whereas indolent B-cell lymphomas are incurable and often need several therapies. The purpose of this review is to explore the current advancements achieved in B-cell lymphomas metabolism and how these indicators help to early detect metabolic changes in B-cell lymphomas and the use of predictive biological markers in refractory or relapsed disease. Since the year 1920, the Warburg effect has been known as an integral part of metabolic reprogramming. Compared to normal cells, cancerous cells require more glucose. These cancer cells undergo aerobic glycolysis instead of oxidative phosphorylation to metabolize glucose and form lactate as an end product. With the help of these metabolic alterations, a novel biomass is generated by the formation of various precursors. An aggressive metabolic phenotype is an aerobic glycolysis that has the advantage of producing high-rate ATP and preparing the biomass for the amino acid, as well as fatty acid, synthesis needed for a rapid proliferation of cells, while aerobic glycolysis is commonly thought to be the dominant metabolism in cancer cells. Later on, many metabolic biomarkers, such as increased levels of lactate dehydrogenase (LDH), plasma lactate, and deficiency of thiamine in B-cell lymphoma patients, were discovered. Various kinds of molecules can be used as biomarkers, such as genes, proteins, or hormones, because they all refer to body health. Here, we focus only on significant metabolic biomarkers in B-cell lymphomas. In conclusion, many metabolic biomarkers have been shown to have clinical validity, but many others have not been subjected to extensive testing to demonstrate their clinical usefulness in B-cell lymphoma. Furthermore, they play an essential role in the discovery of new therapeutic targets.
    Keywords:  B-cell lymphoma; biomarkers; metabolism; prognosis; therapeutic targets
    DOI:  https://doi.org/10.3390/diagnostics12020394
  28. ACS Omega. 2022 Feb 15. 7(6): 5231-5241
    Anticancer Biosurfactant-Loaded PLA-PEG Nanoparticles Induce Apoptosis in Human MDA-MB-231 Breast Cancer Cells.
    Aishani Wadhawan, Joga Singh, Himani Sharma, Shristi Handa, Gurpal Singh, Ravinder Kumar, Ravi Pratap Barnwal, Indu Pal Kaur, Mary Chatterjee.
      Despite various advancements in cancer therapies, treating cancer efficiently without side effects is still a major concern for researchers. Anticancer drugs from natural sources need to be explored as a replacement for chemo drugs to overcome their limitations. In our previous studies, isolation, characterization, and anticancer properties of a novel biosurfactant from Candida parapsilosis were reported. In this study, we report the cytotoxicity of the polymeric nanoparticles of this novel biosurfactant toward breast cancer cells. Biosurfactant-encapsulated polymeric nanoparticles of polylactic acid-poly(ethylene glycol) (PLA-PEG) copolymers were synthesized by the double emulsion solvent evaporation method. Folic acid (FA) was used as a targeting ligand to actively deliver the anticancer cargo to the cancer site. The encapsulation efficiency of nanoparticles was observed as 84.9%, and Fickian diffusion was observed as a kinetic model for the release of biosurfactant from nanoparticles. The controlled delivery of the biosurfactant was noticed when encapsulated in PLA-PEG copolymer nanoparticles. Additionally, it was observed that FA enhanced the uptake and cytotoxicity of biosurfactant-loaded nanoparticles in MDA-MB-231 cancer cells compared to biosurfactant-loaded plain nanoparticles. Induction of apoptosis was observed in cancer cells by these nanoparticles. We explore a potential anticancer agent that can be further analyzed for its efficiency and can be used as an alternative tool.
    DOI:  https://doi.org/10.1021/acsomega.1c06338
  29. Cancers (Basel). 2022 Feb 11. pii: 902. [Epub ahead of print]14(4):
    Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy.
    Maaike Van Trimpont, Evelien Peeters, Yanti De Visser, Amanda M Schalk, Veerle Mondelaers, Barbara De Moerloose, Arnon Lavie, Tim Lammens, Steven Goossens, Pieter Van Vlierberghe.
      L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.
    Keywords:  acute lymphoblastic leukemia; asparaginase; asparagine; glutamine; solid cancers
    DOI:  https://doi.org/10.3390/cancers14040902
  30. Opt Express. 2022 Jan 03. 30(1): 125-137
    Gold nanodoughnut as an outstanding nanoheater for photothermal applications.
    Javier González-Colsa, Guillermo Serrera, José María Saiz, Dolores Ortiz, Francisco González, Fernando Bresme, Fernando Moreno, Pablo Albella.
      Photoinduced hyperthermia is a cancer therapy technique that induces death to cancerous cells via heat generated by plasmonic nanoparticles. While previous studies have shown that some nanoparticles can be effective at killing cancer cells under certain conditions, there is still a necessity (or the need) to improve its heating efficiency. In this work, we perform a detailed theoretical study comparing the thermoplasmonic response of the most effective nanoparticle geometries up to now with a doughnut-shaped nanoparticle. We numerically demonstrate that the latter exhibits a superior tunable photothermal response in practical illumination conditions (unpolarized light). Furthermore, we show that nanoparticle heating in fluidic environments, i.e., nanoparticles undergoing Brownian rotations, strongly depends on the particle orientation with respect to the illumination source. We conclude that nanodoughnuts are the best nanoheaters in our set of structures, with an average temperature increment 40% higher than the second best nanoheater (nanodisk). Furthermore, nanodoughnuts feature a weak dependence on orientation, being therefore ideal candidates for photothermal therapy applications. Finally, we present a designing guide, covering a wide range of toroid designs, which can help on its experimental implementation.
    DOI:  https://doi.org/10.1364/OE.446637
  31. Pharmaceutics. 2022 Feb 13. pii: 407. [Epub ahead of print]14(2):
    PEGylated Chitosan Nanoparticles Encapsulating Ascorbic Acid and Oxaliplatin Exhibit Dramatic Apoptotic Effects against Breast Cancer Cells.
    Sherif Ashraf Fahmy, Asmaa Ramzy, Asmaa A Mandour, Soad Nasr, Anwar Abdelnaser, Udo Bakowsky, Hassan Mohamed El-Said Azzazy.
      This study aims to design a pH-responsive dual-loaded nanosystem based on PEGylated chitosan nanoparticles loaded with ascorbic acid (AA) and oxaliplatin (OX) for the effective treatment of breast cancer. In this regard, non-PEGylated and PEGylated chitosan nanoparticles (CS NPs) loaded with either ascorbic acid (AA), oxaliplatin (OX), or dual-loaded with AA-OX were fabricated using the ionotropic gelation method. The hydrodynamic diameters of the fabricated AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs were 157.20 ± 2.40, 188.10 ± 9.70, and 261.10 ± 9.19 nm, respectively. While the hydrodynamic diameters of the designed AA/PEG-CS NPs, OX/PEG-CS NPs, and AA-OX/PEG-CS NPs were 152.20 ± 2.40, 156.60 ± 4.82, and 176.00 ± 4.21 nm, respectively. The ζ-potential of the prepared nanoparticles demonstrated high positive surface charges of +22.02 ± 1.50, +22.58 ± 1.85 and +40.4 ± 2.71 mV for AA/CS NPs, OX/CS NPs, and AA-OX/CS NPs, respectively. The ζ-potential of the PEGylated CS NPs was reduced owing to the shielding of the positive charges by the PEG chains. Additionally, all the prepared nanoparticles exhibited high entrapment efficiencies (EE%) and spherical-shaped morphology. The chemical features of the prepared nanoparticles were investigated using Fourier transform infrared (FTIR) spectroscopy. Release studies showed the capability of the prepared non-PEGylated and PEGylated chitosan NPs to release their cargo in the acidic environment of cancer tissue (pH 5.5). Furthermore, the AA/CS NPs, AA/PEG-CS NPs, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs and AA-OX/PEG-CS NPs exhibited remarkable cytotoxic activities against breast adenocarcinoma (MCF-7) cells with IC50 values of 44.87 ± 11.49, 23.3 ± 3.73, 23.88 ± 6.29, 17.98 ± 3.99, 18.69 ± 2.22, and 7.5 ± 0.69 µg/mL, respectively; as compared to free AA and OX (IC50 of 150.80 ± 26.50 and 147.70 ± 63.91 µg/mL, respectively). Additionally, treatment of MCF-7 cells with IC50 concentrations of AA, AA/CS NPs, AA/PEG-CS NPs, OX, OX/CS NPs, OX/PEG-CS NPs, AA-OX/CS NPs or AA-OX/PEG-CS NPs increased the percentages of early apoptotic cells to 5.28%, 9.53%, 11.20%, 5.27%, 13.80%, 8.43%, 2.32%, and 10.10%, respectively, and increased the percentages of late apoptotic cells to 0.98%, 0.37%, 2.41%, 2.06%, 0.97%, 9.66%, 56%, and 81.50%, respectively. These results clearly indicate that PEGylation enhances the apoptotic effect of AA and OX alone, in addition to potentiating the apoptotic effect of AA and OX when combined on MCF-7 cells. In conclusion, PEGylated chitosan nanoparticles encapsulating AA, OX, or AA and OX represent an effective formula for induction of apoptosis in MCF-7 cells.
    Keywords:  PEG; ascorbic acid (vitamin C); breast cancer; chitosan nanoparticles; ionic gelation method; oxaliplatin
    DOI:  https://doi.org/10.3390/pharmaceutics14020407
  32. Pharmaceutics. 2022 Feb 15. pii: 422. [Epub ahead of print]14(2):
    A Nanosized Codelivery System Based on Intracellular Stimuli-Triggered Dual-Drug Release for Multilevel Chemotherapy Amplification in Drug-Resistant Breast Cancer.
    Yufan Guo, Shuo Liu, Fazhen Luo, Dongyun Tang, Tianshu Yang, Xiuru Yang, Yan Xie.
      Lacking nano-systems for precisely codelivering the chemotherapeutics paclitaxel (PTX) and the natural P-glycoprotein (P-gp) inhibitor, quercetin (QU), into cancer cells and controlling their intracellular release extremely decreased the anticancer effects in multidrug resistant (MDR) tumors. To overcome this hurdle, we constructed hybrid polymeric nanoparticles (PNPs) which consist of redox-sensitive PTX/polyethyleneimine-tocopherol hydrogen succinate-dithioglycollic acid PNPs and pH-sensitive hyaluronic acid-QU conjugates. The obtained hybrid PNPs can be internalized into drug-resistant breast cancer cells by the hyaluronic acid/CD44-mediated endocytosis pathway and escape from the lysosome through the "proton sponge effect". Under the trigger of intracellular stimuli, the nanoplatform used the pH/glutathione dual-sensitive disassembly to release QU and PTX. The PTX diffused into microtubules to induce tumor cell apoptosis, while QU promoted PTX retention by down-regulating P-gp expression. Moreover, tocopherol hydrogen succinate and QU disturbed mitochondrial functions by generating excessive reactive oxygen species, decreasing the mitochondrial membrane potential, and releasing cytochrome c into the cytosol which consequently achieved intracellular multilevel chemotherapy amplification in MDR cancers. Importantly, the PNPs substantially suppressed tumors growth with an average volume 2.54-fold lower than that of the control group in the MCF-7/ADR tumor-bearing nude mice model. These presented PNPs would provide a valuable reference for the coadministration of natural compounds and anticarcinogens for satisfactory combination therapy in MDR cancers.
    Keywords:  MDR cancer therapy; chemotherapy amplification; codelivery system; hybrid polymeric nanoparticles; stimuli-responsiveness
    DOI:  https://doi.org/10.3390/pharmaceutics14020422
  33. Obesity (Silver Spring). 2022 Mar;30(3): 587-598
    Obesity and breast cancer: Preventive and therapeutic possibilities for bariatric surgery.
    Trevor D Crafts, Jennifer E Tonneson, Bruce M Wolfe, Andrea M Stroud.
      Breast cancer is the most common and second deadliest malignancy in women. With rising obesity rates and building evidence for a strong association with obesity, the incidence of breast cancer can be expected to increase. Weight loss reduces breast cancer risk, the mechanisms of which are still poorly understood. As an effective therapy for obesity, bariatric surgery may be a powerful tool in breast cancer prevention and treatment. This review details the potential physiologic mechanisms that may underlie this association, as well as recently published studies that reinforce the link between bariatric surgery and a reduction in incident breast cancer. The use of bariatric surgery as an adjunct therapy in endometrial cancer also raises the potential for similar use in select breast cancer patients. Despite the expanding potential applications of bariatric surgery in this field, publications to date have been strictly observational, highlighting a need for future clinical trials.
    DOI:  https://doi.org/10.1002/oby.23369
  34. Phytomedicine. 2022 Feb 18. pii: S0944-7113(22)00076-9. [Epub ahead of print]99 153998
    Synergism of ellagic acid in combination with radiotherapy and chemotherapy for cancer treatment.
    Peiyu Xue, Guangjie Zhang, Jie Zhang, Li Ren.
       BACKGROUND: Ellagic acid (EA) is a polyphenol compound abundant in berries, walnuts, pecans, pomegranate, cranberries, and other plant foods and exerts a wide array of biological properties. In particular, EA has received considerable research attention in anti-cancer therapy. EA administered alone has been shown to exert effects against human cancers through multiple pathways. In addition, EA may increase tumor sensitivity to chemotherapy and radiotherapy. Namely, EA combination with a relatively low dosage of therapeutic drugs or optimized radiation dose could improve the treatment outcome. More importantly, EA could counteract chemotherapy-related adverse reactions.
    PURPOSE: This review aims to summarize the in vitro and in vivo experimental evidence of synergism of EA in radiotherapy/chemotherapy for the treatment of cancers. In addition, the preventive effect of EA to counteract chemotherapy-induced toxicity is also discussed.
    METHODS: The searches were performed in the PubMed, Web of Science and Google scholar and introduced the information about the role of EA in cancer treatment.
    RESULTS: EA exhibits synergistic effects in radiotherapy/chemotherapy for the treatment of cancers and exerts a great potential in reducing the side effects of chemotherapy and radiotherapy due to its biological activities, such as antioxidant and anti-inflammatory activities.
    CONCLUSION: EA could be a promising drug adjuvant for cancer treatment. In the near future, novel strategies for EA delivery systems that overcome the low EA solubility and bioavailability should be studied further to fully exploit the therapeutic potential of EA.
    Keywords:  Anti-cancer activity; Chemotherapy-induced toxicity; Ellagic acid; Synergistic effects
    DOI:  https://doi.org/10.1016/j.phymed.2022.153998
  35. Crit Rev Food Sci Nutr. 2022 Feb 24. 1-20
    Fruit peel bioactives, valorisation into nanoparticles and potential applications: A review.
    Rajat Suhag, Rohit Kumar, Atul Dhiman, Arun Sharma, Pramod K Prabhakar, Krishna Gopalakrishnan, Ritesh Kumar, Anurag Singh.
      Nanotechnology is a rapidly growing field with profound applications in different domains, particularly in food science and technology. Nanoparticles (NPs) synthesis, an integral part of nanotechnology-based applications, is broadly classified into chemical, physical and biosynthesis methods. Chemically sensitive and energy-intensive procedures employed for NPs synthesis are some of the limits of traditional chemical approaches. Recent research has focused on developing easy, nontoxic, cost-effective, and environment-friendly NPs synthesis during the last decade. Biosynthesis approaches have been developed to achieve this goal as it is a viable alternative to existing chemical techniques for the synthesis of metallic nanomaterials. Fruit peels contain abundant bioactive compounds including phenols, flavonoids, tannins, triterpenoids, steroids, glycosides, carotenoids, anthocyanins, ellagitannins, vitamin C, and essential oils with substantial health benefits, anti-bacterial and antioxidant properties, generally discarded as byproduct or waste by the fruit processing industry. NPs synthesized using bioactive compounds from fruit peel has futuristic applications for an unrealized market potential for nutraceutical and pharmaceutical delivery. Numerous studies have been conducted for the biosynthesis of metallic NPs such as silver (AgNPs), gold (AuNPs), zinc oxide, iron, copper, palladium and titanium using fruit peel extract, and their synthesis mechanism have been reported in the present review. Additionally, NPs synthesis methods and applications of fruit peel NPs have been discussed.
    Keywords:  Biological synthesis; eco-friendly; food packaging; silver nanoparticles; waste utilization
    DOI:  https://doi.org/10.1080/10408398.2022.2043237
  36. Crit Rev Food Sci Nutr. 2022 Feb 22. 1-20
    A review on enzymatic acylation as a promising opportunity to stabilizing anthocyanins.
    Eduardo Leonarski, Karina Cesca, Débora de Oliveira, Acácio A F Zielinski.
      Anthocyanins are naturally occurring bioactive compounds found mainly in fruits, vegetables, and grains. They are usually extracted due to their biological properties and great potential for technological applications. These compounds have characteristic pH-dependent colorations that are natural dyes since they come in different colors. However, they are susceptible to processing conditions, remarkably light, temperature, and oxygen. The acylated anthocyanins showed better stability characteristics, and therefore, an acylation process of these compounds could improve their applications. The enzymatic acylation was effective and showed promising results. The current review provides an overview of the works that performed enzymatic acylation of anthocyanins and studies on the stability, antioxidant activity, and lipophilicity. In general, enzymatically acylated anthocyanins showed better stability to light and temperature than non-acylated compounds. In addition, they were liposoluble, a characteristic that allows their addition to products with lipid matrices. The results showed that these compounds formed by enzymatic acylation have perspectives of application mainly as natural colorants in food products. Therefore, the enzymatic acylation of anthocyanins appears viable to increase the industrial applicability of anthocyanins. There are still some gaps to be filled in process optimization, the reuse of enzymes, and toxicity analysis of the acylated compounds formed.
    Keywords:  Natural colorants; antioxidant activity; lipase; lipophilicity; photostability; thermostability
    DOI:  https://doi.org/10.1080/10408398.2022.2041541
  37. Small. 2022 Feb 25. e2200116
    Oxygen Self-Supply Engineering-Ferritin for the Relief of Hypoxia in Tumors and the Enhancement of Photodynamic Therapy Efficacy.
    Yang Zhu, Duo Jin, Manman Liu, Yi Dai, Li Li, Xinwei Zheng, Lulu Wang, Aizong Shen, Jianing Yu, Sisi Wu, Yun Wu, Kai Zhong, Junjie Cheng, Yangzhong Liu.
      Hypoxia is a hallmark of the tumor microenvironment (TME) that promotes tumor development and metastasis. Photodynamic therapy (PDT) is a promising strategy in the treatment of tumors, but it is limited by the lack of oxygen in TME. In this work, an O2 self-supply PDT system is constructed by co-encapsulation of chlorin e6 (Ce6) and a MnO2 core in an engineered ferritin (Ftn), generating a nanozyme promoted PDT nanoformula (Ce6/Ftn@MnO2 ) for tumor therapy. Ce6/Ftn@MnO2 exhibits a uniform small size (15.5 nm) and high stability due to the inherent structure of Ftn. The fluorescence imaging and immunofluorescence analysis demonstrate the pronounced accumulation of Ce6/Ftn@MnO2 in the tumors of mice, and the treatment significantly decreases the expression of hypoxia-inducible factor (HIF)-1α. The Ce6/Ftn@MnO2 nanoplatform exerts a more potent anti-tumor efficacy with negligible damage to normal tissues compared to the treatment with free Ce6. Moreover, the weak acidity and the presence of H2 O2 in TME significantly enhances the r1 relativity of Ce6/Ftn@MnO2 , resulting in a prominent enhancement of MRI imaging in the tumor. This bio-mimic Ftn strategy not only improves the in vivo distribution and retention of Ce6, but also enhances the effectiveness and precision of PDT by TME modulation.
    Keywords:  ferritin; manganese dioxide; photodynamic therapy; tumor therapies
    DOI:  https://doi.org/10.1002/smll.202200116
  38. Front Mol Biosci. 2021 ;8 788279
    Aspirin Repurposing in Folate-Decorated Nanoparticles: Another Way to Target Breast Cancer.
    Fariha Kanwal, Mingming Ma, Muhammad Fayyaz Ur Rehman, Fahim-Ullah Khan, Shai E Elizur, Aima Iram Batool, Chi Chiu Wang, Tahira Tabassum, Changrui Lu, Yao Wang.
      Breast cancer affects more than 1 million women per year worldwide. Through this study, we developed a nanoparticle-based drug delivery system to target breast cancer cells. Aspirin has been found to inhibit thromboembolic diseases with its tumor-preventing activity. As a consequence, it relieves disease symptoms and severity. Here, mesoporous silica nanoparticles (MNPs) have been used to deliver aspirin to the tumor location. MNP-based aspirin in folic acid (F)-conjugated polydopamine (MNP-Asp-PD-PG-F) vehicles are prepared for targeted breast cancer therapy. The vehicle hinges on MNP altered with polymer polyethylene glycol (PG), polydopamine (PD), and F. The delivery vehicle was studied for in vitro drug release, cytotoxicity, and breast cancer cell proliferation. F-conjugated drug delivery vehicles let MNPs achieve an elevated targeting efficacy, ideal for cancer therapy. It was also observed that compared to free aspirin, our drug delivery system (MNP-Asp-PD-PG-F) has a higher cytotoxic and antiproliferative effect on breast cancer cells. The drug delivery system can be proposed as a targeted breast cancer therapy that could be further focused on other targeted cancer therapies. Delivering aspirin by the PD-PG-F system on the tumor sites promises a therapeutic potential for breast cancer treatment.
    Keywords:  aspirin; breast cancer; mesoporous silica; nanomedicine; nanoparticle
    DOI:  https://doi.org/10.3389/fmolb.2021.788279
  39. Pharmaceuticals (Basel). 2022 Feb 02. pii: 187. [Epub ahead of print]15(2):
    Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy.
    William A Denny.
      The presence of "hypoxic" tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic "hypoxia-activated prodrugs" designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.
    Keywords:  cancer therapy; hypoxia; nitroaromatics; one-electron reduction potentials; reductive fragmentation; triggers
    DOI:  https://doi.org/10.3390/ph15020187
  40. J Mater Chem B. 2022 Feb 23.
    Tumor redox microenvironment modulating composite hydrogels for enhanced sonodynamic therapy of colorectal cancer.
    Weikai Chen, Chenxi Zhang, Dagui Chen, Yinghua Li, Shunli Wu, Can Xu, Li Su, Qin Zhang.
      Effective treatment of colorectal cancer is important to improve the quality of life for patients, which however remains a great challenge in the clinic. Herein, we report the construction of a composite hydrogel that can modulate the tumor redox microenvironment for enhanced sonodynamic therapy (SDT) of colorectal cancer. Such composite hydrogels consist of sonosensitizer protoporphyrin IX (PpIX)-conjugated manganese oxide (MnO2) nanoparticles and a glutathione (GSH) inhibitor after Ca2+ induced in situ gelation in the tumor site. In the acidic tumor microenvironment, MnO2 nanoparticles can produce oxygen to relieve hypoxia and thus amplify the generation of reactive oxygen species (ROS) via the SDT effect. Meanwhile, the GSH inhibitor blocks the intracellular synthesis of GSH, thus leading to further enhanced SDT action. As such, composite hydrogel-mediated enhanced SDT can obviously inhibit the growth of subcutaneous colorectal cancer in mouse models. This study thus offers a tumor microenvironment modulating platform for enhanced therapy of colorectal cancer.
    DOI:  https://doi.org/10.1039/d2tb00170e
  41. J Biomed Sci. 2022 Feb 21. 29(1): 14
    Application of engineered extracellular vesicles for targeted tumor therapy.
    Fusheng Zhang, Jinshuai Guo, Zhenghou Zhang, Meiqi Duan, Guang Wang, Yiping Qian, Haiying Zhao, Zhi Yang, Xiaofeng Jiang.
      All cells, including prokaryotes and eukaryotes, could release extracellular vesicles (EVs). EVs contain many cellular components, including RNA, and surface proteins, and are essential for maintaining normal intercellular communication and homeostasis of the internal environment. EVs released from different tissues and cells exhibit excellent properties and functions (e.g., targeting specificity, regulatory ability, physical durability, and immunogenicity), rendering them a potential new option for drug delivery and precision therapy. EVs have been demonstrated to transport antitumor drugs for tumor therapy; additionally, EVs' contents and surface substance can be altered to improve their therapeutic efficacy in the clinic by boosting targeting potential and drug delivery effectiveness. EVs can regulate immune system function by affecting the tumor microenvironment, thereby inhibiting tumor progression. Co-delivery systems for EVs can be utilized to further improve the drug delivery efficiency of EVs, including hydrogels and liposomes. In this review, we discuss the isolation technologies of EVs, as well as engineering approaches to their modification. Moreover, we evaluate the therapeutic potential of EVs in tumors, including engineered extracellular vesicles and EVs' co-delivery systems.
    Keywords:  Drug delivery system; Extracellular vesicles; Mesenchymal stem cells; Targeted tumor therapy
    DOI:  https://doi.org/10.1186/s12929-022-00798-y
  42. Pharmaceutics. 2022 Feb 13. pii: 405. [Epub ahead of print]14(2):
    Photosensitive EGFR-Targeted Nanocarriers for Combined Photodynamic and Local Chemotherapy.
    Elena de Las Heras, M Lluïsa Sagristá, Montserrat Agut, Santi Nonell.
      The major limitation of any cancer therapy lies in the difficulty of precisely controlling the localization of the drug in the tumor cells. To improve this drawback, our study explores the use of actively-targeted chemo-photo-nanocarriers that recognize and bind to epidermal growth factor receptor-overexpressing cells and promote the local on-demand release of the chemotherapeutic agent doxorubicin triggered by light. Our results show that the attachment of high concentrations of doxorubicin to cetuximab-IRDye700DX-mesoporous silica nanoparticles yields efficient and selective photokilling of EGFR-expressing cells mainly through singlet oxygen-induced release of the doxorubicin from the nanocarrier and without any dark toxicity. Therefore, this novel triply functionalized nanosystem is an effective and safe nanodevice for light-triggered on-demand doxorubicin release.
    Keywords:  EGFR; cetuximab; chemotherapy; drug delivery; mesoporous silica nanoparticles; photodynamic therapy; singlet oxygen
    DOI:  https://doi.org/10.3390/pharmaceutics14020405
  43. Adv Healthc Mater. 2022 Feb 22. e2200044
    A Facile and Universal Method for Preparing Polyethylene glycol-Metal Hybrid Nanoparticles and Their Application in Tumor Theranostics.
    Zefeng Chen, Yaoxun Zeng, Niping Chen, Mingxia Zhang, Yakun Wang, Zhenxing Pan, Jiongpeng Yuan, Zhaoyi Ye, Xiaojing Li, Wangqing Bian, Haihong Li, Kun Zhang, Yan He, Xujie Liu.
      Metal ions are of widespread interest owing to their brilliant biomedical function. However, a simple and universal nanoplatform designed for assembling a range of functional metal ions have not been explored. In this study, we proposed a concept of PEG-mediated transport of metal ions. 31 types of PEG-Metal hybrid nanoparticles (P-MNPs) were successfully synthesized through anionic ring-open polymerization (ROP), "thiol-ene" click reaction, and subsequent incorporation with multiple metal ions. Compared with other methods, the facile method proposed in this study can provide a feasible approach to design MNPs (mostly <200 nm) containing different metal ions and thus to explore their potential for cancer theranostics. As a proof-of-concept demonstration, four types P-MNPs, i.e., PEG-Metal hybrid copper nanoparticles (PEG-Cu NPs), ruthenium nanoparticles (PEG-Ru NPs), and manganese nanoparticles (PEG-Mn NPs) or gadolinium nanoparticles (PEG-Gd NPs), have been proven to be tailored for chemodynamic therapy (CDT), photothermal therapy (PTT) and magnetic resonance imaging (MRI) of tumors, respectively. The prepared PEG-Cu NPs, PEG-Ru NPs, and PEG-Mn NPs or PEG-Gd NPs have outstanding tumor cell selectivity, excellent photothermal conversion efficiency (η ≈ 39%), and high longitudinal relaxivity coefficient (r1), respectively. Overall, the study provides several metal ions based nanomaterials with versatile functions for broad applications in cancer theranostics. Furthermore, we offer a promising tool that can be utilized for processing other metal-based nanoparticles and exploring their potential in biomedicine field. This article is protected by copyright. All rights reserved.
    Keywords:  coordination assembly; metal ions; nanoparticle engineering; polyethylene glycol; tumor theranostics
    DOI:  https://doi.org/10.1002/adhm.202200044
  44. Nutrients. 2022 Feb 19. pii: 882. [Epub ahead of print]14(4):
    Role of Vitamin C in Selected Malignant Neoplasms in Women.
    Anna Markowska, Michał Antoszczak, Janina Markowska, Adam Huczyński.
      Since the first reports describing the anti-cancer properties of vitamin C published several decades ago, its actual effectiveness in fighting cancer has been under investigation and widely discussed. Some scientific reports indicate that vitamin C in high concentrations can contribute to effective and selective destruction of cancer cells. Furthermore, preclinical and clinical studies have shown that relatively high doses of vitamin C administered intravenously in 'pharmacological concentrations' may not only be well-tolerated, but significantly improve patients' quality of life. This seems to be particularly important, especially for terminal cancer patients. However, the relatively high frequency of vitamin C use by cancer patients means that the potential clinical benefits may not be obvious. For this reason, in this review article, we focus on the articles published mainly in the last two decades, describing possible beneficial effects of vitamin C in preventing and treating selected malignant neoplasms in women, including breast, cervical, endometrial, and ovarian cancer. According to the reviewed studies, vitamin C use may contribute to an improvement of the overall quality of life of patients, among others, by reducing chemotherapy-related side effects. Nevertheless, new clinical trials are needed to collect stronger evidence of the role of this nutrient in supportive cancer treatment.
    Keywords:  breast cancer; cervical cancer; endometrial cancer; l-ascorbic acid; ovarian cancer; vitamin C
    DOI:  https://doi.org/10.3390/nu14040882
  45. Theranostics. 2022 ;12(4): 1756-1768
    A light-driven dual-nanotransformer with deep tumor penetration for efficient chemo-immunotherapy.
    Jiahui Peng, Fangman Chen, Yulu Liu, Fan Zhang, Lei Cao, Qiannan You, Dian Yang, Zhimin Chang, Mingfeng Ge, Li Li, Zheng Wang, Qian Mei, Dan Shao, Meiwan Chen, Wen-Fei Dong.
      Designing a transformable nanosystem with improved tumor accumulation and penetration by tuning multiple physicochemical properties remains a challenge. Here, a near-infrared (NIR) light-driven nanosystem with size and charge dual-transformation for deep tumor penetration is developed. Methods: The core-shell nanotransformer is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles as a reactive oxygen species (ROS)-responsive core with an indocyanine green (ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell. After loading doxorubicin (DOX), negatively charged nanomedicine prevents DOX leakage, rendering prolonged blood circulation time and high tumor accumulation. Results: Upon NIR light irradiation, mild photothermal effects facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive charge reversal. Meanwhile, ICG-generated ROS cleave the diselenide bond of the organosilica core, resulting in rapid matrix degradation that produces DOX-containing smaller fragments. Such a light-driven dual-transformable nanomedicine simultaneously promotes deep tumor penetration and implements sufficient chemotherapy, along with evoking robust immunogenic cell death effects in vitro and in vivo. With the combination of a programmed cell death protein-1 (PD-1) checkpoint blockade, the nanotransformer remarkably blocks primary tumor growth and pulmonary metastasis of breast cancer with low systemic toxicity. Conclusions: This study develops a promising strategy to realize high tumor accumulation and deep penetration of light-transformable nanomedicine for efficient and safe chemo-immunotherapy.
    Keywords:  immunotherapy; light response; mesoporous organosilica nanoparticles; phototherapy; tumor penetration
    DOI:  https://doi.org/10.7150/thno.68756
  46. Nanomedicine. 2022 Feb 19. pii: S1549-9634(22)00030-2. [Epub ahead of print] 102544
    Design and preparation of a Theranostic Peptideticle for targeted Cancer therapy: Peptide-based Codelivery of doxorubicin/curcumin and graphene quantum dots.
    Soroush Moasses Ghafary, Elnaz Rahimjazi, Hadise Hamzehil, Sayed Mostafa Modarres Mousavi, Maryam Nikkhah, Saman Hosseinkhani.
      Although, chemotherapy has known as a powerful medication for cancer treatment over the years, there is an important necessity for designing a novel targeted drug delivery system to overcome the drawbacks of this conventional method including undesired side effects on normal cells and drug resistance. The structural differences between the surface of cancerous and normal cells allow to design and engineer targeted drug delivery systems for cancer treatment. Integrins as one of the cell surface receptors over-expressed in cancer cells could potentially be suitable candidates for targeting cancer cells. In the present study, the novel nano-carriers based on designed MiRGD peptides and graphene quantum dots (GQDs) have been used for targeted delivery of doxorubicin (Dox) and curcumin (Cur) as hydrophilic and hydrophobic drug models, respectively. The prepared nano-composites characterized by UV-Vis and Photoluminescence (PL) spectroscopies, Zeta-Sizer and Transmission Electron Microscopy (TEM). Altogether, and the results of cellular uptake and fluorimetric assays performed in HUVEC and HFF cells as models of αv integrin-over-expressed cancer and normal cells, respectively, besides, in-vivo study on breast cancer bearing BALB/c mice, demonstrated that the prepared nano-composites can be considered as suitable multifunctional theranostic peptideticles for targeted drug delivery and tracking.
    Keywords:  Drug delivery; Graphene quantum dots; In vivo imaging; Theranostic
    DOI:  https://doi.org/10.1016/j.nano.2022.102544
  47. Phytomedicine. 2022 Feb 17. pii: S0944-7113(22)00066-6. [Epub ahead of print]99 153988
    Natural products in the treatment of pulmonary emphysema: Therapeutic effects and mechanisms of action.
    Sayed Vahid Jasemi, Hosna Khazaei, Saeideh Momtaz, Mohammad Hosein Farzaei, Javier Echeverría.
       BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a class of lung diseases including chronic bronchitis, asthma, and emphysema. Long-time smoking is considered the main reason for developing emphysema. Emphysema can be defined as damage to the walls of the air sacs (alveoli) of the lung. It has been demonstrated that natural compounds with antioxidant and anti-inflammatory effects can effectively improve or protect the lung against this disease. This paper is dedicated to systematically review the effective natural compounds in the treatment of pulmonary emphysema.
    PURPOSE: This is the first systematic and comprehensive review on the role of plant-derived secondary metabolites in managing and/or treating pulmonary emphysema STUDY DESIGN AND METHODS: A systematic and comprehensive review was done based on Scopus, PubMed, and Cochrane Library databases were searched using the "emphysema", "plant", "herb", and "phytochemical" keywords. Non-English, review, and repetitive articles were excluded from the study. Search results were included in the Prisma diagram.
    RESULTS: From a total of 1285 results, finally, 22 articles were included in the present study. The results show that some herbs such as Scutellaria baicalensis Georgi and Monascus adlay and some phytochemicals such as gallic acid and quercetin and blackboard tree indole alkaloids affect more factors in improving the lung emphysema. Also, some natural compounds such as marijuana smoke and humic acid also play an aggravating role in this disease. It also seems that some of the medicinal plants such as PM014 herbal formula, pomegranate juice and açaí berry sometimes have side effects that are inconsistent with their therapeutic effects.
    CONCLUSION: We concluded that natural compounds can effectively improve pulmonary emphysema due to their antioxidant, anti-inflammatory, and anti-apoptotic properties. However, additional studies are suggested to prove efficacy and side effects.
    Keywords:  Chronic obstructive pulmonary disease; Lung diseases; Medicinal plants; Natural compounds; Phytochemicals; Pulmonary emphysema
    DOI:  https://doi.org/10.1016/j.phymed.2022.153988
  48. Front Oncol. 2022 ;12 842406
    Ailanthone Inhibits Proliferation, Migration and Invasion of Osteosarcoma Cells by Downregulating the Serine Biosynthetic Pathway.
    Yawen Zhang, Runze Gong, Yong Liu, Xipeng Sun, Jinrong Liang, Yan Zhou, Yaling Wang, Wenxi Yu, Yonggang Wang, Lina Tang, Aina He, Zan Shen, Yang Yao, Haiyan Hu, Xin Liu, Jianjun Zhang.
      Osteosarcoma (OS) is the most common primary bone sarcoma, chemoresistance becomes an obstacle to its treatment. Metabolic reprogramming is a hallmark of malignancy, targeting the metabolic pathways might provide a reasonable therapeutic strategy for OS. Here we demonstrated that Ailanthone (AIL), a major component of the Chinese medicine Ailanthus altissima, significantly suppressed OS cell growth in vitro and in vivo. Furthermore, AIL dose-dependently inhibited cell migration and invasion, induced cell cycle arrest and apoptosis in OS cells. Combined transcriptomics, proteomics and metabolomics analyses revealed that AIL induced widespread changes in metabolic programs in OS cells, while the serine biosynthetic pathway (SSP) was the most significantly altered pathway. qRT-PCR and Western blot assay confirmed that the transcript and protein levels of the SSP genes (PHGDH, PSAT1 and PSPH) were downregulated dose-dependently by AIL. In addition, we found out that many downstream pathways of the SSP including the one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism were downregulated after AIL treatment. In the revere test, PHGDH overexpression but not exogenous serine supplementation clearly attenuated the effects of AIL on OS cells. Taken together, AIL exerts antitumor effects on OS through mediating metabolic reprogramming, at least in part, by suppressing the SSP. Our findings suggest that AIL could emerge as a potential therapeutic strategy in OS.
    Keywords:  PHGDH; ailanthone; cancer metabolism; multiomics analysis; osteosarcoma; serine biosynthesis
    DOI:  https://doi.org/10.3389/fonc.2022.842406
  49. Front Pharmacol. 2021 ;12 802785
    Fabrication of pH/Redox Dual-Responsive Mixed Polyprodrug Micelles for Improving Cancer Chemotherapy.
    Ji Luo, Shuguang Zhang, Peiyao Zhu, Wenke Liu, Jiang Du.
      In this work, we prepared pH/redox dual-responsive mixed polyprodrug micelles (MPPMs), which were co-assembled from two polyprodrugs, namely, poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with doxorubicin (DOX) via redox-sensitive disulfide bonds (mPEG-b-PAE-ss-DOX) and poly(ethylene glycol) methyl ether-b-poly (β-amino esters) conjugated with DOX via pH-sensitive cis-aconityl bonds (mPEG-b-PAE-cis-DOX) for effective anticancer drug delivery with enhanced therapeutic efficacy. The particle size of MPPMs was about 125 nm with low polydispersity index, indicating the reasonable size and uniform dispersion. The particle size, zeta-potential, and critical micelle concentration (CMC) of MPPMs at different mass ratios of the two kinds of polyprodrugs were dependent on pH value and glutathione (GSH) level, suggesting the pH and redox responsiveness. The drug release profiles in vitro of MPPMs at different conditions were further studied, showing the pH-and redox-triggered drug release mechanism. Confocal microscopy study demonstrated that MPPMs can effectively deliver doxorubicin molecules into MDA-MB-231 cells. Cytotoxicity assay in vitro proved that MPPMs possessed high toxic effect against tumor cells including A549 and MDA-MB-231. The results of in vivo experiments demonstrated that MPPMs were able to effectively inhibit the tumor growth with reduced side effect, leading to enhanced survival rate of tumor-bearing mice. Taken together, these findings revealed that this pH/redox dual-responsive MPPMs could be a potential nanomedicine for cancer chemotherapy. Furthermore, it could be a straightforward way to fabricate the multifunctional system basing on single stimuli-responsive polyprodrugs.
    Keywords:  cancer chemotherapy; controlled release; drug delivery; pH/redox responsive; polyprodrug
    DOI:  https://doi.org/10.3389/fphar.2021.802785
  50. Cancers (Basel). 2022 Feb 10. pii: 877. [Epub ahead of print]14(4):
    HSA-Binding Prodrugs-Based Nanoparticles Endowed with Chemo and Photo-Toxicity against Breast Cancer.
    Valentina Rapozzi, Francesca Moret, Luca Menilli, Andrea Guerrini, Daniele Tedesco, Marina Naldi, Manuela Bartolini, Mariachiara Gani, Sonia Zorzet, Marta Columbaro, Celeste Milani, Cecilia Martini, Claudia Ferroni, Greta Varchi.
      Exploiting the tumor environment features (EPR effect, elevated glutathione, reactive oxygen species levels) might allow attaining a selective and responsive carrier capable of improving the therapeutic outcome. To this purpose, the in situ covalent binding of drugs and nanoparticles to circulating human serum albumin (HSA) might represent a pioneering approach to achieve an effective strategy. This study describes the synthesis, in vitro and in vivo evaluation of bioresponsive HSA-binding nanoparticles (MAL-PTX2S@Pba), co-delivering two different paclitaxel (PTX) prodrugs and the photosensitizer pheophorbide a (Pba), for the combined photo- and chemo-treatment of breast cancer. Stable and reproducible MAL-PTX2S@Pba nanoparticles with an average diameter of 82 nm and a PTX/Pba molar ratio of 2.5 were obtained by nanoprecipitation. The in vitro 2D combination experiments revealed that MAL-PTX2S@Pba treatment induces a strong inhibition of cell viability of MDA-MB-231, MCF7 and 4T1 cell lines, whereas 3D experiments displayed different trends: while MAL-PTX2S@Pba effectiveness was confirmed against MDA-MB-231 spheroids, the 4T1 model exhibited marked resistance. Lastly, despite using a low PTX-PDT regimen (e.g., 8.16 mg/Kg PTX and 2.34 mg/Kg Pba), our formulation showed to foster primary tumor reduction and curb lung metastases growth in 4T1 tumor-bearing mice, thus setting the basis for further preclinical validations.
    Keywords:  albumin-binding; breast cancer; combination therapy; nanoparticles; paclitaxel; pheophorbide a; prodrugs
    DOI:  https://doi.org/10.3390/cancers14040877
  51. Pharmaceutics. 2022 Jan 29. pii: 327. [Epub ahead of print]14(2):
    Lactate-Loaded Nanoparticles Induce Glioma Cytotoxicity and Increase the Survival of Rats Bearing Malignant Glioma Brain Tumor.
    Víctor Chavarria, Emma Ortiz-Islas, Alelí Salazar, Verónica Pérez-de la Cruz, Alejandra Espinosa-Bonilla, Rubén Figueroa, Alma Ortíz-Plata, Julio Sotelo, Francisco Javier Sánchez-García, Benjamín Pineda.
      A glioblastoma is an aggressive form of a malignant glial-derived tumor with a poor prognosis despite multimodal therapy approaches. Lactate has a preponderant role in the tumor microenvironment, playing an immunoregulatory role as well as being a carbon source for tumor growth. Lactate homeostasis depends on the proper functioning of intracellular lactate regulation systems, such as transporters and enzymes involved in its synthesis and degradation, with evidence that an intracellular lactate overload generates metabolic stress on tumor cells and tumor cell death. We propose that the delivery of a lactate overload carried in nanoparticles, allowing the intracellular release of lactate, would compromise the survival of tumor cells. We synthesized and characterized silica and titania nanoparticles loaded with lactate to evaluate the cellular uptake, metabolic activity, pH modification, and cytotoxicity on C6 cells under normoxia and chemical hypoxia, and, finally, determined the survival of an orthotopic malignant glioma model after in situ administration. A dose-dependent reduction in metabolic activity of treated cells under normoxia was found, but not under hypoxia, independent of glucose concentration. Lactated-loaded silica nanoparticles were highly cytotoxic (58.1% of dead cells) and generated significant supernatant acidification. In vivo, lactate-loaded silica nanoparticles significantly increased the median survival time of malignant glioma-bearing rats (p = 0.005) when administered in situ. These findings indicate that lactate-loaded silica nanoparticles are cytotoxic on glioma cells in vitro and in vivo.
    Keywords:  cytotoxicity; glioma; in situ therapy; lactate-loaded nanoparticle; metabolism
    DOI:  https://doi.org/10.3390/pharmaceutics14020327
  52. Polymers (Basel). 2022 Feb 11. pii: 687. [Epub ahead of print]14(4):
    Applications of the ROS-Responsive Thioketal Linker for the Production of Smart Nanomedicines.
    Arianna Rinaldi, Riccardo Caraffi, Maria Vittoria Grazioli, Natalia Oddone, Luciana Giardino, Giovanni Tosi, Maria Angela Vandelli, Laura Calzà, Barbara Ruozi, Jason Thomas Duskey.
      Reactive oxygen species (ROS)-sensitive drug delivery systems (DDS) specifically responding to altered levels of ROS in the pathological microenvironment have emerged as an effective means to enhance the pharmaceutical efficacy of conventional nanomedicines, while simultaneously reducing side effects. In particular, the use of the biocompatible, biodegradable, and non-toxic ROS-responsive thioketal (TK) functional group in the design of smart DDS has grown exponentially in recent years. In the design of TK-based DDS, different technological uses of TK have been proposed to overcome the major limitations of conventional DDS counterparts including uncontrolled drug release and off-target effects. This review will focus on the different technological uses of TK-based biomaterials in smart nanomedicines by using it as a linker to connect a drug on the surface of nanoparticles, form prodrugs, as a core component of the DDS to directly control its structure, to control the opening of drug-releasing gates or to change the conformation of the nano-systems. A comprehensive view of the various uses of TK may allow researchers to exploit this reactive linker more consciously while designing nanomedicines to be more effective with improved disease-targeting ability, providing novel therapeutic opportunities in the treatment of many diseases.
    Keywords:  ROS-responsive biomaterials; nanomedicine; nanoparticles; smart drug delivery systems; thioketal
    DOI:  https://doi.org/10.3390/polym14040687
  53. Int J Mol Sci. 2022 Feb 18. pii: 2286. [Epub ahead of print]23(4):
    An Engineered Nanocomplex with Photodynamic and Photothermal Synergistic Properties for Cancer Treatment.
    Eli Varon, Gaddi Blumrosen, Moshe Sinvani, Elina Haimov, Shlomi Polani, Michal Natan, Irit Shoval, Avi Jacob, Ayelet Atkins, David Zitoun, Orit Shefi.
      Photodynamic therapy (PDT) and photothermal therapy (PTT) are promising therapeutic methods for cancer treatment; however, as single modality therapies, either PDT or PTT is still limited in its success rate. A dual application of both PDT and PTT, in a combined protocol, has gained immense interest. In this study, gold nanoparticles (AuNPs) were conjugated with a PDT agent, meso-tetrahydroxyphenylchlorin (mTHPC) photosensitizer, designed as nanotherapeutic agents that can activate a dual photodynamic/photothermal therapy in SH-SY5Y human neuroblastoma cells. The AuNP-mTHPC complex is biocompatible, soluble, and photostable. PDT efficiency is high because of immediate reactive oxygen species (ROS) production upon mTHPC activation by the 650-nm laser, which decreased mitochondrial membrane potential (∆ψm). Likewise, the AuNP-mTHPC complex is used as a photoabsorbing (PTA) agent for PTT, due to efficient plasmon absorption and excellent photothermal conversion characteristics of AuNPs under laser irradiation at 532 nm. Under the laser irradiation of a PDT/PTT combination, a twofold phototoxicity outcome follows, compared to PDT-only or PTT-only treatment. This indicates that PDT and PTT have synergistic effects together as a combined therapeutic method. Our study aimed at applying the AuNP-mTHPC approach as a potential treatment of cancer in the biomedical field.
    Keywords:  biomaterials; cancer; engineering; nanoparticles; phototherapy
    DOI:  https://doi.org/10.3390/ijms23042286
  54. Pharmaceuticals (Basel). 2022 Jan 21. pii: 126. [Epub ahead of print]15(2):
    Enhancing the Bioavailability and Efficacy of Vismodegib for the Control of Skin Cancer: In Vitro and In Vivo Studies.
    Heba F Salem, Amr Gamal, Haitham Saeed, Marwa Kamal, Alaa S Tulbah.
      Skin cancer is the most frequent cancer throughout the world. Vismodegib (VSD) is a hedgehog blocker approved for the prevention and treatment of skin cancer. VSD, however, is poorly bioavailable and has been linked to side effects. This work focused on designing a nano-invasome gel as a vehicle for enhancing the permeation, bioavailability, and efficacy of VSD. Additionally, the combined effect of terpenes and ethanol was studied on the permeation of VSD compared with liposomes. The prepared VSD-loaded invasomes (VLI) formulation included cineole (1%v/v), cholesterol (0.15%w/w), phospholipid (2%w/w), and ethanol (3%v/v) and displayed an entrapment efficiency of 87.73 ± 3.82%, a vesicle size of 188.27 ± 3.25 nm, and a steady-state flux of 9.83 ± 0.11 µg/cm2/h. The VLI formulation was vigorously stirred into a carbopol base before being characterized in vivo to investigate the permeation, bioavailability, and efficacy of VSD. The VLI gel enhanced the dermal permeation of VSD and, as a result, had 3.59 times higher bioavailability with excellent antitumor action as compared to oral VSD. In summary, as an alternative to oral administration for skin cancer treatment, invasomes are efficient carriers for delivering VSD and enhancing its transdermal flux into deep skin layers.
    Keywords:  bioavailability; invasomes; skin cancer; terpenes; vismodegib
    DOI:  https://doi.org/10.3390/ph15020126
  55. Pharmaceutics. 2022 Feb 15. pii: 421. [Epub ahead of print]14(2):
    Single and Multiple Stimuli-Responsive Polymer Particles for Controlled Drug Delivery.
    Aida López Ruiz, Ann Ramirez, Kathleen McEnnis.
      Polymers that can change their properties in response to an external or internal stimulus have become an interesting platform for drug delivery systems. Polymeric nanoparticles can be used to decrease the toxicity of drugs, improve the circulation of hydrophobic drugs, and increase a drug's efficacy. Furthermore, polymers that are sensitive to specific stimuli can be used to achieve controlled release of drugs into specific areas of the body. This review discusses the different stimuli that can be used for controlled drug delivery based on internal and external stimuli. Internal stimuli have been defined as events that evoke changes in different characteristics, inside the body, such as changes in pH, redox potential, and temperature. External stimuli have been defined as the use of an external source such as light and ultrasound to implement such changes. Special attention has been paid to the particular chemical structures that need to be incorporated into polymers to achieve the desired stimuli response. A current trend in this field is the incorporation of several stimuli in a single polymer to achieve higher specificity. Therefore, to access the most recent advances in stimuli-responsive polymers, the focus of this review is to combine several stimuli. The combination of different stimuli is discussed along with the chemical structures that can produce it.
    Keywords:  drug delivery; polymer particles; stimuli-responsive
    DOI:  https://doi.org/10.3390/pharmaceutics14020421
  56. ACS Appl Bio Mater. 2022 Feb 24.
    Folic Acid-Adorned Curcumin-Loaded Iron Oxide Nanoparticles for Cervical Cancer.
    Marzieh Ramezani Farani, Maryam Azarian, Hamid Heydari Sheikh Hossein, Zohreh Abdolvahabi, Zahra Mohammadi Abgarmi, Arash Moradi, Seyyedeh Maedeh Mousavi, Milad Ashrafizadeh, Pooyan Makvandi, Mohammad Reza Saeb, Navid Rabiee.
      Cancer is a deadly disease that has long plagued humans and has become more prevalent in recent years. The common treatment modalities for this disease have always faced many problems and complications, and this has led to the discovery of strategies for cancer diagnosis and treatment. The use of magnetic nanoparticles in the past two decades has had a significant impact on this. One of the objectives of the present study is to introduce the special properties of these nanoparticles and how they are structured to load and transport drugs to tumors. In this study, iron oxide (Fe3O4) nanoparticles with 6 nm sizes were coated with hyperbranched polyglycerol (HPG) and folic acid (FA). The functionalized nanoparticles (10-20 nm) were less likely to aggregate compared to non-functionalized nanoparticles. HPG@Fe3O4 and FA@HPG@Fe3O4 nanoparticles were compared in drug loading procedures with curcumin. HPG@Fe3O4 and FA@HPG@Fe3O4 nanoparticles' maximal drug-loading capacities were determined to be 82 and 88%, respectively. HeLa cells and mouse L929 fibroblasts treated with nanoparticles took up more FA@HPG@Fe3O4 nanoparticles than HPG@Fe3O4 nanoparticles. The FA@HPG@Fe3O4 nanoparticles produced in the current investigation have potential as anticancer drug delivery systems. For the purpose of diagnosis, incubation of HeLa cells with nanoparticles decreased MRI signal enhancement's percentage and the largest alteration was observed after incubation with FA@HPG@Fe3O4 nanoparticles.
    Keywords:  MRI; cervical cancer therapy; curcumin; iron oxide nanoparticles; polyglycerol; targeted delivery
    DOI:  https://doi.org/10.1021/acsabm.1c01311
  57. J Agric Food Chem. 2022 Feb 25.
    Redox-Based Strategy for Selectively Inducing Energy Crisis Inside Cancer Cells: An Example of Modifying Dietary Curcumin to Target Mitochondria.
    Ya-Long Zheng, Zhi-Shan Tu, Hong-Mei Cui, Shuai Yan, De-Chen Duan, Wei Tang, Fang Dai, Bo Zhou.
      Reprograming of energy metabolism is a major hallmark of cancer, but its effective intervention is still a challenging task due to metabolic heterogeneity and plasticity of cancer cells. Herein, we report a general redox-based strategy for meeting the challenge. The strategy was exemplified by a dietary curcumin analogue (MitoCur-1) that was designed to target mitochondria (MitoCur-1). By virtue of its electrophilic and mitochondrial-targeting properties, MitoCur-1 generated reactive oxygen species (ROS) more effectively and selectively in HepG2 cells than in L02 cells via the inhibition of mitochondrial antioxidative thioredoxin reductase 2 (TrxR2). The ROS generation preferentially mediated the energy crisis of HepG2 cells in a dual-inhibition fashion against both mitochondrial and glycolytic metabolisms, which could hit the metabolic plasticity of HepG2 cells. The ROS-dependent energy crisis also allowed its preferential killing of HepG2 cells (IC50 = 1.4 μM) over L02 cells (IC50 = 9.1 μM), via induction of cell-cycle arrest, apoptosis and autophagic death, and its high antitumor efficacy in vivo, in nude mice bearing HepG2 tumors (15 mg/kg). These results highlight that inhibiting mitochondrial TrxR2 to produce ROS by electrophiles is a promising redox-based strategy for the effective intervention of cancer cell energy metabolic reprograming.
    Keywords:  curcumin; metabolic reprograming; mitochondria; reactive oxygen species; thioredoxin reductase
    DOI:  https://doi.org/10.1021/acs.jafc.1c07690
  58. Int J Biol Macromol. 2022 Feb 16. pii: S0141-8130(22)00322-1. [Epub ahead of print]205 90-109
    3D printed tablets containing oxaliplatin loaded alginate nanoparticles for colon cancer targeted delivery. An in vitro/in vivo study.
    Seyedeh Zahra Mirdamadian, Jaleh Varshosaz, Mohsen Minaiyan, Azade Taheri.
      This study aimed to develop a colon-targeted tablet of oxaliplatin (OP) using the combination of nanotechnology and fused deposition modeling (FDM) 3D printing to improve its antitumor activity, tumor targetability, and safety profile. Eudragit L100-55 filament containing OP loaded alginate nanoparticles (OP-NPs) were fabricated using hot-melt extrusion method and printed by an FDM printer to 3D printed tablets with good uniformity in the drug content and selective release of OP in the colonic environment. The antitumor effect of 3D printed tablets containing OP-NPs in CT-26 tumor-bearing mice was evaluated compared to intravenous and oral administration of OP solution, and compressed tablets containing OP-NPs, which were prepared by direct compression method with the same formulation. The antitumor effect of 3D printed tablets containing OP-NPs was remarkable and comparable with intravenous OP solution (p ˃ 0.05) with a better safety profile, whereas compressed tablets did not show any significant antitumor effect, probably in terms of non-selective drug release in stomach and upper intestine environments. This study highlights the potential of the combination of nanotechnology and 3D printing in the preparation of colon-specific drug delivery systems of chemotherapeutic drugs with good antitumor activity, tumor targetability, and safety profile for colorectal cancer treatment.
    Keywords:  Alginate nanoparticle; Colorectal cancer; Eudragit L100-55; FDM 3D printing; Oxaliplatin
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.080
  59. Pharmaceutics. 2022 Feb 21. pii: 456. [Epub ahead of print]14(2):
    Progress and Viewpoints of Multifunctional Composite Nanomaterials for Glioblastoma Theranostics.
    Ming-Hsien Chan, Wen-Tse Huang, Aishwarya Satpathy, Ting-Yi Su, Michael Hsiao, Ru-Shi Liu.
      The most common malignant tumor of the brain is glioblastoma multiforme (GBM) in adults. Many patients die shortly after diagnosis, and only 6% of patients survive more than 5 years. Moreover, the current average survival of malignant brain tumors is only about 15 months, and the recurrence rate within 2 years is almost 100%. Brain diseases are complicated to treat. The reason for this is that drugs are challenging to deliver to the brain because there is a blood-brain barrier (BBB) protection mechanism in the brain, which only allows water, oxygen, and blood sugar to enter the brain through blood vessels. Other chemicals cannot enter the brain due to their large size or are considered harmful substances. As a result, the efficacy of drugs for treating brain diseases is only about 30%, which cannot satisfy treatment expectations. Therefore, researchers have designed many types of nanoparticles and nanocomposites to fight against the most common malignant tumors in the brain, and they have been successful in animal experiments. This review will discuss the application of various nanocomposites in diagnosing and treating GBM. The topics include (1) the efficient and long-term tracking of brain images (magnetic resonance imaging, MRI, and near-infrared light (NIR)); (2) breaking through BBB for drug delivery; and (3) natural and chemical drugs equipped with nanomaterials. These multifunctional nanoparticles can overcome current difficulties and achieve progressive GBM treatment and diagnosis results.
    Keywords:  FDA-proved drugs; glioblastoma; magnetic resonance imaging nanoparticles; near-infrared phototherapy; near-infrared probes
    DOI:  https://doi.org/10.3390/pharmaceutics14020456
  60. Int J Biol Macromol. 2022 Feb 17. pii: S0141-8130(22)00283-5. [Epub ahead of print]205 211-219
    Biofunctionalized Chrysin-conjugated gold nanoparticles neutralize Leishmania parasites with high efficacy.
    Shweta Raj, Santanu Sasidharan, Timir Tripathi, Prakash Saudagar.
      Current treatments for leishmaniasis involve various drugs, including miltefosine and amphotericin B, which are associated with several side effects and high costs. Long-term use of these drugs may lead to the development of resistance, thereby reducing their efficiency. Chrysin (CHY) is a well-known, non-toxic flavonoid with antioxidant, antiviral, anti-inflammatory, anti-cancer, hepatoprotective, and neuroprotective properties. Recently we have shown that CHY targets the MAP kinase 3 enzyme of Leishmania and neutralizes the parasite rapidly. However, CHY is associated with low bioavailability, poor absorption, and rapid excretion issues, limiting its usage. In this study, we developed and tested a novel CHY-gold nanoformulation with improved efficacy against the parasites. The reducing power of CHY was utilized to reduce and conjugate with gold nanoparticles. Gold nanoparticles, which are already known for their anti-leishmanial properties, along with conjugated CHY, exhibited a decreased parasite burden in mammalian macrophages. Our findings showed that this biofunctionalized nanoformulation could be used as a potential therapeutic tool against leishmaniasis.
    Keywords:  Chrysin; Gold nanoparticles; Leishmania; Nanoformulation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.047
  61. Pharmaceuticals (Basel). 2022 Jan 26. pii: 149. [Epub ahead of print]15(2):
    Photolytic Controlled Release Formulation of Methotrexate Loaded in Chitosan/TiO2 Nanoparticles for Breast Cancer.
    Nusaiba Al-Nemrawi, Fatima Hameedat, Belal Al-Husein, Sukaina Nimrawi.
      A new system composed of chitosan nanoparticles loaded with methotrexate (MTX-CS-NPs) and functionalized with photocatalytic TiO2 nanoparticles (TiO2-NPs) was prepared. This system is expected to initiate polymeric rupture of MTX-CS-NPs and subsequently release MTX, upon illumination with UV light. MTX-CS-NPs were prepared and characterized in terms of particle size, charge, polydispersity and drug release before and after coating with TiO2-NPs. The release of MTX in vitro was studied in dark, light and UV light. Finally, coated and uncoated MTX-CS-NPs were studied in vitro using MCF-7 cell line. The functionalized NPs were larger in size, more polydisperse and carried higher positive charges compared to the unfunctionalized NPs. The entrapment efficacy was high reaching 75% and was not affected by coating with MTX-CS-NPs. Further, less than 5% of methotrexate was released after 80 h from uncoated NPs and the release was not enhanced by UV illumination of the particles. In contrast, the release from functionalized NPs was enhanced, reaching 40% after 80 h, as the particles were stroked with UV light and as the amount of TiO2-NPs used in coating increased. Finally, coating the MTX-CS-NPs with TiO2-NPs significantly enhanced their cytotoxicity on MCF-7 cells. The coated MTX-CS-NPs recorded low cell viabilities compared to the other formulations. In conclusion, the drug release of MTX-CS-NPs could be triggered and controlled remotely by coating with TiO2-NPs, which maybe more effective in cancer treatment.
    Keywords:  TiO2 nanoparticles; UV light; breast cancer; chitosan nanoparticle; methotrexate
    DOI:  https://doi.org/10.3390/ph15020149
  62. Mar Drugs. 2022 Feb 15. pii: 141. [Epub ahead of print]20(2):
    An Overview of Potential Seaweed-Derived Bioactive Compounds for Pharmaceutical Applications.
    Silvia Lomartire, Ana M M Gonçalves.
      Nowadays, seaweeds are widely involved in biotechnological applications. Due to the variety of bioactive compounds in their composition, species of phylum Ochrophyta, class Phaeophyceae, phylum Rhodophyta and Chlorophyta are valuable for the food, cosmetic, pharmaceutical and nutraceutical industries. Seaweeds have been consumed as whole food since ancient times and used to treat several diseases, even though the mechanisms of action were unknown. During the last decades, research has demonstrated that those unique compounds express beneficial properties for human health. Each compound has peculiar properties (e.g., antioxidant, antimicrobial, antiviral activities, etc.) that can be exploited to enhance human health. Seaweed's extracted polysaccharides are already involved in the pharmaceutical industry, with the aim of replacing synthetic compounds with components of natural origin. This review aims at a better understanding of the recent uses of algae in drug development, with the scope of replacing synthetic compounds and the multiple biotechnological applications that make up seaweed's potential in industrial companies. Further research is needed to better understand the mechanisms of action of seaweed's compounds and to embrace the use of seaweeds in pharmaceutical companies and other applications, with the final scope being to produce sustainable and healthier products.
    Keywords:  bioactive compounds; health benefits; pharmaceutical application; seaweed; sustainability
    DOI:  https://doi.org/10.3390/md20020141
  63. Antioxidants (Basel). 2022 Feb 09. pii: 341. [Epub ahead of print]11(2):
    Pre-Exposure to Stress-Inducing Agents Increase the Anticancer Efficacy of Focused Ultrasound against Aggressive Prostate Cancer Cells.
    Hakm Y Murad, Partha K Chandra, Charles A Kelly, Namrata Khurana, Heng Yu, Emma P Bortz, Shirley N Hong, Debasis Mondal, Damir B Khismatullin.
      Despite the initial success in treatment of localized prostate cancer (PCa) using surgery, radiation or hormonal therapy, recurrence of aggressive tumors dictates morbidity and mortality. Focused ultrasound (FUS) is being tested as a targeted, noninvasive approach to eliminate the localized PCa foci, and strategies to enhance the anticancer potential of FUS have a high translational value. Since aggressive cancer cells utilize oxidative stress (Ox-stress) and endoplasmic reticulum stress (ER-stress) pathways for their survival and recurrence, we hypothesized that pre-treatment with drugs that disrupt stress-signaling pathways in tumor cells may increase FUS efficacy. Using four different PCa cell lines, i.e., LNCaP, C4-2B, 22Rv1 and DU145, we tested the in vitro effects of FUS, alone and in combination with two clinically tested drugs that increase Ox-stress (i.e., CDDO-me) or ER-stress (i.e., nelfinavir). As compared to standalone FUS, significant (p < 0.05) suppressions in both survival and recurrence of PCa cells were observed following pre-sensitization with low-dose CDDO-me (100 nM) and/or nelfinavir (2 µM). In drug pre-sensitized cells, significant anticancer effects were evident at a FUS intensity of as low as 0.7 kW/cm2. This combined mechanochemical disruption (MCD) approach decreased cell proliferation, migration and clonogenic ability and increased apoptosis/necrosis and reactive oxygen species (ROS) production. Furthermore, although activated in cells that survived standalone FUS, pre-sensitization with CDDO-me and/or nelfinavir suppressed both total and activated (phosphorylated) NF-κB and Akt protein levels. Thus, a combined MCD therapy may be a safe and effective approach towards the targeted elimination of aggressive PCa cells.
    Keywords:  CDDO-me; ER-stress; aggressive phenotype; combined mechanochemical disruption; focused ultrasound; nelfinavir; oxidative stress; prostate cancer
    DOI:  https://doi.org/10.3390/antiox11020341
  64. Nanomaterials (Basel). 2022 Feb 09. pii: 584. [Epub ahead of print]12(4):
    Chitosan-Crosslinked Low Molecular Weight PEI-Conjugated Iron Oxide Nanoparticle for Safe and Effective DNA Delivery to Breast Cancer Cells.
    Guanyou Lin, Jianxi Huang, Mengyuan Zhang, Shanshan Chen, Miqin Zhang.
      Breast cancer has attracted tremendous research interest in treatment development as one of the major threats to public health. The use of non-viral carriers for therapeutic DNA delivery has shown promise in treating various cancer types, including breast cancer, due to their high DNA loading capacity, high cell transfection efficiency, and design versatility. However, cytotoxicity and large sizes of non-viral DNA carriers often raise safety concerns and hinder their applications in the clinic. Here we report the development of a novel nanoparticle formulation (termed NP-Chi-xPEI) that can safely and effectively deliver DNA into breast cancer cells for successful transfection. The nanoparticle is composed of an iron oxide core coated with low molecular weight (800 Da) polyethyleneimine crosslinked with chitosan via biodegradable disulfide bonds. The NP-Chi-xPEI can condense DNA into a small nanoparticle with the overall size of less than 100 nm and offer full DNA protection. Its biodegradable coating of small-molecular weight xPEI and mildly positive surface charge confer extra biocompatibility. NP-Chi-xPEI-mediated DNA delivery was shown to achieve high transfection efficiency across multiple breast cancer cell lines with significantly lower cytotoxicity as compared to the commercial transfection agent Lipofectamine 3000. With demonstrated favorable physicochemical properties and functionality, NP-Chi-xPEI may serve as a reliable vehicle to deliver DNA to breast cancer cells.
    Keywords:  breast cancer; gene therapy; iron oxide nanoparticles
    DOI:  https://doi.org/10.3390/nano12040584
  65. Antioxidants (Basel). 2022 Jan 28. pii: 258. [Epub ahead of print]11(2):
    Correlation between Chemical Characterization and Biological Activity: An Urgent Need for Human Studies Using Extra Virgin Olive Oil.
    Stefania De Santis, Maria Lisa Clodoveo, Filomena Corbo.
      Extra virgin olive oil (EVOO) is one of the most important functional foods from the Mediterranean Diet due to its beneficial effect on human health in terms of prevention and/or adjuvant treatment of different pathological conditions. The positive effects linked to EVOO consumption are not only due to its major (monounsaturated fatty acids), but also to its minor components (phenolics), whose roles were greatly re-evaluated in the last years. Notwithstanding the huge number of studies demonstrating the antioxidant, anti-inflammatory and anti-cancer properties of EVOO's phenolic compounds, only their antioxidant ability was supported by a Health Claim. However, to bear the claim, a specific phenolic composition is needed, thus reinforcing the need to correlate the characterization of the phenolic compounds to their biological activity. In fact, although the chemical characterization of VOO's phenolic compounds was extensively studied, its correlation with biological effects is only partially investigated; this is especially true for human studies. This review aims to study the correlation between the chemical characterization of EVOO's phenolics and the biological effects in terms of antioxidant/anti-inflammatory potentials, with a focus on the human studies and the relative concern on getting a specific Health Claim.
    Keywords:  anti-inflammatory potential; antioxidant activity; chemical characterization; extra virgin olive oil; health claim; human studies; polyphenols
    DOI:  https://doi.org/10.3390/antiox11020258
  66. Biomaterials. 2022 Feb 19. pii: S0142-9612(22)00064-3. [Epub ahead of print]282 121425
    Engineered nanomaterials for synergistic photo-immunotherapy.
    Ranran Guo, Siqi Wang, Lin Zhao, Qida Zong, Tiancheng Li, Guixia Ling, Peng Zhang.
      Nanomaterial-synergized photodynamic therapy (PDT) and photothermal therapy (PTT), as efficient and non-invasive treatment modalities, have shown significant advantages in fighting different types of cancer. However, neither PTT nor PDT can completely eradicate tumors due to distant metastasis and recurrence of tumors. Recently, photo-immunotherapy have attracted great attention as phototherapy has been reported to participate in immunotherapy by triggering immunogenic cell death (ICD), resulting in the secretion of tumor specific antigen (TSAs) and damage-associated molecular patterns (DAMPs). In particular, emerging interests are biased towards manipulating nanomaterials to form unique drug delivery systems, which are necessary for the combination of phototherapy and immunotherapy to eliminate metastatic tumor cells by promoting the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs). This review elaborates on the latest strategies on engineering nanomaterials to enhance the anti-cancer efficiency of synergistic photo-immunotherapy, with emphasis on the activation of anti-tumor immune response, the reversal of tumor immunosuppressive microenvironment (TIME), the regulation of the interaction between immunosuppressive cells and tumor cells, the infiltration of immune cells and improved efficiency of photo-immunotherapy-induced ICD. Current challenges and future opportunities in engineering nanomaterials to modulate synergistic photo-immunotherapy are also discussed.
    Keywords:  Cancer therapy; Nanomaterial; Photodynamic therapy; Photothermal therapy; Synergistic photo-immunotherapy
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121425
  67. ACS Appl Mater Interfaces. 2022 Feb 24.
    Targeted Polymeric Nanoparticles Based on Mangiferin for Enhanced Protection of Pancreatic β-Cells and Type 1 Diabetes Mellitus Efficacy.
    Mengdi Wang, Zhuoran Zhang, Qingqing Huo, Maolong Wang, Yong Sun, Hongling Liu, Jing Chang, Bin He, Yan Liang.
      Mangiferin (MGF) is found in many natural plants, such as Rhizoma Anemarrhenae, and has anti-diabetes effects. However, its clinical applications and development are limited by poor solubility and low-concentration enrichment in pancreatic islets. In this paper, targeted polymeric nanoparticles were constructed for MGF delivery with the desired drug loading content (6.86 ± 0.60%), excellent blood circulation, and missile-like delivery to the pancreas. Briefly, Glucagon-like peptide 1 (GLP-1) as an active targeting agent to the pancreas was immobilized on the block copolymer polyethyleneglycol-polycaprolactone (PEG-PCL) to obtain final GLP-1-PEG-PCL amphiphiles. Spherical MGF-loaded polymeric nanoparticles were acquired from the self-assembly of the targeted GDPP nanoparticles and MGF with a homogeneous size of 158.9 ± 1.7 nm and a negative potential for a good steady state in circulation. In this drug vehicle, GLP-1 acts as the missile vanguard via the GLP-1 receptor on the surface of the pancreas for improving the accumulation and efficiency of MGF in the pancreas, the hypoglycemic effect of MGF, and the restorative effect on pancreatic islets, which were investigated. As compared to free MGF, MGF/GDPP nanoparticles appeared to be more concentrated in the pancreas, with better blood glucose and glucose tolerance, enhanced insulin levels, increased β-cell proliferation, reduced β-cell apoptosis, and islet repair in vivo. This targeted drug delivery system provided a novel strategy and hope for enhancing MGF delivery and anti-diabetes efficacy.
    Keywords:  diabetes mellitus; drug delivery; mangiferin; pancreatic β-cell; polymeric nanoparticles
    DOI:  https://doi.org/10.1021/acsami.1c22964
  68. Drug Deliv. 2022 Dec;29(1): 664-678
    Metal nanoparticles as a promising technology in targeted cancer treatment.
    Jia-Jie Xu, Wan-Chen Zhang, Ya-Wen Guo, Xiao-Yi Chen, You-Ni Zhang.
      Traditional anticancer treatments have several limitations, but cancer is still one of the deadliest diseases. As a result, new anticancer drugs are required for the treatment of cancer. The use of metal nanoparticles (NPs) as alternative chemotherapeutic drugs is on the rise in cancer research. Metal NPs have the potential for use in a wide range of applications. Natural or surface-induced anticancer effects can be found in metals. The focus of this review is on the therapeutic potential of metal-based NPs. The potential of various types of metal NPs for tumor targeting will be discussed for cancer treatment. The in vivo application of metal NPs for solid tumors will be reviewed. Risk factors involved in the clinical application of metal NPs will also be summarized.
    Keywords:  Cancer treatment; hyperthermia; metal nanoparticles; radiation therapy; targeting
    DOI:  https://doi.org/10.1080/10717544.2022.2039804
  69. Pharmaceutics. 2022 Jan 27. pii: 302. [Epub ahead of print]14(2):
    Strategies to Overcome Biological Barriers Associated with Pulmonary Drug Delivery.
    Adam J Plaunt, Tam L Nguyen, Michel R Corboz, Vladimir S Malinin, David C Cipolla.
      While the inhalation route has been used for millennia for pharmacologic effect, the biological barriers to treating lung disease created real challenges for the pharmaceutical industry until sophisticated device and formulation technologies emerged over the past fifty years. There are now several inhaled device technologies that enable delivery of therapeutics at high efficiency to the lung and avoid excessive deposition in the oropharyngeal region. Chemistry and formulation technologies have also emerged to prolong retention of drug at the active site by overcoming degradation and clearance mechanisms, or by reducing the rate of systemic absorption. These technologies have also been utilized to improve tolerability or to facilitate uptake within cells when there are intracellular targets. This paper describes the biological barriers and provides recent examples utilizing formulation technologies or drug chemistry modifications to overcome those barriers.
    Keywords:  inhaled drug delivery; liposome formulation; prodrug
    DOI:  https://doi.org/10.3390/pharmaceutics14020302
  70. Adv Sci (Weinh). 2022 Feb 22. e2106015
    Engineering Robust Ag-Decorated Polydopamine Nano-Photothermal Platforms to Combat Bacterial Infection and Prompt Wound Healing.
    Xiaoliang Qi, Yijing Huang, Shengye You, Yajing Xiang, Erya Cai, Ruiting Mao, Wenhao Pan, Xianqin Tong, Wei Dong, Fangfu Ye, Jianliang Shen.
      Polydopamine (PDA) nanoparticles have emerged as an attractive biomimetic photothermal agent in photothermal antibacterial therapy due to their ease of synthesis, good biodegradability, long-term safety, and excellent photostability. However, the therapeutic effects of PDA nanoparticles are generally limited by the low photothermal conversion efficiency (PCE). Herein, PDA@Ag nanoparticles are synthesized via growing Ag on the surface of PDA nanoparticles and then encapsulated into a cationic guar gum (CG) hydrogel network. The optimized CG/PDA@Ag platform exhibits a high PCE (38.2%), which is more than two times higher than that of pure PDA (16.6%). More importantly, the formulated CG/PDA@Ag hydrogel with many active groups can capture and kill bacteria through effective interactions between hydrogel and bacteria, thereby benefiting the antibacterial effect. As anticipated, the designed CG/PDA@Ag system combined the advantages of PDA@Ag nanoparticles (high PCE) and hydrogel (preventing aggregation of PDA@Ag nanoparticles and possessing inherent antibacterial ability) is demonstrated to have superior antibacterial efficacy both in vitro and in vivo. This study develops a facile approach to boost the PCE of PDA for photothermal antibacterial therapy, providing a significant step forward in advancing the application of PDA nano-photothermal agents.
    Keywords:  Ag-decorated polydopamine nanoparticles; antibacterial therapy; photothermal agent; photothermal conversion efficiency; polysaccharide hydrogel
    DOI:  https://doi.org/10.1002/advs.202106015
  71. ACS Appl Bio Mater. 2022 Feb 22.
    Nontoxic Metal-Free Visible Light-Responsive Carbon Nitride Quantum Dots Cause Oxidative Stress and Cancer-Specific Membrane Damage.
    Pranjali Yadav, Mimansa, Kamalakannan Kailasam, Asifkhan Shanavas.
      Graphitic carbon nitride (also known as g-CN or g-C3N4) has the intrinsic ability to generate electron-hole pairs under visible light illumination, resulting in the generation of reactive oxygen species (ROS). We report g-CN quantum dots (g-CNQDs) as a standalone photodynamic transducer for imparting significant oxidative stress in glioma cells, manifested by the loss of mitochondrial membrane potential. With an optimized treatment time, visible light source, and exposure window, the photodynamic treatment with g-CNQDs could achieve ∼90% cancer cell death via apoptosis. The g-CNQDs, otherwise biocompatible with normal cells up to 5 mg/mL, showed ∼20% necrotic cancer cell death in the absence of light due to membrane damage induced by a charge shielding effect at the acidic pH prevailing in the tumor environment. Acute toxicity analysis in C57BL/6 mice with intravenously injected g-CNQDs at a 20 mg/kg dose showed no signs of inflammatory response or organ damage.
    Keywords:  anticancer; apoptosis; g-C3N4; graphitic carbon nitride; membrane damage; photodynamic therapy; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsabm.1c01219
  72. Nutrients. 2022 Feb 11. pii: 757. [Epub ahead of print]14(4):
    Effects of Olive Oil and Its Components on Intestinal Inflammation and Inflammatory Bowel Disease.
    Josip Vrdoljak, Marko Kumric, Marino Vilovic, Dinko Martinovic, Iris Jeroncic Tomic, Mladen Krnic, Tina Ticinovic Kurir, Josko Bozic.
      With the rising global burden of inflammatory bowel disease (IBD) and the rising costs of novel biological drugs, there is an increasing need for dietary approaches and functional foods that could modulate the course of IBD. The Mediterranean diet has proven to be efficacious in managing chronic inflammatory diseases, and recent studies have also shown its benefits in the setting of IBD. Since olive oil and its compounds have been shown to provide a considerable anti-inflammatory effect, in this review, we aim to discuss the latest evidence concerning the impact of olive oil and its bioactive compounds on IBD. Numerous preclinical studies have exhibited solid evidence on the mechanisms by which polyphenol-rich extra-virgin olive oil (EVOO) or specific polyphenols like hydroxytyrosol (HT) provide their anti-inflammatory, antioxidative, antitumour, and microbiota-modulation effects. Accordingly, several human studies that explored the effects of olive oil on patients with IBD further confirmed the evidence brought forward by preclinical studies. Nevertheless, there is a need for larger-scale, multicentric, randomized control trials that would finally elucidate olive oil's level of efficacy in modulating the course of IBD.
    Keywords:  Mediterranean diet; inflammatory bowel disease; olive oil; polyphenols
    DOI:  https://doi.org/10.3390/nu14040757
  73. Theranostics. 2022 ;12(4): 1683-1714
    Tumor-derived extracellular vesicles as messengers of natural products in cancer treatment.
    Yuanxin Xu, Kuanhan Feng, Huacong Zhao, Liuqing Di, Lei Wang, Ruoning Wang.
      Extracellular vesicles (EVs) are kinds of two-layer vesicles secreted by cells. They play significant roles in mediating component exchange between cells, signal transduction, and pathological development. Among them, the tumor-derived EVs (TDEVs) are found related to the tumor microenvironment and cancer development. TDEVs can be designed as a natural drug carrier with high tumor targeting and permeability. In recent years, drug delivery systems (DDS) based on TDEVs for cancer treatments have received considerable attention. In this review, the biological characteristics of TDEVs are introduced, especially the effect on the tumor. Furthermore, the various approaches to constructing DDS based on TDEVs are summarized. Then we listed examples of TDEVs successfully constructing treatment systems. The use of chemical drugs, biological drugs, and engineered drugs as encapsulated drugs are respectively introduced, particularly the application progress of active ingredients in traditional Chinese medicine. Finally, this article introduces the latest clinical research progress, especially the marketed preparations and challenges of clinical application of TDEVs.
    Keywords:  Cancer therapy; Clinical research progress; Drug delivery systems; Exosomes; Tumor-derived extracellular vesicles
    DOI:  https://doi.org/10.7150/thno.67775
  74. Nutrients. 2022 Feb 09. pii: 734. [Epub ahead of print]14(4):
    Dietary Natural Compounds and Vitamins as Potential Cofactors in Uterine Fibroids Growth and Development.
    Iwona Szydłowska, Jolanta Nawrocka-Rutkowska, Agnieszka Brodowska, Aleksandra Marciniak, Andrzej Starczewski, Małgorzata Szczuko.
      An analysis of the literature generated within the past 20 year-span concerning risks of uterine fibroids (UFs) occurrence and dietary factors was carried out. A link between Vitamin D deficiency and UFs formation is strongly indicated, making it a potent compound in leiomyoma therapy. Analogs of the 25-hydroxyvitamin D3, not susceptible to degradation by tissue 24-hydroxylase, appear to be especially promising and tend to show better therapeutic results. Although research on the role of Vitamin A in the formation of fibroids is contradictory, Vitamin A-enriched diet, as well as synthetic retinoid analogues, may be preventative or limit the growth of fibroids. Unambiguous conclusions cannot be drawn regarding Vitamin E and C supplementation, except for alpha-tocopherol. Alpha-tocopherol as a phytoestrogen taking part in the modulation of estrogen receptors (ERs) involved in UF etiology, should be particularly avoided in therapy. A diet enriched in fruits and vegetables, as sources of carotenoids, polyphenols, quercetin, and indole-3-carbinol, constitutes an easily modifiable lifestyle element with beneficial results in patients with UFs. Other natural substances, such as curcumin, can reduce the oxidative stress and protect against inflammation in leiomyoma. Although the exact effect of probiotics on uterine fibroids has not yet been thoroughly evaluated at this point, the protective role of dairy products, i.e., yogurt consumption, has been indicated. Trace elements such as selenium can also contribute to antioxidative and anti-inflammatory properties of a recommended diet. In contrast, heavy metals, endocrine disrupting chemicals, cigarette smoking, and a diet low in antioxidants and fiber were, alongside genetic predispositions, associated with UFs formation.
    Keywords:  curcumin; diet; green tea; selenium; trace elements; uterine fibroids; vitamin A, C, D, E
    DOI:  https://doi.org/10.3390/nu14040734
  75. Adv Drug Deliv Rev. 2022 Feb 18. pii: S0169-409X(22)00058-8. [Epub ahead of print] 114168
    Enhanced antimicrobial activity through the combination of antimicrobial photodynamic therapy and low-frequency ultrasonic irradiation.
    Ying Wang, Yixuan Xu, Xianghuan Guo, Lei Wang, Jing Zeng, Haixia Qiu, Yizhou Tan, Defu Chen, Hongyou Zhao, Ying Gu.
      The rapid increase of antibiotic resistance in pathogenic microorganisms has become one of the most severe threats to human health. Antimicrobial photodynamic therapy (aPDT), a light-based regimen, has offered a compelling nonpharmacological alternative to conventional antibiotics. The activity of aPDT is based on cytotoxic effect of reactive oxygen species (ROS), which are generated through the photosensitized reaction between photon, oxygen and photosensitizer. However, limited by the penetration of light and photosensitizers in human tissues and/or the infiltration of oxygen and photosensitizers in biofilms, the eradication of deeply located or biofilm-associated infections by aPDT remains challenging. Ultrasound irradiation bears a deeper penetration in human tissues than light and, sequentially, can promote drug delivery through cavitation effect. As such, the combination of ultrasound and aPDT represents a potent antimicrobial strategy. In this review, we summarized the recent progresses in the area of the combination therapy using ultrasound and aPDT, and discussed the potential mechanisms underlying enhanced antimicrobial effect by this combination therapy. The future research directions are also highlighted.
    Keywords:  antimicrobial photodynamic therapy (aPDT); combination therapy; enhancement effect; microorganism; synergistic effect; ultrasonic irradiation
    DOI:  https://doi.org/10.1016/j.addr.2022.114168
  76. Antioxidants (Basel). 2022 Feb 16. pii: 402. [Epub ahead of print]11(2):
    Recent Advances in Drumstick (Moringa oleifera) Leaves Bioactive Compounds: Composition, Health Benefits, Bioaccessibility, and Dietary Applications.
    Piyush Kashyap, Shiv Kumar, Charanjit Singh Riar, Navdeep Jindal, Poonam Baniwal, Raquel P F Guiné, Paula M R Correia, Rahul Mehra, Harish Kumar.
      Based on the availability of many nutrients, Moringa oleifera tree leaves have been widely employed as nutrients and nutraceuticals in recent years. The leaves contain a small amount of anti-nutritional factors and are abundant in innumerable bioactive compounds. Recently, in several in vivo and in vitro investigations, moringa leaves' bioactive components and functionality are highlighted. Moringa leaves provide several health advantages, including anti-diabetic, antibacterial, anti-cancer, and anti-inflammatory properties. The high content of phytochemicals, carotenoids, and glucosinolates is responsible for the majority of these activities as reported in the literature. Furthermore, there is growing interest in using moringa as a value-added ingredient in the development of functional foods. Despite substantial study into identifying and measuring these beneficial components from moringa leaves, bioaccessibility and bioavailability studies are lacking. This review emphasizes recent scientific evidence on the dietary and bioactive profiles of moringa leaves, bioavailability, health benefits, and applications in various food products. This study highlights new scientific data on the moringa leaves containing nutrient and bioactive profiles, bioavailability, health benefits, and uses in various food items. Moringa has been extensively used as a health-promoting food additive because of its potent protection against various diseases and the widespread presence of environmental toxins. More research is needed for utilization as well as to study medicinal effects and bioaccesibility of these leaves for development of various drugs and functional foods.
    Keywords:  Moringa oleifera; antioxidants; bioaccessibility; phytochemicals; therapeutic applications
    DOI:  https://doi.org/10.3390/antiox11020402
  77. Light Sci Appl. 2022 Feb 21. 11(1): 38
    Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors.
    Elena I Shramova, Stepan P Chumakov, Victoria O Shipunova, Anastasiya V Ryabova, Georgij B Telegin, Andrei V Kabashin, Sergey M Deyev, Galina M Proshkina.
      Photodynamic therapy (PDT) is one of the most appealing photonic modalities for cancer treatment based on anticancer activity of light-induced photosensitizer-mediated reactive oxygen species (ROS), but a limited depth of light penetration into tissues does not make possible the treatment of deep-seated neoplasms and thus complicates its widespread clinical adoption. Here, we introduce the concept of genetically encoded bioluminescence resonance energy transfer (BRET)-activated PDT, which combines an internal light source and a photosensitizer (PS) in a single-genetic construct, which can be delivered to tumors seated at virtually unlimited depth and then triggered by the injection of a substrate to initiate their treatment. To illustrate the concept, we engineered genetic NanoLuc-miniSOG BRET pair, combining NanoLuc luciferase flashlight and phototoxic flavoprotein miniSOG, which generates ROS under luciferase-substrate injection. We prove the concept feasibility in mice bearing NanoLuc-miniSOG expressing tumor, followed by its elimination under the luciferase-substrate administration. Then, we demonstrate a targeted delivery of NanoLuc-miniSOG gene, via tumor-specific lentiviral particles, into a tumor, followed by its successful elimination, with tumor-growth inhibition (TGI) coefficient exceeding 67%, which confirms a great therapeutic potential of the proposed concept. In conclusion, this study provides proof-of-concept for deep-tissue "photodynamic" therapy without external light source that can be considered as an alternative for traditional PDT.
    DOI:  https://doi.org/10.1038/s41377-022-00729-4
  78. Front Bioeng Biotechnol. 2022 ;10 788128
    An Insight to Brain Targeting Utilizing Polymeric Nanoparticles: Effective Treatment Modalities for Neurological Disorders and Brain Tumor.
    Annu, Ali Sartaj, Zufika Qamar, Shadab Md, Nabil A Alhakamy, Sanjula Baboota, Javed Ali.
      The delivery of therapeutic molecules to the brain remains an unsolved problem to the researchers due to the existence of the blood-brain barrier (BBB), which halts the entry of unwanted substances to the brain. Central nervous system (CNS) disorders, mainly Parkinson's disease, Alzheimer's disease, schizophrenia, brain tumors, and stroke, are highly prevalent globally and are a growing concern for researchers due to restricting the delivery of pharmaceutical drugs to the brain. So effective treatment modalities are essential to combat the growing epidemic of CNS diseases. Recently, the growing attention in the field of nanotechnology has gained the faith of researchers for the delivery of therapeutics to the brain by targeting them to the specific target site. Polymeric nanoparticles (PNPs) emerge out to be an instrumental approach in drug targeting to the brain by overcoming the physiological barrier, biomedical barrier, and BBB. Preclinical discovery has shown the tremendous potential and versatility of PNPs in encapsulating several drugs and their targeting to the deepest regions of the brain, thus improving therapeutic intervention of CNS disorders. The current review will summarize advances in the development of PNPs for targeting therapeutics to the brain and the functional and molecular effects obtained in the preclinical model of most common CNS diseases. The advancement of PNPs in clinical practice and their prospect in brain targeting will also be discussed briefly.
    Keywords:  blood–brain barrier; brain targeting; central nervous system disorders; drug delivery; polymeric nanoparticles
    DOI:  https://doi.org/10.3389/fbioe.2022.788128
  79. Theranostics. 2022 ;12(4): 1800-1815
    Re-engineering the inner surface of ferritin nanocage enables dual drug payloads for synergistic tumor therapy.
    Zhuoran Wang, Yue Zhao, Shuai Zhang, Xuehui Chen, Guoming Sun, Baoli Zhang, Bing Jiang, Yili Yang, Xiyun Yan, Kelong Fan.
      Rationale: With the advantages of tumor-targeting, pH-responsive drug releasing, and biocompatibility, ferritin nanocage emerges as a promising drug carrier. However, its wide applications were significantly hindered by the low loading efficiency of hydrophobic drugs. Herein, we redesigned the inner surface of ferritin drug carrier (ins-FDC) by fusing the C- terminus of human H ferritin (HFn) subunit with optimized hydrophobic peptides. Methods: Hydrophobic and hydrophilic drugs were encapsulated into the ins-FDC through the urea-dependent disassembly/reassembly strategy and the natural drug entry channel of the protein nanocage. The morphology and drug loading/releasing abilities of the drug-loaded nanocarrier were then examined. Its tumor targeting character, system toxicity, application in synergistic therapy, and anti-tumor action were further investigated. Results: After optimization, 39 hydrophobic Camptothecin and 150 hydrophilic Epirubicin were encapsulated onto one ins-FDC nanocage. The ins-FDC nanocage exhibited programed drug release pattern and increased the stability and biocompatibility of the loaded drugs. Furthermore, the ins-FDC possesses tumor targeting property due to the intrinsic CD71-binding ability of HFn. The loaded drugs may penetrate the brain blood barrier and accumulate in tumors in vivo more efficiently. As a result, the drugs loaded on ins-FDC showed reduced side effects and significantly enhanced efficacy against glioma, metastatic liver cancer, and chemo-resistant breast tumors. Conclusions: The ins-FDC nanocarrier offers a promising novel means for the delivery of hydrophobic compounds in cancer treatments, especially for the combination therapies that use both hydrophobic and hydrophilic chemotherapeutics.
    Keywords:  dual drug payloads; hydrophobic drugs loading; inner surface engineering; re-design of ferritin nanocage; synergistic tumor therapy
    DOI:  https://doi.org/10.7150/thno.68459
  80. J Zhejiang Univ Sci B. 2022 Feb 15. pii: 1673-1581(2022)02-0089-13. [Epub ahead of print]23(2): 89-101
    Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications.
    Zhaoshi Bai, Yaling Peng, Xinyue Ye, Zhixian Liu, Yupeng Li, Lingman Ma.
      Cancer is the leading cause of death worldwide. Drugs play a pivotal role in cancer treatment, but the complex biological processes of cancer cells seriously limit the efficacy of various anticancer drugs. Autophagy, a self-degradative system that maintains cellular homeostasis, universally operates under normal and stress conditions in cancer cells. The roles of autophagy in cancer treatment are still controversial because both stimulation and inhibition of autophagy have been reported to enhance the effects of anticancer drugs. Thus, the important question arises as to whether we should try to strengthen or suppress autophagy during cancer therapy. Currently, autophagy can be divided into four main forms according to its different functions during cancer treatment: cytoprotective (cell survival), cytotoxic (cell death), cytostatic (growth arrest), and nonprotective (no contribution to cell death or survival). In addition, various cell death modes, such as apoptosis, necrosis, ferroptosis, senescence, and mitotic catastrophe, all contribute to the anticancer effects of drugs. The interaction between autophagy and these cell death modes is complex and can lead to anticancer drugs having different or even completely opposite effects on treatment. Therefore, it is important to understand the underlying contexts in which autophagy inhibition or activation will be beneficial or detrimental. That is, appropriate therapeutic strategies should be adopted in light of the different functions of autophagy. This review provides an overview of recent insights into the evolving relationship between autophagy and cancer treatment.
    Keywords:  Autophagy; Cancer treatment; Cell death mode; Precision treatment
    DOI:  https://doi.org/10.1631/jzus.B2100804
  81. Drug Deliv Transl Res. 2022 Feb 25.
    Nanotechnological approaches for pentamidine delivery.
    Ilaria Andreana, Valeria Bincoletto, Paola Milla, Franco Dosio, Barbara Stella, Silvia Arpicco.
      Pentamidine (PTM), which is a diamine that is widely known for its antimicrobial activity, is a very interesting drug whose mechanism of action is not fully understood. In recent years, PTM has been proposed as a novel potential drug candidate for the treatment of mental illnesses, myotonic dystrophy, diabetes, and tumors. Nevertheless, the systemic administration of PTM causes severe side effects, especially nephrotoxicity. In order to efficiently deliver PTM and reduce its side effects, several nanosystems that take advantage of the chemical characteristics of PTM, such as the presence of two positively charged amidine groups at physiological pH, have been proposed as useful delivery tools. Polymeric, lipidic, inorganic, and other types of nanocarriers have been reported in the literature for PTM delivery, and they are all in different development phases. The available approaches for the design of PTM nanoparticulate delivery systems are reported in this review, with a particular emphasis on formulation strategies and in vitro/in vivo applications. Furthermore, a critical view of the future developments of nanomedicine for PTM applications, based on recent repurposing studies, is provided. Created with BioRender.com.
    Keywords:  Drug delivery; Liposomes; Nanoparticles; Pentamidine; Repurposing
    DOI:  https://doi.org/10.1007/s13346-022-01127-4
  82. Lasers Surg Med. 2022 Feb 23.
    Fabrication and characterization of chitosan nanoparticles using the coffee-ring effect for photodynamic therapy.
    Alina Bekmukhametova, Mir Muhammad Nasir Uddin, Jessica Houang, Chandra Malladi, Laurel George, Richard Wuhrer, Shital K Barman, Ming J Wu, Damia Mawad, Antonio Lauto.
       BACKGROUND AND OBJECTIVES: Biocompatible nanoparticles have been increasingly used in a variety of medical applications, including photodynamic therapy. Although the impact of synthesis parameters and purification methods is reported in previous studies, it is still challenging to produce a reliable protocol for the fabrication, purification, and characterization of nanoparticles in the 200-300 nm range that are highly monodisperse for biomedical applications.
    STUDY DESIGN/MATERIALS AND METHODS: We investigated the synthesis of chitosan nanoparticles in the 200-300 nm range by evaluating the chitosan to sodium tripolyphosphate (TPP) mass ratio and acetic acid concentration of the chitosan solution. Chitosan nanoparticles were also crosslinked to rose bengal and incubated with human breast cancer cells (MCF-7) to test photodynamic activity using a green laser (λ = 532 nm, power = 90 mW).
    RESULTS: We established a simple protocol to fabricate and purify biocompatible nanoparticles with the most frequent size occurring between 200 and 300 nm. This was achieved using a chitosan to TPP mass ratio of 5:1 in 1% v/v acetic acid at a pH of 5.5. The protocol involved the formation of nanoparticle coffee rings that showed the particle shape to be spherical in the first approximation. Photodynamic treatment with rose bengal-nanoparticles killed ~98% of cancer cells.
    CONCLUSION: A simple protocol was established to prepare and purify spherical and biocompatible chitosan nanoparticles with a peak size of ~200 nm. These have remarkable antitumor activity when coupled with photodynamic treatment.
    Keywords:  breast cancer cells; functionalised nanoparticles; photodynamic therapy; scanning electron microscopy
    DOI:  https://doi.org/10.1002/lsm.23530
  83. Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2107266119. [Epub ahead of print]119(8):
    Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.
    Zuen Ren, Huizhi Liang, Phillip M Galbo, Malindrie Dharmaratne, Ameya S Kulkarni, Atefeh Taherian Fard, Marie Louise Aoun, Nuria Martinez-Lopez, Kimita Suyama, Outhiriaradjou Benard, Wei Zheng, Yang Liu, Joseph Albanese, Deyou Zheng, Jessica C Mar, Rajat Singh, Michael B Prystowsky, Larry Norton, Rachel B Hazan.
      In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.
    Keywords:  HIF1α; ROS signaling; breast cancer; glutathione peroxidase 2; metabolism
    DOI:  https://doi.org/10.1073/pnas.2107266119
  84. Polim Med. 2022 Feb 23.
    A critical review on the extraction and pharmacotherapeutic activity of piperine.
    Mohd Imran, Monalisha Samal, Abdul Qadir, Asad Ali, Showkat R Mir.
      Black pepper (Piper nigrum L.) is a climbing perennial plant in the Piperaceae family. Pepper has been known since antiquity for its use both as a medicine and a spice. It is particularly valued for its pungency attributed to its principal constituent - piperine. This review summarizes the information on the biological source of piperine, its extraction and isolation strategies, physicochemical properties, and pharmacological activity - analgesic, immunomodulatory, anti-depressive, anti-diarrheal, hepatoprotective, etc. The effect of piperine on biotransformation of co-administered drugs is also presented in this review, along with the mechanisms involved in its bioavailability-enhancing effect. Its important medicinal uses, including anti-hepatotoxic, anti-diarrheal, anti-depressive, analgesic, and immunomodulatory effects, besides many other traditional uses, are compiled. Based on an exhaustive review of literature, it may be concluded that piperine is a very promising alkaloid found in members of the Piperaceae family.
    Keywords:  Piper nigrum; bioavailability enhancement; extraction; pepper; piperine
    DOI:  https://doi.org/10.17219/pim/145512
  85. Antioxidants (Basel). 2022 Jan 27. pii: 248. [Epub ahead of print]11(2):
    Health Benefits and Applications of Goji Berries in Functional Food Products Development: A Review.
    Bojana B Vidović, Danijel D Milinčić, Mirjana D Marčetić, Jelena D Djuriš, Tijana D Ilić, Aleksandar Ž Kostić, Mirjana B Pešić.
      Goji berries have long been used for their nutritional value and medicinal purposes in Asian countries. In the last two decades, goji berries have become popular around the world and are consumed as a functional food due to wide-range bioactive compounds with health-promoting properties. In addition, they are gaining increased research attention as a source of functional ingredients with potential industrial applications. This review focuses on the antioxidant properties of goji berries, scientific evidence on their health effects based on human interventional studies, safety concerns, goji berry processing technologies, and applications of goji berry-based ingredients in developing functional food products.
    Keywords:  antioxidant properties; bioactive compounds; food product development; goji; health benefits; processing
    DOI:  https://doi.org/10.3390/antiox11020248
  86. Cancers (Basel). 2022 Feb 10. pii: 885. [Epub ahead of print]14(4):
    Cannabidiol (CBD) in Cancer Management.
    Kylie O'Brien.
      The plant Cannabis sativa has been in use medicinally for several thousand years. It has over 540 metabolites thought to be responsible for its therapeutic effects. Two of the key phytocannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). Unlike THC, CBD does not have potentially intoxicating effects. Preclinical and clinical research indicates that CBD has a wide range of therapeutic effects, and many of them are relevant to the management of cancer. In this article, we explore some of the potential mechanisms of action of CBD in cancer, and evidence of its efficacy in the integrative management of cancer including the side effects associated with its treatment, demonstrating its potential for integration with orthodox cancer care.
    Keywords:  cancer; cannabidiol; cannabis; endocannabinoid system; tumours
    DOI:  https://doi.org/10.3390/cancers14040885
  87. Front Cell Dev Biol. 2022 ;10 813581
    Interplay Between m6A RNA Methylation and Regulation of Metabolism in Cancer.
    Youchaou Mobet, Xiaoyi Liu, Tao Liu, Jianhua Yu, Ping Yi.
      Methylation of adenosine in RNA to N6-methyladenosine (m6A) is widespread in eukaryotic cells with his integral RNA regulation. This dynamic process is regulated by methylases (editors/writers), demethylases (remover/erasers), and proteins that recognize methylation (effectors/readers). It is now evident that m6A is involved in the proliferation and metastasis of cancer cells, for instance, altering cancer cell metabolism. Thus, determining how m6A dysregulates metabolic pathways could provide potential targets for cancer therapy or early diagnosis. This review focuses on the link between the m6A modification and the reprogramming of metabolism in cancer. We hypothesize that m6A modification could dysregulate the expression of glucose, lipid, amino acid metabolism, and other metabolites or building blocks of cells by adaptation to the hypoxic tumor microenvironment, an increase in glycolysis, mitochondrial dysfunction, and abnormal expression of metabolic enzymes, metabolic receptors, transcription factors as well as oncogenic signaling pathways in both hematological malignancies and solid tumors. These metabolism abnormalities caused by m6A's modification may affect the metabolic reprogramming of cancer cells and then increase cell proliferation, tumor initiation, and metastasis. We conclude that focusing on m6A could provide new directions in searching for novel therapeutic and diagnostic targets for the early detection and treatment of many cancers.
    Keywords:  M6A; cancer; metabolism; metabolite; methylation; oncogenic; reprogramming
    DOI:  https://doi.org/10.3389/fcell.2022.813581
  88. Pharmaceutics. 2022 Jan 20. pii: 240. [Epub ahead of print]14(2):
    Vine Cane Compounds to Prevent Skin Cells Aging through Solid Lipid Nanoparticles.
    Adriana Pereira, Maria João Ramalho, Renata Silva, Vera Silva, Rita Marques-Oliveira, Ana Catarina Silva, Maria Carmo Pereira, Joana A Loureiro.
      The long lifespan of the world's population has been raising interest in the research for new solutions to delay the aging process. With the aim of skin aging prevention, solid lipid nanoparticles (SLNs) were developed in this work for the encapsulation of three lipophilic natural compounds extracted from vine cane-epigallocatechin gallate (EGCG), resveratrol and myricetin. The developed loaded-SLNs proved to be stable, maintaining their adequate physicochemical characteristics for 30 days. In addition, the loaded-SLNs formulations exhibited high encapsulation efficiencies and loading capacities and high intracellular antioxidant activity. The mixture of EGCG-loaded SLNs with resveratrol-loaded SLNs proved to have the highest protection against induced oxidative stress. The in vitro cytotoxicity of the loaded SLNs was also evaluated, showing that the developed formulations are biocompatible for concentrations up to 50 µg/mL and could be safe for use in cosmetics. The encapsulation of EGCG, resveratrol and myricetin in SLNs seems to be a suitable strategy for the delivery of these antioxidants to the skin, improving their bioavailability.
    Keywords:  antioxidant activity; circular economy; free radicals; lipid nanoparticles; natural compounds; skin aging
    DOI:  https://doi.org/10.3390/pharmaceutics14020240
  89. Curr Med Chem. 2022 Feb 24.
    Nutraceutical potential of high-latitude and high-altitude berries rich in ellagitannins.
    Bruno Burlando, Laura Cornara, Raffaella Boggia.
       INTRODUCTION: This review concerns three species of berries, namely, the high-latitude cloudberry (Rubus chamaemorus) and arctic bramble (Rubus arcticus), and the high-altitude yellow raspberry (Rubus ellipticus). These plants are mostly exploited on a local basis as food or traditional remedies but could have a wider usage as nutraceuticals due to their richness in ellagitannins (ETs) and other phenolic compounds. ETs are hexahydroxydiphenoyl esters of carbohydrates and the largest group of hydrolysable tannins. They are distinctly antioxidant and bioactive compounds, and therefore, are considered as the major responsible for the biological properties of ET-rich berries. The health benefits of ETs are mainly due to the release of ellagic acid and to their metabolic transformation by the gut microbiota into urolithins, and include, among others, anti-inflammatory, antiviral, anti-bacterial, and anticancer actions.
    METHODS: Based on the literature searches in the Web of Science, Scopus, and PubMed databases, ethnobotanical, pharmaceutical, medicinal, and nutritional knowledge concerning the three berry species was covered. This includes empirical use of traditional preparations and experimental studies with various extracts and fractions from fruits and other plant portions, covering in vitro, preclinical, and clinical research.
    RESULTS: The complex of data reveals a wide spectrum of potential uses in health care, providing in some cases an experimental confirmation of traditional uses.
    CONCLUSIONS: The examined berry species can act as nutraceutical food producing positive effects on regular consumers but could also be exploited in more technological ways to produce food complements from ET-rich extracts.
    Keywords:  Arctic bramble; cloudberry; ellagitannins; health care; nutraceuticals; yellow raspberry.
    DOI:  https://doi.org/10.2174/0929867329666220224151938
  90. Inflammopharmacology. 2022 Feb 25.
    Advancement of nanomedicines in chronic inflammatory disorders.
    Vikas Jogpal, Mohit Sanduja, Rohit Dutt, Vandana Garg, Tinku.
      Chronic diseases, as stated by the WHO, are a threat to human health which kill 3 out of every 5 people worldwide. Therapeutics for such illnesses can be developed using traditional medicine. However, it is not an easy path from natural products to Western pharmacological and pharmaceutical methods. For several decades, chronic inflammatory disorders, especially in Westernized countries, have increased incidence and prevalence. Several NSAIDs are used to decrease inflammation and pain; however, there are numerous negative consequences of these anti-inflammatory medications, whereas plant-based natural products have anti-inflammatory therapeutic benefits that have little or no adverse effects. Nanoparticles are a new type of drug delivery device that may be designed to provide excellent target selectivity for certain cells and tissues while also having a high drug loading capacity, resulting in better pharmacokinetics, pharmacodynamics (PKPD), and therapeutic bioavailability. The size and polarity of phytochemical compounds make it hard to pass the blood-brain barrier (BBB), blood-vessel endothelial lining, gastrointestinal tract and mucosa. In addition, the gastrointestinal system is enzymatically destroyed. Therefore, nanoparticles or nanocrystals might also be used for encapsulation or conjugation of these chemicals as a method to improve their organic effectiveness through their gastrointestinal stability, absorption rate and dispersion. The therapy of numerous inflammatory illnesses, including arthritis, gastritis, Nephritis, Hepatitis (Type A, B &C), ulcerative colitis, Alzheimer's disease, atherosclerosis, allergic responses (asthma, eczema) or autoimmune disorders, is characterised by nanoparticles. This review paper provides information on the numerous nanosystem described with their probable mechanism to treat chronic inflammatory diseases.
    Keywords:  Chronic inflammatory disorder; Interferon; Nanoparticles; Reactive oxygen species; Severe acute respiratory syndrome
    DOI:  https://doi.org/10.1007/s10787-022-00927-x
  91. Gels. 2022 Jan 28. pii: 81. [Epub ahead of print]8(2):
    Formulation Development and Evaluation of Pravastatin-Loaded Nanogel for Hyperlipidemia Management.
    Gaurav Kant Saraogi, Siddharth Tholiya, Yachana Mishra, Vijay Mishra, Aqel Albutti, Pallavi Nayak, Murtaza M Tambuwala.
      Hyperlipidemia is a crucial risk factor for the initiation and progression of atherosclerosis, ultimately leading to cardiovascular disease. The nanogel-based nanoplatform has emerged as an extremely promising drug delivery technology. Pravastatin Sodium (PS) is a cholesterol-lowering drug used to treat hyperlipidemia. This study aimed to fabricate Pravastatin-loaded nanogel for evaluation of its effect in hyperlipidemia treatment. Pravastatin-loaded chitosan nanoparticles (PS-CS-NPs) were prepared by the ionic gelation method; then, these prepared NPs were converted to nanogel by adding a specified amount of 5% poloxamer solution. Various parameters, including drug entrapment efficacy, in vitro drug release, and hemolytic activity of the developed and optimized formulation, were evaluated. The in vitro drug release of the nanogel formulation revealed the sustained release (59.63% in 24 h) of the drug. The drug excipients compatibility studies revealed no interaction between the drug and the screened excipients. Higher drug entrapment efficacy was observed. The hemolytic activity showed lesser toxicity in nanoformulation than the pure drug solution. These findings support the prospective use of orally administered pravastatin-loaded nanogel as an effective and safe nano delivery system in hyperlipidemia treatment.
    Keywords:  hyperlipidemia; nanogel; polymer; pravastatin
    DOI:  https://doi.org/10.3390/gels8020081
  92. Oxid Med Cell Longev. 2022 ;2022 8214821
    The Pharmacological Activities of Crocus sativus L.: A Review Based on the Mechanisms and Therapeutic Opportunities of its Phytoconstituents.
    Monica Butnariu, Cristina Quispe, Jesús Herrera-Bravo, Javad Sharifi-Rad, Laxman Singh, Nora M Aborehab, Abdelhakim Bouyahya, Alessandro Venditti, Surjit Sen, Krishnendu Acharya, Moein Bashiry, Shahira M Ezzat, William N Setzer, Miquel Martorell, Ksenija S Mileski, Iulia-Cristina Bagiu, Anca Oana Docea, Daniela Calina, William C Cho.
      Crocus species are mainly distributed in North Africa, Southern and Central Europe, and Western Asia, used in gardens and parks as ornamental plants, while Crocus sativus L. (saffron) is the only species that is cultivated for edible purpose. The use of saffron is very ancient; besides the use as a spice, saffron has long been known also for its medical and coloring qualities. Due to its distinctive flavor and color, it is used as a spice, which imparts food preservative activity owing to its antimicrobial and antioxidant activity. This updated review discusses the biological properties of Crocus sativus L. and its phytoconstituents, their pharmacological activities, signaling pathways, and molecular targets, therefore highlighting it as a potential herbal medicine. Clinical studies regarding its pharmacologic potential in clinical therapeutics and toxicity studies were also reviewed. For this updated review, a search was performed in the PubMed, Science, and Google Scholar databases using keywords related to Crocus sativus L. and the biological properties of its phytoconstituents. From this search, only the relevant works were selected. The phytochemistry of the most important bioactive compounds in Crocus sativus L. such as crocin, crocetin, picrocrocin, and safranal and also dozens of other compounds was studied and identified by various physicochemical methods. Isolated compounds and various extracts have proven their pharmacological efficacy at the molecular level and signaling pathways both in vitro and in vivo. In addition, toxicity studies and clinical trials were analyzed. The research results highlighted the various pharmacological potentials such as antimicrobial, antioxidant, cytotoxic, cardioprotective, neuroprotective, antidepressant, hypolipidemic, and antihyperglycemic properties and protector of retinal lesions. Due to its antioxidant and antimicrobial properties, saffron has proven effective as a natural food preservative. Starting from the traditional uses for the treatment of several diseases, the bioactive compounds of Crocus sativus L. have proven their effectiveness in modern pharmacological research. However, pharmacological studies are needed in the future to identify new mechanisms of action, pharmacokinetic studies, new pharmaceutical formulations for target transport, and possible interaction with allopathic drugs.
    DOI:  https://doi.org/10.1155/2022/8214821
  93. Molecules. 2022 Feb 11. pii: 1214. [Epub ahead of print]27(4):
    Cannabis sativa Extract Induces Apoptosis in Human Pancreatic 3D Cancer Models: Importance of Major Antioxidant Molecules Present Therein.
    Fathi Emhemmed, Minjie Zhao, Selvi Yorulmaz, Damien Steyer, Celine Leitao, Marion Alignan, Muriel Cerny, Alexandra Paillard, Franck Milone Delacourt, Diane Julien-David, Christian D Muller.
      In recent years, interest in Cannabis sativa L. has been rising, as legislation is moving in the right direction. This plant has been known and used for thousands of years for its many active ingredients that lead to various therapeutic effects (pain management, anti-inflammatory, antioxidant, etc.). In this report, our objective was to optimize a method for the extraction of cannabinoids from a clone of Cannabis sativa L. #138 resulting from an agronomic test (LaFleur, Angers, FR). Thus, we wished to identify compounds with anticancer activity on human pancreatic tumor cell lines. Three static maceration procedures, with different extraction parameters, were compared based on their median inhibitory concentration (IC50) values and cannabinoid extraction yield. As CBD emerged as the molecule responsible for inducing apoptosis in the human pancreatic cancer cell line, a CBD-rich cannabis strain remains attractive for therapeutic applications. Additionally, while gemcitabine, a gold standard drug in the treatment of pancreatic cancer, only triggers cell cycle arrest in G0/G1, CBD also activates the cell signaling cascade to lead to programmed cell death. Our results emphasize the potential of natural products issued from medicinal hemp for pancreatic cancer therapy, as they lead to an accumulation of intracellular superoxide ions, affect the mitochondrial membrane potential, induce G1 cell cycle arrest, and ultimately drive the pancreatic cancer cell to lethal apoptosis.
    Keywords:  Cannabis sativa L.; ROS; TNF secretion; antioxidants; caspase activation; human; pancreatic cancer; phytocannabinoids; phytochemicals; proapoptotic activity
    DOI:  https://doi.org/10.3390/molecules27041214
  94. Inflammopharmacology. 2022 Feb 25.
    Natural compounds as safe therapeutic options for ulcerative colitis.
    Mukta Gupta, Vijay Mishra, Monica Gulati, Bhupinder Kapoor, Amrinder Kaur, Reena Gupta, Murtaza M Tambuwala.
      Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. Several conventional treatments for UC such as corticosteroids, immunosuppressive agents, tumor necrosis factor antagonist, integrin blockers, and interleukin antagonist, and salicylates are available but are associated with the various limitations and side-effects. None of the above treatments helps to achieve the ultimate goal of the therapy, i.e., maintenance of remission in the long-term. Natural remedies for the treatment of UC show comparatively less side effects as compared to conventional approaches, and affordable. The current review presents details on the role of herbal drugs in the treatment and cure of UC. Google, PubMed, Web of Science, and Scopus portals have been searched for potentially relevant literature to get the latest developments and updated information related to use of natural drugs in the treatment of UC. Natural products have been used over centuries to treat UC. Some of the essential herbal constituents exhibiting antiulcerogenic activity include gymnemic acid (Gymnema sylvestre), shagoal (Zingiber officinale), catechin (Camellia sinensis), curcumin (Curcuma longa), arctigenin (Arctium lappa), and boswellic acid (Boswellia serrata). Although many plant-derived products have been recommended for UC, further research to understand the exact molecular mechanism is still warranted to establish their usefulness clinically.
    Keywords:  Anti-ulcerogenic activity; Herbal constituents; Inflammatory bowel disease; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s10787-022-00931-1
  95. Front Pharmacol. 2022 ;13 814370
    Alpinetin: A Review of Its Pharmacology and Pharmacokinetics.
    Ge Zhao, Yue Tong, Fei Luan, Wenjing Zhu, Chenglin Zhan, Tiantian Qin, Weixiao An, Nan Zeng.
      Flavonoids isolated from medicinal herbs have been utilized as valuable health-care agents due to their virous biological applications. Alpinetin is a natural flavonoid that emerges in many widely used medicinal plants, and has been frequently applied in Chinese patent drugs. Accumulated evidence has demonstrated that alpinetin possesses a broad range of pharmacological activities such as antitumor, antiinflammation, hepatoprotective, cardiovascular protective, lung protective, antibacterial, antiviral, neuroprotective, and other properties through regulating multiple signaling pathways with low systemic toxicity. However, pharmacokinetic studies have documented that alpinetin may have poor oral bioavailability correlated to its extensive glucuronidation. Currently, the reported pharmacological properties and pharmacokinetics profiles of alpinetin are rare to be scientifically reviewed. In this article, we aimed to highlight the mechanisms of action of alpinetin in various diseases to strongly support its curative potentials for prospective clinical applications. We also summarized the pharmacokinetics properties and proposed some viable strategies to convey an appreciable reference for future advances of alpinetin in drug development.
    Keywords:  alpinetin; flavonoids; mechanisms of action; pharmacokinetics; pharmacology
    DOI:  https://doi.org/10.3389/fphar.2022.814370
  96. Cancers (Basel). 2022 Feb 12. pii: 911. [Epub ahead of print]14(4):
    Glycans as Targets for Drug Delivery in Cancer.
    Francisca Diniz, Pedro Coelho, Henrique O Duarte, Bruno Sarmento, Celso A Reis, Joana Gomes.
      Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can be used as direct molecular targets for drug delivery. In the present review, we address the development of strategies, such as monoclonal antibodies, antibody-drug conjugates and nanoparticles that specific and selectively target cancer-associated glycans in tumor cells. The use of nanoparticles for drug delivery encompasses novel applications in cancer therapy, including vaccines encapsulated in synthetic nanoparticles and specific nanoparticles that target glycoproteins or glycan-binding proteins. Here, we highlight their potential to enhance targeting approaches and to optimize the delivery of clinically approved drugs to the tumor microenvironment, paving the way for improved personalized treatment approaches with major potential importance for the pharmaceutical and clinical sectors.
    Keywords:  antibodies; cancer; drug delivery; glycans; glycosylation; nanoparticles
    DOI:  https://doi.org/10.3390/cancers14040911
  97. Pharmaceuticals (Basel). 2022 Feb 10. pii: 211. [Epub ahead of print]15(2):
    Hesperidin-Loaded Lipid Polymer Hybrid Nanoparticles for Topical Delivery of Bioactive Drugs.
    Rajendra Jangde, Gamal Osman Elhassan, Sulekha Khute, Deependra Singh, Manju Singh, Ram Kumar Sahu, Jiyauddin Khan.
      Hesperidin is a bioflavonoid constituent that among many other biological activities shows significant wound healing properties. However, the bioavailability of hesperidin when applied topically is limited due to its low solubility and systemic absorption, so novel dosage forms are needed to improve its therapeutic efficacy. The objectives of this study were to develop hesperidin-loaded lipid-polymer hybrid nanoparticles (HLPHNs) to enhance the delivery of hesperidin to endogenous sites in the wound bed and promote the efficacy of hesperidin. HLPHNs were optimized by response surface methodology (RSM) using the Box-Behnken design. HLPHNs were prepared using an emulsion-solvent evaporation method based on a double emulsion of water-in-oil-in-water (w/o/w) followed by freeze-drying to obtain nanoparticles. The prepared formulations were characterized using various evaluation parameters. In addition, the antioxidant activity of HLPHN 4 was investigated in vitro using the DPPH model. Seventeen different HLPHNs were prepared and the HLPHN4 exhibited the best mean particle size distribution, zeta potential, drug release and entrapment efficiency. The values are 91.43 nm, +23 mV, 79.97% and 92.8%, respectively. Transmission electron microscope showed similar spherical morphology as HLPHN4. Differential scanning calorimetry verified the physical stability of the loaded drug in a hybrid system. In vitro release studies showed uniform release of the drug over 24 h. HLPHN4 showed potent antioxidant activity in vitro in the DPPH model. The results of this study suggest that HLPHNs can achieve sustained release of the drug at the wound site and exhibit potent in vitro antioxidant activity.
    Keywords:  DPPH model; emulsion solvent evaporation; hesperidin; hybrid nanoparticles; sustained release
    DOI:  https://doi.org/10.3390/ph15020211
  98. Pharmaceutics. 2022 Jan 25. pii: 279. [Epub ahead of print]14(2):
    Transferrin Receptor-Targeted Nanocarriers: Overcoming Barriers to Treat Glioblastoma.
    Maria João Ramalho, Joana Angélica Loureiro, Manuel A N Coelho, Maria Carmo Pereira.
      Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor, and the clinically available approaches for its treatment are not curative. Despite the intensive research, biological barriers such as the blood-brain barrier (BBB) and tumor cell membranes are major obstacles to developing novel effective therapies. Nanoparticles (NPs) have been explored as drug delivery systems (DDS) to improve GBM therapeutic strategies. NPs can circumvent many of the biological barriers posed by this devastating disease, enhancing drug accumulation in the target site. This can be achieved by employing strategies to target the transferrin receptor (TfR), which is heavily distributed in BBB and GBM cells. These targeting strategies comprise the modification of NPs' surface with various molecules, such as transferrin (Tf), antibodies, and targeting peptides. This review provides an overview and discussion on the recent advances concerning the strategies to target the TfR in the treatment of GBM, as their benefits and limitations.
    Keywords:  active targeting; blood-brain barrier; brain delivery; functionalized nanoparticles; monoclonal antibody; surface modification; targeting peptides; transferrin
    DOI:  https://doi.org/10.3390/pharmaceutics14020279
  99. Drug Discov Today. 2022 Feb 16. pii: S1359-6446(22)00064-2. [Epub ahead of print]
    Teaching an old dog new tricks: Drug discovery by repositioning natural products and their derivatives.
    Boshi Huang, Yan Zhang.
      Given the substantial cost and low success rate of drug discovery and development, repositioning existing drugs to treat new diseases has gained significant attention in recent years, with potentially lower development costs and shorter time frames. Natural products show great promise in drug repositioning because they have been used for various medical purposes for thousands of years. In this review, we discuss the drug repositioning of six prototypical natural products and their derivatives to reveal new drug-disease associations. We also highlight opportunities and challenges in natural product-based drug repositioning for future reference.
    Keywords:  Drug discovery and development; Drug repositioning; Natural products; New drug-disease associations
    DOI:  https://doi.org/10.1016/j.drudis.2022.02.007
  100. Gels. 2022 Feb 18. pii: 129. [Epub ahead of print]8(2):
    Tacrolimus-Loaded Solid Lipid Nanoparticle Gel: Formulation Development and In Vitro Assessment for Topical Applications.
    Abdul Shakur Khan, Kifayat Ullah Shah, Mohammed Al Mohaini, Abdulkhaliq J Alsalman, Maitham A Al Hawaj, Yousef N Alhashem, Shakira Ghazanfar, Kamran Ahmad Khan, Zahid Rasul Niazi, Arshad Farid.
      The currently available topical formulations of tacrolimus have minimal and variable absorption, elevated mean disposition half-life, and skin irritation effects resulting in patient noncompliance. In our study, we fabricated tacrolimus-loaded solid lipid nanoparticles (SLNs) that were converted into a gel for improved topical applications. The SLNs were prepared using a solvent evaporation method and characterized for their physicochemical properties. The particle size of the SLNs was in the range of 439 nm to 669 nm with a PDI of ≤0.4, indicating a monodispersed system. The Zeta potential of uncoated SLNs (F1-F5) ranged from -25.80 to -15.40 mV. Those values reverted to positive values for chitosan-decorated formulation (F6). The drug content and entrapment efficiency ranged between 0.86 ± 0.03 and 0.91 ± 0.03 mg/mL and 68.95 ± 0.03 and 83.68 ± 0.04%, respectively. The pH values of 5.45 to 5.53 depict their compatibility for skin application. The surface tension of the SLNs decreased with increasing surfactant concentration that could increase the adherence of the SLNs to the skin. The release of drug from gel formulations was significantly retarded in comparison to their corresponding SLN counterparts (p ≤ 0.05). Both SLNs and their corresponding gel achieved the same level of drug permeation, but the retention of the drug was significantly improved with the conversion of SLNs into their corresponding gel formulation (p ≤ 0.05) due to its higher bioadhesive properties.
    Keywords:  chitosan; gel; solid lipid nanoparticles; tacrolimus; topical drug delivery
    DOI:  https://doi.org/10.3390/gels8020129
  101. Molecules. 2022 Feb 09. pii: 1171. [Epub ahead of print]27(4):
    A Review on the Main Phytoconstituents, Traditional Uses, Inventions, and Patent Literature of Gum Arabic Emphasizing Acacia seyal.
    Mohamed A Ashour, Waseem Fatima, Mohd Imran, Mohammed M Ghoneim, Sultan Alshehri, Faiyaz Shakeel.
      Acacia seyal is an important source of gum Arabic. The availability, traditional, medicinal, pharmaceutical, nutritional, and cosmetic applications of gum acacia have pronounced its high economic value and attracted global attention. In addition to summarizing the inventions/patents applications related to gum A. seyal, the present review highlights recent updates regarding its phytoconstituents. Traditional, cosmetic, pharmaceutical, and medicinal uses with the possible mechanism of actions have been also reviewed. The patent search revealed the identification of 30 patents/patent applications of A. seyal. The first patent related to A. seyal was published in 1892, which was related to its use in the prophylaxis/treatment of kidney and bladder affections. The use of A. seyal to treat cancer and osteoporosis has also been patented. Some inventions provided compositions and formulations containing A. seyal or its ingredients for pharmaceutical and medical applications. The inventions related to agricultural applications, food industry, cosmetics, quality control of gum Arabic, and isolation of some chemical constituents (L-rhamnose and arabinose) from A. seyal have also been summarized. The identification of only 30 patents/patent applications from 1892 to 15 November 2021 indicates a steadily growing interest and encourages developing more inventions related to A. seyal. The authors recommend exploring these opportunities for the benefit of society.
    Keywords:  Acacia seyal; Arabic gum; gum Arabic; invention; patent
    DOI:  https://doi.org/10.3390/molecules27041171
  102. Cell Rep Phys Sci. 2022 Jan 19. pii: 100691. [Epub ahead of print]3(1):
    Targeted disruption of tumor vasculature via polyphenol nanoparticles to improve brain cancer treatment.
    Fuyao Liu, Bin Peng, Miao Li, Junning Ma, Gang Deng, Shenqi Zhang, Wendy C Sheu, Pan Zou, Haoan Wu, Jun Liu, Ann T Chen, Farrah S Mohammed, Jiangbing Zhou.
      Despite being effective for many other solid tumors, traditional anti-angiogenic therapy has been shown to be insufficient for the treatment of malignant glioma. Here, we report the development of polyphenol nanoparticles (NPs), which not only inhibit the formation of new vessels but also enable targeted disruption of the existing tumor vasculature. The NPs are synthesized through a combinatory iron-coordination and polymer-stabilization approach, which allows for high drug loading and intrinsic tumor vessel targeting. We study a lead NP consisting of quercetin and find that the NP after intravenous administration preferentially binds to VEGFR2, which is overexpressed in tumor vasculature. We demonstrate that the binding is mediated by quercetin, and the interaction of NPs with VEGFR2 leads to disruption of the existing tumor vasculature and inhibition of new vessel development. As a result, systemic treatment with the NPs effectively inhibits tumor growth and increases drug delivery to tumors.
    DOI:  https://doi.org/10.1016/j.xcrp.2021.100691
  103. Mater Today Bio. 2022 Jan;13 100208
    Towards principled design of cancer nanomedicine to accelerate clinical translation.
    Mohammad Souri, M Soltani, Farshad Moradi Kashkooli, Mohammad Kiani Shahvandi, Mohsen Chiani, Fatemeh Sadat Shariati, Mohammad Reza Mehrabi, Lance L Munn.
      Nanotechnology in medical applications, especially in oncology as drug delivery systems, has recently shown promising results. However, although these advances have been promising in the pre-clinical stages, the clinical translation of this technology is challenging. To create drug delivery systems with increased treatment efficacy for clinical translation, the physicochemical characteristics of nanoparticles such as size, shape, elasticity (flexibility/rigidity), surface chemistry, and surface charge can be specified to optimize efficiency for a given application. Consequently, interdisciplinary researchers have focused on producing biocompatible materials, production technologies, or new formulations for efficient loading, and high stability. The effects of design parameters can be studied in vitro, in vivo, or using computational models, with the goal of understanding how they affect nanoparticle biophysics and their interactions with cells. The present review summarizes the advances and technologies in the production and design of cancer nanomedicines to achieve clinical translation and commercialization. We also highlight existing challenges and opportunities in the field.
    Keywords:  CFL, Cell-free layer; CGMD, Coarse-grained molecular dynamic; Clinical translation; DPD, Dissipative particle dynamic; Drug delivery; Drug loading; ECM, Extracellular matrix; EPR, Permeability and retention; IFP, Interstitial fluid pressure; MD, Molecular dynamic; MDR, Multidrug resistance; MEC, Minimum effective concentration; MMPs, Matrix metalloproteinases; MPS, Mononuclear phagocyte system; MTA, Multi-tadpole assemblies; MTC, Minimum toxic concentration; Nanomedicine; Nanoparticle design; RBC, Red blood cell; TAF, Tumor-associated fibroblast; TAM, Tumor-associated macrophage; TIMPs, Tissue inhibitor of metalloproteinases; TME, Tumor microenvironment; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100208
  104. Colloids Surf B Biointerfaces. 2022 Feb 15. pii: S0927-7765(22)00097-2. [Epub ahead of print]213 112414
    NIR-regulated dual-functional silica nanoplatform for infected-wound therapy via synergistic sterilization and anti-oxidation.
    Lihua Li, Xinyu Sun, Mengna Dong, Hui Zhang, Jiao Wang, Tong Bu, Shuang Zhao, Li Wang.
      Nature-derived bioactive components and photothermal synergistic therapy bring potential strategies for fighting bacterial infection and accelerating would healing by virtue of their excellent therapeutic efficiencies and ignorable side effects, where photothermal property not only acts as sterilization energy but also as a doorkeeper to control the natural component release. Herein, by integrating the excellent antibacterial property of cinnamaldehyde (CA) and the outstanding photothermal performance of copper sulfide nanoparticles (CuS NPs), a multifunctional nanoplatform of SiO2 @CA@CuS nanospheres (NSs) is constructed with silica nanosphere (SiO2 NSs) as carrier. SiO2 @CA@CuS NSs exhibit photothermal property, bacterial absorption capacity, extraordinary antibacterial activity and antioxidant property. Mechanism characteriazation and antibacterial experiment indicate that positive charged SiO2 @CA@CuS can adhere to the negative charged surface of bacteria, and quickly kill bacteria through the synergistic action of the released CA and heat produced under near infrared light (NIR) irradiation at 980 nm. The sterilization efficiencies for Escherichia coli (E. coli) and S. aureus reach 99.86% and 99.84%, respectively. Furthermore, NIR-regulated SiO2 @CA@CuS perform great biocompatibility, as well as effective effects for accelerating S. aureus-infected wound healing at a low photothermal temperature (45 °C) relying on synergistic sterilization and anti-oxidation.
    Keywords:  NIR-induced cinnamaldehyde release; Photothermal property; Silica nanospheres; Synergistic sterilization; Wound healing
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112414
  105. Antioxidants (Basel). 2022 Feb 13. pii: 376. [Epub ahead of print]11(2):
    The Interplay of Ascorbic Acid with Quinones-Chelators-Influence on Lipid Peroxidation: Insight into Anticancer Activity.
    Olga Yu Selyutina, Polina A Kononova, Vladimir E Koshman, Lidiya G Fedenok, Nikolay E Polyakov.
      Ascorbic acid is a multifaceted compound that can perform both antioxidant and pro-oxidant activities in the redox reactions induced by transition metal ions, so its role in nature and especially in the human body is still the subject of debate. In the present study, we have examined the influence of ascorbic acid on lipid peroxidation in a model system that mimics the cell membrane, namely micelles of linoleic acid (LA), induced by chelate complexes of iron and copper ions with quinone-chelator 2-phenyl-4-(butylamino)-naphtholquinoline-7,12-dione (Q1). This quinone effectively generates reactive oxygen species and semiquinone radicals inside cancer cells via a cycling redox reaction. Here it was demonstrated that in the absence of quinone-chelator ascorbic acid significantly accelerates the lipid peroxidation induced by both Fe(II) and Cu(II) ions. It has been shown also that Q1 chelate complexes with Fe(II) and Cu(II) ions are redox active in the LA micelles oxidation. No effect of ascorbate was detected on the reactivity of chelate complex with Fe(II) ions. On the other hand, ascorbate performs pro-oxidant activity in Q1-Cu(II) complex induced reaction. We can conclude that ascorbate-driven redox cycling of Q1 may promote its anti-tumor activity.
    Keywords:  NMR; anthraquinones; anticancer activity; ascorbic acid; linoleic acid; lipid peroxidation
    DOI:  https://doi.org/10.3390/antiox11020376
  106. Oxid Med Cell Longev. 2022 ;2022 9218738
    Polydatin: A Critical Promising Natural Agent for Liver Protection via Antioxidative Stress.
    Dandan Tang, Qing Zhang, Huxinyue Duan, Xun Ye, Jia Liu, Wei Peng, Chunjie Wu.
      Polydatin, one of the natural active small molecules, was commonly applied in protecting and treating liver disorders in preclinical studies. Oxidative stress plays vital roles in liver injury caused by various factors, such as alcohol, viral infections, dietary components, drugs, and other chemical reagents. It is reported that oxidative stress might be one of the main reasons in the progressive development of alcohol liver diseases (ALDs), nonalcoholic liver diseases (NAFLDs), liver injury, fibrosis, hepatic failure (HF), and hepatocellular carcinoma (HCC). In this paper, we comprehensively summarized the pharmacological effects and potential molecular mechanisms of polydatin for protecting and treating liver disorders via regulation of oxidative stress. According to the previous studies, polydatin is a versatile natural compound and exerts significantly protective and curative effects on oxidative stress-associated liver diseases via various molecular mechanisms, including amelioration of liver function and insulin resistance, inhibition of proinflammatory cytokines, lipid accumulation, endoplasmic reticulum stress and autophagy, regulation of PI3K/Akt/mTOR, and activation of hepatic stellate cells (HSCs), as well as increase of antioxidant enzymes (such as catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), glutathione reductase (GR), and heme oxygenase-1 (HO-1)). In addition, polydatin acts as a free radical scavenger against reactive oxygen species (ROS) by its phenolic and ethylenic bond structure. However, further clinical investigations are still needed to explore the comprehensive molecular mechanisms and confirm the clinical treatment effect of polydatin in liver diseases related to regulation of oxidative stress.
    DOI:  https://doi.org/10.1155/2022/9218738
  107. Biomedicines. 2022 Jan 28. pii: 312. [Epub ahead of print]10(2):
    Radiosensitization and Radioprotection by Curcumin in Glioblastoma and Other Cancers.
    Vasiliki Zoi, Vasiliki Galani, Pericles Tsekeris, Athanasios P Kyritsis, George A Alexiou.
      Radiation therapy plays an important role in almost every cancer treatment. However, radiation toxicity to normal tissues, mainly due to the generation of reactive free radicals, has limited the efficacy of radiotherapy in clinical practice. Curcumin has been reported to possess significant antitumor properties. Although curcumin can sensitize cancer cells to irradiation, healthy cells are much less sensitive to this effect, and thus, curcumin is thought to be a potent, yet safe anti-cancer agent. In this review, a summary of the role of curcumin as both a radiosensitizer and radioprotector has been presented, based on the most recent data from the experimental and clinical evaluation of curcumin in different cancer cell lines, animal models, and human patients.
    Keywords:  cancer; curcumin; radiation therapy; radiosensitizer
    DOI:  https://doi.org/10.3390/biomedicines10020312
  108. Molecules. 2022 Feb 17. pii: 1362. [Epub ahead of print]27(4):
    Anti-Cancer Properties of Stevia rebaudiana; More than a Sweetener.
    Nikos Iatridis, Anastasia Kougioumtzi, Katerina Vlataki, Styliani Papadaki, Angeliki Magklara.
      Stevia rebaudiana Bertoni is a perennial shrub from Paraguay that is nowadays widely cultivated, since it is increasingly being utilized as a sugar substitute in various foodstuffs due to its sweetness and minimal caloric content. These properties of the plant's derivatives have spurred research on their biological activities revealing a multitude of benefits to human health, including antidiabetic, anticariogenic, antioxidant, hypotensive, antihypertensive, antimicrobial, anti-inflammatory and antitumor actions. To our knowledge, no recent reviews have surveyed and reported published work solely on the latter. Consequently, our main objective was to present a concise, literature-based review of the biological actions of stevia derivatives in various tumor types, as studied in in vitro and in vivo models of the disease. With global cancer estimates suggesting a 47% increase in cancer cases by 2040 compared to 2020, the data reviewed in this article should provide a better insight into Stevia rebaudiana and its products as a means of cancer prevention and therapy within the context of a healthy diet.
    Keywords:  Stevia rebaudiana; antioxidant; antitumor activity; bioactive compound; breast cancer; cancer prevention; cytotoxicity; gastrointestinal cancer
    DOI:  https://doi.org/10.3390/molecules27041362
  109. Antioxidants (Basel). 2022 Jan 26. pii: 232. [Epub ahead of print]11(2):
    Lycopene: A Natural Arsenal in the War against Oxidative Stress and Cardiovascular Diseases.
    May Nasser Bin-Jumah, Muhammad Shahid Nadeem, Sadaf Jamal Gilani, Bismillah Mubeen, Inam Ullah, Sami I Alzarea, Mohammed M Ghoneim, Sultan Alshehri, Fahad A Al-Abbasi, Imran Kazmi.
      Lycopene is a bioactive red pigment found in plants, especially in red fruits and vegetables, including tomato, pink guava, papaya, pink grapefruit, and watermelon. Several research reports have advocated its positive impact on human health and physiology. For humans, lycopene is an essential substance obtained from dietary sources to fulfil the body requirements. The production of reactive oxygen species (ROS) causing oxidative stress and downstream complications include one of the major health concerns worldwide. In recent years, oxidative stress and its counter strategies have attracted biomedical research in order to manage the emerging health issues. Lycopene has been reported to directly interact with ROS, which can help to prevent chronic diseases, including diabetes and neurodegenerative and cardiovascular diseases. In this context, the present review article was written to provide an accumulative account of protective and ameliorative effects of lycopene on coronary artery disease (CAD) and hypertension, which are the leading causes of death worldwide. Lycopene is a potent antioxidant that fights ROS and, subsequently, complications. It reduces blood pressure via inhibiting the angiotensin-converting enzyme and regulating nitrous oxide bioavailability. It plays an important role in lowering of LDL (low-density lipoproteins) and improving HDL (high-density lipoproteins) levels to minimize atherosclerosis, which protects the onset of coronary artery disease and hypertension. Various studies have advocated that lycopene exhibited a combating competence in the treatment of these diseases. Owing to all the antioxidant, anti-diabetic, and anti-hypertensive properties, lycopene provides a potential nutraceutical with a protective and curing ability against coronary artery disease and hypertension.
    Keywords:  coronary artery disease; hypertension; lycopene; nutraceutical; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11020232
  110. Cancer Cell Int. 2022 Feb 19. 22(1): 88
    HOXA7 promotes the metastasis of KRAS mutant colorectal cancer by regulating myeloid-derived suppressor cells.
    Yunzhi Dang, Jiao Yu, Shuhong Zhao, Ximing Cao, Qing Wang.
       BACKGROUND: KRAS mutation accounts for 30-50% of human colorectal cancer (CRC) cases. Due to the scarcity of effective treatment options, KRAS mutant CRC is difficult to treat in the clinic. Metastasis is still the major cause of the high mortality associated with KRAS mutant CRC, but the exact mechanism remains unclear. Here, we report a unique function of Homeobox 7 (HOXA7) in driving KRAS mutant CRC metastasis and explore therapeutic strategies for subpopulations of patients with this disease.
    METHODS: The expression of HOXA7 in a human CRC cohort was measured by immunohistochemistry. The function of HOXA7 in KRAS mutant CRC metastasis was analyzed with the cecum orthotopic model.
    RESULTS: Elevated HOXA7 expression was positively correlated with lymph node metastasis, distant metastasis, poor tumor differentiation, high TNM stage, and poor prognosis in CRC patients. Furthermore, HOXA7 was an independent prognostic marker in KRAS mutant CRC patients (P < 0.001) but not in KRAS wild-type CRC patients (P = 0.575). Overexpression of HOXA7 improved the ability of KRAS mutant CT26 cells to metastasize and simultaneously promoted the infiltration of myeloid-derived suppressor cells (MDSCs). When MDSC infiltration was blocked by a CXCR2 inhibitor, the metastasis rate of CT26 cells was markedly suppressed. The combination of the CXCR2 inhibitor SB265610 and programmed death-ligand 1 antibody (anti-PD-L1) could largely inhibit the metastasis of KRAS mutant CRC.
    CONCLUSIONS: HOXA7 overexpression upregulated CXCL1 expression, which promoted MDSC infiltration. Interruption of this loop might provide a promising treatment strategy for HOXA7-mediated KRAS mutant CRC metastasis.
    Keywords:  Colorectal cancer; HOXA7; Metastasis; Myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1186/s12935-022-02519-9
  111. Int J Nanomedicine. 2022 ;17 733-750
    Investigating the Impact of Optimized Trans-Cinnamic Acid-Loaded PLGA Nanoparticles on Epithelial to Mesenchymal Transition in Breast Cancer.
    Noha M Badawi, Yasmeen M Attia, Dina M El-Kersh, Olfat A Hammam, Maha K A Khalifa.
       Purpose: To design and optimize trans-cinnamic acid-loaded PLGA nanoparticles (CIN-PLGA-NPs) and assess its inhibitory effect on epithelial-mesenchymal transition (EMT) in triple-negative breast cancer.
    Methods: The quality by design approach was used to correlate the formulation parameters (PLGA amount and Poloxamer188 concentration) and critical quality attributes (entrapment efficiency percent, particle size and zeta potential). Design of CIN-PLGA-NPs formulations was done based on central composite response surface design and formulated by nanoprecipitation method. In addition, the optimized CIN-PLGA-NPs formulation was further evaluated for morphology using transmission electron microscopy and in vitro dissolution test. The cytotoxicity of CIN-PLGA-NPs optimized formula in comparison to the free trans-cinnamic acid (CIN-Free) was investigated in vitro using MDA-MB-231, triple-negative breast cancer cells, followed by scratch wound assay for evaluating the impact on the migratory potential of MDA-MB-231 cells. In vivo antitumor activity was evaluated using Ehrlich ascites carcinoma solid tumor animal model where tumor volumes were measured at different time points and necrotic/apoptotic indices were estimated in tumor sections. EMT markers, E- and N-cadherin, were assessed in solid tumors as well.
    Results: The optimized formulation showed entrapment efficiency of 76.98%, particle size of 186.3 nm with a smooth spherical surface and zeta potential of -28.47 mV indicating its stability. Furthermore, CIN-PLGA-NPs optimized formula released 60.8±1.89% of the total CIN-Free within 24 hours compared to 29±1.25% of the raw CIN-Free indicating improved dissolution rate. The optimized formula showed superior cytotoxicity on MDA-MB-231 cells compared to its free counterpart as well as increased wound closure percentage along with reduced tumor size in mice and increased necrotic and apoptotic indices. Tumor levels of E-cadherin and N-cadherin were indicative of EMT inhibition.
    Conclusion: Our findings proved the capability of PLGA nanoparticles in loading trans-cinnamic acid in addition to enhancing its antitumor efficacy in triple-negative breast cancer possibly via inhibiting EMT.
    Keywords:  PLGA nanoparticles; breast cancer; epithelial-mesenchymal transition; quality by design; trans-cinnamic acid
    DOI:  https://doi.org/10.2147/IJN.S345870
  112. Molecules. 2022 Feb 17. pii: 1372. [Epub ahead of print]27(4):
    A Review of Liposomes as a Drug Delivery System: Current Status of Approved Products, Regulatory Environments, and Future Perspectives.
    Peng Liu, Guiliang Chen, Jingchen Zhang.
      Liposomes have been considered promising and versatile drug vesicles. Compared with traditional drug delivery systems, liposomes exhibit better properties, including site-targeting, sustained or controlled release, protection of drugs from degradation and clearance, superior therapeutic effects, and lower toxic side effects. Given these merits, several liposomal drug products have been successfully approved and used in clinics over the last couple of decades. In this review, the liposomal drug products approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are discussed. Based on the published approval package in the FDA and European public assessment report (EPAR) in EMA, the critical chemistry information and mature pharmaceutical technologies applied in the marketed liposomal products, including the lipid excipient, manufacturing methods, nanosizing technique, drug loading methods, as well as critical quality attributions (CQAs) of products, are introduced. Additionally, the current regulatory guidance and future perspectives related to liposomal products are summarized. This knowledge can be used for research and development of the liposomal drug candidates under various pipelines, including the laboratory bench, pilot plant, and commercial manufacturing.
    Keywords:  drug delivery; drug loading; lipid excipient; liposomes; marketed products
    DOI:  https://doi.org/10.3390/molecules27041372
  113. Pharmaceutics. 2022 Jan 20. pii: 241. [Epub ahead of print]14(2):
    EGFR-Targeted Photodynamic Therapy.
    Luca Ulfo, Paolo Emidio Costantini, Matteo Di Giosia, Alberto Danielli, Matteo Calvaresi.
      The epidermal growth factor receptor (EGFR) plays a pivotal role in the proliferation and metastatization of cancer cells. Aberrancies in the expression and activation of EGFR are hallmarks of many human malignancies. As such, EGFR-targeted therapies hold significant potential for the cure of cancers. In recent years, photodynamic therapy (PDT) has gained increased interest as a non-invasive cancer treatment. In PDT, a photosensitizer is excited by light to produce reactive oxygen species, resulting in local cytotoxicity. One of the critical aspects of PDT is to selectively transport enough photosensitizers to the tumors environment. Accordingly, an increasing number of strategies have been devised to foster EGFR-targeted PDT. Herein, we review the recent nanobiotechnological advancements that combine the promise of PDT with EGFR-targeted molecular cancer therapy. We recapitulate the chemistry of the sensitizers and their modes of action in PDT, and summarize the advantages and pitfalls of different targeting moieties, highlighting future perspectives for EGFR-targeted photodynamic treatment of cancer.
    Keywords:  EGF; EGFR; PDT; affibodies; antibodies; aptamers; ligands; nanobodies; phages; targeting
    DOI:  https://doi.org/10.3390/pharmaceutics14020241
  114. Z Naturforsch C J Biosci. 2022 Feb 23.
    Synthesis and characterization of silver nanoparticles using curcumin: cytotoxic, apoptotic, and necrotic effects on various cell lines.
    Tunay Karan, Ramazan Erenler, Busra Moran Bozer.
      Nanostructures have distinctive chemical and physical features owing to their surface area and nanoscale size. In this study, silver nanoparticles were synthesized using curcumin, a medicinally valuable natural product. The structure of curcumin-mediated silver nanoparticles (c-AgNPs) was identified by extensive spectroscopic techniques. The maximum absorption was observed at 430 nm in UV-Vis spectrum. The crystal structure of c-AgNPs was identified by XRD. The morphology of the structure was determined by SEM image. The particle size was found as 51.13 nm. The functional groups of curcumin and c-AgNPs were established by FTIR spectroscopy. Cytotoxic activity of c-AgNPs was carried out using A549, DLD-1, and L929 with MTT assay. c-AgNPs revealed excellent activity on DLD-1 cell lines and A549 cell lines at 1.0 mg/mL concentration with the lethal effect of 80%. However, nanoparticles did not show the considerable effect on L929. Moreover, they induced apoptosis. Consequently, c-AgNPs are a promising material for anticancer drugs candidate.
    Keywords:  apoptosis; curcumin; cytotoxicity; necrosis; silver nanoparticles
    DOI:  https://doi.org/10.1515/znc-2021-0298
  115. Diabetes Metab Syndr Obes. 2022 ;15 477-498
    Adherence to Low-Carbohydrate Diets in Patients with Diabetes: A Narrative Review.
    Nitya Kalyani Kumar, Jennifer D Merrill, Scott Carlson, Jashalynn German, William S Yancy.
      Evidence suggests that low carbohydrate (<130 g/day of carbohydrate) (LCD) and very low carbohydrate, ketogenic diets (typically <50 g/day of carbohydrate) (VLCKD) can be effective tools for managing diabetes given their beneficial effects on weight loss and glycemic control. VLCKD also result in favorable lipid profile changes. However, these beneficial effects can be limited by poor dietary adherence. Cultural, religious, and economic barriers pose unique challenges to achieving nutritional compliance with LCD and VLCKD. We review the various methods for assessing adherence in clinical studies and obstacles posed, as well as potential solutions to these challenges.
    Keywords:  adherence; ketogenic diet; low carbohydrate diet; type 2 diabetes
    DOI:  https://doi.org/10.2147/DMSO.S292742
  116. Cancers (Basel). 2022 Feb 15. pii: 963. [Epub ahead of print]14(4):
    Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia.
    Michele Petruzzelli, Miriam Ferrer, Martijn J Schuijs, Sam O Kleeman, Nicholas Mourikis, Zoe Hall, David Perera, Shwethaa Raghunathan, Michele Vacca, Edoardo Gaude, Michael J Lukey, Duncan I Jodrell, Christian Frezza, Erwin F Wagner, Ashok R Venkitaraman, Timotheus Y F Halim, Tobias Janowitz.
      An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
    Keywords:  aerobic glycolysis; cachexia; cancer; host; metabolism; neutrophils
    DOI:  https://doi.org/10.3390/cancers14040963
  117. Pharmaceuticals (Basel). 2022 Feb 03. pii: 190. [Epub ahead of print]15(2):
    Microneedle-Based Natural Polysaccharide for Drug Delivery Systems (DDS): Progress and Challenges.
    Fouad Damiri, Nagavendra Kommineni, Samuel Ogbeide Ebhodaghe, Raviteja Bulusu, Vaskuri G S Sainaga Jyothi, Amany A Sayed, Aeshah A Awaji, Mousa O Germoush, Hamdan S Al-Malky, Mohammed Z Nasrullah, Md Habibur Rahman, Mohamed M Abdel-Daim, Mohammed Berrada.
      In this focused progress review, the most widely accepted methods of transdermal drug delivery are hypodermic needles, transdermal patches and topical creams. However, microneedles (MNs) (or microneedle arrays) are low-invasive 3D biomedical constructs that bypass the skin barrier and produce systemic and localized pharmacological effects. In the past, biomaterials such as carbohydrates, due to their physicochemical properties, have been extensively used to manufacture microneedles (MNs). Due to their wide range of functional groups, carbohydrates enable the design and development of tunable properties and functionalities. In recent years, numerous microneedle products have emerged on the market, although much research needs to be undertaken to overcome the various challenges before the successful introduction of microneedles into the market. As a result, carbohydrate-based microarrays have a high potential to achieve a future step in sensing, drug delivery, and biologics restitution. In this review, a comprehensive overview of carbohydrates such as hyaluronic acid, chitin, chitosan, chondroitin sulfate, cellulose and starch is discussed systematically. It also discusses the various drug delivery strategies and mechanical properties of biomaterial-based MNs, the progress made so far in the clinical translation of carbohydrate-based MNs, and the promotional opportunities for their commercialization. In conclusion, the article summarizes the future perspectives of carbohydrate-based MNs, which are considered as the new class of topical drug delivery systems.
    Keywords:  microneedles; natural polysaccharide; sustained and controlled release; transdermal drug delivery
    DOI:  https://doi.org/10.3390/ph15020190
  118. Biomaterials. 2022 Feb 19. pii: S0142-9612(22)00072-2. [Epub ahead of print]282 121433
    Emerging photodynamic nanotherapeutics for inducing immunogenic cell death and potentiating cancer immunotherapy.
    Shenwu Zhang, Jing Wang, Zhiqiang Kong, Xinxin Sun, Zhonggui He, Bingjun Sun, Cong Luo, Jin Sun.
      Immunotherapy has emerged as a promising cancer treatment modality. Despite the rapid progress in cancer immunotherapy, the therapeutic efficiency and clinical translation of immunotherapy are not as satisfactory as expected, especially for the patients with immune-cold tumors. Immunogenic cell death (ICD) represents a particular form of tumor cell death accompanied by the production of tumor-specific antigens, which facilitates the infiltration of effector T cells and potentiates immune response in solid tumors. Thus, ICD contributes to stimulating immune-cold tumors to immune-hot ones. Increasing evidence shows that photodynamic therapy (PDT) is able to effectively induce ICD. Recently, a variety of photodynamic nanotherapeutics have been developed to induce ICD and to potentiate cancer immunotherapy. Herein, this review outlines the recent advances in the field at the intersection of PDT, nanotechnology and ICD, including PDT-induced ICD, PDT-based synergistic induction of ICD, and multimodal immunotherapy in basis of PDT-induced ICD. Finally, the prospects and challenges of these photodynamic nanotherapeutics in ICD induction-based cancer immunotherapy are discussed.
    Keywords:  Cancer immunotherapy; Immunogenic cell death; Nanotherapeutics; Photodynamic therapy; Synergistic induction
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121433
  119. Plants (Basel). 2022 Feb 18. pii: 549. [Epub ahead of print]11(4):
    Natural Products as Novel Neuroprotective Agents; Computational Predictions of the Molecular Targets, ADME Properties, and Safety Profile.
    Sahar Saleh Alghamdi, Rasha Saad Suliman, Norah Abdulaziz Aljammaz, Khawla Mohammed Kahtani, Dimah Abdulqader Aljatli, Ghadeer M Albadrani.
      Neurodegenerative diseases (NDs) are one of the most challenging public health issues. Despite tremendous advances in our understanding of NDs, little progress has been made in establishing effective treatments. Natural products may have enormous potential in preventing and treating NDs by targeting microglia; yet, there have been several clinical concerns about their usage, primarily due to a lack of scientific evidence for their efficacy, molecular targets, physicochemical properties, and safety. To solve this problem, the secondary bioactive metabolites derived from neuroprotective medicinal plants were identified and selected for computational predictions for anti-inflammatory activity, possible molecular targets, physicochemical properties, and safety evaluation using PASS online, Molinspiration, SwissADME, and ProTox-II, respectively. Most of the phytochemicals were active as anti-inflammatory agents as predicted using the PASS online webserver. Moreover, the molecular target predictions for some phytochemicals were similar to the reported experimental targets. Moreover, the phytochemicals that did not violate important physicochemical properties, including blood-brain barrier penetration, GI absorption, molecular weight, and lipophilicity, were selected for further safety evaluation. After screening 54 neuroprotective phytochemicals, our findings suggest that Aromatic-turmerone, Apocynin, and Matrine are the most promising compounds that could be considered when designing novel neuroprotective agents to treat neurodegenerative diseases via modulating microglial polarization.
    Keywords:  ADME; immune response; medicinal plants; microglia polarization; neuroinflammation; neurological diseases; target production
    DOI:  https://doi.org/10.3390/plants11040549
  120. Oxid Med Cell Longev. 2022 ;2022 1429869
    The Role of Bioactive Compounds in Natural Products Extracted from Plants in Cancer Treatment and Their Mechanisms Related to Anticancer Effects.
    Meng Yuan, Guoqing Zhang, Weijun Bai, Xin Han, Chan Li, Siman Bian.
      Cancer is one of the greatest causes of death worldwide. With the development of surgery, radiotherapy, and medical agents, the outcomes of cancer patients have greatly improved. However, the underlying mechanisms of cancer are not yet fully understood. Recently, natural products have been proven to be beneficial for various conditions and have played important roles in the development of novel therapies. A substantial amount of evidence indicates that bioactive compounds could improve the outcomes of cancer patients via various pathways, such as endoplasmic reticulum stress, epigenetic modification, and modulation of oxidative stress. Here, we review the current evidence of bioactive compounds in natural products for the treatment of cancer and summarize the underlying mechanisms in this pathological process.
    DOI:  https://doi.org/10.1155/2022/1429869
  121. Antioxidants (Basel). 2022 Feb 17. pii: 408. [Epub ahead of print]11(2):
    Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation.
    Anushruti Ashok, Syed Suhail Andrabi, Saffar Mansoor, Youzhi Kuang, Brian K Kwon, Vinod Labhasetwar.
      Free radicals are formed as a part of normal metabolic activities but are neutralized by the endogenous antioxidants present in cells/tissue, thus maintaining the redox balance. This redox balance is disrupted in certain neuropathophysiological conditions, causing oxidative stress, which is implicated in several progressive neurodegenerative diseases. Following neuronal injury, secondary injury progression is also caused by excessive production of free radicals. Highly reactive free radicals, mainly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), damage the cell membrane, proteins, and DNA, which triggers a self-propagating inflammatory cascade of degenerative events. Dysfunctional mitochondria under oxidative stress conditions are considered a key mediator in progressive neurodegeneration. Exogenous delivery of antioxidants holds promise to alleviate oxidative stress to regain the redox balance. In this regard, natural and synthetic antioxidants have been evaluated. Despite promising results in preclinical studies, clinical translation of antioxidants as a therapy to treat neurodegenerative diseases remains elusive. The issues could be their low bioavailability, instability, limited transport to the target tissue, and/or poor antioxidant capacity, requiring repeated and high dosing, which cannot be administered to humans because of dose-limiting toxicity. Our laboratory is investigating nanoparticle-mediated delivery of antioxidant enzymes to address some of the above issues. Apart from being endogenous, the main advantage of antioxidant enzymes is their catalytic mechanism of action; hence, they are significantly more effective at lower doses in detoxifying the deleterious effects of free radicals than nonenzymatic antioxidants. This review provides a comprehensive analysis of the potential of antioxidant therapy, challenges in their clinical translation, and the role nanoparticles/drug delivery systems could play in addressing these challenges.
    Keywords:  CNS; antioxidant enzymes; inflammation; neurodegeneration; polymers; reactive oxygen species
    DOI:  https://doi.org/10.3390/antiox11020408
  122. Pharmaceutics. 2022 Feb 17. pii: 436. [Epub ahead of print]14(2):
    Medicinal Components in Edible Mushrooms on Diabetes Mellitus Treatment.
    Arpita Das, Chiao-Ming Chen, Shu-Chi Mu, Shu-Hui Yang, Yu-Ming Ju, Sing-Chung Li.
      Mushrooms belong to the family "Fungi" and became famous for their medicinal properties and easy accessibility all over the world. Because of its pharmaceutical properties, including anti-diabetic, anti-inflammatory, anti-cancer, and antioxidant properties, it became a hot topic among scientists. However, depending on species and varieties, most of the medicinal properties became indistinct. With this interest, an attempt has been made to scrutinize the role of edible mushrooms (EM) in diabetes mellitus treatment. A systematic contemporary literature review has been carried out from all records such as Science Direct, PubMed, Embase, and Google Scholar with an aim to represents the work has performed on mushrooms focuses on diabetes, insulin resistance (IR), and preventive mechanism of IR, using different kinds of mushroom extracts. The final review represents that EM plays an important role in anticipation of insulin resistance with the help of active compounds, i.e., polysaccharide, vitamin D, and signifies α-glucosidase or α-amylase preventive activities. Although most of the mechanism is not clear yet, many varieties of mushrooms' medicinal properties have not been studied properly. So, in the future, further investigation is needed on edible medicinal mushrooms to overcome the research gap to use its clinical potential to prevent non-communicable diseases.
    Keywords:  diabetes; edible mushroom; insulin resistance; polysaccharide; vitamin D; α-amylase; α-glucosidase
    DOI:  https://doi.org/10.3390/pharmaceutics14020436
  123. Evid Based Complement Alternat Med. 2022 ;2022 6535977
    Treatment of Liver Cancer: Role of the Traditional Mongolian Medicine.
    Xiaomei Bao, Lu Chen, Yiman Liu, Hua Sheng, Kailong Wang, Yanming Luo, Tongling Qin, Ying Liu, Yuling Qiu.
      Liver cancer is an extraordinarily heterogeneous malignancy with relatively high mortality and increasing incidence rate among the so far identified cancers. Improvements in liver cancer therapy have been made in the past decades, but therapeutics against liver cancer are still limited. Traditional Mongolian Medicine, formed and developed by the Mongolian people to maintain health in the medical practice of fighting against diseases, has been recognized as one of the key components of the world healthcare system. Traditional Mongolian Medicine has been used to treat various malignancies, including liver cancer, for a long time in Asia and its advantages have become more and more apparent. Herein, this review made a comprehensive summary of Traditional Mongolian Medicine, including the ideas in the liver cancer treatment, sources of medicines or prescriptions, traditional applications, modern pharmacological research, chemical structure and mechanisms of several monomer compounds isolated from Traditional Mongolian Medicine, with a view to finding promising drugs against liver cancer and expanding the clinical application of Traditional Mongolian Medicine in liver cancer therapy.
    DOI:  https://doi.org/10.1155/2022/6535977
  124. J Control Release. 2022 Feb 16. pii: S0168-3659(22)00094-3. [Epub ahead of print]
    Tumor-permeable smart liposomes by modulating the tumor microenvironment to improve the chemotherapy.
    Andy Samuel Widjaya, Yunhu Liu, Yueying Yang, Weiwei Yin, Jianying Liang, Yanyan Jiang.
      Low levels of accumulation and permeability in tumors are two primary reasons for the limited efficacy of conventional antineoplastic nanodrugs. In the present study, based on an original corosolic acid liposome (CALP) carrier with the functions of cell penetration, tumor permeability and anti-inflammation developed by our previous work, a versatile PTX/CALP was achieved by CALP loading paclitaxel (PTX). Compared to conventional PTX liposomes (PTX/LP) prepared by cholesterol and phospholipid, PTX/CALP exhibited extremely increasing cellular uptake and cytotoxicity in vitro, and in vivo enhancing the accumulation and permeability of tumor, thus significantly improving the antitumor efficacy. Further evidence indicated that PTX/CALP conspicuously promoted the recruitment of CD8+ T cells as well as reduced the infiltration of regulatory T cells and M2 macrophages into tumor by inducing enhanced immunogenic cell death (ICD) and down-regulating the inflammation level. Therefore, the improvement of efficacy was also attributed to the superiorities of PTX/CALP in modulating the inflammatory and immunosuppressive tumor microenvironment. Overall, the smart PTX liposomes based on the multi-functional CALP carrier without any modification could overcome the harsh tumor biological barriers, enhance the induction of ICD and then achieve satisfactory efficacy, suggesting its promising potentials in industrial transfer and clinical application.
    Keywords:  Anti-inflammation; Corosolic acid; Immunomodulation; Liposomes; Paclitaxel
    DOI:  https://doi.org/10.1016/j.jconrel.2022.02.020
  125. Animals (Basel). 2022 Feb 10. pii: 417. [Epub ahead of print]12(4):
    Chitosan Nanoparticles Containing Lipoic Acid with Antioxidant Properties as a Potential Nutritional Supplement.
    Katrin Quester, Sarahí Rodríguez-González, Laura González-Dávalos, Carlos Lozano-Flores, Adriana González-Gallardo, Santino J Zapiain-Merino, Armando Shimada, Ofelia Mora, Rafael Vazquez-Duhalt.
      The addition of the antioxidant α-lipoic acid (ALA) to a balanced diet might be crucial for the prevention of comorbidities such as cardiovascular diseases, diabetes, and obesity. Due to its low half-life and instability under stomach-like conditions, α-lipoic acid was encapsulated into chitosan nanoparticles (Ch-NPs). The resulting chitosan nanoparticles containing 20% w/w ALA (Ch-ALA-NPs) with an average diameter of 44 nm demonstrated antioxidant activity and stability under stomach-like conditions for up to 3 h. Furthermore, fluorescent Ch-ALA-NPs were effectively internalized into 3T3-L1 fibroblasts and were able to cross the intestinal barrier, as evidenced by everted intestine in vitro experiments. Thus, chitosan-based nanoparticles seem to be an attractive administration method for antioxidants, or other sensible additives, in food.
    Keywords:  antioxidant; cell internalization; chitosan nanoparticles; everted intestine; lipoic acid
    DOI:  https://doi.org/10.3390/ani12040417
  126. Molecules. 2022 Feb 16. pii: 1346. [Epub ahead of print]27(4):
    Mitochondrial ROS-Mediated Metabolic and Cytotoxic Effects of Isoproterenol on Cardiomyocytes Are p53-Dependent and Reversed by Curcumin.
    Jin Hee Lee, Da Hae Kim, MinA Kim, Kyung-Ho Jung, Kyung-Han Lee.
      Acute β-adrenergic stimulation contributes to heart failure. Here, we investigated the role of p53 in isoproterenol (ISO)-mediated metabolic and oxidative stress effects on cardiomyocytes and explored the direct protective effects offered by the antioxidant nutraceutical curcumin. Differentiated H9C2 rat cardiomyocytes treated with ISO were assayed for glucose uptake, lactate release, and mitochondrial reactive oxygen species (ROS) generation. Survival was assessed by sulforhodamine B assays. Cardiomyocytes showed significantly decreased glucose uptake and lactate release, as well as increased cellular toxicity by ISO treatment. This was accompanied by marked dose-dependent increases of mitochondria-derived ROS. Scavenging with N-acetyl-L-cysteine (NAC) effectively lowered ROS levels, which completely recovered glycolytic metabolism and survival suppressed by ISO. Mechanistically, ISO reduced extracellular-signal-regulated kinase (ERK) activation, whereas it upregulated p53 expression in an ROS-dependent manner. Silencing of p53 with siRNA blocked the ability of ISO to stimulate mitochondrial ROS and suppress glucose uptake, and partially recovered cell survival. Finally, curcumin completely reversed the metabolic and ROS-stimulating effects of ISO. Furthermore, curcumin improved survival of cardiomyocytes exposed to ISO. Thus, ISO suppresses cardiomyocyte glycolytic metabolism and survival by stimulating mitochondrial ROS in a p53-dependent manner. Furthermore, curcumin can efficiently rescue cardiomyocytes from these adverse effects.
    Keywords:  cardiomyocyte; curcumin; isoproterenol-induced cardiotoxicity; p53; reactive oxygen species
    DOI:  https://doi.org/10.3390/molecules27041346
  127. Pharmaceutics. 2022 Jan 27. pii: 308. [Epub ahead of print]14(2):
    Liposomal-Based Formulations: A Path from Basic Research to Temozolomide Delivery Inside Glioblastoma Tissue.
    Roxana-Maria Amarandi, Alina Ibanescu, Eugen Carasevici, Luminita Marin, Brindusa Dragoi.
      Glioblastoma (GBM) is a lethal brain cancer with a very difficult therapeutic approach and ultimately frustrating results. Currently, therapeutic success is mainly limited by the high degree of genetic and phenotypic heterogeneity, the blood brain barrier (BBB), as well as increased drug resistance. Temozolomide (TMZ), a monofunctional alkylating agent, is the first line chemotherapeutic drug for GBM treatment. Yet, the therapeutic efficacy of TMZ suffers from its inability to cross the BBB and very short half-life (~2 h), which requires high doses of this drug for a proper therapeutic effect. Encapsulation in a (nano)carrier is a promising strategy to effectively improve the therapeutic effect of TMZ against GBM. Although research on liposomes as carriers for therapeutic agents is still at an early stage, their integration in GBM treatment has a great potential to advance understanding and treating this disease. In this review, we provide a critical discussion on the preparation methods and physico-chemical properties of liposomes, with a particular emphasis on TMZ-liposomal formulations targeting GBM developed within the last decade. Furthermore, an overview on liposome-based formulations applied to translational oncology and clinical trials formulations in GBM treatment is provided. We emphasize that despite many years of intense research, more careful investigations are still needed to solve the main issues related to the manufacture of reproducible liposomal TMZ formulations for guaranteed translation to the market.
    Keywords:  characterization; chitosan; glioblastoma; liposome; synthesis; temozolomide
    DOI:  https://doi.org/10.3390/pharmaceutics14020308
  128. J Mater Chem B. 2022 Feb 25.
    Research progress on self-assembled nanodrug delivery systems.
    Li Qiao, Huishu Yang, Shijie Gao, Le Li, Xianjun Fu, Qingcong Wei.
      In recent years, nanodrug delivery systems have attracted increasing attention due to their advantages, such as high drug loading, low toxicity and side effects, improved bioavailability, long circulation time, good targeting and controlled drug release efficiency. Self-assembly technology has developed rapidly in recent decades and plays an important role in the research and development of nanoscience. The combination of nanometer drug delivery and self-assembly technology can realize the self-delivery process of drugs. The facile synthesis process and strong biological affinity can both effectively enhance the therapeutic efficacy and reduce the toxicity of drugs. This combination of technologies has received wide attention in the field of nanobiomedicine. In this review, we summarize the research progress and applications of different types of self-assembled nanodrug delivery systems (amphiphilic block copolymer-based self-assembled drug delivery system, carrier-free nanodrugs, peptide-based self-assembled delivery system, metal-polyphenol self-assembly and natural small-molecule self-assembled nanodrug delivery systems), which are expected to have potential therapeutic value in the field of biomedicine in the future.
    DOI:  https://doi.org/10.1039/d1tb02470a
  129. Nanomaterials (Basel). 2022 Feb 12. pii: 625. [Epub ahead of print]12(4):
    Concentrically Encapsulated Dual-Enzyme Capsules for Synergistic Metabolic Disorder Redressing and Cytotoxic Intermediates Scavenging.
    Chao Deng, Xianghai Li, Qianru Jin, Deliang Yi.
      Enzyme therapy has important implications for the treatment of metabolic disorders and biological detoxification. It remains challenging to prepare enzymatic nanoreactors with high therapeutic efficiency and low emission of cytotoxic reaction intermediates. Here, we propose a novel strategy for the preparation of enzymes-loaded polypeptide microcapsules (EPM) with concentrically encapsulated enzymes to achieve higher cascade reaction rates and minimal emission of cytotoxic intermediates. Mesoporous silica spheres (MSS) are used as a highly porous matrix to efficiently load a therapeutic enzyme (glucose oxidase, GOx), and a layer-by-layer (LbL) assembly strategy is employed to assemble the scavenging enzyme (catalase) and polyelectrolyte multilayers on the MSS surface. After removal of the MSS, a concentrically encapsulated EPM is obtained with the therapeutic enzyme encapsulated inside the capsule, and the scavenging enzyme immobilized in the polypeptide multilayer shell. Performance of the concentrically encapsulated GOx-catalase capsules is investigated for synergistic glucose metabolism disturbance correction and cytotoxic intermediate H2O2 clearance. The results show that the EPM can simultaneously achieve 99% H2O2 clearance and doubled glucose consumption rate. This strategy can be extended to the preparation of other dual- or multi-enzyme therapeutic nanoreactors, showing great promise in the treatment of metabolic disorders.
    Keywords:  capsule; enzyme therapy; mesoporous silica; metabolic disorder redressing; therapeutic nanoreactor
    DOI:  https://doi.org/10.3390/nano12040625
  130. Int J Mol Sci. 2022 Feb 14. pii: 2097. [Epub ahead of print]23(4):
    Targeting KRAS Regulation with PolyPurine Reverse Hoogsteen Oligonucleotides.
    Alexandra Maria Psaras, Simonas Valiuska, Véronique Noé, Carlos J Ciudad, Tracy A Brooks.
      KRAS is a GTPase involved in the proliferation signaling of several growth factors. The KRAS gene is GC-rich, containing regions with known and putative G-quadruplex (G4) forming regions. Within the middle of the G-rich proximal promoter, stabilization of the physiologically active G4mid structure downregulates transcription of KRAS; the function and formation of other G4s within the gene are unknown. Herein we identify three putative G4-forming sequences (G4FS) within the KRAS gene, explore their G4 formation, and develop oligonucleotides targeting these three regions and the G4mid forming sequence. We tested Polypurine Reverse Hoogsteen hairpins (PPRHs) for their effects on KRAS regulation via enhancing G4 formation or displacing G-rich DNA strands, downregulating KRAS transcription and mediating an anti-proliferative effect. Five PPRH were designed, two against the KRAS promoter G4mid and three others against putative G4FS in the distal promoter, intron 1 and exon 5. PPRH binding was confirmed by gel electrophoresis. The effect on KRAS transcription was examined by luciferase, FRET Melt2, qRT-PCR. Cytotoxicity was evaluated in pancreatic and ovarian cancer cells. PPRHs decreased activity of a luciferase construct driven by the KRAS promoter. PPRH selectively suppressed proliferation in KRAS dependent cancer cells. PPRH demonstrated synergistic activity with a KRAS promoter selective G4-stabilizing compound, NSC 317605, in KRAS-dependent pancreatic cells. PPRHs selectively stabilize G4 formation within the KRAS mid promoter region and represent an innovative approach to both G4-stabilization and to KRAS modulation with potential for development into novel therapeutics.
    Keywords:  G-quadruplex; KRAS; PPRH; ovarian cancer; pancreatic cancer
    DOI:  https://doi.org/10.3390/ijms23042097
  131. Polymers (Basel). 2022 Feb 09. pii: 658. [Epub ahead of print]14(4):
    Paclitaxel Drug Delivery Systems: Focus on Nanocrystals' Surface Modifications.
    Razan Haddad, Nasr Alrabadi, Bashar Altaani, Tonglei Li.
      Paclitaxel (PTX) is a chemotherapeutic agent that belongs to the taxane family and which was approved to treat various kinds of cancers including breast cancer, ovarian cancer, advanced non-small-cell lung cancer, and acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma. Several delivery systems for PTX have been developed to enhance its solubility and pharmacological properties involving liposomes, nanoparticles, microparticles, micelles, cosolvent methods, and the complexation with cyclodextrins and other materials that are summarized in this article. Specifically, this review discusses deeply the developed paclitaxel nanocrystal formulations. As PTX is a hydrophobic drug with inferior water solubility properties, which are improved a lot by nanocrystal formulation. Based on that, many studies employed nano-crystallization techniques not only to improve the oral delivery of PTX, but IV, intraperitoneal (IP), and local and intertumoral delivery systems were also developed. Additionally, superior and interesting properties of PTX NCs were achieved by performing additional modifications to the NCs, such as stabilization with surfactants and coating with polymers. This review summarizes these delivery systems by shedding light on their route of administration, the methods used in the preparation and modifications, the in vitro or in vivo models used, and the advantages obtained based on the developed formulations.
    Keywords:  cancer; chemotherapy; drug delivery; nanocrystals; nanotechnology; paclitaxel; surface modification
    DOI:  https://doi.org/10.3390/polym14040658
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