bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022‒03‒13
95 papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development
  1. Construction of pH-sensitive targeted micelle system co-delivery with curcumin and dasatinib and evaluation of anti-liver cancer.
  2. pH-Sensitive and Charge-Reversal Polymeric Nanoplatform Enhanced Photothermal/Photodynamic Synergistic Therapy for Breast Cancer.
  3. Iron out KRAS-driven cancer.
  4. pH/ROS Dual-Responsive Supramolecular Polypeptide Prodrug Nanomedicine Based on Host-Guest Recognition for Cancer Therapy.
  5. Photodynamic Therapeutic Effect of Nanostructured Metal Sulfide Photosensitizers on Cancer Treatment.
  6. Dual-Loaded Liposomes Tagged with Hyaluronic Acid Have Synergistic Effects in Triple-Negative Breast Cancer.
  7. Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer.
  8. The metabolomic landscape plays a critical role in glioma oncogenesis.
  9. Drug delivery system with dual imaging and dual response control drug release functions for chemo-photodynamic synergistic therapy.
  10. Versatile carbon nanoplatforms for cancer treatment and diagnosis: strategies, applications and future perspectives.
  11. A mutation breaks its silence on mutant KRAS.
  12. Polysaccharide-Drug Conjugates: A Tool for Enhanced Cancer Therapy.
  13. From propolis to nanopropolis: An exemplary journey and a paradigm shift of a resinous substance produced by bees.
  14. Metabolic tricks of cancer cells.
  15. Transferrin-modified nanoparticles for targeted delivery of Asiatic acid to glioblastoma cells.
  16. Perspectives and Prospective on Solid Lipid Nanoparticles as Drug Delivery Systems.
  17. Oscillations and Dynamic Symbiosis in Cellular Metabolism in Cancer.
  18. Sustainable Valorization of Tomato By-Products to Obtain Bioactive Compounds: Their Potential in Inflammation and Cancer Management.
  19. Recent Advancements in Mitochondria-Targeted Nanoparticle Drug Delivery for Cancer Therapy.
  20. Molecular imprinting of glycoproteins: From preparation to cancer theranostics.
  21. Polymeric Nanoparticles-Loaded Hydrogels for Biomedical Applications: A Systematic Review on In Vivo Findings.
  22. Small Molecule Compounds of Natural Origin Target Cellular Receptors to Inhibit Cancer Development and Progression.
  23. Curcumin Inhibits Papillary Thyroid Cancer Cell Proliferation by Regulating lncRNA LINC00691.
  24. Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies.
  25. Ultrasound-activated nanomaterials for sonodynamic cancer theranostics.
  26. Superoxide dismutase-loaded porous polymersomes as highly efficient antioxidant nanoparticles targeting synovium for osteoarthritis therapy.
  27. Nano-targeting vascular remodeling in cancer: Recent developments and future directions.
  28. Targeting metabolism to overcome cancer drug resistance: A promising therapeutic strategy for diffuse large B cell lymphoma.
  29. Phytochemical-loaded liposomes for anticancer therapy: an updated review.
  30. Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework.
  31. TRAIL-modified, doxorubicin-embedded periodic mesoporous organosilica nanoparticles for targeted drug delivery and efficient antitumor immunotherapy.
  32. KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer.
  33. Ginkgo biloba: A Treasure of Functional Phytochemicals with Multimedicinal Applications.
  34. Triple-negative breast cancer treatment in xenograft models by bifunctional nanoprobes combined to photodynamic therapy.
  35. Role of Hypoxia in the Interferon Response.
  36. Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies.
  37. Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways.
  38. Contribution of adipocytes in the tumor microenvironment to breast cancer metabolism.
  39. Curcumin-Injected Musca domestica Larval Hemolymph: Cecropin Upregulation and Potential Anticancer Effect.
  40. Natural Bioactives: Back to the Future in the Fight against Human Papillomavirus? A Narrative Review.
  41. Glycolysis in the progression of pancreatic cancer.
  42. Ferroptosis: A New Strategy for Cancer Therapy.
  43. Engineered Nanotechnology: An Effective Therapeutic Platform for the Chronic Cutaneous Wound.
  44. Light-activatable multifunctional paclitaxel nanoprodrug for synergistic chemo-photodynamic therapy in liver cancer.
  45. Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors.
  46. A bone-targeting drug delivery vehicle of a metal-organic framework conjugate with zoledronate combined with photothermal therapy for tumor inhibition in cancer bone metastasis.
  47. Synergistic Anti-tumor Effect of Dichloroacetate and Ivermectin.
  48. The Mediterranean Diet as a Source of Bioactive Molecules with Cannabinomimetic Activity in Prevention and Therapy Strategy.
  49. Pioglitazone-Loaded PLGA Nanoparticles: Towards the Most Reliable Synthesis Method.
  50. Hyaluronic Acid-Zein Core-Shell Nanoparticles Improve the Anticancer Effect of Curcumin Alone or in Combination with Oxaliplatin against Colorectal Cancer via CD44-Mediated Cellular Uptake.
  51. Formulation of Chitosan-Coated Apigenin Bilosomes: In Vitro Characterization, Antimicrobial and Cytotoxicity Assessment.
  52. pH-Responsive Nanocarriers in Cancer Therapy.
  53. Myoglobin: From physiological role to potential implications in cancer.
  54. Fabrication and Assessment of Folic acid Conjugated-Chitosan Modified PLGA Nanoparticle for Delivery of Alpha terpineol in colon Cancer.
  55. Electrospun Nanofibers Revisited: An Update on the Emerging Applications in Nanomedicine.
  56. Drug delivery systems for oral disease applications.
  57. Fate of Bioactive Compounds during Lactic Acid Fermentation of Fruits and Vegetables.
  58. Advancements in Biodegradable Active Films for Food Packaging: Effects of Nano/Microcapsule Incorporation.
  59. Liver Endothelium Promotes HER3-mediated Cell Survival in Colorectal Cancer with Wild-type and Mutant KRAS.
  60. Editorial: Exploration of Natural Product Leads for Multitarget-Based Treatment of Cancer-Computational to Experimental Journey.
  61. The Traditional Uses, Phytochemistry, Pharmacokinetics, Pharmacology, Toxicity, and Applications of Corydalis saxicola Bunting: A Review.
  62. Immunoliposomes: A Targeted Drug Delivery System for Cancer Therapeutics and Vaccination.
  63. Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions.
  64. Pt nanoenzyme decorated yolk-shell nanoplatform as an oxygen generator for enhanced multi-modality imaging-guided phototherapy.
  65. Minerals and Cancer: Overview of the Possible Diagnostic Value.
  66. Metallocatanionic vesicle-mediated enhanced singlet oxygen generation and photodynamic therapy of cancer cells.
  67. Natural Compounds for Counteracting Nonalcoholic Fatty Liver Disease (NAFLD): Advantages and Limitations of the Suggested Candidates.
  68. Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery.
  69. Traditional and Medical Applications of Fasting.
  70. Factors influencing the anticancer effects of metformin on breast cancer outcomes: a systematic review and meta-analysis.
  71. Herbal Phytomedicine 'Irisolidone' in chronic diseases: Biological Efficacy and pharmacological activity.
  72. Treatment of Glaucoma with Natural Products and Their Mechanism of Action: An Update.
  73. Lactoferrin: A Nutraceutical with Activity against Colorectal Cancer.
  74. Novel Pomegranate-Nanoparticles Ameliorate Cisplatin-Induced Nephrotoxicity and Improves Cisplatin Anti-Cancer Efficacy in Ehrlich Carcinoma Mice Model.
  75. The efficacy of non-fasting ketogenic diet protocol in the management of intractable epilepsy in pediatric patients: a single center study from Saudi Arabia.
  76. Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells.
  77. Photodynamic Theranostics of Central Lung Cancer: Capabilities of Early Diagnosis and Minimally Invasive Therapy (Review).
  78. Metformin Intervention-A Panacea for Cancer Treatment?
  79. Breast Cancer Diet "BCD": A Review of Healthy Dietary Patterns to Prevent Breast Cancer Recurrence and Reduce Mortality.
  80. Fortification of foods with nano-iron: its uptake and potential toxicity: current evidence, controversies, and research gaps.
  81. Enhanced tumor homing of pathogen-mimicking liposomes driven by R848 stimulation: A new platform for synergistic oncology therapy.
  82. Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in Triple-Negative Breast Cancer Cells.
  83. An Unrevealed Molecular Function of Corannulene Buckybowl Glycoconjugates in Selective Tumor Annihilation by Targeting the Cancer-Specific Warburg Effect.
  84. Mechanically tuneable physical nanocomposite hydrogels from polyelectrolyte complex templated silica nanoparticles for anionic therapeutic delivery.
  85. Comprehensive analysis of metabolic isozyme targets in cancer.
  86. An overview of the nutritional value, health properties, and future challenges of Chinese bayberry.
  87. Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet.
  88. Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis.
  89. Effects of Intermittent Fasting on Cardiometabolic Health: An Energy Metabolism Perspective.
  90. Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancer via ROS generation and microbiota modulation.
  91. The nanotechnological approach for nasal delivery of peptide drugs: a comprehensive review.
  92. Amphiphilic small molecular mates match hydrophobic drugs to form nanoassemblies based on drug-mate strategy.
  93. Glucose and H2O2 Dual-Responsive Nanocomplex Grafted with Insulin Prodrug for Blood Glucose Regulation.
  94. Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions.
  95. Traditional Chinese Medicine Compound-Loaded Materials in Bone Regeneration.
  1. Drug Deliv. 2022 Dec;29(1): 792-806
    Construction of pH-sensitive targeted micelle system co-delivery with curcumin and dasatinib and evaluation of anti-liver cancer.
    Xiangle Zeng, Yawen Zhang, Xue Xu, Zhuo Chen, Lanlan Ma, Yushuai Wang, Xuliang Guo, Jianchun Li, Xiu Wang.
      Nanomedicine delivery systems can achieve precise drug delivery and reduce toxic side effects compared with traditional drug delivery methods, but further development is still needed to eliminate obstacles such as multiple drug co-delivery, uncontrolled drug-release, and drug-resistance. Herein, we designed a dual drug-loaded nanosystem (THCD-NPs) that selectively transports and targets tumor cells for the treatment of liver cancer. In this drug delivery system, hyaluronic acid (HA)-conjugated curcumin (Cur) and d-α-tocopherol acid polyethylene glycolsuccinate (TPGS) were used as selective drug-carrying vehicles to deliver dasatinib (DAS) to cancer cells for combined administration. The mean size of the nanoparticles was approximately 66.14 ± 4.02 nm with good in vitro stability. The nanoparticles were pH sensitive and could accelerate drug release at low pH conditions. In vitro experiments showed that THCD-NPs were significantly cytotoxic to HepG2 cells and could be effectively taken up by these cells. Detailed investigations also demonstrated its pro-apoptotic activity. In vivo NIR fluorescence imaging showed that the nanoparticles could accumulate efficiently at the tumor site. Meanwhile, in vivo experiments showed that THCD-NPs significantly inhibited tumor growth and reduced the toxic side effects of free drugs in a mouse solid tumor model. In short, the nanoparticles we prepared provide a new idea for the treatment of liver cancer.
    Keywords:  curcumin; dasatinib; hyaluronic acid; pH response; targeted
    DOI:  https://doi.org/10.1080/10717544.2022.2048132
  2. Front Bioeng Biotechnol. 2022 ;10 836468
    pH-Sensitive and Charge-Reversal Polymeric Nanoplatform Enhanced Photothermal/Photodynamic Synergistic Therapy for Breast Cancer.
    Wenyan Wang, Zimu Li, Xiaozhong Nie, Wenfeng Zeng, Yi Zhang, Yimin Deng, Hongzhong Chen, Xiaowei Zeng, Hualin Ma, Yi Zheng, Nansha Gao.
      As reported, breast cancer is one of the most common malignancies in women and has overtaken lung cancer as the most commonly diagnosed cancer worldwide by 2020. Currently, phototherapy is a promising anti-tumor therapy due to its fewer side effects, less invasiveness, and lower cost. However, its application in cancer therapeutics is limited by the incomplete therapeutic effect caused by low drug penetration and monotherapy. Herein, we built a charge-reversal nanoplatform (Ce6-PLGA@PDA-PAH-DMMA NPs), including polydopamine (PDA) and chlorin e6 (Ce6) for enhancing photothermal/photodynamic synergistic therapy. The PAH-DMMA charge-reversal layer enabled Ce6-PLGA@PDA-PAH-DMMA NPs to have long blood circulation at the normal physiological environment and to successfully realize charge reversal under the weakly acidic tumor microenvironment, improving cellular uptake. Besides, in vitro tests demonstrated that Ce6-PLGA@PDA-PAH-DMMA NPs had high photothermal conversion and greater anti-tumor activity than no charge-reversal nanoparticles, which overcame the limited tumor therapeutic efficacy of PTT or photodynamic therapy alone. Overall, the design of pH-responsive and charge-reversal nanoparticles (Ce6-PLGA@PDA-PAH-DMMA NPs) provided a promising approach for synergistic PTT/PDT therapy against breast cancer.
    Keywords:  cancer nanotechnology; charge-reversal; pH-sensitive; photodynamic therapy; photothermal therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.836468
  3. J Exp Med. 2022 Apr 04. pii: e20212166. [Epub ahead of print]219(4):
    Iron out KRAS-driven cancer.
    Guang Lei, Boyi Gan.
      How to specifically target oncogenic KRAS-driven cancers while sparing normal tissues remains an unmet need in cancer therapy. In this issue of JEM, Jiang et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20210739) leveraged KRAS-induced iron addiction in cancer cells to design a clever drug delivery approach to enable selective inhibition of KRAS signaling in mutant KRAS tumors but not in normal tissues, offering a new strategy for treating this largely incurable disease.
    DOI:  https://doi.org/10.1084/jem.20212166
  4. Acta Biomater. 2022 Mar 07. pii: S1742-7061(22)00135-0. [Epub ahead of print]
    pH/ROS Dual-Responsive Supramolecular Polypeptide Prodrug Nanomedicine Based on Host-Guest Recognition for Cancer Therapy.
    Yue Ding, Chenwei Wang, Yuxuan Ma, Lvming Zhu, Bing Lu, Yang Wang, Jin Wang, Tingting Chen, Chang-Ming Dong, Yong Yao.
      Supramolecular nanomedicine assembly combined with polypeptide prodrug could become a powerful strategy to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. Here, we developed a charge-reversal amphiphilic pillar[5]arene-modified polypeptide (P5-PLL-DMA), and reactive oxygen species (ROS)-sensitive polypeptide prodrug (P-PLL-DOX) including a ROS-cleavable thioketal (TK) linker between doxorubicin (DOX) and poly(L-lysine) (PLL), which could assemble via pillar[5]arene host-guest recognition, and further encapsulate chlorin e6 (Ce6) to obtain a supramolecular polypeptide prodrug (SPP-DOX/Ce6). The chemical conjugation to load drugs of DOX and the negatively charge of SPP-DOX/Ce6 could prevent premature drug leakage, and reduce undesirable interaction with serum proteins to enhance stability under physiological conditions (pH 7.4). Simultaneously, the carried charge of SPP-DOX/Ce6 reversed from negative to positive could effectively enhance the cellular internalization for efficient DOX delivery under acidic tumor microenvironment (pH 6.5). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 rapidly cleaved the TK linker to release activated DOX, inducing the tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug based on pillar[5]arene host-guest recognition represents new avenues to develop stimulus responsive prodrug for enhanced cancer therapy with minimized the side effect. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS dual-sensitive supramolecular polypeptide prodrug (SPP-DOX/Ce6) was developed to minimize drug leakage in blood circulation and trigger sufficient drug release at tumor tissue. The chemical conjugation to load drugs of DOX via a ROS-cleavable thioketal (TK) linker and the distinctive charge-reversal capacity of SPP-DOX/Ce6 significantly enhances the stability under physiological conditions (pH 7.4), while facilitates cellular uptake at tumor site (pH 6.8). Upon 660 nm near-infrared light (NIR) irradiation, the ROS generated by encapsulated Ce6 induces the rapid cleavage of TK linker to release activated DOX, achieving a tumor-specific drug delivery. This intelligent supramolecular polypeptide prodrug SPP-DOX/Ce6 provides an effective strategy to construct stimulus responsive prodrug for enhanced cancer therapy.
    Keywords:  charge-reversal; combination therapy; host-guest interactions; polypeptide; supramolecular prodrug
    DOI:  https://doi.org/10.1016/j.actbio.2022.03.004
  5. Nanoscale Res Lett. 2022 Mar 08. 17(1): 33
    Photodynamic Therapeutic Effect of Nanostructured Metal Sulfide Photosensitizers on Cancer Treatment.
    Daysi Diaz-Diestra, Hanna Madadi Gholipour, Marjan Bazian, Bibek Thapa, Juan Beltran-Huarac.
      Photodynamic therapy (PDT) utilizes photosensitizers (PSs) to produce reactive oxygen species (ROSs) upon irradiation, which causes the shutdown of vessels and deprives the tumor of nutrients and oxygen, and in turn induces adverse effects on the immune system. However, significant efforts are needed to increase the efficiency in PDT in terms of light delivery to specific PSs for the clinical treatment of tumors located deep under the skin. Even though PDT offers a disease site-specific treatment modality, current efforts are directed to improve the solubility (in body fluids and injectable solvents), photostability, amphiphilicity (for tissue penetration), elimination, and systemic toxicity of traditional PSs based on porphyrin derivatives. Nanostructured materials show promising features to achieve most of such combined efforts. They can be artificially engineered to carry multiple theranostic agents onto targeted tumor sites. However, recent studies on photosensitive Cd-based nanostructures, mostly used in PDT, indicate that leeching of Cd2+ ions is stimulated when they are exposed to harsh biological conditions for continuous periods of time, thus making them acutely toxic and hindering their applications in in vivo settings. Since nanostructured materials are not completely immune to degradation, great strides have been made to seek new alternatives. In this review, we focus on the latest advances of Cd-free nanostructured metal transition sulfides (MTSs) as alternative PSs and study their high-energy transfer efficiency, rational designs, and potential applications in cancer-targeted PDT. Nanostructured MTSs are discussed in the context of their versatility to serve as phototherapy agents and superior properties, including their strong absorption in the NIR region, excellent photothermal conversion efficiency, controlled reactive oxygen species (ROS) production, versatile surface chemistry, high fluorescence, and structural and thermal stability. We discuss the latest advancements in correlating the self-aggregation of MTSs with their passive tumor cell targeting, highlighting their ability to efficiently produce ROSs, and mitigating their dark toxicity through polymeric functionalization. Treatment of deep-seated tumors by using these PSs upon preferential uptake by tumor tissues (due to the enhanced permeability and retention effect) is also reviewed. We finally summarize the main future perspectives of MTSs as next-generation PSs within the context of cancer theranostics.
    Keywords:  Cancer treatment; Metal sulfides; Photodynamic therapy; Photosensitizers
    DOI:  https://doi.org/10.1186/s11671-022-03674-8
  6. Small. 2022 Mar 11. e2107690
    Dual-Loaded Liposomes Tagged with Hyaluronic Acid Have Synergistic Effects in Triple-Negative Breast Cancer.
    Shiyan Dong, Ye Bi, Xiangshi Sun, Yarong Zhao, Rongze Sun, Fei Hao, Yating Sun, Yifan Wang, Xuefeng Li, Weiye Deng, Xuan Liu, JongHoon Ha, Lirong Teng, Ping Gong, Jing Xie, Betty Y S Kim, Zhaogang Yang, Wen Jiang, Lesheng Teng.
      Triple-negative breast cancer (TNBC) is the most lethal subtypes of breast cancer. Although chemotherapy is considered the most effective strategy for TNBC, most chemotherapeutics in current use are cytotoxic, meaning they target antiproliferative activity but do not inhibit tumor cell metastasis. Here, a TNBC-specific targeted liposomal formulation of epalrestat (EPS) and doxorubicin (DOX) with synergistic effects on both tumor cell proliferation and metastasis is described. These liposomes are biocompatible and effectively target tumor cells owing to hyaluronic acid (HA) modification on their surface. This active targeting, mediated by CD44-HA interaction, allows DOX and EPS to be delivered simultaneously to tumor cells in vivo, where they suppress not only TNBC tumor growth and the epithelial-mesenchymal transition, but also cancer stem cells, which collectively suppress tumor growth and metastasis of TNBC and may also act to prevent relapse of TNBC.
    Keywords:  antimetastasis; epalrestat; liposomes; targeted delivery; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/smll.202107690
  7. Nutr Cancer. 2022 Mar 10. 1-18
    Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer.
    Malihe Mohamadian, Afsane Bahrami, Maryam Moradi Binabaj, Fereshteh Asgharzadeh, Gordon A Ferns.
      Ovarian cancer is the fifth most common gynecological cancer in women globally. Conventional chemotherapy is the first therapeutic approach in the treatment of ovarian cancer, but its success is limited by severe side effects, transient response, and the high prevalence of relapse. Curcumin is a natural product found in the rhizome extract of Curcuma longa and has been extensively used over the last decades for its unique biological and medicinal properties, which include: having antioxidant, analgesic, anti-inflammation, and anti-tumor activities. Curcumin exerts its anticancer properties against ovarian cancer via multiple mechanisms: interfering with cellular interactions necessary for metastasis and recurrence of OC cells, increasing pro-apoptotic proteins as well as inducing or suppressing generation of different molecules such as cytokines, transcription factors, enzymes, protein kinases, and growth factors. Moreover, curcumin down-regulates various signaling pathways such as PI3K/Akt, Wnt/β-catenin, JAK/STAT3, and MEK/ERK1/2 axes, which at least in part have a role in inhibiting further tumor proliferation, growth, and angiogenesis. In this review, we overview the potential of incorporating curcumin into the treatment of ovarian cancer. In particular, we summarize the preclinical evidence supporting its use in combination with current chemotherapeutic regimens as well as new analogues and formulations under investigation.
    DOI:  https://doi.org/10.1080/01635581.2022.2049321
  8. Cancer Sci. 2022 Mar 10.
    The metabolomic landscape plays a critical role in glioma oncogenesis.
    Kenta Masui, Webster K Cavenee, Paul S Mischel, Noriyuki Shibata.
      Cancer cells depend on metabolic reprogramming for survival, undergoing profound shifts in nutrient-sensing, nutrient uptake and flux through anabolic pathways, in order to drive nucleotide, lipid, and protein synthesis and provide key intermediates needed for those pathways. Although metabolic enzymes themselves can be mutated, including to generate oncometabolites, this is a relatively rare event in cancer. Usually, gene amplification, overexpression, and/or downstream signal transduction upregulate rate-limiting metabolic enzymes and limit feedback loops, to drive persistent tumor growth. Recent molecular genetic advances revealed discrete links between oncogenotypes and the resultant metabolic phenotypes. However, more comprehensive approaches are needed to unravel the dynamic spatio-temporal regulatory map of enzymes and metabolites that enable cancer cells to adapt to their microenvironment to maximize tumor growth. Proteomic and metabolomic analyses are powerful tools for analyzing a repertoire of metabolic enzymes as well as intermediary metabolites, and in conjunction with other omic approaches could provide critical information in this regard. Here, we provide an overview of cancer metabolism, especially from an "omics" perspective and with a particular focus on the genomically well-characterized malignant tumor, glioblastoma. We further discuss how metabolomics could be leveraged to improve the management of patients, by linking cancer cell genotype, epigenotype and phenotype through metabolic reprogramming.
    Keywords:  OMICS; epigenetics; glioblastoma; mTOR complex; metabolome
    DOI:  https://doi.org/10.1111/cas.15325
  9. J Inorg Biochem. 2022 Jan 15. pii: S0162-0134(22)00006-X. [Epub ahead of print]230 111717
    Drug delivery system with dual imaging and dual response control drug release functions for chemo-photodynamic synergistic therapy.
    Zhi-Yuan Wu, Zui-Harng Lee, Yu-Ya Huang, Min-Hsuan Tsou, Hsiu-Mei Lin.
      Traditional treatment of cancers such as chemotherapy still causes many side effects after the treatment even nowadays, therefore combination therapies by using drug delivery systems are valued by more and more scientists. However, loading multiple drugs in the nanoparticles for drug delivery system may cause insufficient drugs or functional groups, which might let the nanomaterial have fewer functions. Therefore, making the mesoporous silica nanoparticles (MSNs) have photodynamic therapy function by "doping " lanthanide ions into the material structure, can evade this problem. Moreover, with the doping of lanthanide metals, the MSNs can have not only dual imaging functions of both magnetic resonance imaging and fluorescence, but also achieve photodynamic function. To feature the material with more function, chemotherapeutic drug-doxorubicin was loaded into the pores of MSNs and then bonded hyaluronic acid which is the active target and a gatekeeper, on the surface of MSNs. Finally, an all-in-one drug delivery system" Hyaluronidase and pH-responsive mesoporous silica nanoparticles with dual-imaging activity for chemo-photodynamic therapy" is synthesized. The first part in this experiment was to confirm the physical properties of the lanthanides dopped MSN and its photodynamic treatment effect. The second part was to confirm that each organic molecule had been successfully bonded to the surface of the MSN and achieve pH and Hyaluronidase response drug release effect, The last part was to prove that the drug delivery system had a significant anticancer effect through cell experiments.
    Keywords:  Combination therapies; Drug delivery system; Hyaluronic acid; Hyaluronidase; Mesoporous silica nanoparticle; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.jinorgbio.2022.111717
  10. Theranostics. 2022 ;12(5): 2290-2321
    Versatile carbon nanoplatforms for cancer treatment and diagnosis: strategies, applications and future perspectives.
    Lu Tang, Jing Li, Ting Pan, Yue Yin, Yijun Mei, Qiaqia Xiao, Ruotong Wang, Ziwei Yan, Wei Wang.
      Despite the encouraging breakthroughs in medical development, cancer remains one of the principle causes of death and threatens human health around the world. Conventional treatment strategies often kill cancer cells at the expense of serious adverse effects or great pain, which yet is not able to achieve an effective cure. Therefore, it is urgent to seek for other novel anticancer approaches to improve the survival rate and life quality of cancer patients. During the past decades, nanotechnology has made tremendous progress in cancer therapy due to many advantages such as targeted drug delivery, decreased dosage-related adverse effects and prolonged drug circulation time. In the context of nanomedicine, carbon nanomaterials occupy very significant positions. Owing to their innate outstanding optical, thermal, electronic, and mechanic features, easy functionalization possibility and large surface for drug loading, carbon nanomaterials serve as not only drug carriers, but also multifunctional platforms to combine with diverse treatment and diagnosis modalities against cancer. Therefore, developing more carbon-based nanoplatforms plays a critical role in cancer theranostics and an update overview that summarizes the recent achievement of carbon nanomaterial-mediated anticancer theranostic approaches is of necessity. In this review, five typical and widely investigated carbon nanomaterials including graphene, graphdiyne, fullerene, carbon nanotubes and carbon quantum dots are introduced in detail from the aspect of treatment strategies based on both cancer cells and tumor microenvironment-involved therapeutic targets. Meanwhile, modern diagnostic methods and clinical translatability of carbon nanomaterials will be highlighted as well.
    Keywords:  Cancer theranostics, Nanotechnology; Carbon materials; Synergistic strategy; Targeted drug delivery
    DOI:  https://doi.org/10.7150/thno.69628
  11. Sci Signal. 2022 Mar 08. 15(724): eabp8972
    A mutation breaks its silence on mutant KRAS.
    Amy E Baek.
      Leveraging silent mutations and alternative splicing enables targeting of a KRAS mutant.
    DOI:  https://doi.org/10.1126/scisignal.abp8972
  12. Polymers (Basel). 2022 Feb 27. pii: 950. [Epub ahead of print]14(5):
    Polysaccharide-Drug Conjugates: A Tool for Enhanced Cancer Therapy.
    Neena Yadav, Arul Prakash Francis, Veeraraghavan Vishnu Priya, Shankargouda Patil, Shazia Mustaq, Sameer Saeed Khan, Khalid J Alzahrani, Hamsa Jameel Banjer, Surapaneni Krishna Mohan, Ullas Mony, Rukkumani Rajagopalan.
      Cancer is one of the most widespread deadly diseases, following cardiovascular disease, worldwide. Chemotherapy is widely used in combination with surgery, hormone and radiation therapy to treat various cancers. However, chemotherapeutic drugs can cause severe side effects due to non-specific targeting, poor bioavailability, low therapeutic indices, and high dose requirements. Several drug carriers successfully overcome these issues and deliver drugs to the desired sites, reducing the side effects. Among various drug delivery systems, polysaccharide-based carriers that target only the cancer cells have been developed to overcome the toxicity of chemotherapeutics. Polysaccharides are non-toxic, biodegradable, hydrophilic biopolymers that can be easily modified chemically to improve the bioavailability and stability for delivering therapeutics into cancer tissues. Different polysaccharides, such as chitosan, alginates, cyclodextrin, pullulan, hyaluronic acid, dextran, guar gum, pectin, and cellulose, have been used in anti-cancer drug delivery systems. This review highlights the recent progress made in polysaccharides-based drug carriers in anti-cancer therapy.
    Keywords:  cancer; chemotherapy; drug delivery; polysaccharides; toxicity
    DOI:  https://doi.org/10.3390/polym14050950
  13. Phytother Res. 2022 Mar 08.
    From propolis to nanopropolis: An exemplary journey and a paradigm shift of a resinous substance produced by bees.
    Shamama Javed, Bharti Mangla, Waquar Ahsan.
      Propolis, a natural resinous mixture produced by honey bees is poised with diverse biological activities. Owing to the presence of flavonoids, phenolic acids, terpenes, and sesquiterpenes, propolis has garnered versatile applications in pharmaceutical industry. The biopharmaceutical issues associated with propolis often beset its use as being too hydrophobic in nature; it is not absorbed in the body well. To combat the problem, various nanotechnological approaches for the development of novel drug delivery systems are generally applied to improve its bioavailability. This paradigm shift and transition of conventional propolis to nanopropolis are evident from the literature wherein a multitude of studies are available on nanopropolis with improved bioavailability profile. These approaches include preparation of gold nanoparticles, silver nanoparticles, magnetic nanoparticles, liposomes, liquid crystalline formulations, solid lipid nanoparticles, mesoporous silica nanoparticles, etc. Nanopropolis has further been explored to assess the potential benefits of propolis for the development of futuristic useful products such as sunscreens, creams, mouthwashes, toothpastes, and nutritional supplements with improved solubility, bioavailability, and penetration profiles. However, more high-quality clinical studies assessing the effects of propolis either alone or in combination with synthetic drugs as well as natural products are warranted and its safety needs to be firmly established.
    Keywords:  bioavailability; chemical composition; extraction method; nanoparticles; nanopropolis; resinous gum
    DOI:  https://doi.org/10.1002/ptr.7435
  14. Biochim Biophys Acta Rev Cancer. 2022 Mar 08. pii: S0304-419X(22)00030-0. [Epub ahead of print] 188705
    Metabolic tricks of cancer cells.
    Katerina Hönigova, Jiri Navratil, Barbora Peltanova, Hana Holcova Polanska, Martina Raudenska, Michal Masarik.
      One of the characteristics of cancer cells important for tumorigenesis is their metabolic plasticity. Indeed, in various stress conditions, cancer cells can reshape their metabolic pathways to support the increased energy request due to continuous growth and rapid proliferation. Moreover, selective pressures in the tumor microenvironment, such as hypoxia, acidosis, and competition for resources, force cancer cells to adapt by complete reorganization of their metabolism. In this review, we highlight the characteristics of cancer metabolism and discuss its clinical significance, since overcoming metabolic plasticity of cancer cells is a key objective of modern cancer therapeutics and a better understanding of metabolic reprogramming may lead to the identification of possible targets for cancer therapy.
    Keywords:  Cancer metabolism; Cell death; Glutaminolysis; Metabolic symbiosis; Mitochondrial bioenergetics; Warburg effect
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188705
  15. Life Sci. 2022 Mar 02. pii: S0024-3205(22)00135-7. [Epub ahead of print]296 120435
    Transferrin-modified nanoparticles for targeted delivery of Asiatic acid to glioblastoma cells.
    Maria João Ramalho, Maria Bravo, Joana Angélica Loureiro, Jorge Lima, Maria Carmo Pereira.
      AIMS: Glioblastoma (GBM) is the most common and deadliest type of brain cancer, and the current therapeutic options are not curative, imposing the need for novel strategies. Asiatic acid (AA) is a natural compound and has been explored due to its anti-glioma activity and lower toxicity to healthy tissues compared with conventional chemotherapeutic agents. However, its poor water-solubility is an obstacle for clinical application. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were proposed in this work for Asiatic acid (AA) delivery.MAIN METHODS: A central composite design was implemented to optimize the NPs, and their surface was further modified with transferrin (Tf), for targeted delivery to GBM cells. The anti-glioma activity of the NPs was studied in vitro using human GBM cells and immortalized human astrocytes.
    KEY FINDINGS: The NPs exhibited a mean size smaller than 200 nm, with low polydispersity and negative zeta potential, indicating their suitability for brain tumor delivery. The NPs also exhibited high encapsulation efficiency and maintained a slow and controlled release of AA for 20 days. In vitro cell studies showed that NPs were able to maintain the anti-glioma activity of the natural compound and that the surface modification with Tf molecules was able to increase the cellular uptake in GBM cells, enhancing their selectivity and decreasing toxicity in healthy cells.
    SIGNIFICANCE: Overall, this work provided guidance for designing brain-targeting delivery systems of natural compounds.
    Keywords:  Brain tumor; Nanomedicine; Natural compound; Poly(lactic-co-glycolic acid); Transferrin receptor
    DOI:  https://doi.org/10.1016/j.lfs.2022.120435
  16. Molecules. 2022 Feb 24. pii: 1543. [Epub ahead of print]27(5):
    Perspectives and Prospective on Solid Lipid Nanoparticles as Drug Delivery Systems.
    Osama A Madkhali.
      Combating multiple drug resistance necessitates the delivery of drug molecules at the cellular level. Novel drug delivery formulations have made it possible to improve the therapeutic effects of drugs and have opened up new possibilities for research. Solid lipid nanoparticles (SLNs), a class of colloidal drug carriers made of lipids, have emerged as potentially effective drug delivery systems. The use of SLNs is associated with numerous advantages such as low toxicity, high bioavailability of drugs, versatility in the incorporation of hydrophilic and lipophilic drugs, and the potential for production of large quantities of the carrier systems. The SLNs and nanostructured lipid carriers (NLCs) are the two most frequently used types of nanoparticles. These types of nanoparticles can be adjusted to deliver medications in specific dosages to specific tissues, while minimizing leakage and binding to non-target tissues.
    Keywords:  antibiotics; anticancer; drug delivery; solid lipid nanoparticles
    DOI:  https://doi.org/10.3390/molecules27051543
  17. Front Oncol. 2022 ;12 783908
    Oscillations and Dynamic Symbiosis in Cellular Metabolism in Cancer.
    Takashi Amemiya, Tomohiko Yamaguchi.
      The grade of malignancy differs among cancer cell types, yet it remains the burden of genetic studies to understand the reasons behind this observation. Metabolic studies of cancer, based on the Warburg effect or aerobic glycolysis, have also not provided any clarity. Instead, the significance of oxidative phosphorylation (OXPHOS) has been found to play critical roles in aggressive cancer cells. In this perspective, metabolic symbiosis is addressed as one of the ultimate causes of the grade of cancer malignancy. Metabolic symbiosis gives rise to metabolic heterogeneities which enable cancer cells to acquire greater opportunities for proliferation and metastasis in tumor microenvironments. This study introduces a real-time new imaging technique to visualize metabolic symbiosis between cancer-associated fibroblasts (CAFs) and cancer cells based on the metabolic oscillations in these cells. The causality of cellular oscillations in cancer cells and CAFs, connected through lactate transport, is a key point for the development of this novel technique.
    Keywords:  cancer; heterogeneity; malignancy; metabolic oscillations; symbiosis
    DOI:  https://doi.org/10.3389/fonc.2022.783908
  18. Molecules. 2022 Mar 04. pii: 1701. [Epub ahead of print]27(5):
    Sustainable Valorization of Tomato By-Products to Obtain Bioactive Compounds: Their Potential in Inflammation and Cancer Management.
    Tânia Laranjeira, Ana Costa, Catarina Faria-Silva, Daniela Ribeiro, José Miguel P Ferreira de Oliveira, Sandra Simões, Andreia Ascenso.
      Tomato producing and processing industries present undoubted potential for industrial discarded products valorization whether due to the overproduction of fresh tomatoes or to the loss during processing. Although tomato by-products are not yet considered a raw material, several studies have suggested innovative and profitable applications. It is often referred to as "tomato pomace" and is quite rich in a variety of bioactive compounds. Lycopene, vitamin C, β-carotene, phenolic compounds, and tocopherol are some of the bioactives herein discussed. Tomato by-products are also rich in minerals. Many of these compounds are powerful antioxidants with anti-inflammatory properties besides modulating the immune system. Several researchers have focused on the possible application of natural ingredients, especially those extracted from foods, and their physiological and pharmacological effects. Herein, the effects of processing and further applications of the bioactive compounds present in tomato by-products were carefully reviewed, especially regarding the anti-inflammatory and anti-cancer effects. The aim of this review was thus to highlight the existing opportunities to create profitable and innovative applications for tomato by-products in health context.
    Keywords:  anti-cancer; anti-inflammatory; oleoresins; peel; pomace; seeds; tomato; tomato processing industry
    DOI:  https://doi.org/10.3390/molecules27051701
  19. Nanomaterials (Basel). 2022 Feb 23. pii: 743. [Epub ahead of print]12(5):
    Recent Advancements in Mitochondria-Targeted Nanoparticle Drug Delivery for Cancer Therapy.
    Jiangsheng Xu, James G Shamul, Elyahb Allie Kwizera, Xiaoming He.
      Mitochondria are critical subcellular organelles that produce most of the adenosine triphosphate (ATP) as the energy source for most eukaryotic cells. Moreover, recent findings show that mitochondria are not only the "powerhouse" inside cells, but also excellent targets for inducing cell death via apoptosis that is mitochondria-centered. For several decades, cancer nanotherapeutics have been designed to specifically target mitochondria with several targeting moieties, and cause mitochondrial dysfunction via photodynamic, photothermal, or/and chemo therapies. These strategies have been shown to augment the killing of cancer cells in a tumor while reducing damage to its surrounding healthy tissues. Furthermore, mitochondria-targeting nanotechnologies have been demonstrated to be highly efficacious compared to non-mitochondria-targeting platforms both in vitro and in vivo for cancer therapies. Moreover, mitochondria-targeting nanotechnologies have been intelligently designed and tailored to the hypoxic and slightly acidic tumor microenvironment for improved cancer therapies. Collectively, mitochondria-targeting may be a promising strategy for the engineering of nanoparticles for drug delivery to combat cancer.
    Keywords:  cancer therapy; mitochondria; nanoparticle; photodynamic; photothermal
    DOI:  https://doi.org/10.3390/nano12050743
  20. Theranostics. 2022 ;12(5): 2406-2426
    Molecular imprinting of glycoproteins: From preparation to cancer theranostics.
    Muhammad Mujahid Ali, Shoujun Zhu, Farrukh Raza Amin, Dilshad Hussain, Zhenxia Du, Lianghai Hu.
      Glycoprotein imprinted polymers have rapidly grown as excellent receptors for cancer targeting, diagnostics, inhibition, and nanomedicines as they specifically target glycans and glycosites overexpressed in various tumors. Compared to natural antibodies, they are easy to synthesize, stable, and cost-efficient. Currently, no study specifically discusses glycoproteins imprinting strategies for cancer theranostics. In this review, firstly we explored various factors involved in designing and synthesis of glycoprotein imprinted materials, including, the characteristics and choice of monomers for imprinting, types of templates and their interactions involved, and the imprinting methods. Secondly, the integration of these MIPs with different probes that have been applied for in vitro and in vivo targeting for cancer diagnostics including biosensing and bioimaging, and image-guided therapeutic applications as nanomedicines. These Glycoprotein imprinted polymers have been found to specifically target the glycoprotein biomarkers and glycosylated cell receptors overexpressed in different cancers and have been reported as excellent diagnostic tools. As nanomedicines, they have been potentially employed in various modes of cancer therapy such as targeted drug delivery, photodynamic therapy, photothermal therapy, and nanoMIPs themselves as therapeutics for locally killing tumor cells. Although the research is still in its early stages and no real-world clinical trials on humans have been conducted, nanoMIPs have a promising future in this field. We believe these findings will pave the way for MIPs in advanced diagnostics, antibody treatment, and immunotherapy as future nanomedicine for real-world cancer theranostics.
    Keywords:  Biosensing; Cancer theranostics; Glycoproteins; Molecularly imprinting; Proteomics
    DOI:  https://doi.org/10.7150/thno.69189
  21. Polymers (Basel). 2022 Mar 02. pii: 1010. [Epub ahead of print]14(5):
    Polymeric Nanoparticles-Loaded Hydrogels for Biomedical Applications: A Systematic Review on In Vivo Findings.
    Débora Nunes, Stéphanie Andrade, Maria João Ramalho, Joana A Loureiro, Maria Carmo Pereira.
      Clinically available medications face several hurdles that limit their therapeutic activity, including restricted access to the target tissues due to biological barriers, low bioavailability, and poor pharmacokinetic properties. Drug delivery systems (DDS), such as nanoparticles (NPs) and hydrogels, have been widely employed to address these issues. Furthermore, the DDS improves drugs' therapeutic efficacy while reducing undesired side effects caused by the unspecific distribution over the different tissues. The integration of NPs into hydrogels has emerged to improve their performance when compared with each DDS individually. The combination of both DDS enhances the ability to deliver drugs in a localized and targeted manner, paired with a controlled and sustained drug release, resulting in increased drug therapeutic effectiveness. With the incorporation of the NPs into hydrogels, it is possible to apply the DDS locally and then provide a sustained release of the NPs in the site of action, allowing the drug uptake in the required location. Additionally, most of the materials used to produce the hydrogels and NPs present low toxicity. This article provides a systematic review of the polymeric NPs-loaded hydrogels developed for various biomedical applications, focusing on studies that present in vivo data.
    Keywords:  administration routes; cancer therapy; chronic wound treatment; drug release; local delivery; nanomaterials; polymers; thermosensitive hydrogel
    DOI:  https://doi.org/10.3390/polym14051010
  22. Int J Mol Sci. 2022 Feb 28. pii: 2672. [Epub ahead of print]23(5):
    Small Molecule Compounds of Natural Origin Target Cellular Receptors to Inhibit Cancer Development and Progression.
    Jinhua Wang, Dangdang Li, Bo Zhao, Juhyok Kim, Guangchao Sui, Jinming Shi.
      Receptors are macromolecules that transmit information regulating cell proliferation, differentiation, migration and apoptosis, play key roles in oncogenic processes and correlate with the prognoses of cancer patients. Thus, targeting receptors to constrain cancer development and progression has gained widespread interest. Small molecule compounds of natural origin have been widely used as drugs or adjuvant chemotherapeutic agents in cancer therapies due to their activities of selectively killing cancer cells, alleviating drug resistance and mitigating side effects. Meanwhile, many natural compounds, including those targeting receptors, are still under laboratory investigation for their anti-cancer activities and mechanisms. In this review, we classify the receptors by their structures and functions, illustrate the natural compounds targeting these receptors and discuss the mechanisms of their anti-cancer activities. We aim to provide primary knowledge of mechanistic regulation and clinical applications of cancer therapies through targeting deregulated receptors.
    Keywords:  cancers; natural compounds; receptors
    DOI:  https://doi.org/10.3390/ijms23052672
  23. Anal Cell Pathol (Amst). 2022 ;2022 5946670
    Curcumin Inhibits Papillary Thyroid Cancer Cell Proliferation by Regulating lncRNA LINC00691.
    Zhihua Li, Youbing Gao, Lijun Li, Shanshan Xie.
      Papillary thyroid cancer (PTC) is a type of epithelial-derived differentiated TC that reportedly accounts for a majority of TCs. Curcumin, a polyphenolic compound and a member of the Zingiberaceae (ginger) family derived from turmeric plants, can exhibit anticancer effects. Herein, we aimed to investigate the effect of curcumin on PTC and elucidate underlying mechanisms. Accordingly, PTC B-CPAP cells were treated with curcumin, in combination with/without long noncoding RNA LINC00691 inhibition, to determine the effect of curcumin and its relationship with LINC00691 in PTC cells. We observed that curcumin treatment decreased B-CPAP cell proliferation and promoted apoptosis. Curcumin inhibited LINC00691 expression in B-CPAP cells. Curcumin administration or si-LINC00691 transfection alone promoted ATP levels, inhibited glucose uptake and lactic acid levels, and inhibited lactate dehydrogenase A and hexokinase 2 protein expression in B-CPAP cells, which were further enhanced by combination treatment. Moreover, curcumin administration or si-LINC00691 transfection alone inhibited p-Akt activity, further suppressed by combination treatment. Akt inhibition promoted apoptosis and suppressed the Warburg effect in B-CPAP cells. In conclusion, our findings indicate that curcumin promotes apoptosis and suppresses proliferation and the Warburg effect by inhibiting LINC00691 in B-CPAP cells. The precise molecular mechanism might be mediated through the Akt signaling pathway, providing a theoretical basis for the treatment of PTC with curcumin.
    DOI:  https://doi.org/10.1155/2022/5946670
  24. Front Pharmacol. 2022 ;13 801733
    Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies.
    Rajeev K Singla, Sahar Behzad, Johra Khan, Christos Tsagkaris, Rupesh K Gautam, Rajat Goyal, Hitesh Chopra, Bairong Shen.
      Endometrial cancer (EC) is the sixth most prevalent type of cancer among women. Kinases, enzymes mediating the transfer of adenosine triphosphate (ATP) in several signaling pathways, play a significant role in carcinogenesis and cancer cells' survival and proliferation. Cyclin-dependent kinases (CDKs) are involved in EC pathogenesis; therefore, CDK inhibitors (CDKin) have a noteworthy therapeutic potential in this type of cancer, particularly in EC type 1. Natural compounds have been used for decades in the treatment of cancer serving as a source of anticancer bioactive molecules. Many phenolic and non-phenolic natural compounds covering flavonoids, stilbenoids, coumarins, biphenyl compounds, alkaloids, glycosides, terpenes, and terpenoids have shown moderate to high effectiveness against CDKin-mediated carcinogenic signaling pathways (PI3K, ERK1/2, Akt, ATM, mTOR, TP53). Pharmaceutical regimens based on two natural compounds, trabectedin and ixabepilone, have been investigated in humans showing short and midterm efficacy as second-line treatments in phase II clinical trials. The purpose of this review is twofold: the authors first provide an overview of the involvement of kinases and kinase inhibitors in the pathogenesis and treatment of EC and then discuss the existing evidence about natural products' derived kinase inhibitors in the management of the disease and outline relevant future research.
    Keywords:  endometrial cancer; hormone-sensitive cancer; medicinal plants; metastasis; natural products
    DOI:  https://doi.org/10.3389/fphar.2022.801733
  25. Drug Discov Today. 2022 Mar 02. pii: S1359-6446(22)00086-1. [Epub ahead of print]
    Ultrasound-activated nanomaterials for sonodynamic cancer theranostics.
    Nan Wu, Ching-Hsiang Fan, Chih-Kuang Yeh.
      Despite intensive efforts to develop diagnostic and therapeutic tools, the successful treatment of cancer is still hampered by the obscure boundary between cancerous cells and normal cells, recurrence of the cancer, and the development of drug resistance during chemotherapy. In recent years, sonodynamic therapy (SDT), employing therapeutic ultrasound with sonosensitizers, has attracted attention as a potentially promising approach for cancer therapy. This review describes the current understanding of the mechanisms and the preclinical and clinical efficacy of SDT-based applications in tumors, providing an insight into the therapeutic potential offered by SDT. The limitations and future directions of this emerging treatment are also discussed.
    Keywords:  cancer application; reactive oxygen species; sonodynamic therapy; tumor microenvironment; ultrasound
    DOI:  https://doi.org/10.1016/j.drudis.2022.02.025
  26. Biomaterials. 2022 Feb 23. pii: S0142-9612(22)00076-X. [Epub ahead of print]283 121437
    Superoxide dismutase-loaded porous polymersomes as highly efficient antioxidant nanoparticles targeting synovium for osteoarthritis therapy.
    Tao Gui, Lijun Luo, Bonirath Chhay, Leilei Zhong, Yulong Wei, Lutian Yao, Wei Yu, Jun Li, Charles L Nelson, Andrew Tsourkas, Ling Qin, Zhiliang Cheng.
      Oxidative stress and the reactive oxygen species (ROS) have important roles in osteoarthritis (OA) development and progression. Scavenging ROS by exogenous antioxidant enzymes could be a promising approach for OA treatment. However, the direct use of antioxidant enzymes, such as superoxide dismutase (SOD), is challenging due to a lack of effective drug delivery system to knee joints. This study utilized a highly efficient antioxidative nanoparticle based on SOD-loaded porous polymersome nanoparticles (SOD-NPs) for delivery of SOD to mouse knee joints. The resultant SOD-NPs had prolonged mouse joint retention time with predominant accumulation in synovium but not in articular cartilage. Examining human synovial explants revealed that SOD-NPs minimize oxidative damages induced by OA-like insults. Intra-articular injections of SOD-NPs in mice receiving OA surgery were effective in attenuating OA initiation and preventing its further progression. Mechanistically, SOD-NPs reduced ROS production and the synthesis of catabolic proteases in both articular cartilage and synovium. Hence, our work demonstrates the therapeutic potential of SOD-NPs and indicate that targeting synovium holds a great promise for OA therapy.
    Keywords:  Antioxidant nanoparticles; Osteoarthritis; Porous polymersomes; Superoxide dismutase; Synovium
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121437
  27. Semin Cancer Biol. 2022 Mar 04. pii: S1044-579X(22)00051-7. [Epub ahead of print]
    Nano-targeting vascular remodeling in cancer: Recent developments and future directions.
    Roberta Giordo, Zena Wehbe, Panagiotis Paliogiannis, Ali H Eid, Arduino A Mangoni, Gianfranco Pintus.
      Tumor growth and progression are strictly dependent on the adequate blood supply of oxygen and nutrients. The formation of new blood vessels and vascular networks is essential to ensure this demand. Blood vessels also facilitate the invasion of cancer cells into nearby tissues and their subsequent metastasis. Tumor cells represent the main driver of the neovascularization process through the direct or indirect, by neighboring non-cancer cells, release of pro-angiogenic molecules. The mediators (e.g., growth factors and extracellular matrix components), signaling pathways, cellular components, and processes (e.g., endothelial cell proliferation and migration) activated in tumor angiogenesis are similar to those involved in normal vascular development, except they lack efficient control mechanisms. Consequently, newly formed tumor vessels are typically fragile and hyperpermeable with a reduced and erratic blood flow. Targeting the tumor vasculature has been the focus of intense research over the last 20 years. However, despite the initial interest and expectations, the systemic use of anti-angiogenic drugs has not always led to therapeutic breakthroughs and, in some cases, has been associated with the development of tumor adaptive resistance resulting in a more aggressive phenotype. Therefore, new therapeutic approaches have focused on combining anti-angiogenic agents with chemotherapy or immunotherapy and/or optimizing (normalizing) the structure and function of tumor blood vessels to ensure a more efficient drug delivery. In this context, nanomedicine offers the significant advantage of targeting and releasing anti-angiogenic drugs at specific sites, minimizing toxicity in healthy tissues. Several nanoparticles possess intrinsic modulatory effects on angiogenesis, while others have been developed to facilitate drug delivery in association with chemotherapy, thermotherapy, radiotherapy or in response to specific stimuli within the tumor environment (e.g., enzymes, ions, redox potential) or exogenous stimuli (e.g., temperature, electricity, magnetic fields, and ultrasound). Other nanoparticles can modify, under specific conditions, their physical properties (e.g., dimensions, structure, and interactions) to increase penetration in tumor cells. This review provides a comprehensive appraisal of the critical modulators of tumor vascular biology, the most promising nano-strategies that specifically target such modulators, and the directions for future research and clinical applications.
    Keywords:  Angiogenesis; Drug-delivery; Nanomedicine; Nanotechnologies; Therapy; Tumor; Vascular remodeling
    DOI:  https://doi.org/10.1016/j.semcancer.2022.03.001
  28. Drug Resist Updat. 2022 Mar;pii: S1368-7646(22)00021-8. [Epub ahead of print]61 100822
    Targeting metabolism to overcome cancer drug resistance: A promising therapeutic strategy for diffuse large B cell lymphoma.
    Manfei Pi, Huixian Kuang, Chunyan Yue, Qixuan Yang, Anqin Wu, Yuhua Li, Yehuda G Assaraf, Dong-Hua Yang, Shaojie Wu.
      Cancer cell metabolism including aerobic glycolysis, amino acid and fatty acid metabolism, has been extensively studied. Metabolic reprogramming is a major hallmark of cancer, which promotes cancer cell proliferation, progression and metastasis, as well as provokes resistance to chemotherapeutic drugs. Several signal transduction pathways, such as BCR, MEK/ERK, Notch, NF-κB and PI3K/AKT/mTOR, regulate tumor metabolism, hence promoting tumor cell growth, proliferation and progression. Therefore, targeting metabolic enzymes, metabolites or their signal transduction pathways may constitute a promising therapeutic strategy to enhance cancer treatment efficacy. Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of non-Hodgkin lymphoma (NHL), and one-third of DLBCL patients suffer from relapsed/refractory disease after chemotherapy. The mechanisms underlying drug resistance are complex, including target gene mutations, metabolic reprogramming, aberrant signal transduction pathways, enhanced drug efflux via overexpression of multidrug efflux transporters like P-glycoprotein, upregulation of anti-apoptotic proteins, drug sequestration and enhanced DND repair. This review delineates the distinct metabolic reprogramming patterns and the association between metabolism and anticancer drug resistance in DLBCL as well as the emerging strategies to surmount chemoresistance in DLBCL.
    Keywords:  cancer drug resistance; diffuse large B cell lymphoma; tumor metabolism
    DOI:  https://doi.org/10.1016/j.drup.2022.100822
  29. Nanomedicine (Lond). 2022 Mar 09.
    Phytochemical-loaded liposomes for anticancer therapy: an updated review.
    Vivek P Chavda, Disha Vihol, Bhavya Mehta, Dhruvil Shah, Manan Patel, Lalitkumar K Vora, Miguel Pereira-Silva, Ana Cláudia Paiva-Santos.
      The major obstacles observed in current chemotherapy are severe adverse effects, narrow therapeutic indexes and multidrug resistance. Anticancer phytochemicals are extracted and purified from natural plants, providing alternative therapeutic approaches with recognized biomedical benefits. However, poor bioavailability, high dose requirements and non-specific targeting have made those molecules less effective. To tackle those issues, liposomal nanovesicles for phytochemical delivery are taken into consideration for improving the therapeutic effectiveness by increasing transportation across cell barriers and conferring attractive cancer-specific targeting capabilities. In the present review, the liposomal approaches of anticancer phytochemicals are discussed, and recent advances in these formulations applied to cancer phytotherapy are further reviewed by an informed approach.
    Keywords:  anticancer; liposome; marketed product; nanoformulation; patent; phytochemical
    DOI:  https://doi.org/10.2217/nnm-2021-0463
  30. Biomaterials. 2022 Mar 01. pii: S0142-9612(22)00088-6. [Epub ahead of print]283 121449
    Microenvironment-driven sequential ferroptosis, photodynamic therapy, and chemotherapy for targeted breast cancer therapy by a cancer-cell-membrane-coated nanoscale metal-organic framework.
    Wei-Lun Pan, Yong Tan, Wei Meng, Nai-Han Huang, Yi-Bang Zhao, Zhi-Qiang Yu, Zhong Huang, Wen-Hua Zhang, Bin Sun, Jin-Xiang Chen.
      Designing and developing nanomedicine based on the tumor microenvironment (TME) for effective cancer treatment is highly desirable. In this work, polyvinyl pyrrolidone (PVP) dispersed nanoscale metal-organic framework (NMOF) of Fe-TCPP (TCPP = tetrakis (4-carboxyphenyl) porphyrin) loaded with hypoxia-activable prodrug tirapazamine (TPZ) and coated by the cancer cell membrane (CM) is constructed (the formed nanocomposite denoted as PFTT@CM). Due to the functionalization with the homologous cancer cell membrane, PFTT@CM is camouflaged to evade the immune clearance and preferentially accumulates at the tumor site. Once internalized by cancer cells, PFTT@CM is activated by the TME through redox reaction and Fenton reaction between Fe3+ in nano-platform and endogenous glutathione (GSH) and hydrogen peroxide (H2O2) to promote GSH exhausting as well as •OH and O2 production, which triggers ferroptosis and dramatically enhances photodynamic therapy (PDT) efficacy. Subsequently, the PDT process mediated by TCPP and light would consume oxygen and aggravate tumor hypoxia to further activate the prodrug TPZ for cancer chemotherapy. As a consequence, the TME-driven PFTT@CM nano-platform not only demonstrated its TME modulation ability but also showed a sequential synergistic therapy, which eventually inhibited the cancer cell proliferation. This multimodal nano-platform is expected to shed light on the design of TME-activatable reaction to reinforce the synergistic therapeutic outcome and facilitate the development of effective cancer nanomedicine.
    Keywords:  Cancer cell membrane coating; Chemotherapy; Ferroptosis; Homologous targeting; Photodynamic therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121449
  31. Acta Biomater. 2022 Mar 05. pii: S1742-7061(22)00132-5. [Epub ahead of print]
    TRAIL-modified, doxorubicin-embedded periodic mesoporous organosilica nanoparticles for targeted drug delivery and efficient antitumor immunotherapy.
    Xinyao Feng, Fangshen Li, Liangliang Zhang, Wenmo Liu, Xupu Wang, Rui Zhu, Zhen-An Qiao, Bin Yu, Xianghui Yu.
      Traditional anticancer treatments directly target tumor cells. In contrast, cancer immunotherapy fortifies host immunity. Nanoparticles that incorporate both immunomodulatory and chemotherapeutic agents regulate the tumor microenvironment by activating immune cells and enhancing antitumor immunity. Nanoparticle-based cancer immunotherapy has received considerable attention and has been extensively studied in recent years. In this study, we developed a targeted drug delivery system to enhance immunotherapeutic efficacy and overcome drug resistance by inducing tumor apoptosis and immunogenic cell death (ICD), and activating immune cells. Periodic mesoporous organosilica nanoparticles (PMOs) bore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on their surfaces, and their inner cores were loaded with doxorubicin (DOX). TRAIL enhanced the nanoparticle-targeting capacity and worked synergistically with DOX against breast cancer cells in vitro and in vivo. Furthermore, we revealed for the first time the ability of PMOs to activate dendritic cells (DCs) and elevate ICD levels of DOX in vitro, and TRAIL further enhances the immunomodulatory function of PMOs. Systemic exposure to DOX@PMO-hT induced an immune response, activated DCs and CD4+ and CD8+ T cells, and significantly suppressed tumor growth in a 4T1-bearing immunocompetent mouse model. Overall, our study demonstrates that TRAIL-modified, DOX-embedded PMO nanoparticles represent a good candidate for tumor-targeted immunotherapy, which has relatively superior therapeutic efficacy and highly promising future application prospects. STATEMENT OF SIGNIFICANCE: This study revealed for the first time the ability of PMOs to elevate ICD levels and activate DCs in vitro. The results explained the immunomodulatory function of PMOs and demonstrated the synergistic effects of TRAIL and DOX in triple-negative breast cancer. In addition, immunomodulatory effects of the drug delivery vectors constructed in this study were verified in vivo.
    Keywords:  Nanoparticle; Synergistic effect; TRAIL; Tumor immunotherapy
    DOI:  https://doi.org/10.1016/j.actbio.2022.03.001
  32. Front Oncol. 2022 ;12 826073
    KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer.
    Emerik Osterlund, Ari Ristimäki, Soili Kytölä, Teijo Kuopio, Eetu Heervä, Timo Muhonen, Päivi Halonen, Raija Kallio, Leena-Maija Soveri, Jari Sundström, Mauri Keinänen, Annika Ålgars, Raija Ristamäki, Halfdan Sorbye, Per Pfeiffer, Luís Nunes, Tapio Salminen, Annamarja Lamminmäki, Markus J Mäkinen, Tobias Sjöblom, Helena Isoniemi, Bengt Glimelius, Pia Osterlund.
      Background: KRAS mutations, present in over 40% of metastatic colorectal cancer (mCRC), are negative predictive factors for anti-EGFR therapy. Mutations in KRAS-G12C have a cysteine residue for which drugs have been developed. Published data on this specific mutation are conflicting; thus, we studied the frequency and clinical characteristics in a real-world and population-based setting.Methods: Patients from three Nordic population-based cohorts and the real-life RAXO-study were combined. RAS and BRAF tests were performed in routine healthcare, except for one cohort. The dataset consisted of 2,559 patients, of which 1,871 could be accurately classified as KRAS, NRAS, and BRAF-V600E. Demographics, treatments, and outcomes were compared using logistic regression. Overall survival (OS) was estimated with Kaplan-Meier, and differences were compared using Cox regression, adjusted for baseline factors.
    Results: The KRAS-G12C frequency was 2%-4% of all tested in the seven cohorts (mean 3%) and 4%-8% of KRAS mutated tumors in the cohorts (mean 7%). Metastasectomies and ablations were performed more often (38% vs. 28%, p = 0.040), and bevacizumab was added more often (any line 74% vs. 59%, p = 0.007) for patients with KRAS-G12C- vs. other KRAS-mutated tumors, whereas chemotherapy was given to similar proportions. OS did not differ according to KRAS mutation, neither overall (adjusted hazard ratio (HR) 1.03; 95% CI 0.74-1.42, reference KRAS-G12C) nor within treatment groups defined as "systemic chemotherapy, alone or with biologics", "metastasectomy and/or ablations", or "best supportive care", RAS and BRAF wild-type tumors (n = 548) differed similarly to KRAS-G12C, as to other KRAS- or NRAS-mutated (n = 66) tumors.
    Conclusions: In these real-life and population-based cohorts, there were no significant differences in patient characteristics and outcomes between patients with KRAS-G12C tumors and those with other KRAS mutations. This contrasts with the results of most previous studies claiming differences in many aspects, often with worse outcomes for those with a KRAS-G12C mutation, although not consistent. When specific drugs are developed, as for this mutation, differences in outcome will hopefully emerge.
    Keywords:  KRAS mutation; KRAS-G12C mutation; colorectal cancer; metastatic; population-based; real-world
    DOI:  https://doi.org/10.3389/fonc.2022.826073
  33. Evid Based Complement Alternat Med. 2022 ;2022 8288818
    Ginkgo biloba: A Treasure of Functional Phytochemicals with Multimedicinal Applications.
    Noor-E-Tabassum, Rajib Das, Mashia Subha Lami, Arka Jyoti Chakraborty, Saikat Mitra, Trina Ekawati Tallei, Rinaldi Idroes, Amany Abdel-Rahman Mohamed, Md Jamal Hossain, Kuldeep Dhama, Gomaa Mostafa-Hedeab, Talha Bin Emran.
      Ginkgo biloba is an ancient plant species that is thought to provide a variety of health benefits to living organisms and contains plenty of bioactive components, making it a chemically diversified plant. G. biloba has been shown to have a variety of medicinal and pharmacological properties, including anticancer, antidementia, antidiabetic, antiobesity, antilipidemic, antimicrobial, antioxidant, antilipid peroxidation, antiplatelet, anti-inflammatory, hepatoprotective, antidepressant, antiaging, immunomodulatory, antihypertensive, and neuroprotective effects and is frequently used to treat neurological, cardiovascular, and respiratory diseases, such as tardive dyskinesia. Therefore, this review described the therapeutic applications of G. biloba. In addition to describing the therapeutic potential, this review also evaluates the chemical constituents, toxicity, adverse effect, synergistic effect, and the clinical studies of this plant which have been utilized for therapeutic benefits but have demonstrated other consequences. The capacity of G. biloba components to act as free radical scavengers is critical, and combining its extract with other plant extracts has been shown to synergistically boost antioxidant properties. G. biloba used long-term or at high doses that resulted in some adverse effects. Severe drug interactions have also been reported in both animals and humans when combined with other medications. The available data established from both preclinical and clinical studies confirm the potential of G. biloba plant extract in various diseases. Besides, the safety and efficacy of G. biloba continue to require verification through additional experimentation to guide medicinal use.
    DOI:  https://doi.org/10.1155/2022/8288818
  34. Photodiagnosis Photodyn Ther. 2022 Mar 06. pii: S1572-1000(22)00085-0. [Epub ahead of print] 102796
    Triple-negative breast cancer treatment in xenograft models by bifunctional nanoprobes combined to photodynamic therapy.
    Viviane Paula Dos Santos Jesus, Paula Fonseca Antunes Vieira, Ricardo Cesar Cintra, Luciana Barros Sant'Anna, Denise Maria Zezell, Maiara Lima Castilho, Leandro Raniero.
      Triple-negative breast cancer (TNBC) overexpresses the Epidermal Growth Factor Receptor (EGFR), a characteristic of different types of tumors, linked to worse disease prognosis and risk of recurrence. Conventional treatments are aggressive and, on several occasions, have a poor prognosis, which may be related to the clinical heterogeneity of tumors, among other factors. Therefore, the improvement and development of new methods are notorious. Photodynamic Therapy (PDT) is an effective method for treating different types of cancer by using radiation to activate a photosensitizing agent (drug) in molecular oxygen presence, promoting cell death. Aiming to urge new treatments against breast cancer, drug uptake in target cells could contribute to PDT efficiency. This association is less invasive and has fewer side effects, increasing quality of life and survival rate. Accordingly, we developed a bifunctional nanoprobe (BN), used in PDT as an alternative treatment method in vivo against breast cancer. The BN uses gold nanoparticles with active targeting through the Epidermal Growth Factor (EGF) protein and Chlorine e6 (Ce6) carriers. We evaluated the therapeutic efficacy of in vivo xenograft in 4 groups: Saline, BN, Ce6+PDT, and BN+PDT. As a result, we observed that the BN+PDT group exhibited an excellent effect with greater selectivity to tumor tissue and tissue damage when compared to the Saline, BN, and Ce6+PDT groups. The results indicate a potential impact on breast cancer treatment in vivo, promising therapeutic benefits against cancer. In conclusion, our data propose that the BN developed heightened PDT efficacy through cellular DNA repair effects and tumor microenvironment.
    Keywords:  Breast Cancer; Nanoparticle; Photodinamic Therapy; Photosensitizer
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102796
  35. Front Immunol. 2022 ;13 821816
    Role of Hypoxia in the Interferon Response.
    Esther Arnaiz, Adrian L Harris.
      In solid tumors, as the tumor grows and the disease progresses, hypoxic regions are often generated, but in contrast to most normal cells which cannot survive under these conditions, tumour cells adapt to hypoxia by HIF-driven mechanisms. Hypoxia can further promote cancer development by generating an immunosuppressive environment within the tumour mass, which allows tumour cells to escape the immune system recognition. This is achieved by recruiting immunosuppressive cells and by upregulating molecules which block immune cell activation. Hypoxia can also confer resistance to antitumor therapies by inducing the expression of membrane proteins that increase drug efflux or by inhibiting the apoptosis of treated cells. In addition, tumor cells require an active interferon (IFN) signalling pathway for the success of many anticancer therapies, such as radiotherapy or chemotherapy. Therefore, hypoxic effects on this pathway needs to be addressed for a successful treatment.
    Keywords:  IFN; cancer; hypoxia; therapy; type I IFN
    DOI:  https://doi.org/10.3389/fimmu.2022.821816
  36. Front Oncol. 2022 ;12 796832
    Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies.
    Anne-Laure Désage, Camille Léonce, Aurélie Swalduz, Sandra Ortiz-Cuaran.
      Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.
    Keywords:  KRAS G12C; acquired resistance; adagrasib; non-small cell lung cancer (NSCLC); sotorasib
    DOI:  https://doi.org/10.3389/fonc.2022.796832
  37. Cancers (Basel). 2022 Mar 03. pii: 1311. [Epub ahead of print]14(5):
    Comprehensive Metabolic Profiling of MYC-Amplified Medulloblastoma Tumors Reveals Key Dependencies on Amino Acid, Tricarboxylic Acid and Hexosamine Pathways.
    Khoa Pham, Allison R Hanaford, Brad A Poore, Micah J Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S Slusher, Charles G Eberhart, Eric H Raabe.
      Reprograming of cellular metabolism is a hallmark of cancer. Altering metabolism allows cancer cells to overcome unfavorable microenvironment conditions and to proliferate and invade. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC defines a subset of poor-prognosis medulloblastoma. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in three different conditions-in vitro, in flank xenografts and in orthotopic xenografts in the cerebellum. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and in vitro MYC-amplified cells. Compared to normal brain, MYC-amplified medulloblastoma orthotopic xenograft tumors showed upregulation of the TCA cycle as well as the synthesis of nucleotides, hexosamines, amino acids and glutathione. There was significantly higher glucose uptake and usage in orthotopic xenograft tumors compared to flank xenograft tumors and cells in culture. In orthotopic tumors, glucose was the main carbon source for the de novo synthesis of glutamate, glutamine and glutathione through the TCA cycle. In vivo, the glutaminase II pathway was the main pathway utilizing glutamine. Glutathione was the most abundant upregulated metabolite in orthotopic tumors compared to normal brain. Glutamine-derived glutathione was synthesized through the glutamine transaminase K (GTK) enzyme in vivo. In conclusion, high MYC medulloblastoma cells have different metabolic profiles in vitro compared to in vivo, and key vulnerabilities may be missed by not performing in vivo metabolic analyses.
    Keywords:  Warburg effect; cancer metabolism; isotope labeling; mass spectrometry; pediatric brain tumor
    DOI:  https://doi.org/10.3390/cancers14051311
  38. Cancer Lett. 2022 Mar 03. pii: S0304-3835(22)00091-X. [Epub ahead of print]534 215616
    Contribution of adipocytes in the tumor microenvironment to breast cancer metabolism.
    Xiaodan Lyu, Qian Zhang, Hamza M Fares, Yifan Wang, Yi Han, Li Sun.
      Breast cancer is considered the most common malignancy, with the profound ability to perform a wide range of metabolic reprogramming. Within the breast cancer microenvironment, highly available cancer-associated adipocytes interact with cancer cells by releasing various adipocytokines and metabolites. Obesity is also an important factor in this manner, where the accumulation of adipose tissue next to tumor tissue is linked to the increased incidence, progression, and metastasis of breast cancer. The metabolic changes caused by the crosstalk between breast cancer cells and dysfunctional adipose tissue include glucose, lipid, and amino acid metabolism. Thus, preventing this interaction between breast cancer cells and dysfunctional adipose tissue might develop a promising therapeutic strategy against breast cancer. This review focused on the metabolic changes responsible for inducing the crosstalk between breast cancer cells and adipocytes. We also reviewed the recent updates in therapeutics designed to disrupt this interaction.
    Keywords:  Breast carcinoma; Cancer-associated adipocytes; Metabolic reprogramming; Obesity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2022.215616
  39. Molecules. 2022 Feb 27. pii: 1570. [Epub ahead of print]27(5):
    Curcumin-Injected Musca domestica Larval Hemolymph: Cecropin Upregulation and Potential Anticancer Effect.
    Shaymaa Mahmoud, Sobhy Hassab El-Nabi, Asmaa Hawash, Hesham R El-Seedi, Shaden A M Khalifa, Sami Ullah, Abdullah G Al-Sehemi, Islam M El-Garawani.
      Over recent decades, much attention has been given to imply the natural products in cancer therapy alone or in combination with other established procedures. Insects have a rich history in traditional medicine across the globe, which holds promise for the future of natural product drug discovery. Cecropins, peptides produced by insects, are components of a defense system against infections and are well known to exert antimicrobial and antitumor capabilities. The present study aimed to investigate, for the first time, the role of curcumin in enhancing the anticancer effect of Musca domestica larval hemolymph. Third larval instars of M. domestica were injected with curcumin and the hemolymph was picked at 4, 8, and 24 h post-curcumin injection. M. domestica cecropin A (MdCecA) was evaluated in control and injected larval hemolymphs. The cytotoxicity on breast cancer cell lines (MCF-7) and normal Vero cells was assessed to be comparable to control larval hemolymph. Curcumin-injected larval hemolymphs exhibited significant cytotoxicity with respect to the uninjected ones against MCF-7; however, Vero cells showed no cytotoxicity. The IC50 was 106 ± 2.9 and 388 ± 9.2 μg/mL for the hemolymphs of injected larvae at 4 and 8 h, respectively, while the control larval hemolymph revealed the IC50 of >500 μg/mL. For mechanistic anticancer evaluation, concentrations of 30, 60, and 100 μg/mL of curcumin-injected larval hemolymphs were examined. A significant G2/M cell cycle arrest was observed, confirming the anti-proliferative properties of hemolymphs over the tested concentrations. The MdCecA transcripts were significantly (p < 0.05) upregulated at 4 and 8 h post-injection, while a significant downregulation was observed after 24 h. Cecropin quantification by LC-MS revealed that MdCecA peptides have the highest expression in the hemolymph of the treated larvae at 8 h relative to the control group. The upregulation of cecropin expression at mRNA and protein levels may be attributed to the curcumin stimulation and linked to the increased cytotoxicity toward the cancer cell line. In conclusion, the results suggest that the apoptotic and anti-proliferative effects of M. domestica hemolymph on MCF-7 cells following the curcumin injection can be used as a natural candidate in future pharmaceutical industries.
    Keywords:  M. domestica larva; MCF-7; apoptosis; cecropin; curcumin; cytotoxicity; hemolymph
    DOI:  https://doi.org/10.3390/molecules27051570
  40. J Clin Med. 2022 Mar 07. pii: 1465. [Epub ahead of print]11(5):
    Natural Bioactives: Back to the Future in the Fight against Human Papillomavirus? A Narrative Review.
    Silvia Massa, Riccardo Pagliarello, Francesca Paolini, Aldo Venuti.
      Human papillomavirus (HPV) still represents an important threat to health worldwide. Better therapy in terms of further improvement of outcomes and attenuation of related side-effects is desirable. The pharmaceutical industry has always targeted natural substances-phytochemicals in particular-to identify lead compounds to be clinically validated and industrially produced as antiviral and anticancer drugs. In the field of HPV, numerous naturally occurring bioactives and dietary phytochemicals have been investigated as potentially valuable in vitro and in vivo. Interference with several pathways and improvement of the efficacy of chemotherapeutic agents have been demonstrated. Notably, some clinical trials have been conducted. Despite being endowed with general safety, these natural substances are in urgent need of further assessment to foresee their clinical exploitation. This review summarizes the basic research efforts conducted so far in the study of anti-HPV properties of bio-actives with insights into their mechanisms of action and highlights the variety of their natural origin in order to provide comprehensive mapping throughout the different sources. The clinical studies available are reported, as well, to highlight the need of uniformity and consistency of studies in the future to select those natural compounds that may be suited to clinical application.
    Keywords:  HPV; algal; bioactives; chemoprevention; combination treatments; marine; microbial compounds; natural; phytochemicals
    DOI:  https://doi.org/10.3390/jcm11051465
  41. Am J Cancer Res. 2022 ;12(2): 861-872
    Glycolysis in the progression of pancreatic cancer.
    Xinyao Chang, Xingchen Liu, Haoze Wang, Xuan Yang, Yan Gu.
      Metabolic reprogramming, as a key hallmark of cancers, leads to the malignant behavior of pancreatic cancer, which is closely related to tumor development and progression, as well as the supportive tumor microenvironments. Although cells produce adenosine triphosphate (ATP) from glucose by glycolysis when lacking oxygen, pancreatic cancer cells elicit metabolic conversion from oxide phosphorylation to glycolysis, which is well-known as "Warburg effect". Glycolysis is critical for cancer cells to maintain their robust biosynthesis and energy requirement, and it could promote tumor initiation, invasion, angiogenesis, and metastasis to distant organs. Multiple pathways are involved in the alternation of glycolysis for pancreatic cancer cells, including UHRF1/SIRT4 axis, PRMT5/FBW7/cMyc axis, JWA/AMPK/FOXO3a/FAK axis, KRAS/TP53/TIGAR axis, etc. These signaling pathways play an important role in glycolysis and are potential targets for the treatment of pancreatic cancer. Mutations in glycolytic enzymes (such as LDH, PKM2, and PGK1) also contribute to the early diagnosis and monitoring of pancreatic cancer. In this review, we summarized the recent advances on the mechanisms for glycolysis in pancreatic cancer and the function of glycolysis in the progression of pancreatic cancer, which suggested new targets for cancer diagnosis and treatment.
    Keywords:  Pancreatic cancer; glycolysis; metabolism; tumor microenvironment; tumor progression
  42. Front Oncol. 2022 ;12 830561
    Ferroptosis: A New Strategy for Cancer Therapy.
    Yu Chen, Zhihua Fan, Shen Hu, Chengchao Lu, Yi Xiang, Shuzhi Liao.
      Ferroptosis is a newly discovered form of iron-dependent cell death, which is different from other death forms. The main characteristics of ferroptosis are: (1) Amino acid metabolism. (2) Iron metabolism; (3) Lipid metabolism and Reactive oxygen species (ROS). Ferroptosis is related to the occurrence and development of a variety of cancers, especially in the drug resistance. This article reviews the research progress of iron death in tumors, and provides a theoretical reference for its further research and clinical application.
    Keywords:  cancer; clinical application; ferroptosis; iron; programmed cell death
    DOI:  https://doi.org/10.3389/fonc.2022.830561
  43. Nanomaterials (Basel). 2022 Feb 25. pii: 778. [Epub ahead of print]12(5):
    Engineered Nanotechnology: An Effective Therapeutic Platform for the Chronic Cutaneous Wound.
    Suhasini Mallick, Moupriya Nag, Dibyajit Lahiri, Soumya Pandit, Tanmay Sarkar, Siddhartha Pati, Nilesh Prakash Nirmal, Hisham Atan Edinur, Zulhisyam Abdul Kari, Muhammad Rajaei Ahmad Mohd Zain, Rina Rani Ray.
      The healing of chronic wound infections, especially cutaneous wounds, involves a complex cascade of events demanding mutual interaction between immunity and other natural host processes. Wound infections are caused by the consortia of microbial species that keep on proliferating and produce various types of virulence factors that cause the development of chronic infections. The mono- or polymicrobial nature of surface wound infections is best characterized by its ability to form biofilm that renders antimicrobial resistance to commonly administered drugs due to poor biofilm matrix permeability. With an increasing incidence of chronic wound biofilm infections, there is an urgent need for non-conventional antimicrobial approaches, such as developing nanomaterials that have intrinsic antimicrobial-antibiofilm properties modulating the biochemical or biophysical parameters in the wound microenvironment in order to cause disruption and removal of biofilms, such as designing nanomaterials as efficient drug-delivery vehicles carrying antibiotics, bioactive compounds, growth factor antioxidants or stem cells reaching the infection sites and having a distinct mechanism of action in comparison to antibiotics-functionalized nanoparticles (NPs) for better incursion through the biofilm matrix. NPs are thought to act by modulating the microbial colonization and biofilm formation in wounds due to their differential particle size, shape, surface charge and composition through alterations in bacterial cell membrane composition, as well as their conductivity, loss of respiratory activity, generation of reactive oxygen species (ROS), nitrosation of cysteines of proteins, lipid peroxidation, DNA unwinding and modulation of metabolic pathways. For the treatment of chronic wounds, extensive research is ongoing to explore a variety of nanoplatforms, including metallic and nonmetallic NPs, nanofibers and self-accumulating nanocarriers. As the use of the magnetic nanoparticle (MNP)-entrenched pre-designed hydrogel sheet (MPS) is found to enhance wound healing, the bio-nanocomposites consisting of bacterial cellulose and magnetic nanoparticles (magnetite) are now successfully used for the healing of chronic wounds. With the objective of precise targeting, some kinds of "intelligent" nanoparticles are constructed to react according to the required environment, which are later incorporated in the dressings, so that the wound can be treated with nano-impregnated dressing material in situ. For the effective healing of skin wounds, high-expressing, transiently modified stem cells, controlled by nano 3D architectures, have been developed to encourage angiogenesis and tissue regeneration. In order to overcome the challenge of time and dose constraints during drug administration, the approach of combinatorial nano therapy is adopted, whereby AI will help to exploit the full potential of nanomedicine to treat chronic wounds.
    Keywords:  artificial intelligence; biofilm; chronic wound; nanocomposite; nanoparticle
    DOI:  https://doi.org/10.3390/nano12050778
  44. Biofactors. 2022 Mar 07.
    Light-activatable multifunctional paclitaxel nanoprodrug for synergistic chemo-photodynamic therapy in liver cancer.
    Hanzhang Zhu, Weijiang Zhou, Yafeng Wan, Jun Lu, Ke Ge, Changku Jia.
      Paclitaxel (Ptx) is widely utilized to treat liver cancer, and the treatment benefit of reactive oxygen species (ROS)-responsive Ptx nanoprodrug is investigated in this study. The one-step nano-precipitation method was utilized to self-assembly DSPE-PEG2000 -thioketal linker (TK)-Ptx with pyropheophorbide acid nanoparticles (PPa NPs) to form PPa/Ptx NPs. Dynamic light scattering and transmission electron microscopy were used for characterization, and 2'-7'dichlorofluorescin diacetate staining was utilized for intracellular ROS detection. HepG2 cells viability and tumor growth rate of HepG2 bearing mice were assayed. Hematoxylin and eosin staining, proliferating cell nuclear antigen detection, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay were utilized for histology assessment. PPa/Ptx NPs incubation with light irradiation showed superior cytotoxicity to HepG2 cells with increased intracellular ROS production than PPa/Ptx NPs incubation without light irradiation or PPa NPs incubation with light irradiation. At the same time, PPa/Ptx NPs with light irradiation could significantly decrease the tumor growth in vivo as indicated by diminished tumor volume with the largest necrotic area, the highest rate of apoptotic cells, and the least proliferating cells. PPa/Ptx NPs show synergistic chemo-photodynamic characteristics, which could be considered as a promising treatment option for liver cancer.
    Keywords:  chemotherapy; liver cancer; paclitaxel; photodynamic therapy
    DOI:  https://doi.org/10.1002/biof.1832
  45. J Exp Med. 2022 Apr 04. pii: e20210739. [Epub ahead of print]219(4):
    Ferrous iron-activatable drug conjugate achieves potent MAPK blockade in KRAS-driven tumors.
    Honglin Jiang, Ryan K Muir, Ryan L Gonciarz, Adam B Olshen, Iwei Yeh, Byron C Hann, Ning Zhao, Yung-Hua Wang, Spencer C Behr, James E Korkola, Michael J Evans, Eric A Collisson, Adam R Renslo.
      KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
    DOI:  https://doi.org/10.1084/jem.20210739
  46. Biomater Sci. 2022 Mar 07.
    A bone-targeting drug delivery vehicle of a metal-organic framework conjugate with zoledronate combined with photothermal therapy for tumor inhibition in cancer bone metastasis.
    Ting Ge, Zhang Weiwei, Fei Ge, Longbao Zhu, Ping Song, Wanzheng Li, Lin Gui, Wan Dong, Yugui Tao, Kai Yang.
      Chemotherapy is a conventional treatment method for metastatic bone cancer, but it has limitations, such as lower drug-targeting of bone tissues and serious side effects. Bone metastasis almost always occurs in advanced cancer, and most patients in this period have strong drug resistance, which further worsens the curative effect. To address the above-mentioned difficulties, a drug delivery platform is proposed in this paper that accomplishes the bone-targeting of drugs to efficiently inhibit tumors. First, the anti-cancer drugs 5-fluorouracil (5-Fu) and indocyanine green (ICG) were loaded into a zeolitic imidazolate framework (ZIF-90) to form 5-Fu/ICG@ZIF-90. Polyethylene glycol with zoledronic acid (ZOL) was encapsulated using 5-Fu/ICG@ZIF-90 to synthesize 5-Fu/ICG@ZIF-90-PEG-ZOL nanoparticles, which showed dimensional stability, good thermal stability, and bone-targeting ability. Second, the in vitro anti-cancer activity of the designed platform was investigated using cytotoxicity, apoptosis, live-dead staining, cell cycle, and cell ultrathin section analysis. The results indicated that the nanoparticles inhibited MCF-7 cell activity when chemotherapy was combined with PTT. Finally, H&E staining and TUNEL detection were performed in mouse organs and tumors. The nanoparticles combined with photothermal therapy (PTT) and triggered by near-infrared irradiation induce apoptosis of tumor cells in vivo, displaying a better efficacy of combined chemotherapy and photothermal therapy. Experiments conducted on the 5-Fu/ICG@ZIF-90-PEG-ZOL nanoparticles demonstrated their promising performance for cancer bone metastasis inhibition.
    DOI:  https://doi.org/10.1039/d1bm01717a
  47. Cureus. 2022 Feb;14(2): e21884
    Synergistic Anti-tumor Effect of Dichloroacetate and Ivermectin.
    Tatsuaki Ishiguro, Ryumei H Ishiguro, Miyu Ishiguro, Atsushi Toki, Hiroshi Terunuma.
      We formerly reported that the combination of dichloroacetate, omeprazole, and tamoxifen blocked cancer progression by reducing lactic acid production and inducing superoxide production. Recently, ivermectin, a well-known anti-parasite drug, was reported to share the same mechanisms with them and have anti-tumor activity. Here, we present three patients in whom the combination of dichloroacetate, omeprazole (plus tamoxifen), and ivermectin dramatically relieved the symptoms accompanying cancer and sarcoma progression.
    Keywords:  cancer; dichloroacetate; ivermectin; omeprazole; sarcoma; tamoxifen
    DOI:  https://doi.org/10.7759/cureus.21884
  48. Nutrients. 2022 Jan 21. pii: 468. [Epub ahead of print]14(3):
    The Mediterranean Diet as a Source of Bioactive Molecules with Cannabinomimetic Activity in Prevention and Therapy Strategy.
    Riccardo Vago, Francesco Fiorio, Francesco Trevisani, Andrea Salonia, Francesco Montorsi, Arianna Bettiga.
      The endocannabinoid system is a complex lipid signaling network that has evolved to be a key regulator of pro-homeostatic pathways for the organism. Its involvement in numerous processes has rendered it a very suitable target for pharmacological studies regarding metabolic syndrome, obesity and other lifestyle-related diseases. Cannabinomimetic molecules have been found in a large variety of foods, most of which are normally present in the Mediterranean diet. The majority of these compounds belong to the terpene and polyphenol classes. While it is known that they do not necessarily act directly on the cannabinoid receptors CB1 and CB2, their ability to regulate their expression levels has already been shown in some disease-related models, as well as their ability to modulate the activity of other components of the system. In this review, evidence was gathered to support the idea that phytocannabinoid dietary intake may indeed be a viable strategy for disease prevention and may be helpful in maintaining the health status. In an era where personalized nutrition is becoming more and more a reality, having new therapeutic targets could become an important resource.
    Keywords:  Mediterranean diet; endocannabinoid system; personalized nutrition; polyphenols; terpenes
    DOI:  https://doi.org/10.3390/nu14030468
  49. Int J Mol Sci. 2022 Feb 25. pii: 2522. [Epub ahead of print]23(5):
    Pioglitazone-Loaded PLGA Nanoparticles: Towards the Most Reliable Synthesis Method.
    Biagio Todaro, Aldo Moscardini, Stefano Luin.
      Recent findings have proved the benefits of Pioglitazone (PGZ) against atherosclerosis and type 2 diabetes. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this drug in nanoparticles (NPs) can minimize uncontrolled issues. In this context, drug delivery approaches based on several poly(lactic-co-glycolic acid) (PLGA) nanoparticles have been rising in popularity due to their promising capabilities. However, a fully reliable and reproducible synthetic methodology is still lacking. In this work, we present a rational optimization of the most critical formulation parameters for the production of PGZ-loaded PLGA NPs by the single emulsification-solvent evaporation or nanoprecipitation methods. We examined the influence of several variables (e.g., component concentrations, phases ratio, injection flux rate) on the synthesis of the PGZ-NPs. In addition, a comparison of these synthetic methodologies in terms of nanoparticle size, polydispersity index (PDI), zeta potential (ζp), drug loading (DL%), entrapment efficiency (EE%), and stability is offered. According to the higher entrapment efficiency content, enhanced storage time and suitable particle size, the nanoprecipitation approach appears to be the simplest, most rapid and most reliable synthetic pathway for these drug nanocarriers, and we demonstrated a very slow drug release in PBS for the best formulation obtained by this synthesis.
    Keywords:  PLGA; drug loading; drug release kinetics; encapsulation efficiency; nanoprecipitation; pioglitazone; polymeric nanoparticles synthesis; single emulsification-solvent evaporation
    DOI:  https://doi.org/10.3390/ijms23052522
  50. Molecules. 2022 Feb 23. pii: 1498. [Epub ahead of print]27(5):
    Hyaluronic Acid-Zein Core-Shell Nanoparticles Improve the Anticancer Effect of Curcumin Alone or in Combination with Oxaliplatin against Colorectal Cancer via CD44-Mediated Cellular Uptake.
    Lu Liu, Shufang Yang, Feng Chen, Ka-Wing Cheng.
      Curcumin (CUR) has been reported to enhance the chemotherapeutic efficacy of oxaliplatin (OXA) in colorectal cancer (CRC) and inhibit OXA-induced side effects. However, shortcomings, including poor solubility and sensitivity to metabolic transformation, have greatly undermined its value in clinical applications. In this study, the potential of CUR-encapsulated hyaluronic acid (HA)-zein composite nanoparticles (HZ-CUR) as an oral adjuvant for OXA-based chemotherapy was assessed in representative CRC models in mice. Cell viability and colony formation assays in three human CRC cell lines showed that HZ-CUR had a stronger anti-CRC effect than free CUR when given alone and a stronger synergistic effect when combined with OXA, especially in HCT116 and HT29 cell lines. Western blotting, cellular uptake, and RNA interference assays revealed that OXA-induced upregulation of CD44 likely contributed to enhanced cellular uptake of HZ-CUR and thus the enhanced anticancer effect. The significantly improved anti-CRC effects and potential underlying mechanism of HZ-CUR alone and in combination with OXA were further validated in a subcutaneous xenograft and an in situ CRC model in mice. These findings support that HZ-CUR may be an effective oral adjuvant for OXA-based CRC chemotherapy that would not only improve its efficacy but also help reduce the associated side effects.
    Keywords:  cellular uptake; colorectal cancer; curcumin; hyaluronic acid–zein composite nanoparticles; oxaliplatin
    DOI:  https://doi.org/10.3390/molecules27051498
  51. Polymers (Basel). 2022 Feb 25. pii: 921. [Epub ahead of print]14(5):
    Formulation of Chitosan-Coated Apigenin Bilosomes: In Vitro Characterization, Antimicrobial and Cytotoxicity Assessment.
    Syed Sarim Imam, Sultan Alshehri, Mohammad A Altamimi, Raed Khalid Hassan Almalki, Afzal Hussain, Sarah I Bukhari, Wael A Mahdi, Wajhul Qamar.
      We prepared apigenin (APG)-loaded bilosomes (BLs) and evaluated them for vesicle size, zeta-potential and encapsulation efficiency. The formulations were prepared with cholesterol (CHL), sodium deoxy cholate (SDC), Tween 80 (T80) and phosphatidylcholine (PC) using solvent evaporation method. The prepared formulations showed the optimum result was coated with much mucoadhesive polymer chitosan (CH, 0.25 and 0.5% w/v). The chitosan-coated bilosomes (CH-BLs) were further evaluated for surface morphology, drug-polymer interaction, mucoadhesion, permeation, antimicrobial activity and cell viability. The prepared APG-BLs showed nano-metric size (211 ± 2.87 nm to 433 ± 1.98 nm), polydispersibility index <0.5, negative zeta potential (-15 to -29 mV) and enhanced encapsulation efficiency (69.5 ± 0.93 to 81.9 ± 1.3%). Based on these findings, selected formulation (F2) was further coated with chitosan and showed a marked increase in vesicle size (298 ± 3.56 nm), a positive zeta potential (+17 mV), superior encapsulation efficiency (88.1 ± 1.48%) and improved drug release (69.37 ± 1.34%). Formulation F2C1 showed significantly enhanced permeation and mucoadhesion (p < 0.05) compared to formulation F2 due to the presence of CH as a mucoadhesive polymer. The presence of CH on the surfaces of BLs helps to open the tight membrane junctions and leads to enhanced permeation. A TEM study revealed non-aggregated smooth surface vesicles. The antimicrobial and cell viability assessment revealed better effects in terms of zone of inhibition and cell line assessment against two different cancer cell line. From the study, it can be concluded that APG-CHBLs could be a superior alternative to conventional delivery systems.
    Keywords:  antimicrobial; apigenin; bilosomes; cell viability; chitosan
    DOI:  https://doi.org/10.3390/polym14050921
  52. Polymers (Basel). 2022 Feb 26. pii: 936. [Epub ahead of print]14(5):
    pH-Responsive Nanocarriers in Cancer Therapy.
    Nour M AlSawaftah, Nahid S Awad, William G Pitt, Ghaleb A Husseini.
      A number of promising nano-sized particles (nanoparticles) have been developed to conquer the limitations of conventional chemotherapy. One of the most promising methods is stimuli-responsive nanoparticles because they enable the safe delivery of the drugs while controlling their release at the tumor sites. Different intrinsic and extrinsic stimuli can be used to trigger drug release such as temperature, redox, ultrasound, magnetic field, and pH. The intracellular pH of solid tumors is maintained below the extracellular pH. Thus, pH-sensitive nanoparticles are highly efficient in delivering drugs to tumors compared to conventional nanoparticles. This review provides a survey of the different strategies used to develop pH-sensitive nanoparticles used in cancer therapy.
    Keywords:  cancer; drug delivery; nanoparticles; pH
    DOI:  https://doi.org/10.3390/polym14050936
  53. Biochim Biophys Acta Rev Cancer. 2022 Mar 02. pii: S0304-419X(22)00031-2. [Epub ahead of print] 188706
    Myoglobin: From physiological role to potential implications in cancer.
    Islam E Elkholi, Marwa E Elsherbiny, Marwan Emara.
      Myoglobin (MB) belongs to the well-studied globin proteins superfamily. It has been extensively studied for its physiological roles in oxygen storage and transport for about a century now. However, the last two decades shed the light on unexpected aspects for MB research. Myoglobin has been suggested as a scavenger for nitric oxide and reactive oxygen species (ROS). Furthermore, MB was found to be expressed and regulated in different tissues, beyond the muscle lineage, including cancers. Current evidence suggest that MB is directly regulated by hypoxia and might be contributing to the metabolic rewiring in cancer tissues. In this article, we first discuss the MB physiological roles and then focus on the latter potential roles and regulatory networks of MB in cancer.
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188706
  54. J Biomater Sci Polym Ed. 2022 Mar 08. 1-17
    Fabrication and Assessment of Folic acid Conjugated-Chitosan Modified PLGA Nanoparticle for Delivery of Alpha terpineol in colon Cancer.
    Amir Rahmati, Masoud Homayouni Tabrizi, Ehsan Karimi, Bahar Zarei.
      Aim: The objective of this study was to fabrication of α-terpineol-PLGA nanoparticles coated with folic acid-chitosan (αT-PCF-NPs) as well as evaluates their anticancer effects.Materials and methods: αT-PCF-NPs were synthesized using the nanoprecipitation method and characterized by Dynamic light scattering (DLS), Zeta potential (ZP), Scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) analysis. Folic acid (FA) binding rate and entrapment efficiency of α-T were assessed by HPLC method. MTT assay was performed for cytotoxicity assessment. Quantitative polymerase chain reaction (qPCR) analysis, acridine orange and propodium iodide (AO/PI) staining and cell cycle analysis were done to assess the pro-apoptotic properties of αT-PCF-NPs. Molecular analysis for angiogenesis and antioxidant properties and murine colon cancer model for antitumor effects of αT-PCF-NPs were used.Results: The % FA-binding and encapsulation efficiency of α-T in αT-PCF-NPs (Particle size of 263.95 nm, polydispersity index (PDI) of 0.25, and surface charge of +38.20 mV) was reported to be 67% and 88.1% respectively. The higher inhibitory effect of αT-PCF-NPs on cancer cells compared to HFF cells was confirmed. The pro-apoptotic effect of αT-PCF-NPs was showed by increased SubG1 phase cells, AO/PI staining results and up and down regulation Bax and Bcl-2 as pro and anti-apoptotic genes in HT-29 cells. Antioxidant (SOD) and angiogenesis genes (VEGF and VEGF-R) were inhibited by αT-PCF-NPs exposure in HT-29 cells and also decreased the size of murine tumors was confirmed in exposure of αT-PCF-NPs.Conclusion: αT-PCF-NPs can be considered as a promising anticancer drug for colon cancer.
    Keywords:  Alpha terpineol; Chitosan; Colon cancer; PLGA Nanoparticle
    DOI:  https://doi.org/10.1080/09205063.2022.2051693
  55. Materials (Basel). 2022 Mar 04. pii: 1934. [Epub ahead of print]15(5):
    Electrospun Nanofibers Revisited: An Update on the Emerging Applications in Nanomedicine.
    Nehal E Elsadek, Abdalrazeq Nagah, Tarek M Ibrahim, Hitesh Chopra, Ghada A Ghonaim, Sherif E Emam, Simona Cavalu, Mohamed S Attia.
      Electrospinning (ES) has become a straightforward and customizable drug delivery technique for fabricating drug-loaded nanofibers (NFs) using various biodegradable and non-biodegradable polymers. One of NF's pros is to provide a controlled drug release through managing the NF structure by changing the spinneret type and nature of the used polymer. Electrospun NFs are employed as implants in several applications including, cancer therapy, microbial infections, and regenerative medicine. These implants facilitate a unique local delivery of chemotherapy because of their high loading capability, wide surface area, and cost-effectiveness. Multi-drug combination, magnetic, thermal, and gene therapies are promising strategies for improving chemotherapeutic efficiency. In addition, implants are recognized as an effective antimicrobial drug delivery system overriding drawbacks of traditional antibiotic administration routes such as their bioavailability and dosage levels. Recently, a sophisticated strategy has emerged for wound healing by producing biomimetic nanofibrous materials with clinically relevant properties and desirable loading capability with regenerative agents. Electrospun NFs have proposed unique solutions, including pelvic organ prolapse treatment, viable alternatives to surgical operations, and dental tissue regeneration. Conventional ES setups include difficult-assembled mega-sized equipment producing bulky matrices with inadequate stability and storage. Lately, there has become an increasing need for portable ES devices using completely available off-shelf materials to yield highly-efficient NFs for dressing wounds and rapid hemostasis. This review covers recent updates on electrospun NFs in nanomedicine applications. ES of biopolymers and drugs is discussed regarding their current scope and future outlook.
    Keywords:  biopolymers; electrospinning; implants; nanofibers; nanomedicine; targeted delivery; wound healing
    DOI:  https://doi.org/10.3390/ma15051934
  56. J Appl Oral Sci. 2022 ;pii: S1678-77572022000100406. [Epub ahead of print]30 e20210349
    Drug delivery systems for oral disease applications.
    Yue Zhang, Ruining Jiang, Lei Lei, Yingming Yang, Tao Hu.
      There are many restrictions on topical medications for the oral cavity. Various factors affect the topical application of drugs in the oral cavity, an open and complex environment. The complex physical and chemical environment of the oral cavity, such as saliva and food, will influence the effect of free drugs. Therefore, drug delivery systems have served as supporting structures or as carriers loading active ingredients, such as antimicrobial agents and growth factors (GFs), to promote antibacterial properties, tissue regeneration, and engineering for drug diffusion. These drug delivery systems are considered in the prevention and treatment of dental caries, periodontal disease, periapical disease, the delivery of anesthetic drugs, etc. These carrier materials are designed in different ways for clinical application, including nanoparticles, hydrogels, nanofibers, films, and scaffolds. This review aimed to summarize the advantages and disadvantages of different carrier materials. We discuss synthesis methods and their application scope to provide new perspectives for the development and preparation of more favorable and effective local oral drug delivery systems.
    DOI:  https://doi.org/10.1590/1678-7757-2021-0349
  57. Foods. 2022 Mar 02. pii: 733. [Epub ahead of print]11(5):
    Fate of Bioactive Compounds during Lactic Acid Fermentation of Fruits and Vegetables.
    Spiros Paramithiotis, Gitishree Das, Han-Seung Shin, Jayanta Kumar Patra.
      Consumption of lactic acid fermented fruits and vegetables has been correlated with a series of health benefits. Some of them have been attributed to the probiotic potential of lactic acid microbiota, while others to its metabolic potential and the production of bioactive compounds. The factors that affect the latter have been in the epicenter of intensive research over the last decade. The production of bioactive peptides, vitamins (especially of the B-complex), gamma-aminobutyric acid, as well as phenolic and organosulfur compounds during lactic acid fermentation of fruits and vegetables has attracted specific attention. On the other hand, the production of biogenic amines has also been intensively studied due to the adverse health effects caused by their consumption. The data that are currently available indicate that the production of these compounds is a strain-dependent characteristic that may also be affected by the raw materials used as well as the fermentation conditions. The aim of the present review paper is to collect all data referring to the production of the aforementioned compounds and to present and discuss them in a concise and comprehensive way.
    Keywords:  GABA; bioactive peptides; biogenic amines; organosulfur compounds; phenolic compounds; vitamins
    DOI:  https://doi.org/10.3390/foods11050733
  58. Foods. 2022 Mar 06. pii: 760. [Epub ahead of print]11(5):
    Advancements in Biodegradable Active Films for Food Packaging: Effects of Nano/Microcapsule Incorporation.
    Fatemeh Baghi, Adem Gharsallaoui, Emilie Dumas, Sami Ghnimi.
      Food packaging plays a fundamental role in the modern food industry as a main process to preserve the quality of food products from manufacture to consumption. New food packaging technologies are being developed that are formulated with natural compounds by substituting synthetic/chemical antimicrobial and antioxidant agents to fulfill consumers' expectations for healthy food. The strategy of incorporating natural antimicrobial compounds into food packaging structures is a recent and promising technology to reach this goal. Concepts such as "biodegradable packaging", "active packaging", and "bioactive packaging" currently guide the research and development of food packaging. However, the use of natural compounds faces some challenges, including weak stability and sensitivity to processing and storage conditions. The nano/microencapsulation of these bioactive compounds enhances their stability and controls their release. In addition, biodegradable packaging materials are gaining great attention in the face of ever-growing environmental concerns about plastic pollution. They are a sustainable, environmentally friendly, and cost-effective alternative to conventional plastic packaging materials. Ultimately, a combined formulation of nano/microencapsulated antimicrobial and antioxidant natural molecules, incorporated into a biodegradable food packaging system, offers many benefits by preventing food spoilage, extending the shelf life of food, reducing plastic and food waste, and preserving the freshness and quality of food. The main objective of this review is to illustrate the latest advances in the principal biodegradable materials used in the development of active antimicrobial and antioxidant packaging systems, as well as the most common nano/microencapsulated active natural agents incorporated into these food-packaging materials.
    Keywords:  active packaging; antimicrobial agent; antioxidant agent; biodegradable packaging; biopolymers; nano/microencapsulation
    DOI:  https://doi.org/10.3390/foods11050760
  59. Mol Cancer Res. 2022 Mar 11. pii: molcanres.0633.2021. [Epub ahead of print]
    Liver Endothelium Promotes HER3-mediated Cell Survival in Colorectal Cancer with Wild-type and Mutant KRAS.
    Moeez Rathore, Wei Zhang, Michel'le Wright, Rajat Bhattacharya, Fan Fan, Ali Vaziri-Gohar, Jordan Winter, Zhenghe Wang, Sanford D Markowitz, Joseph Willis, Lee M Ellis, Rui Wang.
      We previously identified that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer (CRC) growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic CRC (mCRC) in the liver. Meanwhile, KRAS mutations occur in 40-50% of mCRC and render CRC resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and CRC response to HER3 inhibition. In the present study, we used primary ECs isolated from non-neoplastic liver tissues to recapitulate the liver EC microenvironment. We demonstrated that liver EC-secreted factors activated CRC-associated HER3, and increased CRC cell survival in vitro and promoted CRC patient-derived xenograft tumor growth in vivo. Moreover, we determined that blocking HER3, either by siRNA knockdown or the humanized antibody seribantumab, blocked EC-induced CRC survival in vitro in both KRAS wild-type and mutant CRC cells, and the HER3 antibody seribantumab significantly decreased CRC tumor growth and sensitized tumors to chemotherapy in an orthotopic xenograft model with CRC tumors developed in the liver. In summary, our findings demonstrated that blocking HER3 had significant effects on attenuating liver EC-induced CRC cell survival independent of the KRAS mutation status. Implications: This body of work highlighted a potential strategy of using HER3 antibodies in combination with standard chemotherapy agents for treating patients with either KRAS wild-type or KRAS mutant mCRC.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0633
  60. Front Pharmacol. 2022 ;13 850151
    Editorial: Exploration of Natural Product Leads for Multitarget-Based Treatment of Cancer-Computational to Experimental Journey.
    Rajeev K Singla, Marcus T Scotti, Supratik Kar.
      
    Keywords:  anti-cancer lead; chembioinformatics; herbal medicine; natural anti-cancer agents; secondary metabolites
    DOI:  https://doi.org/10.3389/fphar.2022.850151
  61. Front Pharmacol. 2022 ;13 822792
    The Traditional Uses, Phytochemistry, Pharmacokinetics, Pharmacology, Toxicity, and Applications of Corydalis saxicola Bunting: A Review.
    Yanru Guo, Linjun Zhao, Botao Chang, Jia Yu, Jiangping Bao, Qi Yao, Jun Luo.
      Background: Corydalis saxicola Bunting (CSB) is a perennial herb belonging to genus Corydalis (Papaveraceae), called "Yan-huang-lian" in the Chinese folk. Traditionally, it is used to treat acute conjunctivitis, corneal pannus, acute abdominal pain, hemorrhoidal bleeding, haematochezia, swelling, hepatitis, cirrhosis and liver cancer based on traditional Chinese medicine (TCM) concepts. Purpose: This review aims to summarize and analyze the pharmacokinetics, pharmacological and toxicological properties of CSB and its extracts; to highlight the relevance of modern pharmacology to traditional pharmacology; also to assess its therapeutic potential. Methods: CSB related literatures were searched and screened from databases including PubMed, Web of Science and CNKI. The selected literatures provided reliable source identification evidences. Results: In traditional medicine concepts, CSB has the effects of clearing away heat and detoxification, eliminating dampness, relieving pain, and stopping bleeding. Its modern pharmacology includes hepatoprotective, anticancer, anti-inflammatory, analgesic, antibacterial, anti-oxidative effects. Further, some pharmacological effects support its traditional uses. The CSB total alkaloids (CSBTA) are the main constituents isolated from this plant, and they exert the major of the pharmacological effects. Toxicological studies have shown that the toxicity of CSBTA is mild and reversible in rodents and beagle dogs. Conclusion: Although the present study summarizes the botany, phytochemistry, pharmacokinetics, pharmacology, toxicity, and applications of this plant, it is still necessary to systemically evaluate the chemistry, safety and parameters related to drug metabolism of the extracts or compounds from this plant before or in clinical trials in the future. Meanwhile, cancers and inflammatory-related diseases may be new research directions of this ethnomedicine.
    Keywords:  Corydalis saxicola bunting; pharmacokinetics; pharmacology; phytochemistry; toxicity; traditional uses
    DOI:  https://doi.org/10.3389/fphar.2022.822792
  62. Curr Pharm Biotechnol. 2022 Mar 09.
    Immunoliposomes: A Targeted Drug Delivery System for Cancer Therapeutics and Vaccination.
    Reena Gupta, Jitendra Gupta, Abhishek Pathak.
      Cancer has become one of the world's most lethal and life-threatening disorders, resulting in many deaths. Drug targeting and managing drug delivery are concepts that are implemented to increase a drug's therapeutic index by enhancing its specificity to particular cells, tissues, or organs, and reducing its action and harmful side effects. Liposomes have proven to be one of the most innovative drug delivery systems in medicine. Immunoliposomes, also known as antibody-coupled liposomes, have gained a lot of attention as a homing device for targeted therapies. Monoclonal antibodies or antibody fragments that combine with liposomes to create immunoliposomes have been considered a leading technique for targeted delivery. Various functionalization strategies are adopted for the non-covalent and covalent binding of monoclonal antibodies and their components to liposomal surfaces, such as thiolation, amide bonds, hydrazone bonds, and electrostatic interactions, hydrophobic interactions, hydrogen bonding, etc. for cancer-specific targeting. This review emphasized an overview of various stimulus-responsive immunoliposomes capable of regulating drug release in response to an exogenous magnetic field, changes in temperature or pH, enzyme concentration, endogenous stimuli, and applications of immunoliposomes in vaccination and cancer therapeutics and endogenous immune response stimulation.
    Keywords:  Cancer; Drug Delivery; Drug Targeting; Immunoliposome; Monoclonal Antibodies.; Vaccination
    DOI:  https://doi.org/10.2174/1389201023666220309154439
  63. Acta Pharm Sin B. 2022 Feb;12(2): 532-557
    Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions.
    Leilei Fu, Wenke Jin, Jiahui Zhang, Lingjuan Zhu, Jia Lu, Yongqi Zhen, Lan Zhang, Liang Ouyang, Bo Liu, Haiyang Yu.
      Drug repurposing or repositioning has been well-known to refer to the therapeutic applications of a drug for another indication other than it was originally approved for. Repurposing non-oncology small-molecule drugs has been increasingly becoming an attractive approach to improve cancer therapy, with potentially lower overall costs and shorter timelines. Several non-oncology drugs approved by FDA have been recently reported to treat different types of human cancers, with the aid of some new emerging technologies, such as omics sequencing and artificial intelligence to overcome the bottleneck of drug repurposing. Therefore, in this review, we focus on summarizing the therapeutic potential of non-oncology drugs, including cardiovascular drugs, microbiological drugs, small-molecule antibiotics, anti-viral drugs, anti-inflammatory drugs, anti-neurodegenerative drugs, antipsychotic drugs, antidepressants, and other drugs in human cancers. We also discuss their novel potential targets and relevant signaling pathways of these old non-oncology drugs in cancer therapies. Taken together, these inspiring findings will shed new light on repurposing more non-oncology small-molecule drugs with their intricate molecular mechanisms for future cancer drug discovery.
    Keywords:  Anti-inflammatory drug; Anti-viral drug; Cancer therapy; Cardiovascular drug; Drug repurposing; Microbiological drug; Non-oncology drug; Small-molecule antibiotics
    DOI:  https://doi.org/10.1016/j.apsb.2021.09.006
  64. J Colloid Interface Sci. 2022 Feb 12. pii: S0021-9797(22)00266-1. [Epub ahead of print]616 759-768
    Pt nanoenzyme decorated yolk-shell nanoplatform as an oxygen generator for enhanced multi-modality imaging-guided phototherapy.
    Kai Yan, Chenglong Mu, Cheng Zhang, Qunna Xu, Zushun Xu, Daquan Wang, Xunan Jing, Lingjie Meng.
      The unsatisfactory efficacy of conventional theranostic agents in ablating tumor poses urgent demands on the development of high-performance integrated theranostic agents utilizing rising nanotechnology. To cope with the existing limitations, here we presented an intelligent nanoplatform based on yolk-shell Fe3O4@polydopamine prepared by mussel-inspired polydopamine chemistry and sacrificial template method as well as subsequent incorporation of Pt nanoparticles and chlorine 6 (Ce6) by in situ reduction and electrostatic adsorption for photodynamic therapy (PDT) and photothermal (PTT). The resultant nanoplatform could effectively deliver photosensitizer Ce6 to tumor sites, then promoting the decomposition of endogenous H2O2 to oxygen, finally achieving enhanced PDT therapy, which is demonstrated by in vitro and in vivo evaluations. Importantly, the generated oxygen bubbles could improve the echogenicity signal of yolk-shell microspheres and thereby provide enhanced ultrasonic (US) signal for imaging solid tumors. Overall, the synergistic combination of magnetic Fe3O4, green polydopamine, catalytic Pt nanoparticles, photosensitive Ce6 enabled the hybrid nanoplatform to have good biocompatibility, efficient tumor accumulation, excellent phototherapy efficiency, high T2-weighted magnetic resonance imaging (MRI) and fluorescence imaging ability (FL). Our study integrating the merits of PDT/PTT and US/MRI/FL into a single nanoplatform will open an avenue of therapeutic strategy toward biomedical applications.
    Keywords:  Multi-modality imaging; Photodynamic therapy; Photothermal therapy; Yolk-shell nanoplatform
    DOI:  https://doi.org/10.1016/j.jcis.2022.02.042
  65. Cancers (Basel). 2022 Feb 28. pii: 1256. [Epub ahead of print]14(5):
    Minerals and Cancer: Overview of the Possible Diagnostic Value.
    Sascha Venturelli, Christian Leischner, Thomas Helling, Olga Renner, Markus Burkard, Luigi Marongiu.
      Cancer is the second leading cause of death worldwide and is expected to increase by one-third over the next two decades, in parallel with the growing proportion of the elderly population. Treatment and control of cancer incidence is a global issue. Since there is no clear way to prevent or cure this deadly malignancy, diagnostic, predictive, and prognostic markers for oncological diseases are of great therapeutic value. Minerals and trace elements are important micronutrients for normal physiological function of the body. They are abundant in natural food sources and are regularly included in dietary supplements whereas highly processed industrial food often contains reduced or altered amounts of them. In modern society, the daily intake, storage pools, and homeostasis of these micronutrients are dependent on certain dietary habits and can be thrown out of balance by malignancies. The current work summarizes the data on minerals and trace elements associated with abnormal accumulation or depletion states in tumor patients and discusses their value as potential tumor-associated biomarkers that could be introduced into cancer therapy.
    Keywords:  biomarkers; calcium; cancer; copper; iodine; iron; minerals; phosphorus; selenium; zinc
    DOI:  https://doi.org/10.3390/cancers14051256
  66. J Mater Chem B. 2022 Mar 09.
    Metallocatanionic vesicle-mediated enhanced singlet oxygen generation and photodynamic therapy of cancer cells.
    Bunty Sharma, Akhil Jain, Lluïsa Pérez-García, Julie A Watts, Frankie J Rawson, Ganga Ram Chaudhary, Gurpreet Kaur.
      In clinics, photodynamic therapy (PDT) is established as a non-invasive therapeutic modality for certain types of cancers and skin disease. However, due to poor water solubility, photobleaching, and the dark toxicity of photosensitizers (PSs), further developments are required to improve the efficiency of PDT. Herein, we report the role of metallocatanionic vesicles (MCVs) in enhancing the phototoxicity of methylene blue (MB) against cancer cells. These MCVs were prepared via a facile and quick solution-solution mixing method using a cationic single-chain metallosurfactant (FeCPC I) in combination with anionic sodium oleate (Na Ol). For singlet oxygen (1O2) generation and PDT studies, two fractions of FeCPC I : Na Ol, i.e., 30 : 70 (V37) and 70 : 30 (V73), were chosen based on their long-term stability in aqueous media. A cationic PS MB was loaded into these vesicles. The MB-loaded MCV 30 : 70 and 70 : 30 fractions enhanced the 1O2 generation by 0.10- and 0.40-fold, respectively, compared with MB alone. Upon illumination using a 650 nm laser, these MB-loaded V73 and V37 MCVs significantly decreased the metabolic activity of MCF-7 cells by ≤50% at a concentration of 0.75 μM. Furthermore, the SOSG assay revealed that the synthesized MCVs enhanced the intracellular 1O2 compared with MB alone. The MB-loaded V73 MCVs showed the highest 1O2-mediated membrane damage and cell-killing effect, as confirmed using the differential nuclear staining assay (DNS), which is attributed to the cellular uptake profile of the different MCV fractions. Altogether, this work shows the advantage of using these biocompatible and dual-charge MCVs as promising delivery vehicles that can enhance the 1O2 generation from the PS. This work suggests the future application of these Fe-MCVs in magnetically guided PDT.
    DOI:  https://doi.org/10.1039/d2tb00011c
  67. Int J Mol Sci. 2022 Mar 02. pii: 2764. [Epub ahead of print]23(5):
    Natural Compounds for Counteracting Nonalcoholic Fatty Liver Disease (NAFLD): Advantages and Limitations of the Suggested Candidates.
    Noel Salvoza, Pablo J Giraudi, Claudio Tiribelli, Natalia Rosso.
      The booming prevalence of nonalcoholic fatty liver disease (NAFLD) in adults and children will threaten the health system in the upcoming years. The "multiple hit" hypothesis is the currently accepted explanation of the complex etiology and pathophysiology of the disease. Some of the critical pathological events associated with the development of NAFLD are insulin resistance, steatosis, oxidative stress, inflammation, and fibrosis. Hence, attenuating these events may help prevent or delay the progression of NAFLD. Despite an increasing understanding of the mechanisms involved in NAFLD, no approved standard pharmacological treatment is available. The only currently recommended alternative relies on lifestyle modifications, including diet and physical activity. However, the lack of compliance is still hampering this approach. Thus, there is an evident need to characterize new therapeutic alternatives. Studies of food bioactive compounds became an attractive approach to overcome the reticence toward lifestyle changes. The present study aimed to review some of the reported compounds with beneficial properties in NAFLD; namely, coffee (and its components), tormentic acid, verbascoside, and silymarin. We provide details about their protective effects, their mechanism of action in ameliorating the critical pathological events involved in NAFLD, and their clinical applications.
    Keywords:  NAFLD; NASH; caffeic acid; caffeine; chicoric acid; coffee; silymarin; tormentic acid; verbascoside
    DOI:  https://doi.org/10.3390/ijms23052764
  68. Asian J Pharm Sci. 2022 Jan;17(1): 70-86
    Polymeric microneedle-mediated sustained release systems: Design strategies and promising applications for drug delivery.
    Li Yang, Yao Yang, Hongzhong Chen, Lin Mei, Xiaowei Zeng.
      Parenteral sustained release drug formulations, acting as preferable platforms for long-term exposure therapy, have been wildly used in clinical practice. However, most of these delivery systems must be given by hypodermic injection. Therefore, issues including needle-phobic, needle-stick injuries and inappropriate reuse of needles would hamper the further applications of these delivery platforms. Microneedles (MNs) as a potential alternative system for hypodermic needles can benefit from minimally invasive and self-administration. Recently, polymeric microneedle-mediated sustained release systems (MN@SRS) have opened up a new way for treatment of many diseases. Here, we reviewed the recent researches in MN@SRS for transdermal delivery, and summed up its typical design strategies and applications in various diseases therapy, particularly focusing on the applications in contraception, infection, cancer, diabetes, and subcutaneous disease. An overview of the present clinical translation difficulties and future outlook of MN@SRS was also provided.
    Keywords:  Long-term exposure therapy; Microneedles; Sustained release; Transdermal drug delivery
    DOI:  https://doi.org/10.1016/j.ajps.2021.07.002
  69. Nutrients. 2022 Jan 19. pii: 433. [Epub ahead of print]14(3):
    Traditional and Medical Applications of Fasting.
    Francesco Visioli, Carla Mucignat-Caretta, Francesca Anile, Stefan-Alexandru Panaite.
      Fasting has been practiced for millennia, for religious, ethical, or health reasons. It is also commonplace among different species, from humans, to animals, to lower eukaryotes. Research on fasting is gaining traction based on recent studies that show its role in many adaptive cellular responses such as the reduction of oxidative damage and inflammation, increase of energy metabolism, and in boosting cellular protection. In this expert review, we recount the historical evolution of fasting and we critically analyze its current medical applications, including benefits and caveats. Based on the available data, we conclude that the manipulation of dietary intake, in the form of calorie restriction, intermittent fasting, dietary restriction with the exclusion of some nutrients, prolonged fasting, and so forth, is anthropologically engraved in human culture possibly because of its positive health effects. Indeed, many studies show that fasting ameliorates many biochemical parameters related to cardiovascular and cancer risk, and neurodegeneration. Mechanistic studies are plentiful, but largely limited to cell cultures or laboratory animals. Understandably, there are no controlled trials of any form of fasting that gauge the effects on [any cause] mortality. Physicians should be aware that misinformation is pervasive and that their patients often adopt dietary regimens that are far from being clinically validated. Moreover, doctors are often unaware of their patients' religious or traditional fasting and of its potential health effects. Based on current evidence, no long-term fasting should be undertaken without medical supervision until future research will hopefully help shed further light on fasting and its effects on human health.
    Keywords:  chemoprevention; evolution; fasting; health-span; longevity
    DOI:  https://doi.org/10.3390/nu14030433
  70. Expert Rev Anticancer Ther. 2022 Mar 08.
    Factors influencing the anticancer effects of metformin on breast cancer outcomes: a systematic review and meta-analysis.
    Hadeer Ehab Barakat, Raghda R S Hussein, Ahmed Abdullah Elberry, Mamdouh Ahmed Zaki, Mamdouh Elsherbiny Ramadan.
      INTRODUCTION: Several clinical trials have attempted to find evidence that supports the use of metformin as an anticancer treatment. However, the observed effects on various breast cancer (BC) outcomes have been heterogeneous.AREAS COVERED: Based on the outcomes of previous clinical trials, this review discusses the patients' characteristics, cancer intrinsic subtypes, cancer stage, and anticancer treatments that may influence the anticancer effect of metformin on BC outcomes. Additionally, the safety and tolerability of metformin addition to various anticancer regimens are reviewed.
    EXPERT OPINION: Metformin is a challenging anticancer agent in BC cohorts, besides being safe and well-tolerated at antidiabetic doses. Survival benefits of metformin have been observed in BC patients with: hormone receptor-positive, human epidermal growth factor receptor-2 overexpression, and high insulin like growth factor-1 receptor expression on the tumor surface. Moreover, patients with diabetes receiving metformin experienced better survival outcomes compared to diabetic patients not receiving metformin. Additionally, metformin has anti-proliferative activity in patients with BC who have high insulin resistance and high body mass index. Besides, metformin has been shown to decrease metastatic events, and enhance the level of metabolic- and insulin-related biomarkers associated with carcinogenesis. Finally, most adverse events following metformin treatment were low-grade GIT toxicities.
    Keywords:  anticancer; breast cancer; metformin; surrogate endpoints; survival outcomes
    DOI:  https://doi.org/10.1080/14737140.2022.2051482
  71. Recent Adv Antiinfect Drug Discov. 2022 Mar 04.
    Herbal Phytomedicine 'Irisolidone' in chronic diseases: Biological Efficacy and pharmacological activity.
    Dinesh Kumar Patel.
      BACKGROUND: Plant derived products have been used in the medicine as a source of bioactive molecules due to its therapeutic potential. Nowadays plants derived products have been used for the development of novel drug leads. Polyphenols are an important class of secondary metabolites found to be present in plant material and their derived products. Polyphenols are having an important role in the nutrition for human beings. It also has a significant role in plant resistance against pests and diseases. Scientific studies have proven the biological importance of flavonoids in medicine and other allied health sectors. Anti-oxidant, analgesic, anti-microbial, anti-inflammatory, anti-viral, anti-tumor and anti-allergic activities are the important pharmacological features of flavonoids. Irisolidone is an important isoflavone found to be present in Pueraria lobata flowers.METHODS: In order to know the medicinal importance and therapeutic benefit of irisolidone, numerous scientific research data have been collected from Google, Google Scholar, PubMed, Science Direct and Scopus. Pharmacological activities scientific data of irisolidone has been collected and analyzed in the present works to know the health beneficial aspects of irisolidone. Detailed pharmacological activities of irisolidone have been investigated through scientific data analysis of scientific research works.
    RESULTS: Scientific research data analysis of irisolidone revealed the anti-inflammatory, anti-angiogenic, anti-cancer, anti-platelet, anti-oxidant, anti-hyperlipidemic, immunomodulating, hepatoprotective and estrogenic activities. However biological effect of irisolidone on gastric system, aldose reductase enzymes, malignant gliomas and JC virus has been also investigated. Scientific data analysis revealed the significance of analytical tools for separation and identification of irisolidone.
    CONCLUSION: Present work signified the biological importance and therapeutic potential of irisolidone in the medicine.
    Keywords:  Anti-inflammatory; anti-cancer; anti-platelet; antiallergic; antioxidant; immunomodulating; irisolidone
    DOI:  https://doi.org/10.2174/1574891X16666220304231934
  72. Nutrients. 2022 Jan 26. pii: 534. [Epub ahead of print]14(3):
    Treatment of Glaucoma with Natural Products and Their Mechanism of Action: An Update.
    Ru Hui Sim, Srinivasa Rao Sirasanagandla, Srijit Das, Seong Lin Teoh.
      Glaucoma is one of the leading causes of irreversible blindness. It is generally caused by increased intraocular pressure, which results in damage of the optic nerve and retinal ganglion cells, ultimately leading to visual field dysfunction. However, even with the use of intraocular pressure-lowering eye drops, the disease still progresses in some patients. In addition to mechanical and vascular dysfunctions of the eye, oxidative stress, neuroinflammation and excitotoxicity have also been implicated in the pathogenesis of glaucoma. Hence, the use of natural products with antioxidant and anti-inflammatory properties may represent an alternative approach for glaucoma treatment. The present review highlights recent preclinical and clinical studies on various natural products shown to possess neuroprotective properties for retinal ganglion cells, which thereby may be effective in the treatment of glaucoma. Intraocular pressure can be reduced by baicalein, forskolin, marijuana, ginsenoside, resveratrol and hesperidin. Alternatively, Ginkgo biloba, Lycium barbarum, Diospyros kaki, Tripterygium wilfordii, saffron, curcumin, caffeine, anthocyanin, coenzyme Q10 and vitamins B3 and D have shown neuroprotective effects on retinal ganglion cells via various mechanisms, especially antioxidant, anti-inflammatory and anti-apoptosis mechanisms. Extensive studies are still required in the future to ensure natural products' efficacy and safety to serve as an alternative therapy for glaucoma.
    Keywords:  glaucoma; herbs; intraocular pressure; retinal ganglion cells; traditional medicine
    DOI:  https://doi.org/10.3390/nu14030534
  73. Front Pharmacol. 2022 ;13 855852
    Lactoferrin: A Nutraceutical with Activity against Colorectal Cancer.
    Gerardo Ramírez-Rico, Maria Elisa Drago-Serrano, Nidia León-Sicairos, Mireya de la Garza.
      Homeostasis in the human body results from the tight regulation of several events, since too little inflammation disrupts the process of tissue repair and remodeling, whereas too much exerts a collateral effect by causing tissue damage with life-threatening consequences. In some clinical conditions, such as inflammatory bowel disease (IBD), inflammation functions as a double-edged sword by either enabling or inhibiting cancer development and progression. Generally, cancer develops through evasion mechanisms that regulate cell growth, causing a high rate of uncontrolled proliferation, and mechanisms for evading cell death, such as apoptosis. Moreover, chronic inflammation is a factor that contributes to colorectal cancer (CRC), as observed in individuals with IBD; all these conditions favor an increased rate of angiogenesis and eventual metastasis. Lactoferrin (Lf) is a mammalian iron-binding multifunctional glycoprotein regarded as a natural compound that up- and downregulates both humoral and cellular components of immunity involved in regulating the inflammatory response and maintaining gut homeostasis. Human and bovine Lf share high sequence homology and have very similar antimicrobial, anti-inflammatory, and immunomodulatory activities. Bovine Lf from milk is considered a safe molecule and is commercially available in large quantities. This review mainly focuses on the regulatory effects of orally administered bovine Lf on the inflammatory response associated with CRC; this approach indicates that CRC is one of the most frequently diagnosed cancers and affects the intestinal tract with high clinical and epidemiologic relevance. Thus, this review may provide foundations for the potential use of bovine Lf alone or as a natural adjunct agent to increase the effectiveness and reduce the side effects of anticancer chemotherapy.
    Keywords:  bowel; clinical trials; colorectal cancer; inflammation; lactoferrin
    DOI:  https://doi.org/10.3389/fphar.2022.855852
  74. Molecules. 2022 Feb 28. pii: 1605. [Epub ahead of print]27(5):
    Novel Pomegranate-Nanoparticles Ameliorate Cisplatin-Induced Nephrotoxicity and Improves Cisplatin Anti-Cancer Efficacy in Ehrlich Carcinoma Mice Model.
    Steve Harakeh, Mohammed S Almuhayawi, Isaac O Akefe, Saber H Saber, Soad K Al Jaouni, Torki Alzughaibi, Yousef Almehmadi, Soad Shaker Ali, Dhruba J Bharali, Shaker Mousa.
      Cisplatin (CISP) is one of the most widely used anti-cancer chemotherapeutic agents with remarkable efficacy against various types of cancers. However, it has been associated with nephrotoxicity amongst other undesirable side effects. Pomegranate (PE) is a potent antioxidant and anti-inflammatory agent effective against cancer, with a superior benefit of not being associated with the common toxicities related to the use of conventional chemotherapeutic agents. However, the application of PE is limited by its reduced solubility and decreased bioavailability. We investigated the potential of a novel nanoparticle (NP) enclosing PE to enhance its solubility and improve its bioavailability, and efficacy to prevent CISP-associated nephrotoxicity in a mice model of Ehrlich solid carcinoma (ESC). All mice were grouped into four cohorts: (I) control, (II) tumor, (III) CISP, and (IV) CISP + PE-NPs. The data obtained demonstrated that PE-NPs was beneficial in potently ameliorating CISP-induced nephrotoxicity in ESC mice. PE-NPs significantly attenuated CISP-induced oxidative stress and lipid peroxidation in the kidney via improving activities of antioxidants (SOD, GSH, and CAT). Additionally, PE-NPs considerably decreased CISP-induced inflammation in the kidney by decreasing the levels of NF-kB, IL-1β, and TNF-α. Notably, PE-NPs did not assuage the antitumor efficacy of CISP as revealed by histological assessment and tumor weight data. In summary, PE-NPs may be a potent alternative anticancer therapy devoid of nephrotoxicity.
    Keywords:  antioxidant; cisplatin; nano-formulation; nephrotoxicity; pomegranate
    DOI:  https://doi.org/10.3390/molecules27051605
  75. J Int Med Res. 2022 Mar;50(3): 3000605221081714
    The efficacy of non-fasting ketogenic diet protocol in the management of intractable epilepsy in pediatric patients: a single center study from Saudi Arabia.
    Hayat Alameen Ali, Osama Muthaffar, Nahla AlKarim, Husam Kayyali, Ahmed Elmardenly, Abdullah Tamim, Hala Alansari.
      OBJECTIVE: To review the characteristics and outcomes of pediatric patients on a ketogenic diet (KD), an established treatment option for individuals with intractable epilepsy, in a tertiary epilepsy center.METHODS: This retrospective study included pediatric patients diagnosed with intractable epilepsy who had experienced no benefits from at least two appropriately chosen antiseizure medications. All patients were hospitalized, started a KD without fasting, and were observed for complications and tolerance. The etiology of epilepsy, side effects, and KD efficacy on seizure outcomes were also examined.
    RESULTS: Of 16 children included in the study, nine (56%) experienced significant seizure improvement, with three becoming seizure-free during the KD. Ten patients were fed orally, and six were fed through gastrostomy feeding tubes. Most were on a 3:1 ratio, and nine reached ketosis within the first three days of KD initiation. Initial recurrent hypoglycemia was documented in four patients, and four experienced vomiting and acidosis. Most families complied with the diet, and all of the children gained weight during the study period.
    CONCLUSION: Ketogenic diets are an established and effective treatment for childhood epilepsy, with reversible mild adverse effects. A non-fasting KD protocol is a safe and effective option for children with intractable epilepsy.
    Keywords:  Ketogenic diet; antiseizure medications; epilepsy; high fat diet; intractable epilepsy; ketosis; pediatric epilepsy
    DOI:  https://doi.org/10.1177/03000605221081714
  76. Cancers (Basel). 2022 Feb 25. pii: 1205. [Epub ahead of print]14(5):
    Impact of Exogenous Treatment with Histidine on Hepatocellular Carcinoma Cells.
    Yusun Park, Yeonju Han, Dongwoo Kim, Sua Cho, WonJin Kim, Hyemin Hwang, Hye Won Lee, Dai Hoon Han, Kyung Sik Kim, Mijin Yun, Misu Lee.
      Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib, a multi-kinase inhibitor, is the first-line therapy for advanced HCC. However, long-term exposure to sorafenib often results in reduced sensitivity and the development of resistance. Although various amino acids have been shown to contribute to cancer initiation and progression, little is known about the effects of histidine, a dietary essential amino acid that is partially taken up via histidine/large neutral amino acid transporter (LAT1), on cancer cells. In this study, we evaluated the effects of histidine on HCC cells and sensitivity to sorafenib. Remarkably, we found that exogenous histidine treatment induced a reduction in the expression of tumor markers related to glycolysis (GLUT1 and HK2), inflammation (STAT3), angiogenesis (VEGFB and VEGFC), and stem cells (CD133). In addition, LAT1 expression was downregulated in HCC tumor regions with high expression of GLUT1, CD133, and pSTAT3, which are known to induce sorafenib resistance. Finally, we demonstrated that combined treatment with sorafenib and histidine could be a novel therapeutic strategy to enhance the sensitivity to sorafenib, thereby improving long-term survival in HCC.
    Keywords:  cancer metabolism; drug sensitivity; hepatocellular carcinoma; histidine; sorafenib
    DOI:  https://doi.org/10.3390/cancers14051205
  77. Sovrem Tekhnologii Med. 2021 ;13(6): 78-86
    Photodynamic Theranostics of Central Lung Cancer: Capabilities of Early Diagnosis and Minimally Invasive Therapy (Review).
    G V Papayan, A L Akopov.
      The aim of the study was to assess the prospects for central lung cancer (CLC) screening using fluorescent diagnostics and its treatment by endobronchial photodynamic therapy (PDT). Bronchoscopic fluorescent diagnostics using chlorin e6 photosensitizers and a developed instrumental system enable to reveal tumor changes in large bronchi mucosa at early stages, and a developed PDT technique performed under fluorescent control helps achieve personalized treatment. Such an approach is considered as a theranostic technique - photodynamic theranostics. central lung cancer screening requires a fluorescent dye characterized by availability and can be used directly within the examination. Indocyanine green can be used as a dye, its peculiarity is the necessity to excite and record fluorescence in the near-infrared (NIR) wavelength band. First experiments using NIR bands to diagnose a bronchoscopic system showed the detectability of tumor areas using on-site bronchoscopic photodynamic theranostics, which consists in NIR imaging of tumor foci when a standard dose of indocyanine green is administered during the examination.Conclusion: Further progress of early diagnostics and minimally invasive CLC therapy will be determined by the development of new photosensitizers, which should be characterized by a high absorption band in NIR area, quick accumulation in a tumor, high yield of single oxygen in NIR illumination, bright fluorescence, high potential in terms of the induction of an anti-tumor immune response.
    Keywords:  central lung cancer; chlorin е6; fluorescent diagnosis; indocyanine green; lung cancer screening; photodynamic theranostics; photodynamic therapy; photosensitizers
    DOI:  https://doi.org/10.17691/stm2021.13.6.09
  78. Cancers (Basel). 2022 Mar 04. pii: 1336. [Epub ahead of print]14(5):
    Metformin Intervention-A Panacea for Cancer Treatment?
    Angelika Buczyńska, Iwona Sidorkiewicz, Adam Jacek Krętowski, Monika Zbucka-Krętowska, Agnieszka Adamska.
      The molecular mechanism of action and the individual influence of various metabolic pathways related to metformin intervention are under current investigation. The available data suggest that metformin provides many advantages, exhibiting anti-inflammatory, anti-cancer, hepatoprotective, cardioprotective, otoprotective, radioprotective, and radio-sensitizing properties depending on cellular context. This literature review was undertaken to provide novel evidence concerning metformin intervention, with a particular emphasis on cancer treatment and prevention. Undoubtedly, the pleiotropic actions associated with metformin include inhibiting inflammatory processes, increasing antioxidant capacity, and improving glycemic and lipid metabolism. Consequently, these characteristics make metformin an attractive medicament to translate to human trials, the promising results of which were also summarized in this review.
    Keywords:  anti-cancer; antioxidant; metformin
    DOI:  https://doi.org/10.3390/cancers14051336
  79. Nutrients. 2022 Jan 21. pii: 476. [Epub ahead of print]14(3):
    Breast Cancer Diet "BCD": A Review of Healthy Dietary Patterns to Prevent Breast Cancer Recurrence and Reduce Mortality.
    Edda Cava, Paolo Marzullo, Deborah Farinelli, Alessandra Gennari, Chiara Saggia, Sergio Riso, Flavia Prodam.
      Breast cancer (BC) represents the most common cancer in women, while overweight and obesity are the second preventable cause of cancer. Weight gain and fat accumulation are common after BC diagnosis; moreover, weight gain during the treatment decreases the survival rate and increases the risk of recurrence in breast cancer survivors (BCS). To reduce the risk of second primary cancer or BC recurrence, and all-cause mortality in BCS, multiple interventions have been investigated to obtain reduction in weight, BMI and/or waist circumference. The aim of this narrative review is to analyze evidence on BCS for their risk of recurrence or mortality related to increased weight or fat deposition, and the effects of interventions with healthy dietary patterns to achieve a proper weight and to reduce fat-related risk. The primary focus was on dietary patterns instead of single nutrients and supplements, as the purpose was to investigate on secondary prevention in women free from disease at the end of their cancer treatment. In addition, BC relation with insulin resistance, dietary carbohydrate, and glycemic index/glycemic load is discussed. In conclusion, obesity and overweight, low rates of physical activity, and hormone receptor-status are associated with poorer BC-treatment outcomes. To date, there is a lack of evidence to suggest which dietary pattern is the best approach for weight management in BCS. In the future, multimodal lifestyle interventions with dietary, physical activity and psychological support after BC diagnosis should be studied with the aim of reducing the risk of BC recurrence or mortality.
    Keywords:  breast cancer (BC); breast cancer survival; healthy dietary patterns; secondary prevention
    DOI:  https://doi.org/10.3390/nu14030476
  80. Nutr Rev. 2022 Mar 09. pii: nuac011. [Epub ahead of print]
    Fortification of foods with nano-iron: its uptake and potential toxicity: current evidence, controversies, and research gaps.
    Ruchira Ghosh, Jayashree Arcot.
      Iron fortification is a very popular practice in several countries, particularly in countries in which a large proportion of the population is suffering from iron deficiency, as in lower-middle-income countries. Food fortification with iron salts is a difficult operation, because most iron complexes (ferrous sulfate, ferrous chloride) are water soluble, which can cause undesirable alterations to the sensory properties of the food carriers. On the other hand, insoluble iron salts (eg, ferric pyrophosphate) do not have an unpleasant taste or color, but their bioavailability is low. These issues can be addressed with iron nanoparticles. The small particle size has been shown to have a significant impact on iron absorption. Iron nanoparticles with smaller particle sizes have more surface area, which improves their solubility in gastric juice and leads to better bioavailability. When compared with water-soluble iron complexes, nano-sized iron compounds generate negligible organoleptic alterations in food carriers. As a result, iron nanoparticles could be potentially used in food fortification to minimize iron-deficiency anemia. This review focuses on the absorption pathway and the toxicity of various forms of iron nanoparticles. In vitro cell studies and animal studies indicate that nano-sized iron particles can be taken up either by the Divalent Metal Transporter 1 pathway or the endocytic pathway. Nano-sized ferric phosphate and iron(III) oxo hydroxide show the most promising results, based on recent studies on fortification. To date, there are insufficient studies on the maximum intake level and potential adverse effects. Further extensive work is essential before introducing nano-iron compounds as food fortificants.
    Keywords:  absorption pathway; iron; nanoparticles; toxicity
    DOI:  https://doi.org/10.1093/nutrit/nuac011
  81. Acta Pharm Sin B. 2022 Feb;12(2): 924-938
    Enhanced tumor homing of pathogen-mimicking liposomes driven by R848 stimulation: A new platform for synergistic oncology therapy.
    Xiaobei Cheng, Pei Yu, Xiang Zhou, Jiale Zhu, Yubao Han, Chao Zhang, Lingyi Kong.
      Although multifarious tumor-targeting modifications of nanoparticulate systems have been attempted in joint efforts by our predecessors, it remains challenging for nanomedicine to traverse physiological barriers involving blood vessels, tissues, and cell barriers to thereafter demonstrate excellent antitumor effects. To further overcome these inherent obstacles, we designed and prepared mycoplasma membrane (MM)-fused liposomes (LPs) with the goal of employing circulating neutrophils with the advantage of inflammatory cytokine-guided autonomous tumor localization to transport nanoparticles. We also utilized in vivo neutrophil activation induced by the liposomal form of the immune activator resiquimod (LPs-R848). Fused LPs preparations retained mycoplasma pathogen characteristics and achieved rapid recognition and endocytosis by activated neutrophils stimulated by LPs-R848. The enhanced neutrophil infiltration in homing of the inflammatory tumor microenvironment allowed more nanoparticles to be delivered into solid tumors. Facilitated by the formation of neutrophil extracellular traps (NETs), podophyllotoxin (POD)-loaded MM-fused LPs (MM-LPs-POD) were concomitantly released from neutrophils and subsequently engulfed by tumor cells during inflammation. MM-LPs-POD displayed superior suppression efficacy of tumor growth and lung metastasis in a 4T1 breast tumor model. Overall, such a strategy of pathogen-mimicking nanoparticles hijacking neutrophils in situ combined with enhanced neutrophil infiltration indeed elevates the potential of chemotherapeutics for tumor targeting therapy.
    Keywords:  Chemotherapy; Combination therapy; Drug delivery; Liposomes; Nano therapy; Neutrophil infiltration; Pathogen-mediated tumor targeting; Resiquimod
    DOI:  https://doi.org/10.1016/j.apsb.2021.08.018
  82. Cancers (Basel). 2022 Mar 05. pii: 1343. [Epub ahead of print]14(5):
    Dual Effect of Combined Metformin and 2-Deoxy-D-Glucose Treatment on Mitochondrial Biogenesis and PD-L1 Expression in Triple-Negative Breast Cancer Cells.
    Jernej Repas, Mateja Zupin, Maja Vodlan, Peter Veranič, Boris Gole, Uroš Potočnik, Mojca Pavlin.
      Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have not yet been evaluated. In the present study, we explored the effects of metformin, 2DG and their combination (metformin + 2DG) on TNBC cell mitochondria in vitro. Metformin + 2DG increased mitochondrial mass in TNBC cells. This was associated with an increased size but not number of morphologically normal mitochondria and driven by the induction of mitochondrial biogenesis rather than suppressed mitophagy. 2DG and metformin + 2DG strongly induced the unfolded protein response by inhibiting protein N-glycosylation. Together with adequate energy stress, this was one of the possible triggers of mitochondrial enlargement. Suppressed N-glycosylation by 2DG or metformin + 2DG also caused PD-L1 deglycosylation and reduced surface expression in MDA-MB-231 cells. PD-L1 was increased in low glucose and normalized by both drugs. 2DG and metformin + 2DG reduced PD-1 expression in Jurkat cells beyond the effects on activation, while cytokine secretion was mostly preserved. Despite increasing mitochondrial mass in TNBC cells, metformin and 2DG could therefore potentially be used as an adjunct therapy to improve anti-tumor immunity in TNBC.
    Keywords:  2-deoxy-D-glucose; AMPK; ER stress; PD-1/PD-L1 axis; T cells; anchorage-independence; metformin; mitochondrial biogenesis; protein N-glycosylation; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cancers14051343
  83. Adv Sci (Weinh). 2022 Mar 07. e2105315
    An Unrevealed Molecular Function of Corannulene Buckybowl Glycoconjugates in Selective Tumor Annihilation by Targeting the Cancer-Specific Warburg Effect.
    Shengnan Liu, Ziru Sun, Min Liang, Weijie Song, Ru Zhang, Yunli Shi, Yujun Cui, Qingzhi Gao.
      The biomedical application of corannulene π-bowls is historically limited by low solubility and bioavailability despite the potential in their unique electronic properties for new functional materials. Herein, the unexpected role and molecular mechanism of Corranulene π-bowls are uncovered in biomedical applications as an effective anticancer agent for Warburg effect mediated selective tumor targeting. The corannulene triazolyl monosaccharides Cor-sugars exhibit highly potent cytotoxicity against human cancer cells and effectively inhibit xenograft growth of hyperglycolytic tumors. Particularly, the galactose-conjugated Cor-gal exhibits superior in vivo anticancer efficacy in A549 tumor models with outstanding safety profile compared to doxorubicin. Moreover, the combined treatment of Cor-gal with immune checkpoint inhibitor results in an effective synergy in treating H460 human lung carcinoma. An uptake mechanism study reveals that Cor-sugars exploit tumor-specific glucose transporter glucose transporter 1 (GLUT1) for targeted cell delivery and intra-tumoral accumulation through the cancer-specific Warburg effect. Their significant anticancer activity is attributed to multiphasic DNA-binding and cell cycle alteration effects. This study uncovers new molecular properties of corannulene buckybowl and enabling their potential new applications in biomedical engineering.
    Keywords:  DNA binding; Warburg effect; anticancer; corannulene; glucose transporter
    DOI:  https://doi.org/10.1002/advs.202105315
  84. J Colloid Interface Sci. 2022 Feb 23. pii: S0021-9797(22)00278-8. [Epub ahead of print]617 224-235
    Mechanically tuneable physical nanocomposite hydrogels from polyelectrolyte complex templated silica nanoparticles for anionic therapeutic delivery.
    George Newham, Stephen D Evans, Zhan Yuin Ong.
      Hydrogels have shown great promise for drug delivery and tissue engineering but can be limited in practical applications by poor mechanical performance. The incorporation of polymer grafted silica nanoparticles as chemical or physical crosslinkers in in situ polymerised nanocomposite hydrogels has been widely researched to enhance their mechanical properties. Despite the enhanced mechanical stiffness, tensile strength, and self-healing properties, there remains a need for the development of simpler and modular approaches to obtain nanocomposite hydrogels. Herein, we report a facile protocol for the polyelectrolyte complex (PEC) templated synthesis of organic-inorganic hybrid poly(ethylenimine) functionalised silica nanoparticles (PEI-SiNPs) and their use as multifunctional electrostatic crosslinkers with hyaluronic acid (HA) to form nanocomposite hydrogels. Upon mixing, electrostatic interactions between cationic PEI-SiNPs and anionic HA resulted in the formation of a coacervate nanocomposite hydrogel with enhanced mechanical stiffness that can be tuned by varying the ratios of PEI-SiNPs and HA present. The reversible electrostatic interactions within the hydrogel networks also enabled self-healing and thixotropic properties. The excess positive charge present within the PEI-SiNPs facilitated high loading and retarded the release of the anionic anti-cancer drug methotrexate from the nanocomposite hydrogel. Furthermore, the electrostatic complexation of PEI-SiNP and HA was found to mitigate haemotoxicity concerns associated with the use of high molecular weight PEI. The method presented herein offers a simpler and more versatile strategy for the fabrication of coacervate nanocomposite hydrogels with tuneable mechanical stiffness and self-healing properties for drug delivery applications.
    DOI:  https://doi.org/10.1016/j.jcis.2022.02.052
  85. Cancer Res. 2022 Feb 28. pii: canres.CAN-21-3983-E.2021. [Epub ahead of print]
    Comprehensive analysis of metabolic isozyme targets in cancer.
    Michal Marczyk, Vignesh Gunasekharan, David Casadevall, Tao Qing, Julia Foldi, Raghav Sehgal, Naing Lin Shan, Kim R M Blenman, Tess A O'Meara, Sheila Umlauf, Yulia V Surovtseva, Viswanathan Muthusamy, Jesse Rinehart, Rachel J Perry, Richard Kibbey, Christos Hatzis, Lajos Pusztai.
      Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using TCGA mRNA expression data to identify isozymes that become cancer dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the cancer cell line encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase-1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line- and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3983
  86. PeerJ. 2022 ;10 e13070
    An overview of the nutritional value, health properties, and future challenges of Chinese bayberry.
    Shuwen Zhang, Zheping Yu, Li Sun, Haiying Ren, Xiliang Zheng, Senmiao Liang, Xingjiang Qi.
      Chinese bayberry (CB) is among the most popular and valuable fruits in China owing to its attractive color and unique sweet/sour taste. Recent studies have highlighted the nutritional value and health-related benefits of CB. CB has special biological characteristics of evergreen, special aroma, dioecious, nodulation, nitrogen fixation. Moreover, the fruits, leaves, and bark of CB plants harbor a number of bioactive compounds including proanthocyanidins, flavonoids, vitamin C, phenolic acids, and anthocyanins that have been linked to the anti-cancer, anti-oxidant, anti-inflammatory, anti-obesity, anti-diabetic, and neuroprotective properties and to the treatment of cardiovascular and cerebrovascular diseases. The CB fruits have been used to produce a range of products: beverages, foods, and washing supplies. Future CB-related product development is thus expected to further leverage the health-promoting potential of this valuable ecological resource. The present review provides an overview of the botanical characteristics, processing, nutritional value, health-related properties, and applications of CB in order to provide a foundation for further research and development.
    Keywords:  Bioactive compounds; Botanical characteristics; Chinese bayberry; Health function; Nutritional value
    DOI:  https://doi.org/10.7717/peerj.13070
  87. Nutrients. 2022 Mar 03. pii: 1061. [Epub ahead of print]14(5):
    Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet.
    Carla Iacobini, Martina Vitale, Jonida Haxhi, Carlo Pesce, Giuseppe Pugliese, Stefano Menini.
      Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. RCS are generated by the oxidative cleavage and cellular metabolism of lipids and sugars. In addition to causing damage directly, the RCS adducts, advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), cause additional harm by eliciting chronic inflammation through receptor-mediated mechanisms. Hyperglycemia- and dyslipidemia-induced carbonyl stress plays a role in diabetic cardiovascular complications and diabetes-related cancer risk. Moreover, the increased dietary exposure to AGEs/ALEs could mediate the impact of the modern, highly processed diet on cardiometabolic and cancer risk. Finally, the transient carbonyl stress resulting from supraphysiological postprandial spikes in blood glucose and lipid levels may play a role in acute proinflammatory and proatherogenic changes occurring after a calorie dense meal. These findings underline the potential importance of carbonyl stress as a mediator of the cardiometabolic and cancer risk linked to today's unhealthy diet. In this review, current knowledge in this field is discussed along with future research courses to offer new insights and open new avenues for therapeutic interventions to prevent diet-associated cardiometabolic disorders and cancer.
    Keywords:  advanced glycation end-products; cardiovascular disease; carnosine; diabetes mellitus; food processing; inflammation; obesity; oxidative stress; reactive carbonyl species; tumor disease
    DOI:  https://doi.org/10.3390/nu14051061
  88. ACS Nano. 2022 Mar 11.
    Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis.
    Zhaoyou Chu, Hao Chen, Peisan Wang, Wanni Wang, Juan Yang, Jianan Sun, Benjin Chen, Tian Tian, Zhengbao Zha, Hua Wang, Haisheng Qian.
      In this work, a fluoroquinolone antibiotic drug (sparfloxacin (SP)) was selected as a chemotherapy drug and photosensitizer for combined therapy. A facile chemical process was developed to incorporate SP and upconversion nanoparticles (UCNPs) into the thermally sensitive amphiphilic polymer polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane). In vitro and in vivo experiments showed that 60% of the SP molecules can be released from the micelles of thermal-sensitive polymers using a 1 W cm-2 980 nm laser, and this successfully inhibits cell migration and metastasis by inhibiting type II topoisomerases in nuclei. Additionally, intracellular metal ions were chelated by SP to induce cancer cell apoptosis by decreasing the activity of superoxide dismutase and catalase. In particular, the fluoroquinolone molecules produced singlet oxygen (1O2) to kill cancer cells, and this was triggered by UCNPs when irradiation was performed with a 980 nm laser. Overall, SP retained a weak chemotherapeutic effect, achieved enhanced photosensitizer-like effects, and was able to repurpose old drugs to elevate the therapeutic efficacy against cancer, increase the specificity for suppressing tumor migration and proliferation, and enhance apoptosis.
    Keywords:  Sparfloxacin; chemotherapy; photodynamic therapy; photosensitizers; upconversion nanoparticles
    DOI:  https://doi.org/10.1021/acsnano.2c00854
  89. Nutrients. 2022 Jan 23. pii: 489. [Epub ahead of print]14(3):
    Effects of Intermittent Fasting on Cardiometabolic Health: An Energy Metabolism Perspective.
    Manuel Dote-Montero, Guillermo Sanchez-Delgado, Eric Ravussin.
      This review summarizes the effects of different types of intermittent fasting (IF) on human cardiometabolic health, with a focus on energy metabolism. First, we discuss the coordinated metabolic adaptations (energy expenditure, hormonal changes and macronutrient oxidation) occurring during a 72 h fast. We then discuss studies investigating the effects of IF on cardiometabolic health, energy expenditure and substrate oxidation. Finally, we discuss how IF may be optimized by combining it with exercise. In general, IF regimens improve body composition, ectopic fat, and classic cardiometabolic risk factors, as compared to unrestricted eating, especially in metabolically unhealthy participants. However, it is still unclear whether IF provides additional cardiometabolic benefits as compared to continuous daily caloric restriction (CR). Most studies found no additional benefits, yet some preliminary data suggest that IF regimens may provide cardiometabolic benefits in the absence of weight loss. Finally, although IF and continuous daily CR appear to induce similar changes in energy expenditure, IF regimens may differentially affect substrate oxidation, increasing protein and fat oxidation. Future tightly controlled studies are needed to unravel the underlying mechanisms of IF and its role in cardiometabolic health and energy metabolism.
    Keywords:  5:2 diet; Ramadan; alternate-day fasting; cardiovascular health; energy expenditure; exercise; fasting-mimicking diet; fat oxidation; metabolic rate; modified periodic fasting; time-restricted eating; twice-weekly fasting
    DOI:  https://doi.org/10.3390/nu14030489
  90. Acta Pharm Sin B. 2022 Feb;12(2): 907-923
    Natural exosome-like nanovesicles from edible tea flowers suppress metastatic breast cancer via ROS generation and microbiota modulation.
    Qiubing Chen, Qian Li, Yuqi Liang, Menghang Zu, Nanxi Chen, Brandon S B Canup, Liyong Luo, Chenhui Wang, Liang Zeng, Bo Xiao.
      Although several artificial nanotherapeutics have been approved for practical treatment of metastatic breast cancer, their inefficient therapeutic outcomes, serious adverse effects, and high cost of mass production remain crucial challenges. Herein, we developed an alternative strategy to specifically trigger apoptosis of breast tumors and inhibit their lung metastasis by using natural nanovehicles from tea flowers (TFENs). These nanovehicles had desirable particle sizes (131 nm), exosome-like morphology, and negative zeta potentials. Furthermore, TFENs were found to contain large amounts of polyphenols, flavonoids, functional proteins, and lipids. Cell experiments revealed that TFENs showed strong cytotoxicities against cancer cells due to the stimulation of reactive oxygen species (ROS) amplification. The increased intracellular ROS amounts could not only trigger mitochondrial damage, but also arrest cell cycle, resulting in the in vitro anti-proliferation, anti-migration, and anti-invasion activities against breast cancer cells. Further mice investigations demonstrated that TFENs after intravenous (i.v.) injection or oral administration could accumulate in breast tumors and lung metastatic sites, inhibit the growth and metastasis of breast cancer, and modulate gut microbiota. This study brings new insights to the green production of natural exosome-like nanoplatform for the inhibition of breast cancer and its lung metastasis via i.v. and oral routes.
    Keywords:  AF633, Alexa Fluor 633-labeled phalloidin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, urea nitrogen; Breast cancer; CDK, CYCLIN-dependent kinase; CRE, creatinine; DAF-FM DA, 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate; DAPI, 4′,6-diamidino-2-phenylindole; DCFH-DA, dichloro-dihydro-fluorescein diacetate; DGDG, digalactosyl diacylglycerols; DHE, dihydroethidium; DLS, dynamic light scattering; DiO, 3,3′-dioctadecyloxacarbocyanine perchlorate; DiR, 1,1′-dioctadecyl-3,3,3′′,3′-tetramethylindotricarbocyanine iodide; EC, epicatechin; ECG, epicatechin gallate; EGCG, epigallocatechin gallate; Exosome-like nanoparticle; FBS, fetal bovine serum; GIT, gastrointestinal tract; H&E, Hematoxylin & Eosin; HPLC, high-performance liquid chromatography; Intravenous injection; LC‒MS, liquid chromatography‒mass spectrometry; MFI, mean fluorescence intensity; MGDG, monogalactosyl diacylglycerols; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Metastasis; Microbiota modulation; NO, nitrogen monoxide; NPs, nanoparticles; OUT, operational taxonomic unit; Oral administration; PA, phosphatidic acids; PBS, phosphate-buffered saline; PC, phosphatidylcholines; PDI, polydispersity index; PE, phosphatidylethanolamines; PG, phosphatidylglycerol; PI, phosphatidylinositol; PLT, platelets; PMe, phosphatidylmethanol; PS, phosphatidylserine; RBC, red blood cell; RNS, reactive nitrogen species; ROS generation; ROS, reactive oxygen species; SA, superoxide anion; SQDG, sulphoquinovosyl diylyceride; TEM, transmission electron microscopy; TFENs, exosome-like NPs from tea flowers; TG, triglyceride; TUNEL, TdT-mediated dUTP Nick-end labeling; Tea flower; WBC, white blood cell
    DOI:  https://doi.org/10.1016/j.apsb.2021.08.016
  91. J Microencapsul. 2022 Mar 09. 1-29
    The nanotechnological approach for nasal delivery of peptide drugs: a comprehensive review.
    Carine Zuglianello, Elenara Lemos-Senna.
      This review gathers recent studies, patents, and clinical trials involving the nasal administration of peptide drugs to supply a panorama of developing nanomedicine advances in this field. Peptide drugs have been featured in the pharmaceutical market, due to their high efficacy, biological activity, and low immunogenicity. Pharmaceutical industries need technology to circumvent issues relating to peptide stability and bioavailability. The oral route offers very harsh and unfavourable conditions for peptide administration, while the parenteral route is inconvenient and risky for patients. Nasal administration is an attractive alternative, mainly when associated with nanotechnological approaches. Nanomedicines may improve the nasal administration of peptide drugs by providing protection for the macromolecules from enzymes while also increasing their time of retention and permeability in the nasal mucosa. Nanomedicines for nasal administration containing peptide drugs have been acclaimed for both prevention, and treatment, of infections, including the pandemic COVID-19, cancers, metabolic and neurodegenerative diseases.
    Keywords:  drug nanocarriers; lipid nanoparticles; nasal route; peptide drugs; polymer nanoparticles
    DOI:  https://doi.org/10.1080/02652048.2022.2051626
  92. Asian J Pharm Sci. 2022 Jan;17(1): 129-138
    Amphiphilic small molecular mates match hydrophobic drugs to form nanoassemblies based on drug-mate strategy.
    Leiqiang Han, Shuang Liang, Weiwei Mu, Zipeng Zhang, Limin Wang, Shumin Ouyang, Bufan Yao, Yongjun Liu, Na Zhang.
      Nanomedicine has made great progress in the targeted therapy of cancer. Here, we established a novel drug-mate strategy by studying the formulation of nanodrugs at the molecular level. In the drug-mate combination, the drug is a hydrophobic drug that is poorly soluble in water, and the mate is an amphiphilic small molecule (SMA) that has both hydrophilic and lipophilic properties. We proposed that the hydrophobic drug could co-assemble with a suitable SMA on a nanoscale without additive agents. The proof-of-concept methodology and results were presented to support our hypothesis. We selected five hydrophobic drugs and more than ten amphiphilic small molecules to construct a library. Through molecular dynamic simulation and quantum chemistry computation, we speculated that the formation of nanoassemblies was related to the binding energy of the drug-mate, and the drug-mate interaction must overcome drug-drug interaction. Furthermore, the obtained SF/VECOONa nanoassemblieswas selected as a model, which had an ultra-high drug loading content (46%), improved pharmacokinetics, increased bioavailability, and enhanced therapeutic efficacy. In summary, the drug-mate strategy is an essential resource to design exact SMA for many hydrophobic drugs and provides a reference for the design of a carrier-free drug delivery system.
    Keywords:  Drug-mate strategy; Hydrophobic drug; Molecular level; Nanoassemblies; Small molecular mate
    DOI:  https://doi.org/10.1016/j.ajps.2021.11.002
  93. Biomacromolecules. 2022 Mar 11.
    Glucose and H2O2 Dual-Responsive Nanocomplex Grafted with Insulin Prodrug for Blood Glucose Regulation.
    Xiaowen Xu, Yu Ran, Chengyuan Huang, Zongning Yin.
      Although "closed-loop" smart insulin delivery systems have been extensively investigated, the majority of them suffer from low insulin loading efficiency and slow glucose response. Here, we constructed a novel nanocomplex (NC), which was prepared by electrostatic interaction between negatively charged insulin prodrug nanoparticles (NPs) and positively charged polycaprolactone-polyethylenimine (PCL-PEI) micelles. The insulin prodrug was linked to acetalated dextran (AD) via borate ester bonds to form IAD NPs, and glucose oxidase (GOx) was encapsulated in PCL-PEI micelles. The NC was negatively charged with a high insulin grafting rate (0.473 mg/mg), and in vitro experiments revealed that IAD was sensitive to hyperglycemia and H2O2, whereas GOx significantly improved the response to glucose by altering the microenvironment to promote sustained insulin release. Furthermore, compared with free insulin and IAD NPs, subcutaneously injected NCs in diabetic rats had long-term hypoglycemic effects, showing excellent biocompatibility in vitro and in vivo, which had good potential in insulin self-regulation delivery.
    DOI:  https://doi.org/10.1021/acs.biomac.2c00016
  94. Front Immunol. 2022 ;13 826515
    Physiological and Pathophysiological Roles of Metabolic Pathways for NET Formation and Other Neutrophil Functions.
    Darko Stojkov, Lea Gigon, Shuang Peng, Robert Lukowski, Peter Ruth, Alexander Karaulov, Albert Rizvanov, Nickolai A Barlev, Shida Yousefi, Hans-Uwe Simon.
      Neutrophils are the most numerous cells in the leukocyte population and essential for innate immunity. To limit their effector functions, neutrophils are able to modulate glycolysis and other cellular metabolic pathways. These metabolic pathways are essential not only for energy usage, but also for specialized effector actions, such as the production of reactive oxygen species (ROS), chemotaxis, phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs). It has been demonstrated that activated viable neutrophils can produce NETs, which consists of a DNA scaffold able to bind granule proteins and microorganisms. The formation of NETs requires the availability of increased amounts of adenosine triphosphate (ATP) as it is an active cellular and therefore energy-dependent process. In this article, we discuss the glycolytic and other metabolic routes in association with neutrophil functions focusing on their role for building up NETs in the extracellular space. A better understanding of the requirements of metabolic pathways for neutrophil functions may lead to the discovery of molecular targets suitable to develop novel anti-infectious and/or anti-inflammatory drugs.
    Keywords:  glycolysis; metabolic switch; metabolism; neutrophil; neutrophil extracellular traps
    DOI:  https://doi.org/10.3389/fimmu.2022.826515
  95. Front Bioeng Biotechnol. 2022 ;10 851561
    Traditional Chinese Medicine Compound-Loaded Materials in Bone Regeneration.
    Guiwen Shi, Chaohua Yang, Qing Wang, Song Wang, Gaoju Wang, Rongguang Ao, Dejian Li.
      Bone is a dynamic organ that has the ability to repair minor injuries via regeneration. However, large bone defects with limited regeneration are debilitating conditions in patients and cause a substantial clinical burden. Bone tissue engineering (BTE) is an alternative method that mainly involves three factors: scaffolds, biologically active factors, and cells with osteogenic potential. However, active factors such as bone morphogenetic protein-2 (BMP-2) are costly and show an unstable release. Previous studies have shown that compounds of traditional Chinese medicines (TCMs) can effectively promote regeneration of bone defects when administered locally and systemically. However, due to the low bioavailability of these compounds, many recent studies have combined TCM compounds with materials to enhance drug bioavailability and bone regeneration. Hence, the article comprehensively reviewed the local application of TCM compounds to the materials in the bone regeneration in vitro and in vivo. The compounds included icariin, naringin, quercetin, curcumin, berberine, resveratrol, ginsenosides, and salvianolic acids. These findings will contribute to the potential use of TCM compound-loaded materials in BTE.
    Keywords:  bone defect; bone regeneration; bone tissue engineering; drug delivery; osteogenesis; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fbioe.2022.851561
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