bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–05–29
108 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. A Redox-Activatable and Targeted Photosensitizing Agent to Deliver Doxorubicin for Combining Chemotherapy and Photodynamic Therapy.
  2. Recent advances in anti-multidrug resistance for nano-drug delivery system.
  3. Nanoparticles Loaded with Docetaxel and Resveratrol as an Advanced Tool for Cancer Therapy.
  4. Developing dietary interventions as therapy for cancer.
  5. Edible Bioactive Film with Curcumin: A Potential "Functional" Packaging?
  6. Functionalization of Nanoparticulate Drug Delivery Systems and Its Influence in Cancer Therapy.
  7. Efficacy of Polymer-Based Nanomedicine for the Treatment of Brain Cancer.
  8. Enhancing Photodynamic Therapy Efficacy Against Cancer Metastasis by Ultrasound-Mediated Oxygen Microbubble Destruction to Boost Tumor-Targeted Delivery of Oxygen and Renal-Clearable Photosensitizer Micelles.
  9. Mitigation of doxorubicin-induced cardiotoxicity with an H2O2-Activated, H2S-Donating hybrid prodrug.
  10. Editorial: Metabolism Meets Function: The Multifaced Role of Metabolism in Cancer.
  11. Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect.
  12. Bioinspired and Biomimetic Nanomedicines for Targeted Cancer Therapy.
  13. A Review of Metabolic Targets of Anticancer Nutrients and Nutraceuticals in Pre-Clinical Models of Triple-Negative Breast Cancer.
  14. Bioactive Loaded Novel Nano-Formulations for Targeted Drug Delivery and Their Therapeutic Potential.
  15. Advancements in Skin Delivery of Natural Bioactive Products for Wound Management: A Brief Review of Two Decades.
  16. Merging Experimental Design and Nanotechnology for the Development of Optimized Simvastatin Spanlastics: A Promising Combined Strategy for Augmenting the Suppression of Various Human Cancer Cells.
  17. Targeting of Mevalonate-Isoprenoid Pathway in Acute Myeloid Leukemia Cells by Bisphosphonate Drugs.
  18. Gambogic Acid and Piperine Synergistically Induce Apoptosis in Human Cholangiocarcinoma Cell via Caspase and Mitochondria-Mediated Pathway.
  19. The Potential of Chitosan in Nanomedicine: An Overview of the Cytotoxicity of Chitosan Based Nanoparticles.
  20. Ultrasound Triggers Hypericin Activation Leading to Multifaceted Anticancer Activity.
  21. Dextran-Coated Iron Oxide Nanoparticles Loaded with Curcumin for Antimicrobial Therapies.
  22. Green Synthesized Nanoparticles as a Plausible Therapeutic Strategy Against Hepatocellular Carcinoma: An Update on its Preclinical and Clinical Relevance.
  23. Ketogenic Diets and Hepatocellular Carcinoma.
  24. Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment.
  25. Laser-responsive multi-functional nanoparticles for efficient combinational chemo-photodynamic therapy against breast cancer.
  26. Recent Advances in Engineering Nanomedicines for Second Near-Infrared Photothermal-Combinational Immunotherapy.
  27. Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management.
  28. Multifunctional Nanoplatforms as a Novel Effective Approach in Photodynamic Therapy and Chemotherapy, to Overcome Multidrug Resistance in Cancer.
  29. Uses of Natural Honey in Cancer: An Updated Review.
  30. Solid Lipid Nanoparticles for Efficient Oral Delivery of Tyrosine Kinase Inhibitors: A Nano Targeted Cancer Drug Delivery.
  31. Chemical Compounds of Berry-Derived Polyphenols and Their Effects on Gut Microbiota, Inflammation, and Cancer.
  32. Killing three birds with one stone: Near-infrared light triggered nitric oxide release for enhanced photodynamic and anti-inflammatory therapy in refractory keratitis.
  33. Ginsenoside CK induces apoptosis in triple-negative breast cancer cells by targeting glutamine metabolism.
  34. Enhanced postoperative cancer therapy by iron-based hydrogels.
  35. Targeting Energy Metabolism in Cancer Treatment.
  36. New Smoothie Products Based on Pumpkin, Banana, and Purple Carrot as a Source of Bioactive Compounds.
  37. Carbohydrates based stimulus responsive nanocarriers for cancer-targeted chemotherapy: A review of current practices.
  38. Dietary influences on symptomatic and non-symptomatic toxicities during cancer treatment: A narrative review.
  39. Molecular Mechanisms of Chloroquine and Hydroxychloroquine use in Cancer Therapy.
  40. Anti-Inflammatory and Analgesic Evaluation of a Phytochemical Intercalated into Layered Double Hydroxide.
  41. Flavonoids-Based Delivery Systems towards Cancer Therapies.
  42. Kicking KRAS to tackle lung cancer.
  43. Development and evaluation of core-shell nanocarrier system for enhancing the cytotoxicity of doxorubicin/ metformin combination against breast cancer cell line.
  44. Nano-strategies as Oral Drug Delivery Platforms for Treatment of Cancer: Challenges and Future Perspectives.
  45. Prospective Application of Ferroptosis in Hypoxic Cells for Tumor Radiotherapy.
  46. Adenosine Conjugated Docetaxel Nanoparticles-Proof of Concept Studies for Non-Small Cell Lung Cancer.
  47. Current Strategies for Real-Time Enzyme Activation.
  48. Metformin and Cancer, an Ambiguanidous Relationship.
  49. 5-Fluorouracil-Loaded Folic-Acid-Fabricated Chitosan Nanoparticles for Site-Targeted Drug Delivery Cargo.
  50. Novel Microfluidic Swirl Mixers for Scalable Formulation of Curcumin Loaded Liposomes for Cancer Therapy.
  51. Functional Mechanism of Ginsenoside Compound K on Tumor Growth and Metastasis.
  52. Design and Development of a New Type of Hybrid PLGA/Lipid Nanoparticle as an Ursolic Acid Delivery System against Pancreatic Ductal Adenocarcinoma Cells.
  53. Nanobiotechnological prospects of probiotic microflora: Synthesis, mechanism, and applications.
  54. Monoclonal Antibody Functionalized, and L-lysine α-Oxidase Loaded PEGylated-Chitosan Nanoparticle for HER2/Neu Targeted Breast Cancer Therapy.
  55. Biologically Relevant Micellar Nanocarrier Systems for Drug Encapsulation and Functionalization of Metallic Nanoparticles.
  56. New Advances in Nano-Drug Delivery Systems: Helicobacter pylori and Gastric Cancer.
  57. Vesicular Nanocarriers for Phytocompounds in Wound Care: Preparation and Characterization.
  58. Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
  59. Phytochemical Characterization, Antioxidant and Anti-Proliferative Properties of Rubia cordifolia L. Extracts Prepared with Improved Extraction Conditions.
  60. Ferroptosis - A new target of osteoporosis.
  61. Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC).
  62. Preparation of Doxorubicin-Loaded Carboxymethyl-β-Cyclodextrin/Chitosan Nanoparticles with Antioxidant, Antitumor Activities and pH-Sensitive Release.
  63. Xihuang Pill enhances anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway.
  64. Hydrolyzed Flavonoids from Cyrtosperma johnstonii with Superior Antioxidant, Antiproliferative, and Anti-Inflammatory Potential for Cancer Prevention.
  65. The Effects of a Novel Curcumin Derivative Loaded Long-Circulating Solid Lipid Nanoparticle on the MHCC-97H Liver Cancer Cells and Pharmacokinetic Behavior.
  66. Synergistic Antioxidant Activity and Enhanced Stability of Curcumin Encapsulated in Vegetal Oil-Based Microemulsion and Gel Microemulsions.
  67. Hard, Soft, and Hard-and-Soft Drug Delivery Carriers Based on CaCO3 and Alginate Biomaterials: Synthesis, Properties, Pharmaceutical Applications.
  68. Salvia miltiorrhiza in Breast Cancer Treatment: A Review of Its Phytochemistry, Derivatives, Nanoparticles, and Potential Mechanisms.
  69. Nanocrystals: A Deep Insight into Formulation Aspects, Stabilization Strategies and Biomedical Applications.
  70. Honokiol nanosuspensions loaded thermosensitive hydrogels as the local delivery system in combination with systemic paclitaxel for synergistic therapy of breast cancer.
  71. Modulation of the immune system by melatonin; implications for cancer therapy.
  72. Impacts of Oxidative Stress and PI3K/AKT/mTOR on Metabolism and the Future Direction of Investigating Fucoidan-Modulated Metabolism.
  73. Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells.
  74. Chitosan Nanoparticles for Meloxicam Ocular Delivery: Development, In Vitro Characterization, and In Vivo Evaluation in a Rabbit Eye Model.
  75. The Differential Metabolic Response of Oral Squamous Cell Carcinoma Cells and Normal Oral Epithelial Cells to Cisplatin Exposure.
  76. Ferroptosis at the crossroads of tumor-host interactions, metastasis, and therapy response.
  77. Liposomes: structure, composition, types, and clinical applications.
  78. Spatiotemporal feedforward between PKM2 tetramers and mTORC1 prompts mTORC1 activation.
  79. Aucubin Exerts Anticancer Activity in Breast Cancer and Regulates Intestinal Microbiota.
  80. Heptamethine Cyanine-Loaded Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A Review.
  81. Targeted Strategy in Lipid-Lowering Therapy.
  82. Epithelial-mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities.
  83. Enhanced Permeability and Retention Effect: A key facilitator for solid tumor targeting by nanoparticles.
  84. Chinese Herbal Medicine for Primary Liver Cancer Therapy: Perspectives and Challenges.
  85. Chitosan Nanoparticles in Atherosclerosis-Development to Preclinical Testing.
  86. Diclofenac: A Nonsteroidal Anti-Inflammatory Drug Inducing Cancer Cell Death by Inhibiting Microtubule Polymerization and Autophagy Flux.
  87. Complex polymeric nanomicelles co-delivering doxorubicin and dimethoxycurcumin for cancer chemotherapy.
  88. Hypoxia-Responsive Azobenzene-Linked Hyaluronate Dot Particles for Photodynamic Tumor Therapy.
  89. A Focused Insight into Thyme: Biological, Chemical, and Therapeutic Properties of an Indigenous Mediterranean Herb.
  90. A Comprehensive Review of Rosmarinic Acid: From Phytochemistry to Pharmacology and Its New Insight.
  91. Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.
  92. Nanoparticles as Physically- and Biochemically-Tuned Drug Formulations for Cancers Therapy.
  93. Modulation of Inflammation by Plant-Derived Nutraceuticals in Tendinitis.
  94. Repurposing drugs to treat cardiovascular disease in the era of precision medicine.
  95. Vitamin D enhances the sensitivity of breast cancer cells to the combination therapy of photodynamic therapy and paclitaxel.
  96. A Review on Current Designation of Metallic Nanocomposite Hydrogel in Biomedical Applications.
  97. Photodynamic Therapy for Treatment of Disease in Children-A Review of the Literature.
  98. Co-Delivery of Nano-Silver and Vancomycin via Silica Nanopollens for Enhanced Antibacterial Functions.
  99. Amphiphilic Poly-N-vinylpyrrolidone Nanoparticles as Carriers for Nonsteroidal, Anti-Inflammatory Drugs: Pharmacokinetic, Anti-Inflammatory, and Ulcerogenic Activity Study.
  100. How Phosphofructokinase-1 Promotes PI3K and YAP/TAZ in Cancer: Therapeutic Perspectives.
  101. Nanoparticles: Synthesis and Their Role as Potential Drug Candidates for the Treatment of Parasitic Diseases.
  102. Recent Advances in Poly(α-L-glutamic acid)-Based Nanomaterials for Drug Delivery.
  103. Iron oxide nanoflowers encapsulated in thermosensitive fluorescent liposomes for hyperthermia treatment of lung adenocarcinoma.
  104. Effectiveness of beetroot extract in SH-SY5Y neuronal cell protection against Fumonisin B1, Ochratoxin A and its combination.
  105. A comprehensive system review of pharmacological effects and relative mechanisms of Ginsenoside Re: Recent advances and future perspectives.
  106. Critical PDT Theory II: Current Concepts and Indications.
  107. Enhanced Anticancer Activity of Hymenocardia acida Stem Bark Extract Loaded into PLGA Nanoparticles.
  108. Enhanced Brain Delivery via Intranasal Administration of Carbamazepine Loaded Solid Lipid Nanoparticles: Optimization, Pharmacokinetic analysis, In-vitro and In-vivo Drug Release Study.
  1. Mol Pharm. 2022 May 26.
    A Redox-Activatable and Targeted Photosensitizing Agent to Deliver Doxorubicin for Combining Chemotherapy and Photodynamic Therapy.
    Jun Yin, Chengcheng Ouyang, Shuwei Shen, Yaxin Zhou, Guoyi He, Heng Zhang, Kai Zhou, Guoguang Chen, Lili Ren.
      Currently, tumors have become a serious disease threatening human health and life in modern society. Photo-chemo combination therapy is considered to be an important method to improving the efficiency of tumor treatment, especially in the treatment of multi-drug-resistant tumors. However, the application of photo-chemo combination therapy has been limited by the poor water solubility of photosensitizers, low tumor targeting, and high side effects of chemotherapy drugs. In order to solve these problems, a smart nano drug delivery platform FA-PEG-ss-PLL(-g-Ce6) designed and synthesized by us. The smart nano drug carrier uses folic acid (FA) as the targeting group, polyethylene glycol (PEG) as the hydrophilic end, Ce6-grafted polylysine (PLL(-g-Ce6)) as the hydrophobic end, and Chlorin e6 (Ce6) as the photosensitizer of photodynamic therapy, and it connects PEG to PLL by a redox-responsive cleavable disulfide linker (-ss-). Finally, the combination of tumor chemotherapy and photodynamic therapy (PDT) is realized by loading with anticancer drug doxorubicin (DOX) to the intelligent carrier. In vitro experiments showed that the drug loading content (DLC%) of DOX@FA-PEG-ss-PLL(-g-Ce6) nanoparticles (DOX@FPLC NPs) was as high as 14.83%, and the nanoparticles had good serum stability, reduction sensitivity and hemocompatibility. From the cytotoxicity assays in vitro, we found that under 664 nm laser irradiation DOX@FPLC NPs showed stronger toxicity to MCF-7 cells than did DOX, Ce6 + laser, and DOX + Ce6 + laser. Moreover, the antitumor efficiency in vivo and histopathological analysis showed that DOX@FPLC NPs under 664 nm laser irradiation exhibited higher antitumor activity and lower systemic toxicity than single chemotherapy. These results suggested that the FA-PEG-ss-PLL(-g-Ce6) nano drug delivery platform has considerable potential for the combination of chemotherapy and PDT.
    Keywords:  chemotherapy; drug delivery; photodynamic therapy; photosensitizer; tumor
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00855
  2. Drug Deliv. 2022 Dec;29(1): 1684-1697
    Recent advances in anti-multidrug resistance for nano-drug delivery system.
    Changduo Wang, Fashun Li, Tianao Zhang, Min Yu, Yong Sun.
      Chemotherapy for tumors occasionally results in drug resistance, which is the major reason for the treatment failure. Higher drug doses could improve the therapeutic effect, but higher toxicity limits the further treatment. For overcoming drug resistance, functional nano-drug delivery system (NDDS) has been explored to sensitize the anticancer drugs and decrease its side effects, which are applied in combating multidrug resistance (MDR) via a variety of mechanisms including bypassing drug efflux, controlling drug release, and disturbing metabolism. This review starts with a brief report on the major MDR causes. Furthermore, we searched the papers from NDDS and introduced the recent advances in sensitizing the chemotherapeutic drugs against MDR tumors. Finally, we concluded that the NDDS was based on several mechanisms, and we looked forward to the future in this field.
    Keywords:  Multidrug resistance; nano-drug delivery system; nanoparticles
    DOI:  https://doi.org/10.1080/10717544.2022.2079771
  3. Biomedicines. 2022 May 20. pii: 1187. [Epub ahead of print]10(5):
    Nanoparticles Loaded with Docetaxel and Resveratrol as an Advanced Tool for Cancer Therapy.
    Magdalena Jurczyk, Janusz Kasperczyk, Dorota Wrześniok, Artur Beberok, Katarzyna Jelonek.
      A growing interest in the use of a combination of chemosensitizers and cytostatics for overcoming cancer resistance to treatment and the development of their delivery systems has been observed. Resveratrol (Res) presents antioxidant, anti-inflammatory and chemopreventive properties but also limits multidrug resistance against docetaxel (Dtx), which is one of the main causes of failure in cancer therapy with this drug. However, the use of both drugs presents challenges, including poor bioavailability, the unfavourable pharmacokinetics and chemical instability of Res and the poor water solubility and dose-limiting toxicity of Dtx. In order to overcome these difficulties, attempts have been made to create different forms of delivery for both agents. This review is focused on the latest developments in nanoparticles for the delivery of Dtx, Res and for the combined delivery of those two drugs. The aim of this review was also to summarize the synergistic mechanism of action of Dtx and Res on cancer cells. According to recent reports, Dtx and Res loaded in a nano-delivery system exhibit better efficiency in cancer treatment compared to free drugs. Also, the co-delivery of Dtx and Res in one actively targeted delivery system providing the simultaneous release of both drugs in cancer cells has a chance to fulfil the requirements of effective anticancer therapy and reduce limitations in therapy caused by multidrug resistance (MDR).
    Keywords:  anticancer drugs; chemosensitizer; co-delivery; docetaxel; drug delivery; nanoparticles; resveratrol; targeted delivery
    DOI:  https://doi.org/10.3390/biomedicines10051187
  4. Nat Rev Cancer. 2022 May 25.
    Developing dietary interventions as therapy for cancer.
    Samuel R Taylor, John N Falcone, Lewis C Cantley, Marcus D Goncalves.
      Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00485-y
  5. Int J Mol Sci. 2022 May 18. pii: 5638. [Epub ahead of print]23(10):
    Edible Bioactive Film with Curcumin: A Potential "Functional" Packaging?
    Josemar Gonçalves Oliveira Filho, Mariana Buranelo Egea.
      Edible packaging has been developed as a biodegradable and non-toxic alternative to traditional petroleum-based food packaging. Biopolymeric edible films, in addition to their passive protective function, may also play a bioactive role as vehicles for bioactive compounds of importance to human health. In recent years, a new generation of edible food packaging has been developed to incorporate ingredients with functional potential that have beneficial effects on consumer health. Curcumin, a bioactive compound widely used as a natural dye obtained from turmeric rhizomes (Curcuma longa L.), has a broad spectrum of beneficial properties for human health, such as anti-inflammatory, anti-hypertensive, antioxidant, anti-cancer, and other activities. To demonstrate these properties, curcumin has been explored as a bioactive agent for the development of bioactive packaging, which can be referred to as functional packaging and used in food. The aim of this review was to describe the current and potential research on the development of functional-edible-films incorporating curcumin for applications such as food packaging.
    Keywords:  bioactive compounds; edible films; functional foods; turmeric
    DOI:  https://doi.org/10.3390/ijms23105638
  6. Pharmaceutics. 2022 May 23. pii: 1113. [Epub ahead of print]14(5):
    Functionalization of Nanoparticulate Drug Delivery Systems and Its Influence in Cancer Therapy.
    Theodora Amanda Seidu, Perpetua Takunda Kutoka, Dorothy Owusu Asante, Muhammad Asim Farooq, Raphael N Alolga, Wang Bo.
      Research into the application of nanocarriers in the delivery of cancer-fighting drugs has been a promising research area for decades. On the other hand, their cytotoxic effects on cells, low uptake efficiency, and therapeutic resistance have limited their therapeutic use. However, the urgency of pressing healthcare needs has resulted in the functionalization of nanoparticles' (NPs) physicochemical properties to improve clinical outcomes of new, old, and repurposed drugs. This article reviews recent research on methods for targeting functionalized nanoparticles to the tumor microenvironment (TME). Additionally, the use of relevant engineering techniques for surface functionalization of nanocarriers (liposomes, dendrimers, and mesoporous silica) and their critical roles in overcoming the current limitations in cancer therapy-targeting ligands used for targeted delivery, stimuli strategies, and multifunctional nanoparticles-were all reviewed. The limitations and future perspectives of functionalized nanoparticles were also finally discussed. Using relevant keywords, published scientific literature from all credible sources was retrieved. A quick search of the literature yielded almost 400 publications. The subject matter of this review was addressed adequately using an inclusion/exclusion criterion. The content of this review provides a reasonable basis for further studies to fully exploit the potential of these nanoparticles in cancer therapy.
    Keywords:  cancer therapy; dendrimers; liposomes; mesoporous silica NPs; multifunctional nanoparticles (MNPs); surface functionalization
    DOI:  https://doi.org/10.3390/pharmaceutics14051113
  7. Pharmaceutics. 2022 May 13. pii: 1048. [Epub ahead of print]14(5):
    Efficacy of Polymer-Based Nanomedicine for the Treatment of Brain Cancer.
    Tobeka Naki, Blessing A Aderibigbe.
      Malignant brain tumor is a life-threatening disease with a low survival rate. The therapies available for the treatment of brain tumor is limited by poor uptake via the blood-brain barrier. The challenges with the chemotherapeutics used for the treatment of brain tumors are poor distribution, drug toxicity, and their inability to pass via the blood-brain barrier, etc. Several researchers have investigated the potential of nanomedicines for the treatment of brain cancer. Nanomedicines are designed with nanosize particle sizes with a large surface area and are loaded with bioactive agents via encapsulation, immersion, conjugation, etc. Some nanomedicines have been approved for clinical use. The most crucial part of nanomedicine is that they promote drug delivery across the blood-brain barrier, display excellent specificity, reduce drug toxicity, enhance drug bioavailability, and promote targeted drug release mechanisms. The aforementioned features make them promising therapeutics for brain targeting. This review reports the in vitro and in vivo results of nanomedicines designed for the treatment of brain cancers.
    Keywords:  anticancer drugs; blood–brain barrier; brain cancer; drug delivery; nanomedicine; tumor
    DOI:  https://doi.org/10.3390/pharmaceutics14051048
  8. ACS Appl Mater Interfaces. 2022 May 26.
    Enhancing Photodynamic Therapy Efficacy Against Cancer Metastasis by Ultrasound-Mediated Oxygen Microbubble Destruction to Boost Tumor-Targeted Delivery of Oxygen and Renal-Clearable Photosensitizer Micelles.
    Yunxue Xu, Renfa Liu, Huanyu Yang, Shuai Qu, Linxue Qian, Zhifei Dai.
      Hypoxic tumor microenvironment and nonspecific accumulation of photosensitizers are two key factors that limit the efficacy of photodynamic therapy (PDT). Herein, a strategy of oxygen microbubbles (MBs) boosting photosensitizer micelles is developed to enhance PDT efficacy and inhibit tumor metastasis by self-assembling renal-clearable ultrasmall poly(ethylene glycol)-modified protoporphyrin IX micelles (PPM) and perfluoropentane (PFP)-doped oxygen microbubbles (OPMBs), followed by ultrasound imaging-guided OPMB destruction to realize the tumor-targeted delivery of PPM and oxygen in tumor. Doping PFP into oxygen MBs increases the production of MBs and stability of oxygen MBs, allowing for persistent circulation in blood. Following co-injection, destruction of OPMBs with ultrasound leads to ∼2.2-fold increase of tumor-specific PPM accumulation. Furthermore, the burst release of oxygen by MB destruction improves tumor oxygenation from 22 to 50%, which not only raises the production of singlet oxygen but also significantly reduces the expression of hypoxia-inducible factor-1 alpha and related genes, thus preventing angiogenesis and epithelial-mesenchymal transition. It is verified that this strategy effectively eradicates orthotopic breast cancer and inhibits lung metastasis. Furthermore, the survival rate of mice bearing orthotopic pancreatic tumor is significantly extended by such interventional PDT strategy. Therefore, the combination of ultrasmall PPM and OPMBs represents a simple but effective strategy in overcoming the limitations of PDT.
    Keywords:  oxygen microbubbles; photodynamic therapy; renal-clearable nanoparticles; tumor hypoxia; ultrasound-targeted microbubble destruction
    DOI:  https://doi.org/10.1021/acsami.2c06655
  9. Redox Biol. 2022 May 16. pii: S2213-2317(22)00110-0. [Epub ahead of print]53 102338
    Mitigation of doxorubicin-induced cardiotoxicity with an H2O2-Activated, H2S-Donating hybrid prodrug.
    Qiwei Hu, Rama D Yammani, Heather Brown-Harding, David R Soto-Pantoja, Leslie B Poole, John C Lukesh.
      Doxorubicin (DOX) is one of the most effective anticancer agents in clinical oncology. Its continued use, however, is severely limited by its dose-dependent cardiotoxicity which stems, in part, from its overproduction of reactive oxygen species (ROS) and often manifests itself as full-blown cardiomyopathy in patients, years after the cessation of treatment. Therefore, identifying DOX analogs, or prodrugs, with a diminished cardiotoxic profile is highly desirable. Herein, we describe a novel, H2O2-responsive DOX hybrid codrug (mutual prodrug) that has been rationally designed to concurrently liberate hydrogen sulfide (H2S), a purported cardioprotectant with anticancer activity, in an effort to maintain the antitumor effects of DOX while simultaneously reducing its cardiotoxic side effects. Experiments with cardiomyoblast cells in culture demonstrated a rapid accumulation of prodrug into the cells, but diminished apoptotic effects compared with DOX, dependent upon its release of H2S. Cells treated with the prodrug exhibited significantly higher Nrf2 activation relative to DOX-treated cells. Preliminary indications, using a mouse triple-negative breast cancer cell line sensitive to DOX treatment, are that the prodrug maintains considerable toxicity against the tumor-inducing cell line, suggesting significant promise for this prodrug as a cardioprotective chemotherapeutic to replace DOX.
    Keywords:  Cardiotoxicity; Chemotherapeutic; Doxorubicin; Hydrogen peroxide; Hydrogen sulfide
    DOI:  https://doi.org/10.1016/j.redox.2022.102338
  10. Front Oncol. 2022 ;12 906421
    Editorial: Metabolism Meets Function: The Multifaced Role of Metabolism in Cancer.
    Isabella Giacomini, Monica Montopoli.
      
    Keywords:  cancer; cancer metabolism; drug resistance; metabolic reprogramming; targeting metabolism; tumor microenviroment (TME)
    DOI:  https://doi.org/10.3389/fonc.2022.906421
  11. Front Physiol. 2022 ;13 859820
    Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect.
    Pedro Freire Jorge, Matthew L Goodwin, Maurits H Renes, Maarten W Nijsten, Matthew Pamenter.
      Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO2 and lactic acid by a decreased extracellular pH. Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.
    Keywords:  Warburg effect; cancer metabolism; hypoxic metabolic response; hypoxic ventilatory response (HVR); metabolic fuel switching; metabolism; naked mole-rat; thermoregulation
    DOI:  https://doi.org/10.3389/fphys.2022.859820
  12. Pharmaceutics. 2022 May 23. pii: 1109. [Epub ahead of print]14(5):
    Bioinspired and Biomimetic Nanomedicines for Targeted Cancer Therapy.
    Xiaoqiu Xu, Tong Li, Ke Jin.
      Undesirable side effects and multidrug resistance are the major obstacles in conventional chemotherapy towards cancers. Nanomedicines provide alternative strategies for tumor-targeted therapy due to their inherent properties, such as nanoscale size and tunable surface features. However, the applications of nanomedicines are hampered in vivo due to intrinsic disadvantages, such as poor abilities to cross biological barriers and unexpected off-target effects. Fortunately, biomimetic nanomedicines are emerging as promising therapeutics to maximize anti-tumor efficacy with minimal adverse effects due to their good biocompatibility and high accumulation abilities. These bioengineered agents incorporate both the physicochemical properties of diverse functional materials and the advantages of biological materials to achieve desired purposes, such as prolonged circulation time, specific targeting of tumor cells, and immune modulation. Among biological materials, mammalian cells (such as red blood cells, macrophages, monocytes, and neutrophils) and pathogens (such as viruses, bacteria, and fungi) are the functional components most often used to confer synthetic nanoparticles with the complex functionalities necessary for effective nano-biointeractions. In this review, we focus on recent advances in the development of bioinspired and biomimetic nanomedicines (such as mammalian cell-based drug delivery systems and pathogen-based nanoparticles) for targeted cancer therapy. We also discuss the biological influences and limitations of synthetic materials on the therapeutic effects and targeted efficacies of various nanomedicines.
    Keywords:  biohybrid nanoparticles; bioinspired nanomedicine; biomimetic strategy; cancer treatment; targeted drug delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14051109
  13. Nutrients. 2022 May 10. pii: 1990. [Epub ahead of print]14(10):
    A Review of Metabolic Targets of Anticancer Nutrients and Nutraceuticals in Pre-Clinical Models of Triple-Negative Breast Cancer.
    Alleigh Wiggs, Sabrina Molina, Susan J Sumner, Blake R Rushing.
      Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is notoriously aggressive and has poorer outcomes as compared with other breast cancer subtypes. Due to a lack of targeted therapies, TNBC is often treated with chemotherapeutics as opposed to hormone therapy or other targeted therapies available to individuals with estrogen receptor positive (ER+) breast cancers. Because of the lack of treatment options for TNBC, other therapeutic avenues are being explored. Metabolic reprogramming, a hallmark of cancer, provides potential opportunities to target cancer cells more specifically, increasing efficacy and reducing side effects. Nutrients serve a significant role in metabolic processes involved in DNA transcription, protein folding, and function as co-factors in enzyme activity, and may provide novel strategies to target cancer cell metabolism in TNBC. This article reviews studies that have investigated how nutrients/nutraceuticals target metabolic processes in TNBC cells alone or in combination with existing drugs to exert anticancer effects. These agents have been shown to cause perturbations in many metabolic processes related to glucose metabolism, fatty acid metabolism, as well as autophagy and oxidative stress-related metabolism. With this information, we present the potential of nutrients as metabolism-directed anticancer agents and the potential for using these agents alone or in cocktails as a new direction for TNBC therapy.
    Keywords:  breast cancer; metabolic reprogramming; metabolism; metabolomics; nutraceuticals; nutrients; treatment
    DOI:  https://doi.org/10.3390/nu14101990
  14. Pharmaceutics. 2022 May 19. pii: 1091. [Epub ahead of print]14(5):
    Bioactive Loaded Novel Nano-Formulations for Targeted Drug Delivery and Their Therapeutic Potential.
    Sapna Kumari, Anju Goyal, Eda Sönmez Gürer, Evren Algın Yapar, Madhukar Garg, Meenakshi Sood, Rakesh K Sindhu.
      Plant-based medicines have received a lot of attention in recent years. Such medicines have been employed to treat medical conditions since ancient times, and in those times only the observed symptoms were used to determine dose accuracy, dose efficacy, and therapy. Rather than novel formulations, the current research work on plant-based medicines has mostly concentrated on medicinal active phytoconstituents. In the past recent decades, however, researchers have made significant progress in developing "new drug delivery systems" (NDDS) to enhance therapeutic efficacy and reduce unwanted effects of bioactive compounds. Nanocapsules, polymer micelles, liposomes, nanogels, phytosomes, nano-emulsions, transferosomes, microspheres, ethosomes, injectable hydrogels, polymeric nanoparticles, dendrimers, and other innovative therapeutic formulations have all been created using bioactive compounds and plant extracts. The novel formulations can improve solubility, therapeutic efficacy, bioavailability, stability, tissue distribution, protection from physical and chemical damage, and prolonged and targeted administration, to name a few. The current study summarizes existing research and the development of new formulations, with a focus on herbal bioactive components.
    Keywords:  cubosomes; liposomes; nano-formulations; nanomedicines; phytoconstituents; phytosomes
    DOI:  https://doi.org/10.3390/pharmaceutics14051091
  15. Pharmaceutics. 2022 May 17. pii: 1072. [Epub ahead of print]14(5):
    Advancements in Skin Delivery of Natural Bioactive Products for Wound Management: A Brief Review of Two Decades.
    Cameron Ryall, Sanjukta Duarah, Shuo Chen, Haijun Yu, Jingyuan Wen.
      Application of modern delivery techniques to natural bioactive products improves their permeability, bioavailability, and therapeutic efficacy. Many natural products have desirable biological properties applicable to wound healing but are limited by their inability to cross the stratum corneum to access the wound. Over the past two decades, modern systems such as microneedles, lipid-based vesicles, hydrogels, composite dressings, and responsive formulations have been applied to natural products such as curcumin or aloe vera to improve their delivery and efficacy. This article reviews which natural products and techniques have been formulated together in the past two decades and the success of these applications for wound healing. Many cultures prefer natural-product-based traditional therapies which are often cheaper and more available than their synthetic counterparts. Improving natural products' effect can provide novel wound-healing therapies for those who trust traditional compounds over synthetic drugs to reduce medical inequalities.
    Keywords:  advanced delivery; alternative medicine; natural products; traditional medicine; wound healing
    DOI:  https://doi.org/10.3390/pharmaceutics14051072
  16. Pharmaceutics. 2022 May 09. pii: 1024. [Epub ahead of print]14(5):
    Merging Experimental Design and Nanotechnology for the Development of Optimized Simvastatin Spanlastics: A Promising Combined Strategy for Augmenting the Suppression of Various Human Cancer Cells.
    Shaimaa M Badr-Eldin, Hibah M Aldawsari, Nabil A Alhakamy, Usama A Fahmy, Osama A A Ahmed, Thikryat Neamatallah, Singkome Tima, Raghad H Almaghrabi, Fayda M Alkudsi, Asmaa A Alamoudi, Amjad A Alzahrani, Sabna Kotta, Omar D Al-Hejaili.
      Simvastatin (SMV) is an antihyperlipidemic agent that has been investigated as a possible anti-cancer agent. An obstacle to malignant tumor therapy using drugs is the delivery of adequate levels to the cancer cells while minimizing side effects following their systemic administration. To circumvent this challenge, the researchers directed towards the field of nanotechnology to benefit from the nano-size of the formulation in passively targeting the tumor cells. Thus, our study aimed at investigating the potential of a combined mixture-process variable design for optimization of SMV spanlastics (SMV-SPNs) with minimized particle size and maximized zeta potential to enhance the anticancer activity of the drug. The study investigated the effects of Span® 20 and Tween® 80 as mixture components and sonication time as a process variable on particle size, polydispersity index, and zeta potential as responses. SPNs were prepared using an ethanol injection method. Combining the predicted optimized variables' levels is supposed to achieve the set goals with a desirability of 0.821. The optimized spanlastics exhibited a measured globule size of 128.50 nm, PDI of 0.329, and ZP of -29.11 mV. The percentage relative error between predicted responses and the observed ones were less than 5% for the three responses, indicating the optimization technique credibility. A significant improvement in the cytotoxicity of the optimized formulation against three different cancerous cell lines was observed in comparison with SMV. The inhibitory concentration (IC50) values of MCF-7, HCT-116, and HEPG2 were found to be 0.89, 0.39, and 0.06 μM at 24 h incubation. The enhanced cytotoxicity could be assigned to the possible improved permeation and preferential build-up within the cancerous cells by virtue of the minimized size. These findings imply that SMV-SPNs could be an ideal strategy to combat cancer.
    Keywords:  combined mixture-process variable design; in vitro cytotoxicity; optimization; simvastatin; spanlastics
    DOI:  https://doi.org/10.3390/pharmaceutics14051024
  17. Biomedicines. 2022 May 16. pii: 1146. [Epub ahead of print]10(5):
    Targeting of Mevalonate-Isoprenoid Pathway in Acute Myeloid Leukemia Cells by Bisphosphonate Drugs.
    Emanuela Chiarella, Clelia Nisticò, Anna Di Vito, Helen Linda Morrone, Maria Mesuraca.
      Metabolic reprogramming represents a hallmark of tumorigenesis to sustain survival in harsh conditions, rapid growth and metastasis in order to resist to cancer therapies. These metabolic alterations involve glucose metabolism, known as the Warburg effect, increased glutaminolysis and enhanced amino acid and lipid metabolism, especially the cholesterol biosynthesis pathway known as the mevalonate pathway and these are upregulated in several cancer types, including acute myeloid leukemia (AML). In particular, it was demonstrated that the mevalonate pathway has a pivotal role in cellular transformation. Therefore, targeting this biochemical process with drugs such as statins represents a promising therapeutic strategy to be combined with other anticancer treatments. In the last decade, several studies have revealed that amino-bisphosphonates (BP), primarily used for bone fragility disorders, also exhibit potential anti-cancer activity in leukemic cells, as well as in patients with symptomatic multiple myeloma. Indeed, these compounds inhibit the farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway, reducing isoprenoid formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. This, in turn, inhibits the prenylation of small Guanosine Triphosphate-binding proteins, such as Ras, Rho, Rac, Rab, which are essential for regulating cell survival membrane ruffling and trafficking, interfering with cancer key signaling events involved in clonal expansion and maturation block of progenitor cells in myeloid hematological malignancies. Thus, in this review, we discuss the recent advancements about bisphosphonates' effects, especially zoledronate, analyzing the biochemical mechanisms and anti-tumor effects on AML model systems. Future studies will be oriented to investigate the clinical relevance and significance of BP treatment in AML, representing an attractive therapeutic strategy that could be integrated into chemotherapy.
    Keywords:  AML; bisphosphonates; mevalonate pathway; protein isoprenylation; small GTPases
    DOI:  https://doi.org/10.3390/biomedicines10051146
  18. Evid Based Complement Alternat Med. 2022 ;2022 6288742
    Gambogic Acid and Piperine Synergistically Induce Apoptosis in Human Cholangiocarcinoma Cell via Caspase and Mitochondria-Mediated Pathway.
    Rittibet Yapasert, Ratana Banjerdpongchai.
      Most cholangiocarcinoma (CCA) patients undergo chemotherapy as a therapeutic approach due to the disease's frequently late diagnosis. However, because CCA is resistant to currently available treatments, the prognosis for this cancer is still quite poor. Combination therapy has emerged as a novel and promising strategy in cancer treatment, as monotherapy frequently results in tumor recurrence and drug resistance. Gambogic acid has been shown to have a synergism with other compounds in combating certain cancer cells. Moreover, piperine has been shown to improve the efficacy of numerous chemotherapy drugs and other anticancer natural substances. However, no research has been done on the combination of these two compounds in the treatment of bile duct cancer. In this study, the cytotoxic activity was determined by using the MTT assay, and then, the combined effect was assessed by using the combination index (CI). We found that the combination of gambogic acid and piperine inhibited cell viability more effectively than either treatment alone, and it also demonstrated a synergistically cytotoxic effect against CCA cells. Interestingly, the findings allowed the use of lower concentrations of gambogic acid in cancer treatment when combined with piperine, which could reduce its adverse effect on normal cholangiocytes. Furthermore, the combination of the two compounds increased CCA cell death by inducing apoptosis via both the extrinsic and intrinsic or mitochondria-mediated pathways, as determined by caspase-3, -8, and -9 activity and the reduction of mitochondrial transmembrane potential (ΔΨm). It is possible that the use of these two natural compounds together could be a promising strategy for the treatment of bile duct cancer.
    DOI:  https://doi.org/10.1155/2022/6288742
  19. Front Pharmacol. 2022 ;13 880377
    The Potential of Chitosan in Nanomedicine: An Overview of the Cytotoxicity of Chitosan Based Nanoparticles.
    Julie Frigaard, Janicke Liaaen Jensen, Hilde Kanli Galtung, Marianne Hiorth.
      The unique properties and applications of nanotechnology in targeting drug delivery, cosmetics, fabrics, water treatment and food packaging have received increased focus the last two decades. The application of nanoparticles in medicine is rapidly evolving, requiring careful investigation of toxicity before clinical use. Chitosan, a derivative of the natural polysaccharide chitin, has become increasingly relevant in modern medicine because of its unique properties as a nanoparticle. Chitosan is already widely used as a food additive and in food packaging, bandages and wound dressings. Thus, with an increasing application worldwide, cytotoxicity assessment of nanoparticles prepared from chitosan is of great interest. The purpose of this review is to provide an updated status of cytotoxicity studies scrutinizing the safety of chitosan nanoparticles used in biomedical research. A search in Ovid Medline from 23 March 1998 to 4 January 2022, with the combination of the search words Chitosan or chitosan, nanoparticle or nano particle or nanosphere or nanocapsule or nano capsule, toxicology or toxic or cytotoxic and mucosa or mucous membrane resulted in a total of 88 articles. After reviewing all the articles, those involving non-organic nanoparticles and cytotoxicity assays conducted exclusively on nanoparticles with anti-tumor effect (i.e., having cytotoxic effect) were excluded, resulting in 70 articles. Overall, the chitosan nanoparticles included in this review seem to express low cytotoxicity regardless of particle composition or cytotoxicity assay and cell line used for testing. Nonetheless, all new chitosan derivatives and compositions are recommended to undergo careful characterization and cytotoxicity assessment before being implemented on the market.
    Keywords:  cell viability; chitosan; cytotoxicity; drug carriers; drug delivery systems; nanocapsule; nanoparticles
    DOI:  https://doi.org/10.3389/fphar.2022.880377
  20. Pharmaceutics. 2022 May 21. pii: 1102. [Epub ahead of print]14(5):
    Ultrasound Triggers Hypericin Activation Leading to Multifaceted Anticancer Activity.
    Federica Foglietta, Roberto Canaparo, Simone Cossari, Patrizia Panzanelli, Franco Dosio, Loredana Serpe.
      The use of ultrasound (US) in combination with a responsive chemical agent (sonosensitizer) can selectively trigger the agent's anticancer activity in a process called sonodynamic therapy (SDT). SDT shares some properties with photodynamic therapy (PDT), which has been clinically approved, but sets itself apart because of its use of US rather than light to achieve better tissue penetration. SDT provides anticancer effects mainly via the sonosensitizer-mediated generation of reactive oxygen species (ROS), although the precise nature of the underpinning mechanism is still under debate. This work investigates the SDT anticancer activity of hypericin (Hyp) in vitro in two- (2D) and three-dimensional (3D) HT-29 colon cancer models, and uses PDT as a yardstick due to its well-known Hyp phototoxicity. The cancer cell uptake and cellular localization of Hyp were investigated first to determine the proper noncytotoxic concentration and incubation time of Hyp for SDT. Furthermore, ROS production, cell proliferation, and cell death were evaluated after Hyp was exposed to US. Since cancer relapse and transporter-mediated multidrug resistance (MDR) are important causes of cancer treatment failure, the US-mediated ability of Hyp to elicit immunogenic cell death (ICD) and overcome MDR was also investigated. SDT showed strong ROS-mediated anticancer activity 48 h after treatment in both the HT-29 models. Specific damage-associated molecular patterns that are consistent with ICD, such as calreticulin (CRT) exposure and high-mobility group box 1 protein (HMGB1) release, were observed after SDT with Hyp. Moreover, the expression of the ABC transporter, P-glycoprotein (P-gp), in HT-29/MDR cells was not able to hinder cancer cell responsiveness to SDT with Hyp. This work reveals, for the first time, the US responsiveness of Hyp with significant anticancer activity being displayed, making it a full-fledged sonosensitizer for the SDT of cancer.
    Keywords:  colon cancer; hypericin; immunogenic cell death; sonodynamic therapy; sonosensitizer; three-dimensional cell cultures; ultrasound
    DOI:  https://doi.org/10.3390/pharmaceutics14051102
  21. Pharmaceutics. 2022 May 14. pii: 1057. [Epub ahead of print]14(5):
    Dextran-Coated Iron Oxide Nanoparticles Loaded with Curcumin for Antimicrobial Therapies.
    Cristina Chircov, Raluca-Elena Ștefan, Georgiana Dolete, Adriana Andrei, Alina Maria Holban, Ovidiu-Cristian Oprea, Bogdan Stefan Vasile, Ionela Andreea Neacșu, Bianca Tihăuan.
      The current trend in antimicrobial-agent development focuses on the use of natural compounds that limit the toxicity of conventional drugs and provide a potential solution to the antimicrobial resistance crisis. Curcumin represents a natural bioactive compound with well-known antimicrobial, anticancer, and antioxidant properties. However, its hydrophobicity considerably limits the possibility of body administration. Therefore, dextran-coated iron oxide nanoparticles can be used as efficient drug-delivery supports that could overcome this limitation. The iron oxide nanoparticles were synthesized through the microwave-assisted hydrothermal method by varying the treatment parameters (pressure and reaction time). The nanoparticles were subsequently coated with dextran and used for the loading of curcumin (in various concentrations). The drug-delivery systems were characterized through X-ray diffraction (XRD) coupled with Rietveld refinement, transmission electron microscopy (TEM), high-resolution TEM (HR-TEM), selected area electron diffraction (SAED), dynamic light scattering (DLS) and zeta potential, thermogravimetry and differential scanning calorimetry (TG-DSC), vibrating sample magnetometry (VSM), and UV-Vis spectrophotometry, as well as regarding their antimicrobial efficiency and biocompatibility using the appropriate assays. The results demonstrate a promising antimicrobial efficiency, as well as an increased possibility of controlling the properties of the resulted nanosystems. Thus, the present study represents an important step forward toward the development of highly efficient antimicrobial drug-delivery systems.
    Keywords:  antimicrobial therapy; curcumin; dextran; iron oxide nanoparticles; microwave-assisted hydrothermal method
    DOI:  https://doi.org/10.3390/pharmaceutics14051057
  22. Recent Pat Anticancer Drug Discov. 2022 May 23.
    Green Synthesized Nanoparticles as a Plausible Therapeutic Strategy Against Hepatocellular Carcinoma: An Update on its Preclinical and Clinical Relevance.
    Gopika Chandrababu, Sunil Kumar Sah, Ayana R Kumar, Sabitha M, Lekshmi R Nath.
      Green nanotechnology can offer notable advantages over the conventional drug delivery methods in terms of improved drug stability, drug-carrying capacity, site-specificity, feasibility to apply different routes of administration with less systemic toxicities. Metal nanoparticles bio fabricated with phytoconstituents and microbial extracts have gained significant interest for the treatment of various solid tumors including hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is an aggressive cancer with very poor prognosis. The current treatment of HCC fails to provide tumor specificity, causing many systemic toxicities and poor overall survival benefits especially for patients in advanced and terminal stages. A novel therapeutic approach with maximal therapeutic effect and minimum adverse effects are urgently required for HCC patients. Green synthesized metal nanoparticles offer significant anticancer effects along with minimal systemic toxicities because of their site-specific delivery into the tumor microenvironment (TME). Green synthesized metal nanoparticles can therefore be a highly beneficial strategy for the treatment of HCC if properly validated with preclinical and clinical studies. This review focus on the preclinical evidence on the most widely studied green metal nanoparticles such as green synthesized silver nanoparticles, gold nanoparticles and selenium nanoparticles. We have also summarised the clinical studies and the patents approved for nanoparticles against HCC.
    Keywords:  Gold nanoparticles; Green nanoparticles; Green synthesis; Hepatocellular carcinoma; Phytofabrications; Silver nanoparticles
    DOI:  https://doi.org/10.2174/1574892817666220523124437
  23. Front Oncol. 2022 ;12 879205
    Ketogenic Diets and Hepatocellular Carcinoma.
    Yan Lan, Chaonan Jin, Pavitra Kumar, Xia Yu, Cameron Lenahan, Jifang Sheng.
      The ketogenic diet (KD) is a low-carbohydrate, high-fat diet regarded as a potential intervention for cancers owing to its effects on tumor metabolism and behavior. Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer, and its management is worth investigating because of the high fatality rate. Additionally, as the liver is the glucose and lipid metabolism center where ketone bodies are produced, the application of KD to combat HCC is promising. Prior studies have reported that KD could reduce the energy supply and affect the proliferation and differentiation of cancer cells by lowering the blood glucose and insulin levels. Furthermore, KD can increase the expression of hydroxymethylglutaryl-CoA synthase 2 (HMGCS2) in hepatocytes and regulate lipid metabolism to inhibit the progression of HCC. In addition, β-hydroxybutyrate can induce histone hyperacetylation and reduce the expression of inflammatory factors to alleviate damage to hepatocytes. However, there are few relevant studies at present, and the specific effects and safety of KD on HCC warrant further research. Optimizing the composition of KD and combining it with other therapies to enhance its anti-cancer effects warrant further exploration.
    Keywords:  cancer cell metabolism; hepatocellular carcinoma; ketogenic body; ketogenic diet; liver
    DOI:  https://doi.org/10.3389/fonc.2022.879205
  24. ACS Appl Bio Mater. 2022 May 25.
    Ferroptosis-Driven Nanotherapeutics to Reverse Drug Resistance in Tumor Microenvironment.
    Liyun Zhu, Danni Meng, Xu Wang, Xuerui Chen.
      Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, is non-apoptotic programmed cell death highly relevant to tumor development. It was found to manipulate oncogenes and resistant mutations of cancer cells via lipid metabolism pathways converging on phospholipid glutathione peroxidase (GPX4) that squanders lipid peroxides (L-OOH) to block the iron-mediated reactions of peroxides, thus rendering resistant cancer cells vulnerable to ferroptotic cell death. By accumulating ROS and lipid peroxidation (LPO) products to lethal levels in tumor microenvironment (TME), ferroptosis-driven nanotherapeutics show a superior ability of eradicating aggressive malignancies than traditional therapeutic modalities, especially for the drug-resistant tumors with high metastasis tendency. Moreover, Fenton reaction, inhibition of GPX-4, and exogenous regulation of LPO are three major therapeutic strategies to induce ferroptosis in cancer cells, which were generally applied in ferroptosis-driven nanotherapeutics. In this review, we elaborate current trends of ferroptosis-driven nanotherapeutics to reverse drug resistance of tumors in anticancer fields at the intersection of cancer biology, materials science, and chemistry. Finally, their challenges and perspectives toward feasible translational studies are spotlighted, which would ignite the hope of anti-resistant cancer treatment.
    Keywords:  anticancer treatment; drug resistance; ferroptosis; nanotherapeutics; tumor microenvironment
    DOI:  https://doi.org/10.1021/acsabm.2c00199
  25. Colloids Surf B Biointerfaces. 2022 May 17. pii: S0927-7765(22)00257-0. [Epub ahead of print]216 112574
    Laser-responsive multi-functional nanoparticles for efficient combinational chemo-photodynamic therapy against breast cancer.
    Qingran Guan, Yinglan Li, Huaizhen Zhang, Sisi Liu, Zhuang Ding, Zhiping Fan, Qingpeng Wang, Zhengping Wang, Jun Han, Min Liu, Yanna Zhao.
      Herein, novel laser-responsive multi-functional nanoparticles (NPs-Lip@PTX/CyA/Ce6) were fabricated with bovine serum albumins (BSA) based nanoparticles, which simultaneously carried chemotherapeutic drug paclitaxel (PTX) and P-gp inhibitor cyclosporin A (CyA), as core and photosensitizer agent Chlorin e6 (Ce6) loaded Tf-modified liposomal bilayer as shell. NPs-Lip@PTX/CyA/Ce6 exhibited apparent core-shell structure morphology with particle size of 160.9 ± 1.7 nm and zeta potential of - 26.7 ± 0.6 mV, indicating their excellent stability in aqueous solution. Besides, NPs-Lip@PTX/CyA/Ce6 possessed laser-responsive release profiles upon laser irradiation at specific wavelength, which was favor to exert efficient combinatorial chemo-photodynamic therapy and effectively reverse the multiple drug resistance (MDR). Under laser irradiation, as expected, NPs-Lip@PTX/CyA/Ce6 demonstrated superb intracellular ROS productivity and fantastic in vitro and in vivo anti-cancer therapy effect but absent of systemic toxicity. In conclusion, the nano-drug delivery system would be prospectively applied in clinic as resultful therapeutic tactic for investing compositional chemo-photodynamic therapy synergistically.
    Keywords:  Combinatorial chemo-photodynamic therapy; Laser-responsive; Multi-functional nanoparticles
    DOI:  https://doi.org/10.1016/j.colsurfb.2022.112574
  26. Nanomaterials (Basel). 2022 May 12. pii: 1656. [Epub ahead of print]12(10):
    Recent Advances in Engineering Nanomedicines for Second Near-Infrared Photothermal-Combinational Immunotherapy.
    Fengshuo Wang, Jingyi Zhu, Yongtao Wang, Jingchao Li.
      Immunotherapy has emerged as one of the major strategies for cancer treatment. Unlike conventional therapeutic methods, immunotherapy can treat both primary and distant metastatic tumors through triggering systematic antitumor immune responses and can even prevent tumor recurrence after causing the formation of immune memory. However, immunotherapy still has the issues of low patient response rates and severe immune-related adverse events in clinical practices. In this regard, the combination of nanomedicine-mediated therapy with immunotherapy can modulate a tumor immunosuppressive microenvironment and thus amplify antitumor immunity. In particular, second near-infrared (NIR-II) photothermal therapy (PTT), which utilizes light conversions to generate heat for killing cancer cells, has shown unique advantages in combining with immunotherapy. In this review, the recent progress of engineering nanomedicines for NIR-II PTT combinational immunotherapy is summarized. The role of nanomedicine-mediated NIR-II PTT in inducing immunogenic cell death and reprogramming the tumor immunosuppressive microenvironment for facilitating immunotherapy are highlighted. The development of NIR-II-absorbing organic and inorganic nonmetal and inorganic metal nanomedicines for the NIR-II PTT combinational immunotherapy of cancer is also introduced in detail. Lastly, the current challenges and future perspectives of these nanomedicines for combinational immunotherapy are proposed.
    Keywords:  combinational therapy; immunotherapy; optical nanomedicines; photothermal therapy; second near-infrared windows
    DOI:  https://doi.org/10.3390/nano12101656
  27. Drug Deliv. 2022 Dec;29(1): 1663-1674
    Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management.
    Mariam Zewail, Passent M E Gaafar, Mai M Ali, Haidy Abbas.
      Despite the fact of availability of several treatments for breast cancer, most of them fail to attain the desired therapeutic response due to their poor bioavailability, high doses, non-selectivity and as a result systemic toxicity. Here in an attempt made to study the transdermal effect of leflunomide (LEF) against breast cancer. In order to improve the poor physicochemical properties of LEF, it was loaded into cubosomes. Cubosomes were prepared by the emulsification method. Colloidal characteristics of cubosomes including particle size, ζ-potential, entrapment efficiency, in-vitro release profile and ex-vivo permeation were studied. In addition, morphology, stability, cytotoxicity and cell uptake in MDA-MB-231 cell line were carried out for the selected cubosomal formulation. The selected LEF loaded cubosomal formulation showed a small particle size (168 ± 1.08) with narrow size distribution (PI 0.186 ± 0.125) and negative ζ potential (-25.5 ± 0.98). Its Entrapment efficiency (EE%) was 93.2% and showed sustained release profile that extended for 24 h. The selected formulation showed stability when stored at 25 °C for three months in terms of size and EE%. TEM images illustrated the cubic structure of the cubosome. Cell culture results revealed the superiority of LEF cubosomes compared to LEF suspension in their cytotoxic effects with an IC50 close to that of doxorubicin. Furthermore, LEF cell uptake was significantly higher for LEF cubosomes. This may be attributed to the effect of nano-encapsulation on enhancing drug pharmacological effects and uptake indicating the potential usefulness of LEF cubosomes for breast cancer management.
    Keywords:  Cubosomes; antitumor; breast cancer; cell uptake; leflunomide; passive targeting
    DOI:  https://doi.org/10.1080/10717544.2022.2079770
  28. Pharmaceutics. 2022 May 17. pii: 1075. [Epub ahead of print]14(5):
    Multifunctional Nanoplatforms as a Novel Effective Approach in Photodynamic Therapy and Chemotherapy, to Overcome Multidrug Resistance in Cancer.
    Martin Majerník, Rastislav Jendželovský, Jana Vargová, Zuzana Jendželovská, Peter Fedoročko.
      It is more than sixty years since the era of modern photodynamic therapy (PDT) for cancer began. Enhanced selectivity for malignant cells with a reduced selectivity for non-malignant cells and good biocompatibility along with the limited occurrence of side effects are considered to be the most significant advantages of PDT in comparison with conventional therapeutic approaches, e.g., chemotherapy. The phenomenon of multidrug resistance, which is associated with drug efflux transporters, was originally identified in relation to the application of chemotherapy. Unfortunately, over the last thirty years, numerous papers have shown that many photosensitizers are the substrates of efflux transporters, significantly restricting the effectiveness of PDT. The concept of a dynamic nanoplatform offers a possible solution to minimize the multidrug resistance effect in cells affected by PDT. Indeed, recent findings have shown that the utilization of nanoparticles could significantly enhance the therapeutic efficacy of PDT. Additionally, multifunctional nanoplatforms could induce the synergistic effect of combined treatment regimens, such as PDT with chemotherapy. Moreover, the surface modifications that are associated with nanoparticle functionalization significantly improve the target potential of PDT or chemo-PDT in multidrug resistant and cancer stem cells.
    Keywords:  chemotherapy; multidrug resistance; multifunctional nanoplatforms; photodynamic therapy; therapeutic synergism
    DOI:  https://doi.org/10.3390/pharmaceutics14051075
  29. Adv Pharm Bull. 2022 Mar;12(2): 248-261
    Uses of Natural Honey in Cancer: An Updated Review.
    Tahereh Eteraf-Oskouei, Moslem Najafi.
      Cancer was predicted as the leading cause of death and the most important obstacle to the increased life expectancy in the 21st century worldwide. The World Health Organization (WHO) estimated number of new cases of cancers in 2020 about 19 million, and this number is estimated to be more than 295300000 people up to 2040 (more than 55% increase during next 20 years). Standard treatments for cancer include surgery, radiotherapy, and chemotherapy. However, all of these methods have dangerous side effects, so researchers are more interested in finding novel and less risky therapies. In recent years, there has been a great deal of interest in the development of anticancer agents obtained from foods or natural products. The relative safety of natural and food-derived compounds makes them attractive alternatives to conventional cancer treatment drugs. As a result, the majority of people are advised to use complementary and alternative medicine to treat and prevent cancer. In recent years, honey, as a natural product, has attracted many researchers' attention as an alternative to conventional anticancer drugs. Natural honey has long been used as a medicine and nutrient and its beneficial effects on various diseases in animal and human models have been studied. It was found that it has a wide range of therapeutic properties, including antioxidant, antibacterial, antiviral, anti-fungal, anti-diabetic, anti-inflammatory, anti-hypertensive, antiarrhythmic, wound healing, and liver protection benefits. This article aimed to review the role of natural honey in the prevention and treatment of a number of important cancers and their subsequent complications.
    Keywords:  Cancer prevention; Cancer treatment; Human diseases; Natural honey
    DOI:  https://doi.org/10.34172/apb.2022.026
  30. Adv Pharm Bull. 2022 Mar;12(2): 298-308
    Solid Lipid Nanoparticles for Efficient Oral Delivery of Tyrosine Kinase Inhibitors: A Nano Targeted Cancer Drug Delivery.
    Sukanta Satapathy, Chandra Sekhar Patro.
      Tyrosine kinase inhibitors (TKIs) are used as targeted therapy for cancer by inhibiting the signaling pathway and tumor growth. Many TKIs got approved by FDA in recent times for the treatment of cancer by oral route. However, the TKIs have formulation challenges leading to compromised bioavailability which can cause a weak therapeutic response. The cancer nanotherapeutics using nanocarriers based drug delivery has emerged as an advanced tool to provide a solution to formulation challenges and a better cancer therapy by overcoming the limitations in conventional cancer therapy. This review describes the various formulation issues of anticancer drugs with a special reference to TKIs, as well as the capability of solid lipid nanoparticles (SLNs) for an efficient nano targeted cancer drug delivery.
    Keywords:  Bioavailability; Solid lipid Nanoparticles (SLNs); Tyrosine kinase inhibitors (TKIs)
    DOI:  https://doi.org/10.34172/apb.2022.041
  31. Molecules. 2022 May 20. pii: 3286. [Epub ahead of print]27(10):
    Chemical Compounds of Berry-Derived Polyphenols and Their Effects on Gut Microbiota, Inflammation, and Cancer.
    Abdelhakim Bouyahya, Nasreddine El Omari, Naoufal El Hachlafi, Meryem El Jemly, Maryam Hakkour, Abdelaali Balahbib, Naoual El Menyiy, Saad Bakrim, Hanae Naceiri Mrabti, Aya Khouchlaa, Mohamad Fawzi Mahomoodally, Michelina Catauro, Domenico Montesano, Gokhan Zengin.
      Berry-derived polyphenols are bioactive compounds synthesized and secreted by several berry fruits. These polyphenols feature a diversity of chemical compounds, including phenolic acids and flavonoids. Here, we report the beneficial health effects of berry-derived polyphenols and their therapeutical application on gut-microbiota-related diseases, including inflammation and cancer. Pharmacokinetic investigations have confirmed the absorption, availability, and metabolism of berry-derived polyphenols. In vitro and in vivo tests, as well as clinical trials, showed that berry-derived polyphenols can positively modulate the gut microbiota, inhibiting inflammation and cancer development. Indeed, these compounds inhibit the growth of pathogenic bacteria and also promote beneficial bacteria. Moreover, berry-derived polyphenols exhibit therapeutic effects against different gut-microbiota-related disorders such as inflammation, cancer, and metabolic disorders. Moreover, these polyphenols can manage the inflammation via various mechanisms, in particular the inhibition of the transcriptional factor Nf-κB. Berry-derived polyphenols have also shown remarkable effects on different types of cancer, including colorectal, breast, esophageal, and prostate cancer. Moreover, certain metabolic disorders such as diabetes and atherosclerosis were also managed by berry-derived polyphenols through different mechanisms. These data showed that polyphenols from berries are a promising source of bioactive compounds capable of modulating the intestinal microbiota, and therefore managing cancer and associated metabolic diseases. However, further investigations should be carried out to determine the mechanisms of action of berry-derived polyphenol bioactive compounds to validate their safety and examinate their clinical uses.
    Keywords:  berries; cancer; gut microbiota; metabolic disorders; polyphenols
    DOI:  https://doi.org/10.3390/molecules27103286
  32. Biomaterials. 2022 May 19. pii: S0142-9612(22)00217-4. [Epub ahead of print]286 121577
    Killing three birds with one stone: Near-infrared light triggered nitric oxide release for enhanced photodynamic and anti-inflammatory therapy in refractory keratitis.
    Hengrui Zhang, Wenya Jiang, Yaou Peng, Jie Yang, Xiaoying Chu, Ziyue Long, Renlong Li, Qiuwei Liang, Hao Suo, Shuting Wang, Mei Yang, Ji Qi, Dan Ding, Ying-Wei Yang, Bailiang Wang.
      Stubborn resistant bacteria, bacterial biofilms and severe inflammation are challenging issues in refractory keratitis treatment. Herein, we design a multifunctional near-infrared light-responsive nanoplatform for efficient therapy of refractory keratitis based on a "three-birds-with-one-stone" strategy, which integrates the bacteria targeting photodynamic therapy, nitric oxide (NO) sterilization, and NO-mediated anti-inflammatory property into one system. This nanoplatform (UCNANs) is constructed using the dual-emissive upconversion nanoparticles (UCNPs) as cores coated with mesoporous silica for the loading of photosensitizers with aggregation-induced emission (AIE) property and the grafting of NO donors and bacteria targeting molecules. Upon irradiation of 808 nm light, UCNPs simultaneously produce UV emission and visible emission to trigger NO release and reactive oxygen species (ROS) such as superoxide radical (O2•-) generation. Furthermore, O2•- resulting from PDT can react with NO to yield powerful oxidizing and nitrating agent peroxynitrite (ONOO-). The three components work synergistically to enhance the antibacterial outcome confirmed by in vitro and in vivo tests. The short-distance light excitation and excitation light absorption are important reasons for reducing the toxicity of materials, especially ultraviolet light damage. Moreover, bacteria elimination reduced endotoxin secretion and the released NO simultaneously inhibit the NF-κB pathways by regulating the expression of toll-like receptor 2 (TRL2) and tumor necrosis factor-α (TNF-α), which significantly relieves the inflammation of cornea. Given its excellent antibacterial and anti-inflammatory properties, UCNANs provides a competitive strategy for refractory keratitis therapy.
    Keywords:  Aggregation-induced emission; Anti-inflammatory; Antibacterial; Nanomaterials; Photodynamic therapy; Upconversion nanoparticles
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121577
  33. Biochem Pharmacol. 2022 May 23. pii: S0006-2952(22)00195-2. [Epub ahead of print] 115101
    Ginsenoside CK induces apoptosis in triple-negative breast cancer cells by targeting glutamine metabolism.
    Bo Zhang, Rongzhan Fu, Zhiguang Duan, Shihong Shen, Chenhui Zhu, Daidi Fan.
      Breast cancer (BC) has replaced lung cancer as the most common cancer worldwide. Ginsenoside CK (CK) can effectively inhibit triple-negative breast cancer (TNBC), the occurrence and development of which are associated with glutamine addiction. However, the connection between CK and glutamine metabolism in TNBC proliferation and the mechanism of cell death induction remains unclear. Here, we found that high glutamine-addicted TNBC cells were particularly sensitive to CK treatment. CK exerted antitumour activity against TNBC by suppressing glutamine consumption and glutamate production via downregulation of glutaminase 1 (GLS1) expression. CK treatment further decreased cellular ATP production, reduced the utilisation of amino acids associated with glutamine metabolism, and induced glutathione (GSH) depletion and reactive oxygen species (ROS) accumulation, consequently triggering apoptosis in TNBC. Furthermore, CK decreased GLS1 expression in SUM159 xenograft mouse mammary tumours and significantly inhibited tumour growth with few side effects. Together, our data provide a powerful theoretical basis for the application of CK as a glutamine metabolic inhibitor in TNBC treatment.
    Keywords:  GLS1; Ginsenoside CK; apoptosis; glutamine metabolism; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.bcp.2022.115101
  34. Biomater Res. 2022 May 23. 26(1): 19
    Enhanced postoperative cancer therapy by iron-based hydrogels.
    Haomeng Zhang, Meng Zhang, Xinyu Zhang, Yuan Gao, Yanling Ma, Hongyu Chen, Jipeng Wan, Changzhong Li, Fei Wang, Xiao Sun.
      Surgical resection is a widely used method for the treatment of solid tumor cancers. However, the inhibition of tumor recurrence and metastasis are the main challenges of postoperative tumor therapy. Traditional intravenous or oral administration have poor chemotherapeutics bioavailability and undesirable systemic toxicity. Polymeric hydrogels with a three-dimensional network structure enable on-site delivery and controlled release of therapeutic drugs with reduced systemic toxicity and have been widely developed for postoperative adjuvant tumor therapy. Among them, because of the simple synthesis, good biocompatibility, biodegradability, injectability, and multifunctionality, iron-based hydrogels have received extensive attention. This review has summarized the general synthesis methods and construction principles of iron-based hydrogels, highlighted the latest progress of iron-based hydrogels in postoperative tumor therapy, including chemotherapy, photothermal therapy, photodynamic therapy, chemo-dynamic therapy, and magnetothermal-chemical combined therapy, etc. In addition, the challenges towards clinical application of iron-based hydrogels have also been discussed. This review is expected to show researchers broad perspectives of novel postoperative tumor therapy strategy and provide new ideas in the design and application of novel iron-based hydrogels to advance this sub field in cancer nanomedicine.
    Keywords:  Biocompatibility; Iron-based hydrogels; Postoperative; Synergistic cancer therapy
    DOI:  https://doi.org/10.1186/s40824-022-00268-4
  35. Int J Mol Sci. 2022 May 16. pii: 5572. [Epub ahead of print]23(10):
    Targeting Energy Metabolism in Cancer Treatment.
    Joanna Kubik, Ewelina Humeniuk, Grzegorz Adamczuk, Barbara Madej-Czerwonka, Agnieszka Korga-Plewko.
      Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.
    Keywords:  cancer metabolism; cancer treatment; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms23105572
  36. Molecules. 2022 May 10. pii: 3049. [Epub ahead of print]27(10):
    New Smoothie Products Based on Pumpkin, Banana, and Purple Carrot as a Source of Bioactive Compounds.
    Marcin Kidoń, Pascaline Aimee Uwineza.
      Smoothies are fruit- and/or vegetable-based products in form of beverages that are typically semi-liquid, thick in consistency, and mainly consist of purees and juices. Other ingredients, such as yogurt, milk, ice cream, sugar, honey, or simply water may also be added. The present study aimed to elaborate smoothie products based on bananas, pumpkins, and purple carrots. These fruits and vegetables were chosen due to their high bioactive compounds content, potential health benefits, and availability to industry. Five smoothie formulations were produced and analyzed for pH, soluble solids, total phenolic content, anthocyanins, carotenoids, vitamin C, antioxidant activity, instrumental color, and sensory features. From the analysis, the result showed that the obtained smoothies were a good source of total phenolic content (39.1 to 55.9 mg/100 g) and anthocyanin (7.1 to 11.1 mg cyanidin-3-glucoside/100 g), and that they possessed high antioxidant activity (4.3 to 6.2 µM Trolox/g). From sensory evaluation, all the produced smoothies were desirable, but the formulations with banana were scored higher compared to the pumpkin. In conclusion, smoothies composed of pumpkin, banana, and purple carrot can be a good new food product that incorporates nutritional compounds into the human diet.
    Keywords:  anthocyanin; antioxidant activity; carotenoids; fruit; phenolic compounds; smoothie; vegetable; vitamin C
    DOI:  https://doi.org/10.3390/molecules27103049
  37. Expert Opin Drug Deliv. 2022 May 25.
    Carbohydrates based stimulus responsive nanocarriers for cancer-targeted chemotherapy: A review of current practices.
    Cheng-Wu Zhang, Jun-Gang Zhang, Xue Yang, Wen-Lin Du, Zi-Lin Yu, Zhen-Ye Lv, Xiao-Zhou Mou.
       INTRODUCTION: Many nanocarriers have been developed to react physicochemically to exterior stimuli like ultrasonic, light, heat, and magnetic fields, along with various internal stimuli including pH, hypoxia, enzyme, and redox potential. Nanocarriers are capable to respond various stimuli within the cancer cells to enable on-demand drug delivery, activation of bioactive compounds, controlled drug release, and targeting ligands, as well as size, charge, and conformation conversion, enabling sensing and signaling, overcoming multidrug resistance, accurate diagnosis, and precision therapy.
    AREAS COVERED: Carbohydrates are ubiquitous biomolecules with a high proclivity for supramolecular network formation. Numerous carbohydrate-based nanomaterials have been used in biological solicitations and stimuli-based responses. Particular emphasis has been placed on the utilization of carbohydrate-based NPs and nanogels in various fields including imaging, drug administration, and tissue engineering. Because the assembly process is irreversible, carbohydrate-based systems are excellent ingredients for the development of stimulus-responsive nanocarriers for cancer-targeted chemotherapy. This review aims to summarise current research on carbohydrate-based nanomaterials, with an emphasis on stimuli-sensitive nanocarriers for cancer-targeted chemotherapy.
    EXPERT OPINION: Carbohydrates-based stimulus-responsive nanomaterials have been proved highly efficient for targeted delivery of anticancer drugs, thus leading to effective chemotherapy with minimum off-target effects.
    Keywords:  Carbohydrates; cancer; chemotherapy; nanocarriers; nanomaterials; stimulus-responsive
    DOI:  https://doi.org/10.1080/17425247.2022.2081320
  38. Cancer Treat Rev. 2022 May 13. pii: S0305-7372(22)00072-X. [Epub ahead of print]108 102408
    Dietary influences on symptomatic and non-symptomatic toxicities during cancer treatment: A narrative review.
    Alan J Kim, David S Hong, Goldy C George.
      The general nutritional status of cancer patients could be a central determinant of cancer treatment-related toxicity and an indicator of cancer symptoms such as cancer-related cachexia and weight loss. This narrative scientific review covers the impact of dietary patterns (for example, Mediterranean diet, short-term fasting, ketogenic diet), dietary components (for example, fruits and vegetables, fish oils, turmeric/curcumin, dietary fiber, phytochemicals, vitamin/mineral dietary supplements), and the gut microbiota on symptoms, toxicities, and adverse events associated with cancer treatment. Although several studies have produced controversial or inconclusive results, some promising preclinical studies and initial clinical trials suggest that dietary interventions may alleviate certain cancer treatment-related symptoms and toxicities. Possible mechanisms by which dietary components may influence symptomatic and non-symptomatic toxicities during cancer treatment include through impacting inflammation, oxidative stress, muscle mass, cardiac health and regulating the gut microbiome. Current ongoing studies will continue to shed light on whether specific dietary interventions, with a special emphasis on the gut microbiota, are an effective method to improve cancer treatment outcomes. Future studies should examine the synergistic effects of combining different nutritional interventions and establish diet-related guidelines for cancer treatment.
    Keywords:  Cancer; Diet; Microbiome; Nutrition; Symptom; Toxicities
    DOI:  https://doi.org/10.1016/j.ctrv.2022.102408
  39. Anticancer Agents Med Chem. 2022 May 19.
    Molecular Mechanisms of Chloroquine and Hydroxychloroquine use in Cancer Therapy.
    Juan Bautista De Sanctis, Jaime Charris, Zuleyma Blanco, Hegira Ramírez, Gricelis Patricia Martínez, Michael Rodney Mijares.
      Tumour relapse, chemotherapy resistance, and metastasis continue to be unsolved issues in cancer therapy. A recent approach has been to scrutinise drugs used in the clinic for other illnesses and modify their structure to increase selectivity to cancer cells. Chloroquine (CQ) and hydroxychloroquine (HCQ), known antimalarials, have successfully treated autoimmune and neoplastic diseases. CQ and HCQ, well-known lysosomotropic agents, induce apoptosis, downregulate autophagy, and modify the tumour microenvironment. Moreover, they affect the Toll 9 / NF-κB receptor pathway, activate stress response pathways, enhance p53 activity and CXCR4-CXCL12 expression in cancer cells, which would help explain their effects in cancer treatment. These compounds can normalise the tumour-associated vasculature, promote the activation of the immune system, change the phenotype of tumour-associated macrophages (from M2 to M1), and stimulate cancer-associated fibroblasts. We aim to review the historical aspects of CQ and its derivatives and the most relevant mechanisms that support the therapeutic use of CQ and HCQ for the treatment of cancer.
    Keywords:  Repurposing Drugs in Oncology; apoptosis; chemotherapy; chloroquine; hydroxychloroquine; metastasis; non-small cell lung cancer
    DOI:  https://doi.org/10.2174/1871520622666220519102948
  40. Pharmaceutics. 2022 Apr 25. pii: 934. [Epub ahead of print]14(5):
    Anti-Inflammatory and Analgesic Evaluation of a Phytochemical Intercalated into Layered Double Hydroxide.
    Viviane A Guilherme, Vanessa R R Cunha, Eneida de Paula, Daniele R de Araujo, Vera R L Constantino.
      Coumaric acid (CouH), an antioxidant molecule assimilated by food consumption, was intercalated into layered double hydroxide (LDH) nanocarrier, having zinc and aluminium ions in the layers (LDH-Cou), to evaluate its pharmacological activity through in vitro and in vivo assays in mice. Therefore, the following tests were performed: coumarate delivery in saline solution, fibroblasts' cell viability using neutral red, peritonitis induced by carrageenan, formalin test, acetic-acid-induced writhing, and tail-flick assay, for the non-intercalated CouH and the intercalated LDH-Cou system. Furthermore, different pharmacological pathways were also investigated to evaluate their possible anti-inflammatory and antinociceptive mechanisms of action, in comparison to traditionally used agents (morphine, naloxone, caffeine, and indomethacin). The LDH-Cou drug delivery system showed more pronounced anti-inflammatory effect than CouH but not more than that evoked by the classic non-steroidal anti-inflammatory drug (NSAID) indomethacin. For the analgesic effect, according to the tail-flick test, the treatment with LDH-Cou expressively increased the analgesia duration (p < 0.001) by approximately 1.7-1.8 times compared to CouH or indomethacin. Thus, the results pointed out that the LDH-Cou system induced in vivo analgesic and anti-inflammatory activities and possibly uses similar mechanisms to that observed for classic NSAIDs, such as indomethacin.
    Keywords:  3-(4-hydroxyphenyl)-2-propenoic acid; analgesic; anti-inflammatory; coumaric acid; drug delivery systems; hydrotalcite-like material; intercalation compounds; p-hydroxycinnamic acid
    DOI:  https://doi.org/10.3390/pharmaceutics14050934
  41. Bioengineering (Basel). 2022 May 02. pii: 197. [Epub ahead of print]9(5):
    Flavonoids-Based Delivery Systems towards Cancer Therapies.
    Miguel Ferreira, Diana Costa, Ângela Sousa.
      Cancer is the second leading cause of death worldwide. Cervical cancer, for instance, is considered a major scourge in low-income countries. Its development is mostly associated with the human papillomavirus persistent infection and despite the availability of preventive vaccines, they are only widely administered in more developed countries, thus leaving a large percentage of unvaccinated women highly susceptible to this type of cancer. Current treatments are based on invasive techniques, being far from effective. Therefore, the search for novel, advanced and personalized therapeutic approaches is imperative. Flavonoids belong to a group of natural polyphenolic compounds, well recognized for their great anticancer capacity, thus promising to be incorporated in cancer therapy protocols. However, their use is limited due to their low solubility, stability and bioavailability. To surpass these limitations, the encapsulation of flavonoids into delivery systems emerged as a valuable strategy to improve their stability and bioavailability. In this context, the aim of this review is to present the most reliable flavonoids-based delivery systems developed for anticancer therapies and the progress accomplished, with a special focus on cervical cancer therapy. The gathered information revealed the high therapeutic potential of flavonoids and highlights the relevance of delivery systems application, allowing a better understanding for future studies on effective cancer therapy.
    Keywords:  HeLa cells; anticancer activity; cervical cancer; delivery systems; flavonoids; tumor inhibition
    DOI:  https://doi.org/10.3390/bioengineering9050197
  42. Commun Med (Lond). 2021 ;1 18
    Kicking KRAS to tackle lung cancer.
    Ben Abbott.
      KRAS is one of the most commonly mutated oncogenes in lung cancer but has long been considered undruggable. With the recent FDA approval of sotorasib, supported by positive phase II trial data now published in The New England Journal of Medicine, this is no longer the case.
    DOI:  https://doi.org/10.1038/s43856-021-00017-z
  43. J Pharm Sci. 2022 May 22. pii: S0022-3549(22)00213-1. [Epub ahead of print]
    Development and evaluation of core-shell nanocarrier system for enhancing the cytotoxicity of doxorubicin/ metformin combination against breast cancer cell line.
    Alaa Ibrahim, Islam A Khalil, Ibrahim M El-Sherbiny.
      Breast cancer is the most invasive and life-threatening cancer in women. The treatment options are usually a combination of mastectomy, radiation therapy, hormonal therapy and chemotherapy. As a standard practice, doxorubicin (DOX) is one of the commonly used drugs for breast cancer treatment. However, DOX is known to have many harmful adverse effects including its cardiotoxicity. Hence, recent reports used metformin (MET), an anti-diabetic drug, as an adjuvant therapy to decrease the severity of DOX's adverse effects and to improve its ultimate therapeutic outcome. The current study is aimed at co-loading and enhancing the encapsulation efficiency of the hydrophilic DOX and MET in poly(lactic-co-glycolic acid) (PLGA) nanocapsules (NCs) with oil core for breast cancer treatment. The NCs were developed by single emulsification-solvent diffusion technique, and were optimized through using two types of oils, pluronics and PLGA (50:50) of different molecular weights followed by various physicochemical characterizations. The obtained DOX/MET-loaded NCs showed the size and polydispersity index (PDI) of 203.0 ± 3.4 nm and 0.081 ± 0.03, respectively with a surface charge of -2.15 ± 0.2 mV. The entrapment efficiency of DOX and MET were about 93.7% ± 2.9 and 70% ± 1.6, respectively. The developed PLGA core-shell NCs successfully sustained the DOX/MET release for more than 30 days. The in-vitro results showed a significant enhancement in DOX cytotoxic effect as well as a duplication in its apoptotic effect upon addition of MET for both free DOX/MET combination and DOX/MET-loaded PLGA NCs against MCF-7. Besides, flow cytometry demonstrated that the DOX/MET-loaded NCs possess their antitumor effect by preventing DNA replication and cell division. This study provides a promising facile, rapid and reproducible single emulsification-solvent diffusion technique for improving the encapsulation and release of hydrophilic drugs in nanocapsules for biomedical applications.
    Keywords:  Breast Cancer; Doxorubicin; Metformin; Nanocapsule
    DOI:  https://doi.org/10.1016/j.xphs.2022.05.018
  44. AAPS PharmSciTech. 2022 May 23. 23(5): 152
    Nano-strategies as Oral Drug Delivery Platforms for Treatment of Cancer: Challenges and Future Perspectives.
    Sheikh Shahnawaz Quadir, Vinod Saharan, Deepak Choudhary, Harish, C P Jain, Garima Joshi.
      Oral drug administration is the oldest and widely used method for drug administration. The objectives behind developing an oral drug delivery for the treatment of cancer are to achieve low cost treatment by utilizing novel techniques to target cancer through gut-associated lymphoid tissue (GALT) and to enhance patient comfort and compliance through a hospital-free treatment leading to "Chemotherapy at Home." Unfortunately, due to the physiological environment of the GIT and physicochemical properties of drug candidate, the efficacy of oral drug delivery methods is limited in the treatment of cancer. Due to their low hydrophilicity, high P-gp efflux and restricted intestinal permeability most of the anti-cancer drugs fail to achieve oral bioavailability. The review focuses on the efforts, challenges, opportunities and studies conducted by scientists worldwide on the oral administration of anticancer medications via nanocarriers such as liposomes, SLNs and dendrimers, because of their potential to overcome the epithelial barrier associated with GALT, as well as the applications of different polymers in targeting the cancer. The oral delivery can set newer horizons in cancer therapy to make it more patient friendly.
    Keywords:  cancer; drug delivery; nanocarriers; nanotechnology; oral; polymers
    DOI:  https://doi.org/10.1208/s12249-022-02301-0
  45. Antioxidants (Basel). 2022 May 07. pii: 921. [Epub ahead of print]11(5):
    Prospective Application of Ferroptosis in Hypoxic Cells for Tumor Radiotherapy.
    Jing Su, Qin Zhao, Zhuangzhuang Zheng, Huanhuan Wang, Chenbin Bian, Lingbin Meng, Ying Xin, Xin Jiang.
      Radiation therapy plays an increasingly important role in cancer treatment. It can inhibit the progression of various cancers through radiation-induced DNA breakage and reactive oxygen species (ROS) overload. Unfortunately, solid tumors, such as breast and lung cancer, often develop a hypoxic microenvironment due to insufficient blood supply and rapid tumor proliferation, thereby affecting the effectiveness of radiation therapy. Restraining hypoxia and improving the curative effect of radiotherapy have become difficult problems. Ferroptosis is a new type of cell death caused by lipid peroxidation due to iron metabolism disorders and ROS accumulation. It plays an important role in both hypoxia and radiotherapy and can enhance the radiosensitivity of hypoxic tumor cells by amplifying oxidative stress or inhibiting antioxidant regulation. In this review, we summarize the internal relationship and related mechanisms between ferroptosis and hypoxia, thus exploring the possibility of inducing ferroptosis to improve the prognosis of hypoxic tumors.
    Keywords:  AMPK; Nrf-2; ferroptosis; hypoxia; lipid peroxidation; radiotherapy; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/antiox11050921
  46. Pharmaceuticals (Basel). 2022 Apr 28. pii: 544. [Epub ahead of print]15(5):
    Adenosine Conjugated Docetaxel Nanoparticles-Proof of Concept Studies for Non-Small Cell Lung Cancer.
    Hibah M Aldawsari, Sima Singh, Nabil A Alhakamy, Rana B Bakhaidar, Abdulrahman A Halwani, Nagaraja Sreeharsha, Shaimaa M Badr-Eldin.
      Non-small cell lung cancer, a molecularly diverse disease, is the most prevalent cause of cancer mortality globally. Increasing understanding of the clinicopathology of the disease and mechanisms of tumor progression has facilitated early detection and multimodal care. Despite the advancements, survival rates are extremely low due to non-targeted therapeutics and correspondingly increased risk of metastasis. At some phases of cancer, patients need to face the ghost of chemotherapy. It is a difficult decision near the end of life. Such treatments have the capability to prolong survival or reduce symptoms, but can cause serious adverse effects, affecting quality of life of the patient. It is evident that many patients do not die from burden of the disease alone, but they die due to the toxic effect of treatment. Thus, increasing the efficacy is one aspect and decreasing the toxicity is another critical aspect of cancer formulation design. Through our current research, we tried to uncover both mentioned potentials of the formulation. Therefore, we designed actively targeted nanoparticles for improved therapeutics considering the overexpression of adenosine (ADN) receptors on non-small cell lung cancer (NSCLC) cells. Docetaxel (DTX), an essential therapeutic as part of combination therapy or as monotherapy for the treatment of NSCLC, was encapsulated in biodegradable poly(lactic-co-glycolic acid) nanoparticles. ADN was conjugated on the surface of nanoparticles using EDC-NHS chemistry. The particles were characterized in vitro for physicochemical properties, cellular uptake, and biocompatibility. The size and zeta potential of DTX nanoparticles (DPLGA) were found to be 138.4 ± 5.45 nm and -16.7 ± 2.3 mV which were found to change after ADN conjugation. The size was increased to 158.2 ± 6.3 nm, whereas zeta potential was decreased to -11.7 ± 1.4 mV for ADN-conjugated DTX nanoparticles (ADN-DPLGA) indicative of surface conjugation. As observed from transmission electron microscopy (TEM), the nanoparticles were spherical and showed no significant change in encapsulation efficiency even after surface conjugation. Careful and systematic optimization leads to ADN-conjugated PLGA nanoparticles having distinctive characteristic features such as particle size, surface potential, encapsulation efficacy, etc., that may play crucial roles in the fate of nanoparticles (NPs). Consequently, higher cellular uptake in the A549 lung cancer cell line was exhibited by ADN-DPLGA compared to DPLGA, illustrating the role of ADN receptors (ARs) in facilitating the uptake of NPs. Further in vivo pharmacokinetics and tissue distribution experiments revealed prolonged circulation in plasma and significantly higher lung tissue distribution than in other organs, dictating the targeting potential of the developed formulation over naïve drug and unconjugated formulations. Further, in vivo acute toxicity was examined using multiple parameters for non-toxic attributes of the developed formulation compared to other non-targeted organs. Further, it also supports the selection of biocompatible polymers in the formulation. The current study presents a proof-of-concept for a multipronged formulation technology strategy that might be used to maximize anticancer therapeutic responses in the lungs in the treatment of NSCLC. An improved therapeutic and safety profile would help achieve maximum efficacy at a reduced dose that would eventually help reduce the toxicity.
    Keywords:  PLGA; adenosine receptors; docetaxel; lung cancer; nanoparticles
    DOI:  https://doi.org/10.3390/ph15050544
  47. Biomolecules. 2022 Apr 19. pii: 599. [Epub ahead of print]12(5):
    Current Strategies for Real-Time Enzyme Activation.
    Fang Wang, Yuchen Liu, Chang Du, Renjun Gao.
      Enzyme activation is a powerful means of achieving biotransformation function, aiming to intensify the reaction processes with a higher yield of product in a short time, and can be exploited for diverse applications. However, conventional activation strategies such as genetic engineering and chemical modification are generally irreversible for enzyme activity, and they also have many limitations, including complex processes and unpredictable results. Recently, near-infrared (NIR), alternating magnetic field (AMF), microwave and ultrasound irradiation, as real-time and precise activation strategies for enzyme analysis, can address many limitations due to their deep penetrability, sustainability, low invasiveness, and sustainability and have been applied in many fields, such as biomedical and industrial applications and chemical synthesis. These spatiotemporal and controllable activation strategies can transfer light, electromagnetic, or ultrasound energy to enzymes, leading to favorable conformational changes and improving the thermal stability, stereoselectivity, and kinetics of enzymes. Furthermore, the different mechanisms of activation strategies have determined the type of applicable enzymes and manipulated protocol designs that either immobilize enzymes on nanomaterials responsive to light or magnetic fields or directly influence enzymatic properties. To employ these effects to finely and efficiently activate enzyme activity, the physicochemical features of nanomaterials and parameters, including the frequency and intensity of activation methods, must be optimized. Therefore, this review offers a comprehensive overview related to emerging technologies for achieving real-time enzyme activation and summarizes their characteristics and advanced applications.
    Keywords:  activation strategies; alternating magnetic field; enzyme activity; microwave; near infrared; ultrasound irradiation
    DOI:  https://doi.org/10.3390/biom12050599
  48. Pharmaceuticals (Basel). 2022 May 19. pii: 626. [Epub ahead of print]15(5):
    Metformin and Cancer, an Ambiguanidous Relationship.
    Sarah J Skuli, Safwan Alomari, Hallie Gaitsch, A'ishah Bakayoko, Nicolas Skuli, Betty M Tyler.
      The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.
    Keywords:  AMPK; PI3K; cancer metabolism; diabetes; drug repurposing; metformin; therapeutics
    DOI:  https://doi.org/10.3390/ph15050626
  49. Polymers (Basel). 2022 May 13. pii: 2010. [Epub ahead of print]14(10):
    5-Fluorouracil-Loaded Folic-Acid-Fabricated Chitosan Nanoparticles for Site-Targeted Drug Delivery Cargo.
    Shafi Ullah, Abul Kalam Azad, Asif Nawaz, Kifayat Ullah Shah, Muhammad Iqbal, Ghadeer M Albadrani, Fakhria A Al-Joufi, Amany A Sayed, Mohamed M Abdel-Daim.
      Nanoparticles play a vital role in cancer treatment to deliver or direct the drug to the malignant cell, avoiding the attacking of normal cells. The aim of the study is to formulate folic-acid-modified chitosan nanoparticles for colon cancer. Chitosan was successfully conjugated with folic acid to produce a folic acid-chitosan conjugate. The folate-modified chitosan was loaded with 5-FU using the ionic gelation method. The prepared nanoparticles were characterized for size, zeta potential, surface morphology, drug contents, entrapment efficiency, loading efficiency, and in vitro release study. The cytotoxicity study of the formulated nanoparticles was also investigated. The conjugation of folic acid with chitosan was confirmed by FTIR and NMR spectroscopy. The obtained nanoparticles were monodispersed nanoparticles with a suitable average size and a positive surface charge. The size and zeta potential and PDI of the CS-5FU-NPs were 208 ± 15, 26 ± 2, and +20 ± 2, respectively, and those of the FA-CS-5FU-NPs were 235 ± 12 and +20 ± 2, respectively, which are in the acceptable ranges. The drug contents' % yield and the %EE of folate-decorated NPs were 53 ± 1.8% and 59 ± 2%, respectively. The in vitro release of the FA-CS-5FU-NPs and CS-5FU-NPs was in the range of 10.08 ± 0.45 to 96.57 ± 0.09% and 6 ± 0.31 to 91.44 ± 0.21, respectively. The cytotoxicity of the nanoparticles was enhanced in the presence of folic acid. The presence of folic acid in nanoparticles shows much higher cytotoxicity as compared to simple chitosan nanoparticles. The folate-modified nanoparticles provide a potential way to enhance the targeting of tumor cells.
    Keywords:  colon cancer; cytotoxicity; folate-conjugated nanoparticles; targeted delivery
    DOI:  https://doi.org/10.3390/polym14102010
  50. Int J Pharm. 2022 May 24. pii: S0378-5173(22)00412-4. [Epub ahead of print] 121857
    Novel Microfluidic Swirl Mixers for Scalable Formulation of Curcumin Loaded Liposomes for Cancer Therapy.
    Ruicheng Xu, Mhd Anas Tomeh, Siyuan Ye, Peng Zhang, Songwei Lv, Rongrong You, Nan Wang, Xiubo Zhao.
      Liposomes have been widely used in nanomedicine for the delivery of hydrophobic and hydrophilic anticancer agents. The most common applications of these formulations are vaccines and anticancer formulations (e.g., mRNA, small molecule drugs). However, large-scale production with precise control of size and size distribution of the lipid-based drug delivery systems (DDSs) are the major challenges in the pharmaceutical industry. In this study, we used newly designed microfluidic swirl mixers with simple 3D mixing chamber structures to prepare liposomes at a larger scale (up to 320 mL/min or 20 L/h) than the commercially available devices. This design demonstrated high productivity and better control of liposome size and polydispersity index (PDI) than conventional liposome preparation methods. The microfluidic swirl mixer devices were used to produce curcumin-loaded liposomes under different processing conditions which were later characterized and studied in vitro to evaluate their efficiency as DDSs. The obtained results demonstrated that the liposomes can effectively deliver curcumin into cancer cells. Therefore, the microfluidic swirl mixers are promising devices for reproducible and scalable manufacturing of DDSs.
    Keywords:  Drug delivery system; Lipid nanoparticles; Liposomes; Microfluidics; Micromixer; Size distribution
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121857
  51. Integr Cancer Ther. 2022 Jan-Dec;21:21 15347354221101203
    Functional Mechanism of Ginsenoside Compound K on Tumor Growth and Metastasis.
    Jinlong Liu, Yuchen Wang, Zhun Yu, Guangfu Lv, Xiaowei Huang, He Lin, Chao Ma, Zhe Lin, Peng Qu.
      Ginsenosides, as the most important constituents of ginseng, have been extensively investigated in cancer chemoprevention and therapeutics. Among the ginsenosides, Compound K (CK), a rare protopanaxadiol type of ginsenoside, has been most broadly used for cancer treatment due to its high anticancer bioactivity. However, the functional mechanism of CK in cancer is not well known. This review describes the structure, transformation and pharmacological activity of CK and discusses the functional mechanisms of CK and its metabolites, which regulate signaling pathways related to tumor growth and metastasis. CK inhibits tumor growth by inducing tumor apoptosis and tumor cell differentiation, regulates the tumor microenvironment by suppressing tumor angiogenesis-related proteins, and downregulates the roles of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). There is currently much research on the potential development of CK as a new strategy when administered alone or in combination with other compounds.
    Keywords:  Ginsenoside Compound K; antimetastatic; antitumor; biotransformation; pharmacological activity
    DOI:  https://doi.org/10.1177/15347354221101203
  52. Int J Mol Sci. 2022 May 16. pii: 5536. [Epub ahead of print]23(10):
    Design and Development of a New Type of Hybrid PLGA/Lipid Nanoparticle as an Ursolic Acid Delivery System against Pancreatic Ductal Adenocarcinoma Cells.
    Adam Markowski, Anna Jaromin, Paweł Migdał, Ewa Olczak, Adrianna Zygmunt, Magdalena Zaremba-Czogalla, Krzysztof Pawlik, Jerzy Gubernator.
      Despite many attempts, trials, and treatment procedures, pancreatic ductal adenocarcinoma (PDAC) still ranks among the most deadly and treatment-resistant types of cancer. Hence, there is still an urgent need to develop new molecules, drugs, and therapeutic methods against PDAC. Naturally derived compounds, such as pentacyclic terpenoids, have gained attention because of their high cytotoxic activity toward pancreatic cancer cells. Ursolic acid (UA), as an example, possesses a wide anticancer activity spectrum and can potentially be a good candidate for anti-PDAC therapy. However, due to its minimal water solubility, it is necessary to prepare an optimal nano-sized vehicle to overcome the low bioavailability issue. Poly(lactic-co-glycolic acid) (PLGA) polymeric nanocarriers seem to be an essential tool for ursolic acid delivery and can overcome the lack of biological activity observed after being incorporated within liposomes. PLGA modification, with the addition of PEGylated phospholipids forming the lipid shell around the polymeric core, can provide additional beneficial properties to the designed nanocarrier. We prepared UA-loaded hybrid PLGA/lipid nanoparticles using a nanoprecipitation method and subsequently performed an MTT cytotoxicity assay for AsPC-1 and BxPC-3 cells and determined the hemolytic effect on human erythrocytes with transmission electron microscopic (TEM) visualization of the nanoparticles and their cellular uptake. Hybrid UA-loaded lipid nanoparticles were also examined in terms of their stability, coating dynamics, and ursolic acid loading. We established innovative and repeatable preparation procedures for novel hybrid nanoparticles and obtained biologically active nanocarriers for ursolic acid with an IC50 below 20 µM, with an appropriate size for intravenous dosage (around 150 nm), high homogeneity of the sample (below 0.2), satisfactory encapsulation efficiency (up to 70%) and excellent stability. The new type of hybrid UA-PLGA nanoparticles represents a further step in the development of potentially effective PDAC therapies based on novel, biologically active, and promising triterpenoids.
    Keywords:  PLGA; cancer; nanoparticles; nanotechnology; pancreatic cancer; terpenoids; ursolic acid
    DOI:  https://doi.org/10.3390/ijms23105536
  53. Sci Total Environ. 2022 May 24. pii: S0048-9697(22)03309-5. [Epub ahead of print] 156212
    Nanobiotechnological prospects of probiotic microflora: Synthesis, mechanism, and applications.
    Sougata Ghosh, Bishwarup Sarkar, Ajeet Kaushik, Ebrahim Mostafavi.
      Nanotechnology-driven solutions have almost touched every aspect of life, such as therapeutics, cosmetics, agriculture, and the environment. Physical and chemical methods for the synthesis of nanoparticles involve hazardous reaction conditions and toxic reducing as well as stabilizing agents. Hence, environmentally benign green routes are preferred to synthesize nanoparticles with tunable size and shape. Bacteria, fungi, algae, and medicinal plants are employed to synthesize gold, silver, copper, zinc, and other nanoparticles. However, very little literature is available on exploring probiotic bacteria for the synthesis of nanoparticles. In view of the background, this review gives the most comprehensive report on the nanobiotechnological potential of probiotic bacteria like Bacillus licheniformis, Bifidobacterium animalis, Brevibacterium linens, Lactobacillus acidophilus, Lactobacillus casei, and others for the synthesis of gold (AuNPs), selenium (SeNPs), silver (AgNPs), platinum (PtNPs), tellurium nanoparticles (TeNPs), zinc oxide (ZnONPs), copper oxide (CuONPs), iron oxide (Fe3O4NPs), and titanium oxide nanoparticles (TiO2NPs). Both intracellular and extracellular synthesis are involved as potential routes for biofabrication of polydispersed nanoparticles that are spherical, rod, or hexagonal in shape. Capsular exopolysaccharide associated carbohydrates such as galactose, glucose, mannose, and rhamnose, cell membrane-associated diglycosyldiacylglycerol (DGDG), 1,2-di-O-acyl-3-O-[O-α-D-galactopyranosyl-(1 → 2)-α-d-glucopyranosyl]glycerol, triglycosyl diacylglycerol (TGDG), NADH-dependent enzymes, amino acids such as cysteine, tyrosine, and tryptophan amino acid, S-layer proteins (SLP), lacto-N-triose, and lactic acid play a significant role in synthesis and stabilization of the nanoparticles. The biogenic nanoparticles can be recovered by rational treatment with sodium dodecyl sulfate (SDS) and/or sodium hydroxide (NaOH). Eventually, diverse applications like antibacterial, antifungal, anticancer, antioxidant, and other associated activities of the bacteriogenic nanoparticles are also elaborated. Being more biocompatible and effective, probiotic-generated nanoparticles can be explored as novel nutraceuticals for their ability to ensure sustained release and bioavailability of the loaded bioactive ingredients for diagnosis, targeted drug delivery, and therapy.
    Keywords:  Anticancer; Antimicrobial; Biogenic nanoparticles; Mechanism; Probiotics bacteria; Therapeutic applications
    DOI:  https://doi.org/10.1016/j.scitotenv.2022.156212
  54. Pharmaceutics. 2022 Apr 24. pii: 927. [Epub ahead of print]14(5):
    Monoclonal Antibody Functionalized, and L-lysine α-Oxidase Loaded PEGylated-Chitosan Nanoparticle for HER2/Neu Targeted Breast Cancer Therapy.
    Kandasamy Saravanakumar, Anbazhagan Sathiyaseelan, Soyoung Park, Song-Rae Kim, Veeraraghavan Vishnu Priya, Myeong-Hyeon Wang.
      Herein, we designed a nanocarrier to deliver the LO specifically to HER2+ breast cancer (BC) cells, where functionalization of mAb (anti-HER2+) with PEGylated chitosan enabled it to target the HER2+ BC cells. Taking advantage of overexpression of HER2+ in cancer cells, our nanocarrier (CS-LO-PEG-HER NPs) exhibited promising potency and selectivity against HER2+ BC cells (BT474). The CS-LO-PEG-HER NPs demonstrated the cytotoxicity in BT474 cells by promoting reactive oxygen species, mitochondrial membrane potential loss, and nucleus damage. The biocompatibility of CS-LO-PEG-HER NPs was evidenced by the hemolysis assay and H & E staining of major organs. The CS-LO-PEG-HER NPs showed anticancer potency against the BT474-xenograft tumor-bearing mice, as evident by the reduction of tumor size and cell density. These results indicate that CS-LO-PEG-HER NPs are biocompatible with mice while inhibiting tumor growth through alter the oxidative stress. Overall, this work provides a promising approach for the delivery of LO for good therapeutic effect in combination with mAb.
    Keywords:  HER2+; L-lysine α-oxidase; PEGylated chitosan; breast cancer; trastuzumab
    DOI:  https://doi.org/10.3390/pharmaceutics14050927
  55. Nanomaterials (Basel). 2022 May 20. pii: 1753. [Epub ahead of print]12(10):
    Biologically Relevant Micellar Nanocarrier Systems for Drug Encapsulation and Functionalization of Metallic Nanoparticles.
    Victoria Valdivia, Raúl Gimeno-Ferrero, Manuel Pernia Leal, Chiara Paggiaro, Ana María Fernández-Romero, María Luisa González-Rodríguez, Inmaculada Fernández.
      The preparation of new and functional nanostructures has received more attention in the scientific community in the past decade due to their wide application versatility. Among these nanostructures, micelles appear to be one of the most interesting supramolecular organizations for biomedical applications because of their ease of synthesis and reproducibility and their biocompatibility since they present an organization similar to the cell membrane. In this work, we developed micellar nanocarrier systems from surfactant molecules derived from oleic acid and tetraethylene glycol that were able to encapsulate and in vitro release the drug dexamethasone. In addition, the designed micelle precursors were able to functionalize metallic NPs, such as gold NPs and iron oxide NPs, resulting in monodispersed hybrid nanomaterials with high stability in aqueous media. Therefore, a new triazole-derived micelle precursor was developed as a versatile encapsulation system, opening the way for the preparation of new micellar nanocarrier platforms for drug delivery, magnetic resonance imaging, or computed tomography contrast agents for therapeutic and diagnostic applications.
    Keywords:  drug encapsulation; metallic nanoparticle functionalization; micelles
    DOI:  https://doi.org/10.3390/nano12101753
  56. Front Oncol. 2022 ;12 834934
    New Advances in Nano-Drug Delivery Systems: Helicobacter pylori and Gastric Cancer.
    Xiang Zhu, Tingting Su, Shouhua Wang, Huiqing Zhou, Weibin Shi.
      With the development of materials science and biomedicine, the application of nanomaterials in the medical field is further promoted. In the process of the diagnosis and treatment of diseases, a variety of drugs need to be used. It is an ideal state to make these drugs arrive at a specific location at a specific time and release at a specific speed, which can improve the bioavailability of drugs and reduce the adverse effects of drugs on normal tissues. Traditional drug delivery methods such as tablets, capsules, syrups, and ointments have certain limitations. The emergence of a new nano-drug delivery system further improves the accuracy of drug delivery and the efficacy of drugs. It is well known that the development of the cancer of the stomach is the most serious consequence for the infection of Helicobacter pylori. For the patients who are suffering from gastric cancer, the treatments are mainly surgery, chemotherapy, targeted and immune therapy, and other comprehensive treatments. Although great progress has been made, the diagnosis and prognosis of gastric cancer are still poor with patients usually diagnosed with cancer at an advanced stage. Current treatments are of limited benefits for patients, resulting in a poor 5-year survival rate. Nanomaterials may play a critical role in early diagnosis. A nano-drug delivery system can significantly improve the chemotherapy, targeted therapy, and immunotherapy of advanced gastric cancer, reduce the side effects of the original treatment plan and provide patients with better benefits. It is a promising treatment for gastric cancer. This article introduces the application of nanomaterials in the diagnosis and treatment of H. pylori and gastric cancer.
    Keywords:  Helicobacter pylori; gastric cancer; nano-drug delivery systems; nanomaterials; nanoparticles
    DOI:  https://doi.org/10.3389/fonc.2022.834934
  57. Pharmaceutics. 2022 May 05. pii: 991. [Epub ahead of print]14(5):
    Vesicular Nanocarriers for Phytocompounds in Wound Care: Preparation and Characterization.
    Diana Antonia Safta, Cătălina Bogdan, Mirela Liliana Moldovan.
      The need to develop wound healing preparations is a pressing challenge given the limitations of the current treatment and the rising prevalence of impaired healing wounds. Although herbal extracts have been used for many years to treat skin disorders, due to their wound healing, anti-inflammatory, antimicrobial, and antioxidant effects, their efficacy can be questionable because of their poor bioavailability and stability issues. Nanotechnology offers an opportunity to revolutionize wound healing therapies by including herbal compounds in nanosystems. Particularly, vesicular nanosystems exhibit beneficial properties, such as biocompatibility, targeted and sustained delivery capacity, and increased phytocompounds' bioavailability and protection, conferring them a great potential for future applications in wound care. This review summarizes the beneficial effects of phytocompounds in wound healing and emphasizes the advantages of their entrapment in vesicular nanosystems. Different types of lipid nanocarriers are presented (liposomes, niosomes, transferosomes, ethosomes, cubosomes, and their derivates' systems), highlighting their applications as carriers for phytocompounds in wound care, with the presentation of the state-of-art in this field. The methods of preparation, characterization, and evaluation are also described, underlining the properties that ensure good in vitro and in vivo performance. Finally, future directions of topical systems in which vesicle-bearing herbal extracts or phytocompounds can be incorporated are pointed out, as their development is emerging as a promising strategy.
    Keywords:  herbal extracts; lipid vesicles; nanotechnology; phytocompounds; vesicles’ characterization; vesicles’ preparation; vesicular nanosystems; wound healing
    DOI:  https://doi.org/10.3390/pharmaceutics14050991
  58. Gut. 2022 May 27. pii: gutjnl-2021-325117. [Epub ahead of print]
    Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer.
    Maria Chiara De Santis, Luca Gozzelino, Jean Piero Margaria, Andrea Costamagna, Edoardo Ratto, Federico Gulluni, Enza Di Gregorio, Erica Mina, Nicla Lorito, Marina Bacci, Rossano Lattanzio, Gianluca Sala, Paola Cappello, Francesco Novelli, Elisa Giovannetti, Caterina Vicentini, Silvia Andreani, Pietro Delfino, Vincenzo Corbo, Aldo Scarpa, Paolo Ettore Porporato, Andrea Morandi, Emilio Hirsch, Miriam Martini.
       OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified.
    DESIGN: Three independent cohorts of PDAC patients were studied to correlate PI3K-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models.
    RESULTS: PI3K-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.
    CONCLUSION: Loss of PI3K-C2γ prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2γ loss.
    Keywords:  AMINO ACIDS; CELL BIOLOGY; LIPID METABOLISM; PANCREATIC CANCER; SIGNAL TRANSDUCTION
    DOI:  https://doi.org/10.1136/gutjnl-2021-325117
  59. Antioxidants (Basel). 2022 May 20. pii: 1006. [Epub ahead of print]11(5):
    Phytochemical Characterization, Antioxidant and Anti-Proliferative Properties of Rubia cordifolia L. Extracts Prepared with Improved Extraction Conditions.
    Ravikiran B Humbare, Joyita Sarkar, Anjali A Kulkarni, Mugdha G Juwale, Sushil H Deshmukh, Dinesh Amalnerkar, Manohar Chaskar, Maria C Albertini, Marco B L Rocchi, Swapnil C Kamble, Seeram Ramakrishna.
      Rubia cordifolia L. (Rubiaceae) is an important plant in Indian and Chinese medical systems. Extracts prepared from the root, stem and leaf have been used traditionally for the management of various diseases. Some of the known effects are anti-inflammation, neuroprotection, anti-proliferation, immunomodulation and anti-tumor. A comparative account of the extracts derived from different organs that lead to the identification of the most suitable solvent is lacking. We explored the presence of phytochemicals, antioxidant activity and anti-proliferative properties of a variety of solvent-based extracts of root, and methanol extracts of stem and leaf of R. cordifolia L. The antioxidant potential was determined by DPPH, hydrogen peroxide, nitric oxide and total antioxidant assays. The anti-proliferative nature was evaluated by MTT assay on HeLa, ME-180 and HepG2 cells. The composition of the extracts was determined by UPLC-UV-MS. We found that the root extracts had the presence of higher amounts of antioxidants over the stem and leaf extracts. The root extracts prepared in methanol exhibited the highest cytotoxicity in HepG2 cells. The main compounds identified through UPLC-UV-MS of the methanol extract give credibility to the previous results. Our comprehensive study corroborates the preference given to the root over the stem and leaf for extract preparation. In conclusion, we identified the methanol extract of the root to be the most suited to have bioactivity with anti-cancer potential.
    Keywords:  alternative medicine; anti-cancer; cell lines; metabolic profiling; multiple solvents; phenol quenching; polyvinylpolypyrrolidone (PVPP); secondary metabolites
    DOI:  https://doi.org/10.3390/antiox11051006
  60. Exp Gerontol. 2022 May 19. pii: S0531-5565(22)00144-9. [Epub ahead of print]165 111836
    Ferroptosis - A new target of osteoporosis.
    Zhonghua Gao, Zhuoying Chen, Zhifan Xiong, Xiangjie Liu.
      Osteoporosis is a bone metabolic disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture, leading to enhanced skeletal fragility and susceptibility to fracture. Unbalanced bone remodeling is the primary pathogenetic factor of osteoporosis, in which osteoclast-mediated bone resorption exceeds osteoblast-mediated bone formation. Bisphosphonates and calcitonin are among the drugs commonly used to treat osteoporosis, in addition to the bone nutrients vitamin D and calcium supplements. The current treatments effectively prevent further bone loss by inhibiting the excessive activation of osteoclasts, accompanied by various degrees of side effects. Iron, one of the trace elements essential for life activities, has recently been recognized as an independent risk factor for osteoporosis. Abnormal iron metabolism increases the incidence of many bone diseases, especially osteoporosis. Iron metabolism does play a key role in bone homeostasis. Ferroptosis is a novel form of cell death that has been discovered in recent years. Its main features include iron overload and the accumulation of ROS. And lipid peroxidation is the key. There are increasing shreds of evidence that ferroptosis is involved in the occurrence and development of osteoporosis, and its regulation can effectively prevent osteoporosis. Therefore, this review further elucidates the role of ferroptosis in osteoporosis based on the mechanism and its relationship with osteoporosis and provides a new idea for treating osteoporosis.
    Keywords:  Ferroptosis; Lipid peroxidation; Osteoporosis; ROS; iron metabolism
    DOI:  https://doi.org/10.1016/j.exger.2022.111836
  61. Pharmaceuticals (Basel). 2022 Apr 27. pii: 542. [Epub ahead of print]15(5):
    Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC).
    Aiswarya Chaudhuri, Dulla Naveen Kumar, Deepa Dehari, Sanjay Singh, Pradeep Kumar, Pradeep Kumar Bolla, Dinesh Kumar, Ashish Kumar Agrawal.
      Triple-negative breast cancer (TNBC) is considered one of the un-manageable types of breast cancer, involving devoid of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER 2) receptors. Due to their ability of recurrence and metastasis, the management of TNBC remains a mainstay challenge, despite the advancements in cancer therapies. Conventional chemotherapy remains the only treatment regimen against TNBC and suffers several limitations such as low bioavailability, systemic toxicity, less targetability, and multi-drug resistance. Although various targeted therapies have been introduced to manage the hardship of TNBC, they still experience certain limitations associated with the survival benefits. The current research thus aimed at developing and improving the strategies for effective therapy against TNBC. Such strategies involved the emergence of nanoparticles. Nanoparticles are designated as nanocavalries, loaded with various agents (drugs, genes, etc.) to battle the progression and metastasis of TNBC along with overcoming the limitations experienced by conventional chemotherapy and targeted therapy. This article documents the treatment regimens of TNBC along with their efficacy towards different subtypes of TNBC, and the various nanotechnologies employed to increase the therapeutic outcome of FDA-approved drug regimens.
    Keywords:  chemotherapy; nanoparticles; targeted therapy; triple-negative breast cancer (TNBC)
    DOI:  https://doi.org/10.3390/ph15050542
  62. Mar Drugs. 2022 Apr 21. pii: 278. [Epub ahead of print]20(5):
    Preparation of Doxorubicin-Loaded Carboxymethyl-β-Cyclodextrin/Chitosan Nanoparticles with Antioxidant, Antitumor Activities and pH-Sensitive Release.
    Yingqi Mi, Jingjing Zhang, Wenqiang Tan, Qin Miao, Qing Li, Zhanyong Guo.
      In this study, chitosan nanoparticles (HF-CD NPs) were synthesized by an ionic gelation method using negatively charged carboxymethyl-β-cyclodextrin and positively charged 2-hydroxypropyltrimethyl ammonium chloride chitosan bearing folic acid. The surface morphology of HF-CD NPs was spherical or oval, and they possessed relatively small particle size (192 ± 8 nm) and positive zeta potential (+20 ± 2 mV). Meanwhile, doxorubicin (Dox) was selected as model drug to investigate the prepared nanoparticles' potential to serve as a drug delivery carrier. The drug loading efficiency of drug-loaded nanoparticles (HF-Dox-CD NPs) was 31.25%. In vitro release profiles showed that Dox release of nanoparticles represented a pH-sensitive sustained and controlled release characteristic. At the same time, the antioxidant activity of nanoparticles was measured, and chitosan nanoparticles possessed good antioxidant activity and could inhibit the lipid peroxidation inside the cell and avoid material infection. Notably, CCK-8 assay testified that the nanoparticles were safe drug carriers and significantly enhanced the antitumor activity of Dox. The nanoparticles possessed good antioxidant activity, pH-sensitive sustained controlled release, enhanced antitumor activity, and could be expected to serve as a drug carrier in future with broad application prospects.
    Keywords:  antioxidant activity; antitumor activity; chitosan nanoparticles; cyclodextrin; drug release
    DOI:  https://doi.org/10.3390/md20050278
  63. Biomed Pharmacother. 2022 May 20. pii: S0753-3322(22)00470-X. [Epub ahead of print]151 113081
    Xihuang Pill enhances anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway.
    Bo Cao, Shiyuan Wang, Ruisheng Li, Zhihong Wang, Taifeng Li, Yuanyuan Zhang, Bin Dong, Yingying Li, Mengmeng Lin, Xingjie Li, Xiaohe Xiao, Chunyu Li, Guohui Li.
      Lung cancer poses a serious threat to human health. Although targeted therapies have led to breakthroughs in the treatment of lung cancer, drug resistance and side effects limit their clinical applications. Xihuang pill (XHW), a classical anti-cancer traditional Chinese medicine formula, has been clinically proven to be an effective complementary therapy in the treatment of various of cancers. However, the underlying mechanism for its use in combination with anti-cancer drugs remains unclear. Here, we explored the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung cancer (LLC). We used gut microbiota and transcriptomics to elucidate the regulatory properties of XHW in improving anti-lung cancer effect of anlotinib. The results showed that combination treatment of XHW with Anlotinib significantly inhibited tumor growth in LLC-bearing mice. We found that XHW played a key role in the regulation of gut microbiota using 16 s rRNA sequencing analysis. Specifically, XHW increased the proportion of the beneficial bacteria Bacteroides and g_norank_f_Muribaculaceae. Based on transcriptomic analysis of tumor tissues, differentially expressed genes in the combination therapy group were related to biological processes concerning angiogenesis, such as regulation of blood vessel diameter, regulation of tube diameter, and regulation of tube size. Our data suggest that XWH enhances the anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway. Combination therapy with anlotinib and XHW may be a novel therapeutic strategy for lung cancer patients.
    Keywords:  Anlotinib; Gut microbiota; Lung cancer; Transcriptomic; Xihuang pill
    DOI:  https://doi.org/10.1016/j.biopha.2022.113081
  64. Molecules. 2022 May 18. pii: 3226. [Epub ahead of print]27(10):
    Hydrolyzed Flavonoids from Cyrtosperma johnstonii with Superior Antioxidant, Antiproliferative, and Anti-Inflammatory Potential for Cancer Prevention.
    Ornchuma Naksuriya, Krai Daowtak, Singkome Tima, Siriporn Okonogi, Monika Mueller, Stefan Toegel, Ruttiros Khonkarn.
      Cyrtosperma johnstonii is one of the most interesting traditional medicines for cancer treatment. This study aimed to compare and combine the biological activities related to cancer prevention of the flavonoid glycosides rutin (RT) and isorhamnetin-3-o-rutinoside (IRR) and their hydrolysis products quercetin (QT) and isorhamnetin (IR) from C.johnstonii extract. ABTS and MTT assays were used to determine antioxidant activity and cytotoxicity against various cancer cells, as well as normal cells. Anti-inflammatory activities were measured by ELISA. The results showed that the antioxidant activities of the compounds decreased in the order of QT > IR > RT > IRR, while most leukemia cell lines were sensitive to QT and IR with low toxicity towards PBMCs. The reduction of IL-6 and IL-10 secretion by QT and IR was higher than that induced by RT and IRR. The combination of hydrolysis products (QT and IR) possessed a strong synergism in antioxidant, antiproliferative and anti-inflammatory effects, whereas the combination of flavonoid glycosides and their hydrolysis products revealed antagonism. These results suggest that the potential of the combination of hydrolyzed flavonoids from C. johnstonii can be considered as natural compounds for the prevention of cancer.
    Keywords:  Cyrtosperma johnstonii; anti-inflammatory; antioxidant; cytotoxicity; flavonoid glycosides; isorhamnetin; quercetin; synergism
    DOI:  https://doi.org/10.3390/molecules27103226
  65. Int J Nanomedicine. 2022 ;17 2225-2241
    The Effects of a Novel Curcumin Derivative Loaded Long-Circulating Solid Lipid Nanoparticle on the MHCC-97H Liver Cancer Cells and Pharmacokinetic Behavior.
    Yumeng Wei, Ke Li, Wenmei Zhao, Yingmeng He, Hongping Shen, Jiyuan Yuan, Chao Pi, Xiaomei Zhang, Mingtang Zeng, Shaozhi Fu, Xinjie Song, Robert J Lee, Ling Zhao.
       Purpose: The objective of this study was to develop long-circulating solid lipid nanoparticles (LSLN) containing a novel curcumin (CU) derivative (CU1), to improve CU1's pharmacokinetic behavior and its anti-cancer effects in MHCC-97H liver cancer cells.
    Methods: LSLN loaded with CU1 (CU1-LSLN) was optimized and characterized. The cell biological properties and the anti-cancer mechanism of CU1-LSLN on MHCC-97H cells were evaluated by MTT, flow cytometry, Transwell, and Western blot. CU1-LSLN was further evaluated for pharmacokinetic behavior, biodistribution, and liver toxicity in SD rats.
    Results: The optimized CU1-LSLN formulation showed the ideal particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE%), and drug loading (DL%) of 122.10 ± 6.63 nm, 0.19 ± 0.02, -36.30 ± 1.25 mV, 94.98 ± 0.90% and 4.53 ± 0.69%, respectively. X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrometry (FTIR) indicated that CU1 was well encapsulated by LSLN and existed in amorphous form. Storage stability of CU1-LSLN was up to 180 days with a sustained-release of drug over 96 h. The uptake efficiency of CU1-LSLN to MHCC-97H cells was 3.24 and 2.98 times higher than that of CU and CU1 after treatment for 3 h, which helped to enhance the inhibitive effect of CU1-LSLN on the proliferation, migration, and invasion potential of MHCC-97H cells and increased its ability to promote apoptosis. Meanwhile, the expression levels of NF-κB, COX-2, MMP-2, MMP-9, and uPA decreased significantly. In vivo, CU1-LSLN prolonged the retention time of the drug, the area under the curve (AUC) increased significantly (CU: 69.9-fold, CU1: 85.9-fold), and no significant liver toxicity was observed.
    Conclusion: CU1-LSLN is a novel preparation with great potential for treating liver cancer.
    Keywords:  MHCC-97H; curcumin derivative; nanoparticle; pharmacokinetics
    DOI:  https://doi.org/10.2147/IJN.S363237
  66. Antioxidants (Basel). 2022 Apr 27. pii: 854. [Epub ahead of print]11(5):
    Synergistic Antioxidant Activity and Enhanced Stability of Curcumin Encapsulated in Vegetal Oil-Based Microemulsion and Gel Microemulsions.
    Cristina Scomoroscenco, Mircea Teodorescu, Sabina Georgiana Burlacu, Ioana Cătălina Gîfu, Catalin Ionut Mihaescu, Cristian Petcu, Adina Raducan, Petruta Oancea, Ludmila Otilia Cinteza.
      Curcumin, due to its antioxidant, antibacterial, anti-inflammatory, and antitumoral activity, has attracted huge attention in applications in many fields such as pharmacy, medicine, nutrition, cosmetics, and biotechnology. The stability of curcumin-based products and preservation of antioxidant properties are still challenges in practical applications. Stability and antioxidant properties were studied for curcumin encapsulated in O/W microemulsion systems and three related gel microemulsions. Only biodegradable and biocompatible ingredients were used for carriers: grape seed oil as oily phase, Tween 80, and Plurol® Diisostearique CG as a surfactant mix, and ethanol as a co-solvent. For the gel microemulsions, water-soluble polymers, namely Carbopol® 980 NF, chitosan, and sodium hyaluronate were used. The influence of UVC irradiation and heat treatment on the degradation kinetics of curcumin in the formulations was studied. Because of the antioxidant character of the microemulsion oily phase, the possibility of a synergistic effect between grape seed oil and curcumin was explored. In this study, the high efficiency of the studied drug delivery systems to ensure protection from external degradative factors was confirmed. Also, the influence of the encapsulation in microemulsion and derived gel microemulsion systems on the antioxidant capacity curcumin was studied, and a synergistic effect with vegetal oil was demonstrated.
    Keywords:  antioxidant activity; curcumin; grape seed oil; microemulsion; synergism
    DOI:  https://doi.org/10.3390/antiox11050854
  67. Pharmaceutics. 2022 Apr 21. pii: 909. [Epub ahead of print]14(5):
    Hard, Soft, and Hard-and-Soft Drug Delivery Carriers Based on CaCO3 and Alginate Biomaterials: Synthesis, Properties, Pharmaceutical Applications.
    Yanqi Huang, Lin Cao, Bogdan V Parakhonskiy, Andre G Skirtach.
      Because free therapeutic drug molecules often have adverse effects on normal tissues, deliver scanty drug concentrations and exhibit a potentially low efficacy at pathological sites, various drug carriers have been developed for preclinical and clinical trials. Their physicochemical and toxicological properties are the subject of extensive research. Inorganic calcium carbonate particles are promising candidates as drug delivery carriers owning to their hardness, porous internal structure, high surface area, distinctive pH-sensitivity, low degradability, etc, while soft organic alginate hydrogels are also widely used because of their special advantages such as a high hydration, bio-adhesiveness, and non-antigenicity. Here, we review these two distinct substances as well as hybrid structures encompassing both types of carriers. Methods of their synthesis, fundamental properties and mechanisms of formation, and their respective applications are described. Furthermore, we summarize and compare similarities versus differences taking into account unique advantages and disadvantages of these drug delivery carriers. Moreover, rational combination of both carrier types due to their performance complementarity (yin-&yang properties: in general, yin is referred to for definiteness as hard, and yang is broadly taken as soft) is proposed to be used in the so-called hybrid carriers endowing them with even more advanced properties envisioned to be attractive for designing new drug delivery systems.
    Keywords:  alginate hydrogels; calcium carbonate; drug delivery; drug loading; release mechanism
    DOI:  https://doi.org/10.3390/pharmaceutics14050909
  68. Front Pharmacol. 2022 ;13 872085
    Salvia miltiorrhiza in Breast Cancer Treatment: A Review of Its Phytochemistry, Derivatives, Nanoparticles, and Potential Mechanisms.
    Huan Zhao, Bing Han, Xuan Li, Chengtao Sun, Yufei Zhai, Man Li, Mi Jiang, Weiping Zhang, Yi Liang, Guoyin Kai.
      Breast cancer is one of the most deadly malignancies in women worldwide. Salvia miltiorrhiza, a perennial plant that belongs to the genus Salvia, has long been used in the management of cardiovascular and cerebrovascular diseases. The main anti-breast cancer constituents in S. miltiorrhiza are liposoluble tanshinones including dihydrotanshinone I, tanshinone I, tanshinone IIA, and cryptotanshinone, and water-soluble phenolic acids represented by salvianolic acid A, salvianolic acid B, salvianolic acid C, and rosmarinic acid. These active components have potent efficacy on breast cancer in vitro and in vivo. The mechanisms mainly include induction of apoptosis, autophagy and cell cycle arrest, anti-metastasis, formation of cancer stem cells, and potentiation of antitumor immunity. This review summarized the main bioactive constituents of S. miltiorrhiza and their derivatives or nanoparticles that possess anti-breast cancer activity. Besides, the synergistic combination with other drugs and the underlying molecular mechanisms were also summarized to provide a reference for future research on S. miltiorrhiza for breast cancer treatment.
    Keywords:  Salvia miltiorrhiza; bioactive constituent; breast cancer; drug combination; mechanism; nanoparticle
    DOI:  https://doi.org/10.3389/fphar.2022.872085
  69. Recent Pat Nanotechnol. 2022 May 23.
    Nanocrystals: A Deep Insight into Formulation Aspects, Stabilization Strategies and Biomedical Applications.
    Deepika Purohit, Shivkant Sharma, Avneet Kaur Lamba, Sapna Saini, Neha Minocha, Neelam Vashist, Dhirender Kaushik, Parijat Pandey.
       BACKGROUND: Drugs having poor solubility exhibit hurdles in their formulation development due to poor dissolution and low bioavailability issues. Nanocrystallization is a great technique for incorporating poorly soluble drugs and is additionally associated with so many benefits.
    OBJECTIVE: The objective of the present review is to discuss formulation techniques for the generation of nanocrystals (NCs) and to illustrate the various advantages of NCs. The review also spotlights on commonly used stabilizers, guidelines for their safe use for enhancement of NCs and provides a deep sight into various biomedical applications of NCs.
    METHOD: The review was extracted from the study carried out in the general literature to emphasize the importance of NCs in various formulations.
    RESULTS: NCs are a widely accepted approach to enhance drug solubility. There are so many marketed products of nanocrystal drug formulations that are being used to treat life-threatening disorders. Two techniques can be used to formulate NCs, i.e., bottom-up method and top-down method. Their main biomedical applications are found in oral, parenteral, pulmonary, ocular, dermal, and mucosal formulations.
    CONCLUSION: In the present review, different formulation methods of NCs have been discussed in detail, followed by elaborating the advantages and various targeted drug delivery systems covered by NCs formulations. The development of NCs based formulation avoids the limitations of other systems used for targeted drug delivery.
    Keywords:  Bottom-up Technique; Crystal Growth; Homogenization; Nanocrystals; Nanoparticles; Patents
    DOI:  https://doi.org/10.2174/1872210516666220523120313
  70. Eur J Pharm Sci. 2022 May 19. pii: S0928-0987(22)00097-5. [Epub ahead of print] 106212
    Honokiol nanosuspensions loaded thermosensitive hydrogels as the local delivery system in combination with systemic paclitaxel for synergistic therapy of breast cancer.
    Xinyue Lu, Xiaoyu Lu, Pei Yang, Zhenhai Zhang, Huixia Lv.
      Local administration of therapeutic agents provides a favorable approach to enhance drug accumulation at pathological sites. In this study, a novel honokiol nanosuspensions loaded thermosensitive injectable hydrogels (HK-NS-Gel) was designed as the local delivery system for the combination therapy with systemic paclitaxel (PTX). The formed HK-NS-Gel showed superior gelation time and temperature. In vitro release and in vivo drug retention assay showed that HK-NS-Gel can slowly and steadily release the HK during 12 days. Meanwhile, enhanced PTX accumulation in the tumor was observed after intratumoral injection of HK-NS-Gel. In vitro cytotoxicity and cell apoptosis tests against 4T1 cells proved the synergistic effects of free PTX combined with HK-NS-Gel. In vivo antitumor study was conducted on 4T1 bearing mice, indicating that co-administration HK-NS-Gel and PTX could effectively enhance tumor growth suppression, and the tumor inhibitory rate was as high as 72.51%. In conclusion, intravenous delivery of PTX combined with intratumoral delivery of HK-NS-Gel was a promising combination for breast cancer therapy with enhanced therapeutic response and safety.
    Keywords:  Breast cancer; Honokiol; Nanosuspensions; Synergistic chemotherapy; Thermosensitive hydrogel
    DOI:  https://doi.org/10.1016/j.ejps.2022.106212
  71. Int Immunopharmacol. 2022 May 24. pii: S1567-5769(22)00374-5. [Epub ahead of print]108 108890
    Modulation of the immune system by melatonin; implications for cancer therapy.
    Masoud Moslehi, Reza Moazamiyanfar, Mohammad Sedigh Dakkali, Sepideh Rezaei, Nima Rastegar-Pouyani, Emad Jafarzadeh, Kave Mouludi, Ehsan Khodamoradi, Shahram Taeb, Masoud Najafi.
      Immune system interactions within the tumour have a key role in the resistance or sensitization of cancer cells to anti-cancer agents. On the other hand, activation of the immune system in normal tissues following chemotherapy or radiotherapy is associated with acute and late effects such as inflammation and fibrosis. Some immune responses can reduce the efficiency of anti-cancer therapy and also promote normal tissue toxicity. Modulation of immune responses can boost the efficiency of anti-tumour therapy and alleviate normal tissue toxicity. Melatonin is a natural body agent that has shown promising results for modulating tumour response to therapy and also alleviating normal tissue toxicity. This review tries to focus on the immunomodulatory actions of melatonin in both tumour and normal tissues. We will explain how anti-cancer drugs may cause toxicity for normal tissues and how tumours can adapt themselves to ionizing radiation and anti-cancer drugs. Then, cellular and molecular mechanisms of immunoregulatory effects of melatonin alone or combined with other anti-cancer agents will be discussed.
    Keywords:  Anti-tumour immunity; Cancer; Chemotherapy; Immune system; Inflammation; Melatonin; Radiotherapy
    DOI:  https://doi.org/10.1016/j.intimp.2022.108890
  72. Antioxidants (Basel). 2022 May 06. pii: 911. [Epub ahead of print]11(5):
    Impacts of Oxidative Stress and PI3K/AKT/mTOR on Metabolism and the Future Direction of Investigating Fucoidan-Modulated Metabolism.
    Jun-Ping Shiau, Ya-Ting Chuang, Yuan-Bin Cheng, Jen-Yang Tang, Ming-Feng Hou, Ching-Yu Yen, Hsueh-Wei Chang.
      The critical factors for regulating cancer metabolism are oxidative stress and phosphoinositide-3-kinase/AKT serine-threonine kinase/mechanistic target of the rapamycin kinase (PI3K/AKT/mTOR). However, the metabolic impacts of oxidative stress and PI3K/AKT/mTOR on individual mechanisms such as glycolysis (Warburg effect), pentose phosphate pathway (PPP), fatty acid synthesis, tricarboxylic acid cycle (TCA) cycle, glutaminolysis, and oxidative phosphorylation (OXPHOS) are complicated. Therefore, this review summarizes the individual and interacting functions of oxidative stress and PI3K/AKT/mTOR on metabolism. Moreover, natural products providing oxidative stress and PI3K/AKT/mTOR modulating effects have anticancer potential. Using the example of brown algae-derived fucoidan, the roles of oxidative stress and PI3K/AKT/mTOR were summarized, although their potential functions within diverse metabolisms were rarely investigated. We propose a potential application that fucoidan may regulate oxidative stress and PI3K/AKT/mTOR signaling to modulate their associated metabolic regulations. This review sheds light on understanding the impacts of oxidative stress and PI3K/AKT/mTOR on metabolism and the future direction of metabolism-based cancer therapy of fucoidan.
    Keywords:  AKT; PI3K; anticancer; fucoidan; mTOR; metabolism; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11050911
  73. Int J Mol Sci. 2022 May 20. pii: 5709. [Epub ahead of print]23(10):
    Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells.
    Valeria Consoli, Valeria Sorrenti, Valeria Pittalà, Khaled Greish, Agata Grazia D'Amico, Giuseppe Romeo, Sebastiano Intagliata, Loredana Salerno, Luca Vanella.
      The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study's purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO's effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO's implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO's contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.
    Keywords:  HO-1; HO-2; cancer; curcumin; erastin; heme; inducers; inhibitors
    DOI:  https://doi.org/10.3390/ijms23105709
  74. Pharmaceutics. 2022 Apr 20. pii: 893. [Epub ahead of print]14(5):
    Chitosan Nanoparticles for Meloxicam Ocular Delivery: Development, In Vitro Characterization, and In Vivo Evaluation in a Rabbit Eye Model.
    Hebatallah B Mohamed, Mohamed Ali Attia Shafie, Aml I Mekkawy.
      Eye inflammation is considered one of the most common co-morbidities associated with ocular disorders and surgeries. Conventional management of this condition with non-steroidal anti-inflammatory drugs as eye drops is associated with low corneal bioavailability and ocular irritancy. In the current study, we first investigated the capacity of different solvent systems to enhance the solubility of Meloxicam (MLX). Then, we prepared chitosan nanoparticles loaded with meloxicam (MLX-CS-NPs) through electrostatic interaction between the cationic chitosan and the anionic MLX using either 100% v/v polyethylene glycol 400 or 0.25% w/v tripolyphosphate solution as solvents based on the MLX solubility data. In further studies, MLX-CS-NPs were characterized in vitro and assessed for their ex vivo corneal and scleral permeability. The morphology, average particle size (195-597 nm), zeta potential (25-54 mV), and percent entrapment efficiencies (70-96%) of the prepared MLX-CS-NPs were evaluated. The in vitro release study of MLX from the selected MLX-CS-NPs showed a sustained drug release for 72 h with accepted flux and permeation through the cornea and sclera of rabbits. In the in vivo studies, MLX-CS-NPs eye drop dispersion showed enhanced anti-inflammatory activity and no ocular irritancy compared to MLX-eye drop solution. Our findings suggest the potential for using chitosan nanotechnology for ocular delivery of MLX with high contact time and activity.
    Keywords:  anti-inflammatory activity; chitosan nanoparticles; meloxicam; permeability study; polyethylene glycol 400
    DOI:  https://doi.org/10.3390/pharmaceutics14050893
  75. Metabolites. 2022 Apr 25. pii: 389. [Epub ahead of print]12(5):
    The Differential Metabolic Response of Oral Squamous Cell Carcinoma Cells and Normal Oral Epithelial Cells to Cisplatin Exposure.
    Xun Chen, Sufang Kuang, Yi He, Hongyu Li, Chen Yi, Yiming Li, Chao Wang, Guanhui Chen, Shangwu Chen, Dongsheng Yu.
      Metabolic reprogramming is one of the hallmarks of a tumor. It not only promotes the development and progression of tumor but also contributes to the resistance of tumor cells to chemotherapeutics. The difference in the metabolism between drug-resistant and sensitive tumor cells indicates that drug-resistant tumor cells have experienced metabolic adaptation. The metabolic response induced by chemotherapy is dynamic, but the early metabolic response of tumor cells to anticancer drugs and the effect of an initial response on the development of drug resistance have not been well studied. Early metabolic intervention may prevent or slow down the development of drug resistance. The differential metabolic responses of normal cells and tumor cells to drugs are unclear. The specific metabolites or metabolic pathways of tumor cells to chemotherapeutic drugs can be used as the target of metabolic intervention in tumor therapy. In this study, we used comparative metabolomics to analyze the differential metabolic responses of oral cancer cells and normal oral epithelial cells to short-term cisplatin exposure, and to identify the marker metabolites of early response in oral cancer cells. Oral cancer cells showed a dynamic metabolic response to cisplatin. Seven and five metabolites were identified as specific response markers to cisplatin exposure in oral cancer cell SCC-9 and normal oral epithelial cell HOEC, respectively. Glyoxylate and dicarboxylate metabolism and fructose, malate, serine, alanine, sorbose and glutamate were considered as specific enriched metabolic pathways and biomarkers of SCC-9 cells in response to cisplatin, respectively. The existence of differential metabolic responses lays a foundation for tumor chemotherapy combined with metabolic intervention.
    Keywords:  cisplatin exposure; metabolic response; metabolomics; normal oral epithelial cells; oral squamous cell carcinoma cells
    DOI:  https://doi.org/10.3390/metabo12050389
  76. Am J Physiol Cell Physiol. 2022 May 25.
    Ferroptosis at the crossroads of tumor-host interactions, metastasis, and therapy response.
    Yinan Yao, Yuxin Shi, Zizhe Gao, Yutong Sun, Fan Yao, Li Ma.
      Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid peroxides in an iron-dependent manner. Ferroptotic cell death is modulated by many metabolic pathways, such as pathways governing the metabolism of sugars, lipids, amino acids, and iron, as well as mitochondrial activity and redox homeostasis. Tumor metastasis and therapy resistance are the main obstacles to curing cancers. Because tumor cells usually exhibit higher iron dependence than normal cells, they may be more susceptible to ferroptosis despite being resistant to other forms of cell death. Moreover, recent evidence has suggested that ferroptosis is involved in tumor-host interactions, modulates the tumor microenvironment, and serves as an anti-metastatic mechanism. Thus, inducing ferroptosis in tumor cells has the potential to improve cancer treatment. Here, we review ferroptosis-regulating mechanisms and the roles of ferroptosis in malignant progression, including the tumor-host interactions, metastasis, and cancer therapy response.
    Keywords:  Ferroptosis; Metastasis; Therapy response; Tumor-host interactions
    DOI:  https://doi.org/10.1152/ajpcell.00148.2022
  77. Heliyon. 2022 May;8(5): e09394
    Liposomes: structure, composition, types, and clinical applications.
    Hamdi Nsairat, Dima Khater, Usama Sayed, Fadwa Odeh, Abeer Al Bawab, Walhan Alshaer.
      Liposomes are now considered the most commonly used nanocarriers for various potentially active hydrophobic and hydrophilic molecules due to their high biocompatibility, biodegradability, and low immunogenicity. Liposomes also proved to enhance drug solubility and controlled distribution, as well as their capacity for surface modifications for targeted, prolonged, and sustained release. Based on the composition, liposomes can be considered to have evolved from conventional, long-circulating, targeted, and immune-liposomes to stimuli-responsive and actively targeted liposomes. Many liposomal-based drug delivery systems are currently clinically approved to treat several diseases, such as cancer, fungal and viral infections; more liposomes have reached advanced phases in clinical trials. This review describes liposomes structure, composition, preparation methods, and clinical applications.
    Keywords:  Lamellarity; Liposomes; Phospholipids; Stealth liposomes; Vaccinations
    DOI:  https://doi.org/10.1016/j.heliyon.2022.e09394
  78. Phys Biol. 2022 May 25.
    Spatiotemporal feedforward between PKM2 tetramers and mTORC1 prompts mTORC1 activation.
    Yu Xia, ShuMing Wang, Chunbo Song, Ruoyu Luo.
      Most mammalian cells couple glucose availability to anabolic processes via the mTORC1 pathway. However, the mechanism by which fluctuations in glucose availability are rapidly translated into mTORC1 signals remains elusive. Here, we show that cells rapidly respond to changes in glucose availability through the spatial coupling of mTORC1 and tetramers of the key glycolytic enzyme pyruvate kinase M2 (PKM2) on lysosomal surfaces in the late G1/S phases. The lysosomal localization of PKM2 tetramers enables rapid increases in local ATP concentrations around lysosomes to activate mTORC1, while bypassing the need to elevate global ATP levels in the entire cell. In essence, this spatial coupling establishes a feedforward loop to enable mTORC1 to rapidly sense and respond to changes in glucose availability. We further demonstrate that this mechanism ensures robust cell proliferation upon fluctuating glucose availability. Thus, we present mechanistic insights into the rapid response of the mTORC1 pathway to changes in glucose availability. The underlying mechanism may be applicable to the control of other cellular processes.
    Keywords:  Cancer metabolism; PKM2; Spatiotemporal Feedforward; mTORC1
    DOI:  https://doi.org/10.1088/1478-3975/ac7372
  79. Evid Based Complement Alternat Med. 2022 ;2022 4534411
    Aucubin Exerts Anticancer Activity in Breast Cancer and Regulates Intestinal Microbiota.
    Min Shao, Ziyun Kuang, Wenlin Wang, Shengnan Li, Guizhen Li, Yu Song, Haitao Li, Guozhen Cui, Hefeng Zhou.
      Aucubin, a natural compound isolated from herbal medicine, has been reported to possess multiple beneficial properties. In this study, we aimed to verify the anticancer effect of aucubin on breast cancer and investigate the effect of cancer on the intestinal flora and whether aucubin has a therapeutic effect on intestinal problems caused by cancer. We established the breast cancer model with mouse 4T1 cell line and BALB/c mice. Aucubin was given once a day by gavage for 14 days. The results showed that aucubin suppress the growth of tumor in vivo by inducing tumor cell apoptosis. The tumor suppression rate of aucubin could reach 51.31 ± 4.07%. Organ histopathology was evaluated by tissue staining, which demonstrated that aucubin could alleviate the organ inflammatory damage caused by breast cancer without visible side effects. Moreover, aucubin could increase the expression of colonic tight junction protein occluding and adjust the gut microbiome to normal level according to 16S rDNA high-throughput sequencing. Herein, our results provide evidence for developing aucubin as an alternative and safe therapeutic for breast cancer treatment.
    DOI:  https://doi.org/10.1155/2022/4534411
  80. Pharmaceutics. 2022 May 08. pii: 1015. [Epub ahead of print]14(5):
    Heptamethine Cyanine-Loaded Nanomaterials for Cancer Immuno-Photothermal/Photodynamic Therapy: A Review.
    Cátia G Alves, Rita Lima-Sousa, Bruna L Melo, André F Moreira, Ilídio J Correia, Duarte de Melo-Diogo.
      The development of strategies capable of eliminating metastasized cancer cells and preventing tumor recurrence is an exciting and extremely important area of research. In this regard, therapeutic approaches that explore the synergies between nanomaterial-mediated phototherapies and immunostimulants/immune checkpoint inhibitors have been yielding remarkable results in pre-clinical cancer models. These nanomaterials can accumulate in tumors and trigger, after irradiation of the primary tumor with near infrared light, a localized temperature increase and/or reactive oxygen species. These effects caused damage in cancer cells at the primary site and can also (i) relieve tumor hypoxia, (ii) release tumor-associated antigens and danger-associated molecular patterns, and (iii) induced a pro-inflammatory response. Such events will then synergize with the activity of immunostimulants and immune checkpoint inhibitors, paving the way for strong T cell responses against metastasized cancer cells and the creation of immune memory. Among the different nanomaterials aimed for cancer immuno-phototherapy, those incorporating near infrared-absorbing heptamethine cyanines (Indocyanine Green, IR775, IR780, IR797, IR820) have been showing promising results due to their multifunctionality, safety, and straightforward formulation. In this review, combined approaches based on phototherapies mediated by heptamethine cyanine-loaded nanomaterials and immunostimulants/immune checkpoint inhibitor actions are analyzed, focusing on their ability to modulate the action of the different immune system cells, eliminate metastasized cancer cells, and prevent tumor recurrence.
    Keywords:  cancer; heptamethine cyanines; immunotherapy; nanoparticles; phototherapies
    DOI:  https://doi.org/10.3390/pharmaceutics14051015
  81. Biomedicines. 2022 May 08. pii: 1090. [Epub ahead of print]10(5):
    Targeted Strategy in Lipid-Lowering Therapy.
    Ezgi Dayar, Olga Pechanova.
      Dyslipidemia is characterized by a diminished lipid profile, including increased level of total cholesterol and low-density lipoprotein cholesterol (LDL-c) and reduced level of high-density lipoprotein cholesterol (HDL-c). Lipid-lowering agents represent an efficient tool for the prevention or reduction of progression of atherosclerosis, coronary heart diseases and metabolic syndrome. Statins, ezetimibe, and recently proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are the most effective and used drugs in clinical lipid-lowering therapy. These drugs are mainly aimed to lower cholesterol levels by different mechanisms of actions. Statins, the agents of the first-line therapy-known as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors-suppress the liver cholesterol synthesis. Ezetimibe as the second-line therapy can decrease cholesterol by inhibiting cholesterol absorption. Finally, the PCSK9 inhibitors act as an inducer of LDL excretion. In spite of their beneficial lipid-lowering properties, many patients suffer from their serious side effects, route of administration, or unsatisfactory physicochemical characteristics. Clinical demand for dose reduction and the improvement of bioavailability as well as pharmacodynamic and pharmacokinetic profile has resulted in the development of a new targeted therapy that includes nanoparticle carriers, emulsions or vaccination often associated with another more subtle form of administration. Targeted therapy aims to exert a more potent drug profile with lipid-lowering properties either alone or in mutual combination to potentiate their beneficial effects. This review describes the most effective lipid-lowering drugs, their favorable and adverse effects, as well as targeted therapy and alternative treatments to help reduce or prevent atherosclerotic processes and cardiovascular events.
    Keywords:  PCSK9 inhibitors; cholesterol; dyslipidemia; ezetimibe; metabolic syndrome; nanoparticles; statins; targeted therapy
    DOI:  https://doi.org/10.3390/biomedicines10051090
  82. MedComm (2020). 2022 Jun;3(2): e144
    Epithelial-mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities.
    Zhao Huang, Zhe Zhang, Chengwei Zhou, Lin Liu, Canhua Huang.
      Epithelial-mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell-cell junctions and cell-matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.
    Keywords:  EMT; cancer progression; embryogenesis; redox signaling; targeted therapy
    DOI:  https://doi.org/10.1002/mco2.144
  83. Photodiagnosis Photodyn Ther. 2022 May 18. pii: S1572-1000(22)00201-0. [Epub ahead of print] 102915
    Enhanced Permeability and Retention Effect: A key facilitator for solid tumor targeting by nanoparticles.
    Vinod Ravasaheb Shinde, Neeraja Revi, Sivasubramanian Murugappan, Surya Prakash Singh, Aravind Kumar Rengan.
      Exploring the enhanced permeability and retention (EPR) effect through therapeutic nanoparticles has been a subject of considerable interest in tumor biology. This passive targeting based phenomenon exploits the leaky blood vasculature and the defective lymphatic drainage system of the heterogeneous tumor microenvironment resulting in enhanced preferential accumulation of the nanoparticles within the tumor tissues. This article reviews the fundamental studies to assess how the EPR effect plays an essential role in passive targeting. Further, it summarizes various therapeutic modalities of nanoformulation including chemo-photodynamic therapy, intravascular drug release, and photothermal immunotherapy to combat cancer using enhanced EPR effect in neoplasia region.
    Keywords:  Enhanced Permeability and Retention (EPR) effect; Extravasation; Microbubble; Microenvironment; Nanoparticles; Pharmacokinetics; Ultrasound
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102915
  84. Front Pharmacol. 2022 ;13 889799
    Chinese Herbal Medicine for Primary Liver Cancer Therapy: Perspectives and Challenges.
    Kexin Li, Kunmin Xiao, Shijie Zhu, Yong Wang, Wei Wang.
      Primary liver cancer (PLC) is one of the most common solid malignancies. However, PLC drug development has been slow, and first-line treatments are still needed; thus, studies exploring and developing alternative strategies for effective PLC treatment are urgently needed. Chinese herbal medicine (CHM) has long been applied in the clinic due to its advantages of low toxicity and targeting of multiple factors and pathways, and it has great potential for the development of novel natural drugs against PLC. Purpose: This review aims to provide an update on the pharmacological mechanisms of Chinese patent medicines (CPMs) and the latest CHM-derived compounds for the treatment of PLC and relevant clinical evaluations. Materials and Methods: A systematic search of English literature databases, Chinese literature, the Clinical Trials Registry Platform, and the Chinese Clinical Trial Registry for studies of CHMs for PLC treatment was performed. Results: In this review, we summarize the clinical trials and mechanisms of CPMs for PLC treatment that have entered the clinic with the approval of the Chinese medicine regulatory authority. These CPMs included Huaier granules, Ganfule granules, Fufang Banmao capsules, Jinlong capsules, Brucea javanica oil emulsions, and compound kushen injections. We also summarize the latest in vivo, in vitro, and clinical studies of CHM-derived compounds against PLC: icaritin and ginsenoside Rg3. Dilemmas facing the development of CHMs, such as drug toxicity and low oral availability, and future developments are also discussed. Conclusion: This review provides a deeper the understanding of CHMs as PLC treatments and provides ideas for the development of new natural drugs against PLC.
    Keywords:  Chinese herbal medicines; Chinese patent medicine; clinical trials; pharmacological mechanisms; primary liver cancer
    DOI:  https://doi.org/10.3389/fphar.2022.889799
  85. Pharmaceutics. 2022 Apr 25. pii: 935. [Epub ahead of print]14(5):
    Chitosan Nanoparticles in Atherosclerosis-Development to Preclinical Testing.
    Pornsak Sriamornsak, Crispin R Dass.
      Chitosan is a natural biopolymer that is present in an abundant supply in sources such as crustacean shells, mushrooms, and insect exoskeletons. It can be used to make a variety of types of drug formulations and is generally safe to use in vivo; plus, it has inherent cholesterol-reducing properties. While an abundance of papers has tested this biopolymer in nanoparticles in cancer and diabetes research, there is a lag of usage, and hence the paucity of information, in the area of cardiovascular research, specifically in atherosclerosis, the topic of this review. This review highlights some of the deficiencies in this niche area of research, examines the range of chitosan nanoparticles that have been researched to date, and proposes several ways forward to advance this field. Nanoparticles used for both diagnostic and therapeutic purposes are reviewed, with a discussion on how these nanoparticles could be better researched in future and what lays ahead as the field potentially moves towards clinical trials in future.
    Keywords:  atherosclerosis; cardiovascular; chitosan; drug; nanoparticle
    DOI:  https://doi.org/10.3390/pharmaceutics14050935
  86. Antioxidants (Basel). 2022 May 20. pii: 1009. [Epub ahead of print]11(5):
    Diclofenac: A Nonsteroidal Anti-Inflammatory Drug Inducing Cancer Cell Death by Inhibiting Microtubule Polymerization and Autophagy Flux.
    Soohee Choi, Suree Kim, Jiyoung Park, Seung Eun Lee, Chaewon Kim, Dongmin Kang.
      Diclofenac, a nonsteroidal anti-inflammatory drug (NSAID) used to treat inflammatory diseases induces cellular toxicity by increasing the production of reactive oxygen species (ROS) and impairing autophagic flux. In this study, we investigated whether diclofenac induces cancer cell death and the mechanism by which diclofenac causes cell death. We observed that diclofenac induces mitotic arrest with a half-maximal effective concentration of 170 μM and cell death with a half-maximal lethal dose of 200 µM during 18-h incubation in HeLa cells. Cellular microtubule imaging and in vitro tubulin polymerization assays demonstrated that treatment with diclofenac elicits microtubule destabilization. Autophagy relies on microtubule-mediated transport and the fusion of autophagic vesicles. We observed that diclofenac inhibits both phagophore movement, an early step of autophagy, and the fusion of autophagosomes and lysosomes, a late step of autophagy. Diclofenac also induces the fragmentation of mitochondria and the Golgi during cell death. We found that diclofenac induces cell death further in combination with 5-fuorouracil, a DNA replication inhibitor than in single treatment in cancer cells. Pancreatic cancer cells, which have high basal autophagy, are particularly sensitive to cell death by diclofenac. Our study suggests that microtubule destabilization by diclofenac induces cancer cell death via compromised spindle assembly checkpoints and increased ROS through impaired autophagy flux. Diclofenac may be a candidate therapeutic drug in certain type of cancers by inhibiting microtubule-mediated cellular events in combination with clinically utilized nucleoside metabolic inhibitors, including 5-fluorouracil, to block cancer cell proliferation.
    Keywords:  autophagy; cell death; combination cancer therapy; diclofenac; microtubule depolymerization
    DOI:  https://doi.org/10.3390/antiox11051009
  87. Drug Deliv. 2022 Dec;29(1): 1523-1535
    Complex polymeric nanomicelles co-delivering doxorubicin and dimethoxycurcumin for cancer chemotherapy.
    Muhammad Sohail, Bin Yu, Zheng Sun, Jiali Liu, Yanli Li, Feng Zhao, Daquan Chen, Xin Yang, Hui Xu.
      Combinational therapy is a new trend in medical sciences to achieve a maximum therapeutic response of the drugs with a comparatively low incidence of severe adverse effects. To overcome the challenges of conventional formulations for cancer chemotherapy, a polymer-based complex nanomicellar system, namely CPM-DD, was developed co-delivering the anti-cancer agent doxorubicin (DOX) and potent antioxidant dimethoxycurcumin (DiMC). The optimal mass ratio of DOX/DiMC in CPM-DD was determined as 1:6 due to the synergistic antiproliferative effect from in vitro cytotoxicity assay, while the biocompatible diblock copolymer of mPEG2000-PLA5000 was selected for drug entrapment at an optimal feeding ratio of 9:1 to both drugs together. The uniform particles of CPM-DD with suitable particle size (∼30 nm) and stable drug loading content (>9%) could be reliably obtained by self-assembly with the encapsulation yield up to 95%. Molecular dynamics simulation revealed the interaction mechanism responsible for forming these complex nanomicelles. The acid-base interaction between two drugs would significantly improve their binding with the copolymer, thus leading to good colloidal stability and controlled drug release characteristics of CPM-DD. Systematic evaluation based on the MCF-7 breast tumor-bearing nude mice model further demonstrated the characteristics of tissue biodistribution of both drugs delivered by CPM-DD, which were closely related to the drug loading pattern and greatly responsible for the improved anti-cancer potency and attenuated toxicity of this complex formulation. Therefore, all the findings indicated that CPM-DD would be a good alternative to the conventional formulations of DOX and worthy of clinical application for cancer chemotherapy.
    Keywords:  Complex polymeric nanomicelles; combinational cancer chemotherapy; dimethoxycurcumin; doxorubicin
    DOI:  https://doi.org/10.1080/10717544.2022.2073403
  88. Pharmaceutics. 2022 Apr 24. pii: 928. [Epub ahead of print]14(5):
    Hypoxia-Responsive Azobenzene-Linked Hyaluronate Dot Particles for Photodynamic Tumor Therapy.
    Sohyeon Lee, Yoonyoung Kim, Eun Seong Lee.
      In this study, we developed ultra-small hyaluronate dot particles that selectively release phototoxic drugs into a hypoxic tumor microenvironment. Here, the water-soluble hyaluronate dot (dHA) was covalently conjugated with 4,4'-azodianiline (Azo, as a hypoxia-sensitive linker) and Ce6 (as a photodynamic antitumor agent), producing dHA particles with cleavable Azo bond and Ce6 (dHA-Azo-Ce6). Importantly, the inactive Ce6 (self-quenched state) in the dHA-Azo-Ce6 particles was switched to the active Ce6 (dequenched state) via the Azo linker (-N=N-) cleavage in a hypoxic environment. In vitro studies using hypoxia-induced HeLa cells (treated with CoCl2) revealed that the dHA-Azo-Ce6 particle enhanced photodynamic antitumor inhibition, suggesting its potential as an antitumor drug candidate in response to tumor hypoxia.
    Keywords:  chlorin e6; hyaluronate dot particles; hypoxia-sensitive; photodynamic tumor therapy; ultra-small size
    DOI:  https://doi.org/10.3390/pharmaceutics14050928
  89. Nutrients. 2022 May 18. pii: 2104. [Epub ahead of print]14(10):
    A Focused Insight into Thyme: Biological, Chemical, and Therapeutic Properties of an Indigenous Mediterranean Herb.
    Dalal Hammoudi Halat, Maha Krayem, Sanaa Khaled, Samar Younes.
      A perennial wild shrub from the Lamiaceae family and native to the Mediterranean region, thyme is considered an important wild edible plant studied for centuries for its unique importance in the food, pharmaceutical, and cosmetic industry. Thyme is loaded with phytonutrients, minerals and vitamins. It is pungent in taste, yet rich in moisture, proteins, crude fiber, minerals and vitamins. Its chemical composition may vary with geographical location but is mainly composed of flavonoids and antioxidants. Previous studies have illustrated the therapeutic effects of thyme and its essential oils, especially thymol and carvacrol, against various diseases. This is attributed to its multi-pharmacological properties that include, but are not limited to, antioxidant, anti-inflammatory, and antineoplastic actions. Moreover, thyme has long been known for its antiviral, antibacterial, antifungal, and antiseptic activities, in addition to remarkable disruption of microbial biofilms. In the COVID-19 era, some thyme constituents were investigated for their potential in viral binding. As such, thyme presents a wide range of functional possibilities in food, drugs, and other fields and prominent interest as a nutraceutical. The aims of the current review are to present botanical and nutritive values of this herb, elaborate its major constituents, and review available literature on its dietetic and biological activities.
    Keywords:  Thymus vulgaris; anti-inflammatory; anticancer; antimicrobial; antioxidant; carvacrol; thyme essential oil; thymol
    DOI:  https://doi.org/10.3390/nu14102104
  90. Molecules. 2022 May 20. pii: 3292. [Epub ahead of print]27(10):
    A Comprehensive Review of Rosmarinic Acid: From Phytochemistry to Pharmacology and Its New Insight.
    Huaquan Guan, Wenbin Luo, Beihua Bao, Yudan Cao, Fangfang Cheng, Sheng Yu, Qiaoling Fan, Li Zhang, Qinan Wu, Mingqiu Shan.
      Polyphenolic acids are the widely occurring natural products in almost each herbal plant, among which rosmarinic acid (RA, C18H16O8) is well-known, and is present in over 160 species belonging to many families, especially the Lamiaceae. Aside from this herbal ingredient, dozens of its natural derivatives have also been isolated and characterized from many natural plants. In recent years, with the increasing focus on the natural products as alternative treatments, a large number of pharmacological studies have been carried out to demonstrate the various biological activities of RA such as anti-inflammation, anti-oxidation, anti-diabetes, anti-virus, anti-tumor, neuroprotection, hepatoprotection, etc. In addition, investigations concerning its biosynthesis, extraction, analysis, clinical applications, and pharmacokinetics have also been performed. Although many achievements have been made in various research aspects, there still exist some problems or issues to be answered, especially its toxicity and bioavailability. Thus, we hope that in the case of natural products, the present review can not only provide a comprehensive understanding on RA covering its miscellaneous research fields, but also highlight some of the present issues and future perspectives worth investigating later, in order to help us utilize this polyphenolic acid more efficiently, widely, and safely.
    Keywords:  natural product; pharmacokinetics; pharmacology; phytochemistry; rosmarinic acid
    DOI:  https://doi.org/10.3390/molecules27103292
  91. Cancers (Basel). 2022 May 21. pii: 2538. [Epub ahead of print]14(10):
    Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.
    Qi Zhang, Donghai Xiong, Jing Pan, Yian Wang, Micael Hardy, Balaraman Kalyanaraman, Ming You.
      Combined treatment targeting mitochondria may improve the efficacy of lung cancer chemoprevention. Here, mitochondria-targeted honokiol (Mito-HNK), an inhibitor of mitochondrial complex I and STAT3 phosphorylation, and mitochondria-targeted lonidamine (Mito-LND), an inhibitor of mitochondrial complexes I/II and AKT/mTOR/p70S6K signaling, were evaluated for their combinational chemopreventive efficacy on mouse lung carcinogenesis. All chemopreventive treatments began one-week post-carcinogen treatment and continued daily for 24 weeks. No evidence of toxicity (including liver toxicity) was detected by monitoring serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Mito-HNK or Mito-LND treatment alone reduced tumor load by 56% and 48%, respectively, whereas the combination of Mito-HNK and Mito-LND reduced tumor load by 83%. To understand the potential mechanism(s) of action for the observed combinatorial effects, single-cell RNA sequencing was performed using mouse tumors treated with Mito-HNK, Mito-LND, and their combination. In lung tumor cells, Mito-HNK treatment blocked the expression of genes involved in mitochondrial complex ǀ, oxidative phosphorylation, glycolysis, and STAT3 signaling. Mito-LND inhibited the expression of genes for mitochondrial complexes I/II, oxidative phosphorylation, and AKT/mTOR/p70S6K signaling in lung tumor cells. In addition to these changes, a combination of Mito-HNK with Mito-LND decreased arginine and proline metabolism, N-glycan biosynthesis, and tryptophan metabolism in lung tumor cells. Our results demonstrate that Mito-LND enhanced the antitumor efficacy of Mito-HNK, where both compounds inhibited common targets (oxidative phosphorylation) as well as unique targets for each agent (STAT3 and mTOR signaling). Therefore, the combination of Mito-HNK with Mito-LND may present an effective strategy for lung cancer chemoprevention.
    Keywords:  lung cancer; mitochondria-targeted honokiol; mitochondria-targeted lonidamine; mitochondrial bioenergetics; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/cancers14102538
  92. Cancers (Basel). 2022 May 17. pii: 2473. [Epub ahead of print]14(10):
    Nanoparticles as Physically- and Biochemically-Tuned Drug Formulations for Cancers Therapy.
    Valentina Foglizzo, Serena Marchiò.
      Malignant tumors originate from a combination of genetic alterations, which induce activation of oncogenes and inactivation of oncosuppressor genes, ultimately resulting in uncontrolled growth and neoplastic transformation. Chemotherapy prevents the abnormal proliferation of cancer cells, but it also affects the entire cellular network in the human body with heavy side effects. For this reason, the ultimate aim of cancer therapy remains to selectively kill cancer cells while sparing their normal counterparts. Nanoparticle formulations have the potential to achieve this aim by providing optimized drug delivery to a pathological site with minimal accumulation in healthy tissues. In this review, we will first describe the characteristics of recently developed nanoparticles and how their physical properties and targeting functionalization are exploited depending on their therapeutic payload, route of delivery, and tumor type. Second, we will analyze how nanoparticles can overcome multidrug resistance based on their ability to combine different therapies and targeting moieties within a single formulation. Finally, we will discuss how the implementation of these strategies has led to the generation of nanoparticle-based cancer vaccines as cutting-edge instruments for cancer immunotherapy.
    Keywords:  cancer immunotherapy; cancer vaccine; drug delivery; nanoparticles; target therapy
    DOI:  https://doi.org/10.3390/cancers14102473
  93. Nutrients. 2022 May 12. pii: 2030. [Epub ahead of print]14(10):
    Modulation of Inflammation by Plant-Derived Nutraceuticals in Tendinitis.
    Anna-Lena Mueller, Aranka Brockmueller, Ajaikumar B Kunnumakkara, Mehdi Shakibaei.
      Tendinitis (tendinopathy) is a pro-inflammatory and painful tendon disease commonly linked with mechanical overuse and associated injuries, drug abuse, and lifestyle factors (including poor diet and physical inactivity) that causes significant healthcare expenditures due to its high incidence. Nuclear factor kappa B (NF-κB) is one of the major pro-inflammatory transcription factors, along with other inflammation signaling pathways, triggered by a variety of stimuli, including cytokines, endotoxins, physical and chemical stressors, hypoxia, and other pro-inflammatory factors. Their activation is known to regulate the expression of a multitude of genes involved in inflammation, degradation, and cell death. The pathogenesis of tendinitis is still poorly understood, whereas efficient and sustainable treatment is missing. Targeting drug suppression of the key inflammatory regulators represents an effective strategy for tendinitis therapy, but requires a comprehensive understanding of their principles of action. Conventional monotherapies are often ineffective and associated with severe side effects in patients. Therefore, agents that modulate multiple cellular targets represent therapeutic treatment potential. Plant-derived nutraceuticals have been shown to act as multi-targeting agents against tendinitis via various anti-oxidant and anti-inflammatory mechanisms, whereat they were able to specifically modulate numerous signaling pathways, including NF-κB, p38/MAPK, JNK/STAT3, and PI3K/Akt, thus down-regulating inflammatory processes. This review discusses the utility of herbal nutraceuticals that have demonstrated safety and tolerability as anti-inflammatory agents for the prevention and treatment of tendinitis through the suppression of catabolic signaling pathways. Limitations associated with the use of nutraceuticals are also described.
    Keywords:  inflammation; nutraceuticals; polyphenols; tendinitis; tendinopathy; tendon; tissue engineering
    DOI:  https://doi.org/10.3390/nu14102030
  94. Nat Rev Cardiol. 2022 May 23.
    Repurposing drugs to treat cardiovascular disease in the era of precision medicine.
    Mena Abdelsayed, Eric J Kort, Stefan Jovinge, Mark Mercola.
      Drug repurposing is the use of a given therapeutic agent for indications other than that for which it was originally designed or intended. The concept is appealing because of potentially lower development costs and shorter timelines than are needed to produce a new drug. To date, drug repurposing for cardiovascular indications has been opportunistic and driven by knowledge of disease mechanisms or serendipitous observation rather than by systematic endeavours to match an existing drug to a new indication. Innovations in two areas of personalized medicine - computational approaches to associate drug effects with disease signatures and predictive model systems to screen drugs for disease-modifying activities - support efforts that together create an efficient pipeline to systematically repurpose drugs to treat cardiovascular disease. Furthermore, new experimental strategies that guide the medicinal chemistry re-engineering of drugs could improve repurposing efforts by tailoring a medicine to its new indication. In this Review, we summarize the historical approach to repurposing and discuss the technological advances that have created a new landscape of opportunities.
    DOI:  https://doi.org/10.1038/s41569-022-00717-6
  95. Tissue Cell. 2022 May 16. pii: S0040-8166(22)00087-8. [Epub ahead of print]77 101815
    Vitamin D enhances the sensitivity of breast cancer cells to the combination therapy of photodynamic therapy and paclitaxel.
    Xiaojin Liu, Hao Lv, Haibin Shen.
       PURPOSE: Given that Vitamin D (VD) has been confirmed to reinforce the toxic effects of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) towards breast cancer, this study was designed to decipher the combined effects of VD, ALA-PDT and paclitaxel (PTX).
    METHODS: Thiazolyl blue tetrazolium bromide assay was conducted to gauge the viability of breast cancer cells treated with ALA-PDT and PTX alone or in combination. The cell migration, invasion and apoptosis were measured by wound healing, transwell and flow cytometry assays, respectively. Xenograft tumor models were established and tumor volume and weight were recorded. The expression of Bcl-2, Bax and cleaved caspase-3 in cells and tumor tissues was determined by western blot assay.
    RESULTS: Both ALA-PDT and PTX alone inhibited viability in a dose-dependent manner, blocked migration and invasion, boosted apoptosis, down-regulated Bcl-2 expression and upregulated the expression of Bax and cleaved caspase-3 in breast cancer cells. More significant effects on the above-mentioned factors were induced by ALA-PDT and PTX in combination. Moreover, ALA-PDT and PTX in combination also suppressed the growth of xenograft tumors and Bcl-2 expression while promoting the expression of Bax and cleaved caspase-3 in tumors. In contrast, VD had no effect on tumor growth and the expression of Bcl-2, Bax and cleavedcaspase-3, but intensified the combined effects of ALA-PDT and PTX.
    CONCLUSION: VD could enhance the therapeutic effects of ALA-PDT combined with PTX on tumor growth and cell apoptosis.
    Keywords:  ALA-PDT; Apoptosis; Breast cancer; Paclitaxel; Vitamin D
    DOI:  https://doi.org/10.1016/j.tice.2022.101815
  96. Nanomaterials (Basel). 2022 May 10. pii: 1629. [Epub ahead of print]12(10):
    A Review on Current Designation of Metallic Nanocomposite Hydrogel in Biomedical Applications.
    Nur Syafiqah Farhanah Dzulkharnien, Rosiah Rohani.
      In the past few decades, nanotechnology has been receiving significant attention globally and is being continuously developed in various innovations for diverse applications, such as tissue engineering, biotechnology, biomedicine, textile, and food technology. Nanotechnological materials reportedly lack cell-interactive properties and are easily degraded into unfavourable products due to the presence of synthetic polymers in their structures. This is a major drawback of nanomaterials and is a cause of concern in the biomedicine field. Meanwhile, particulate systems, such as metallic nanoparticles (NPs), have captured the interest of the medical field due to their potential to inhibit the growth of microorganisms (bacteria, fungi, and viruses). Lately, researchers have shown a great interest in hydrogels in the biomedicine field due to their ability to retain and release drugs as well as to offer a moist environment. Hence, the development and innovation of hydrogel-incorporated metallic NPs from natural sources has become one of the alternative pathways for elevating the efficiency of therapeutic systems to make them highly effective and with fewer undesirable side effects. The objective of this review article is to provide insights into the latest fabricated metallic nanocomposite hydrogels and their current applications in the biomedicine field using nanotechnology and to discuss the limitations of this technology for future exploration. This article gives an overview of recent metallic nanocomposite hydrogels fabricated from bioresources, and it reviews their antimicrobial activities in facilitating the demands for their application in biomedicine. The work underlines the fabrication of various metallic nanocomposite hydrogels through the utilization of natural sources in the production of biomedical innovations, including wound healing treatment, drug delivery, scaffolds, etc. The potential of these nanocomposites in relation to their mechanical strength, antimicrobial activities, cytotoxicity, and optical properties has brought this technology into a new dimension in the biomedicine field. Finally, the limitations of metallic nanocomposite hydrogels in terms of their methods of synthesis, properties, and outlook for biomedical applications are further discussed.
    Keywords:  drug delivery; hydrogel; metallic; nanocomposite; nanotechnology; tissue engineering; wound care
    DOI:  https://doi.org/10.3390/nano12101629
  97. Children (Basel). 2022 May 10. pii: 695. [Epub ahead of print]9(5):
    Photodynamic Therapy for Treatment of Disease in Children-A Review of the Literature.
    Anna Mazur, Katarzyna Koziorowska, Klaudia Dynarowicz, David Aebisher, Dorota Bartusik-Aebisher.
      Photodynamic therapy is a mode of treatment whereby local irradiation of an administered photosensitizer with light of a specific wavelength generates cytotoxic reactive oxygen species. Despite the upward trend in the popularity of this method in adults, it is not yet commonly used in the treatment of children. Due to certain limitations, underdeveloped treatment regimens and potential side effects, the use of photodynamic therapy in the pediatric population is still in the initial phases of evaluation in clinical trials.
    METHOD: This study is a review of articles in English from the databases PubMed and Web of Science retrieved by applying the search term "photodynamic therapy in children" from 2000-2020.
    RESULTS: Based on the literature review, we analyze selected pediatric clinical cases in which photodynamic therapy was used for treatment in children. Examples of photodynamic therapy for treatment of dermatological diseases, diseases of the mucosa of the upper respiratory tract, halitosis, eye diseases and brain tumors are described. The paper describes the effectiveness of anti-cancer photodynamic therapy, including its use in antibacterial therapy.
    CONCLUSIONS: The results of the analysis suggest the potential of photodynamic therapy for the treatment of various diseases in children.
    Keywords:  photodynamic therapy; therapy in children; treatment
    DOI:  https://doi.org/10.3390/children9050695
  98. Antibiotics (Basel). 2022 May 18. pii: 685. [Epub ahead of print]11(5):
    Co-Delivery of Nano-Silver and Vancomycin via Silica Nanopollens for Enhanced Antibacterial Functions.
    Chengang Ni, Yuening Zhong, Weixi Wu, Yaping Song, Pooyan Makvandi, Chengzhong Yu, Hao Song.
      Infectious diseases caused by bacteria have led to a great threat to public health. With the significant advances in nanotechnology in recent decades, nanomaterials have emerged as a powerful tool to boost antibacterial performance due to either intrinsic bactericidal properties or by enhancing the delivery efficiency of antibiotics for effective pathogen killing. Vancomycin, as one of the most widely employed antimicrobial peptides, has a potent bactericidal activity, but at the same time shows a limited bioavailability. Silver nanoparticles have also been extensively explored and were found to have a well-recognized antibacterial activity and limited resistance potential; however, how to prevent nanosized Ag particles from aggregation in biological conditions is challenging. In this study, we aimed to combine the advantages of both vancomycin and nano-Ag for enhanced bacterial killing, where both antibacterial agents were successfully loaded onto a silica nanoparticle with a pollen-like morphology. The morphology of nano-Ag-decorated silica nanopollens was characterized using transmission electron microscopy and elemental mapping through energy dispersive spectroscopy. Silver nanoparticles with a size of 10-25 nm were observed as well-distributed on the surface of silica nanoparticles of around 200 nm. The unique design of a spiky morphology of silica nano-carriers promoted the adhesion of nanoparticles towards bacterial surfaces to promote localized drug release for bacterial killing, where the bacterial damage was visualized through scanning electron microscopy. Enhanced bactericidal activity was demonstrated through this co-delivery of vancomycin and nano-Ag, decreasing the minimum inhibition concentration (MIC) towards E. coli and S. epidermidis down to 15 and 10 µg/mL. This study provides an efficient antimicrobial nano-strategy to address potential bacterial infections.
    Keywords:  antibacterial; drug delivery; nanomaterials; silica nanoparticles; silver nanoparticles; vancomycin
    DOI:  https://doi.org/10.3390/antibiotics11050685
  99. Pharmaceutics. 2022 Apr 24. pii: 925. [Epub ahead of print]14(5):
    Amphiphilic Poly-N-vinylpyrrolidone Nanoparticles as Carriers for Nonsteroidal, Anti-Inflammatory Drugs: Pharmacokinetic, Anti-Inflammatory, and Ulcerogenic Activity Study.
    Andrey Kuskov, Dragana Nikitovic, Aikaterini Berdiaki, Mikhail Shtilman, Aristidis Tsatsakis.
      Nanoparticles are increasingly utilized as drug delivery agents. Previously, we have developed a drug delivery system based on amphiphilic derivatives of poly-N-vinylpyrrolidone (PVP-OD4000) with excellent biocompatibility. In the current study, we assessed the pharmacokinetics, anti-inflammatory profile, and ulcerogenic potential of indomethacin (IMC)-loaded PVP-OD4000 nanoparticles compared to the free drug. Wistar male rats were utilized for a pharmacokinetics study and an anti-inflammatory study. Loaded IMC exhibited a slower elimination rate (p < 0.05) and a higher blood plasma concentration at 8 and 24 h after intraperitoneal injection compared with free IMC. In addition, decreased uptake of loaded IMC in the liver and kidney compared to free IMC (p < 0.05) was detected. Furthermore, PVP-OD4000 nanoparticles loaded with IMC showed an enhanced anti-inflammatory effect compared to free IMC (p < 0.05) in carrageenan-induced and complete Freund's adjuvant-induced-(CFA) sub-chronic and chronic paw edema treatment (p < 0.01; p < 0.01). Notably, upon oral administration of loaded IMC, animals had a significantly lower ulcer score and Paul's Index (3.9) compared to the free drug (p < 0.05). The obtained results suggest that IMC loaded to PVP nanoparticles exhibit superior anti-inflammatory activity in vivo and a safe gastrointestinal profile and pose a therapeutic alternative for the currently available NSAIDs' administration.
    Keywords:  anti-inflammatory effect; indomethacin; pharmacokinetics; poly-N-vinylpyrrolidone nanoparticles
    DOI:  https://doi.org/10.3390/pharmaceutics14050925
  100. Cancers (Basel). 2022 May 18. pii: 2478. [Epub ahead of print]14(10):
    How Phosphofructokinase-1 Promotes PI3K and YAP/TAZ in Cancer: Therapeutic Perspectives.
    Luca Simula, Marco Alifano, Philippe Icard.
      PI3K/AKT is one of the most frequently altered signaling pathways in human cancers, supporting the activation of many proteins sustaining cell metabolism, proliferation, and aggressiveness. Another important pathway frequently altered in cancer cells is the one regulating the YAP/TAZ transcriptional coactivators, which promote the expression of genes sustaining aerobic glycolysis (such as WNT, MYC, HIF-1), EMT, and drug resistance. Of note, the PI3K/AKT pathway can also regulate the YAP/TAZ one. Unfortunately, although PI3K and YAP inhibitors are currently tested in highly resistant cancers (both solid and hematologic ones), several resistance mechanisms may arise. Resistance mechanisms to PI3K inhibitors may involve the stimulation of alternative pathways (such as RAS, HER, IGFR/AKT), the inactivation of PTEN (the physiologic inhibitor of PI3K), and the expression of anti-apoptotic Bcl-xL and MCL1 proteins. Therefore, it is important to improve current therapeutic strategies to overcome these limitations. Here, we want to highlight how the glycolytic enzyme PFK1 (and its product F-1,6-BP) promotes the activation of both PI3K/AKT and YAP/TAZ pathways by several direct and indirect mechanisms. In turn, PI3K/AKT and YAP/TAZ can promote PFK1 activity and F-1,6-BP production in a positive feedback loop, thus sustaining the Warburg effect and drug resistance. Thus, we propose that the inhibition of PFK1 (and of its key activator PFK2/PFKFB3) could potentiate the sensitivity to PI3K and YAP inhibitors currently tested. Awaiting the development of non-toxic inhibitors of these enzymes, we propose to test the administration of citrate at a high dosage, because citrate is a physiologic inhibitor of both PFK1 and PFK2/PFKFB3. Consistently, in various cultured cancer cells (including melanoma, sarcoma, hematologic, and epithelial cancer cells), this "citrate strategy" efficiently inhibits the IGFR1/AKT pathway, promotes PTEN activity, reduces Bcl-xL and MCL1 expression, and increases sensitivity to standard chemotherapy. It also inhibits the development of sarcoma, pancreatic, mammary HER+ and lung RAS-driven tumors in mice without apparent toxicities.
    Keywords:  F-1,6-BP; PFK1; PI3K; YAP/TAZ; citrate; drug resistance
    DOI:  https://doi.org/10.3390/cancers14102478
  101. Life (Basel). 2022 May 18. pii: 750. [Epub ahead of print]12(5):
    Nanoparticles: Synthesis and Their Role as Potential Drug Candidates for the Treatment of Parasitic Diseases.
    Hammad Ur Rehman Bajwa, Muhammad Kasib Khan, Zaheer Abbas, Roshan Riaz, Tauseef Ur Rehman, Rao Zahid Abbas, Muhammad Tahir Aleem, Asghar Abbas, Mashal M Almutairi, Fahdah Ayed Alshammari, Yasser Alraey, Abdulaziz Alouffi.
      Protozoa, helminths and ectoparasites are the major groups of parasites distributed worldwide. Currently, these parasites are treated with chemotherapeutic antiprotozoal drugs, anti-helminthic and anti-ectoparasitic agents, but, with the passage of time, resistance to these drugs has developed due to overuse. In this scenario, nanoparticles are proving to be a major breakthrough in the treatment and control of parasitic diseases. In the last decade, there has been enormous development in the field of nanomedicine for parasitic control. Gold and silver nanoparticles have shown promising results in the treatments of various types of parasitic infections. These nanoparticles are synthesized through the use of various conventional and molecular technologies and have shown great efficacy. They work in different ways, that include damaging the parasite membrane, DNA (Deoxyribonucleic acid) disruption, protein synthesis inhibition and free-radical formation. These agents are effective against intracellular parasites as well. Other nanoparticles, such as iron, nickel, zinc and platinum, have also shown good results in the treatment and control of parasitic infections. It is hoped that this research subject will become the future of modern drug development. This review summarizes the methods that are used to synthesize nanoparticles and their possible mechanisms of action against parasites.
    Keywords:  mechanisms of action; nanoparticles; parasite control; synthesis
    DOI:  https://doi.org/10.3390/life12050750
  102. Biomolecules. 2022 Apr 25. pii: 636. [Epub ahead of print]12(5):
    Recent Advances in Poly(α-L-glutamic acid)-Based Nanomaterials for Drug Delivery.
    Yu Zhang, Wenliang Song, Yiming Lu, Yixin Xu, Changping Wang, Deng-Guang Yu, Il Kim.
      Poly(α-L-glutamic acid) (PGA) is a class of synthetic polypeptides composed of the monomeric unit α-L-glutamic acid. Owing to their biocompatibility, biodegradability, and non-immunogenicity, PGA-based nanomaterials have been elaborately designed for drug delivery systems. Relevant studies including the latest research results on PGA-based nanomaterials for drug delivery have been discussed in this work. The following related topics are summarized as: (1) a brief description of the synthetic strategies of PGAs; (2) an elaborated presentation of the evolving applications of PGA in the areas of drug delivery, including the rational design, precise fabrication, and biological evaluation; (3) a profound discussion on the further development of PGA-based nanomaterials in drug delivery. In summary, the unique structures and superior properties enables PGA-based nanomaterials to represent as an enormous potential in biomaterials-related drug delivery areas.
    Keywords:  cancer therapy; drug delivery system; nanomaterials; poly(α-L-glutamic acid); prodrugs
    DOI:  https://doi.org/10.3390/biom12050636
  103. Sci Rep. 2022 May 24. 12(1): 8697
    Iron oxide nanoflowers encapsulated in thermosensitive fluorescent liposomes for hyperthermia treatment of lung adenocarcinoma.
    Maria Theodosiou, Elias Sakellis, Nikos Boukos, Vladan Kusigerski, Beata Kalska-Szostko, Eleni Efthimiadou.
      Magnetic hyperthermia (MHT) is in the spotlight of nanomedical research for the treatment of cancer employing magnetic iron oxide nanoparticles and their intrinsic capability for heat dissipation under an alternating magnetic field (AMF). Herein we focus on the synthesis of iron oxide nanoflowers (Nfs) of different sizes (15 and 35 nm) and coatings (bare, citrate, and Rhodamine B) while comparing their physicochemical and magnetothermal properties. We encapsulated colloidally stable citrate coated Nfs, of both sizes, in thermosensitive liposomes via extrusion, and RhB was loaded in the lipid bilayer. All formulations proved hemocompatible and cytocompatible. We found that 35 nm Nfs, at lower concentrations than 15 nm Nfs, served better as nanoheaters for magnetic hyperthermia applications. In vitro, magnetic hyperthermia results showed promising therapeutic and imaging potential for RhB loaded magnetoliposomes containing 35 nm Nfs against LLC and CULA cell lines of lung adenocarcinoma.
    DOI:  https://doi.org/10.1038/s41598-022-12687-3
  104. Food Chem Toxicol. 2022 May 20. pii: S0278-6915(22)00362-3. [Epub ahead of print]165 113164
    Effectiveness of beetroot extract in SH-SY5Y neuronal cell protection against Fumonisin B1, Ochratoxin A and its combination.
    Raquel Penalva-Olcina, Cristina Juan, Mónica Fernández-Franzón, Ana Juan-García.
      Fumonisin B1 (FB1) and ochratoxin A (OTA) are fungal metabolites of worldwide concern because of their effect on human and animal health, as both have been classified by IARC as possible carcinogens (Group 2B). Beetroot is a source of dietary fiber, folic acid, and vitamin C, and some studies have demonstrated their antioxidant activity. Therefore, this work presents the cytoprotective effect of beetroot extract (BRE) on a neuroblastoma cell line (SH-SY5Y cells) exposed to FB1, OTA, and its combination. Cytotoxicity was studied by the MTT ([3-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, for 24 h and 48 h. Simultaneous treatment and pre-treatment strategies were tested with 1:512-1:2 and 1:0 dilutions of BRE, with a concentration range from 0.4 to 100 μM of FB1 and from 0.19 to 50 μM of OTA. IC50 values of 5.8 μM and 9.1 μM at 24 h and 48 h, respectively were obtained for OTA while no cytotoxic effect was detected at the concentrations tested for FB1. Cytoprotection with increased viability was obtained when the simultaneous BRE + OTA strategy was performed. Finally, better protection was observed in the pretreatment strategy in which cells were exposed 24 h previously to BRE, compared to that shown in the simultaneous assay.
    Keywords:  Beetroot; Cytoprotection; FB1; OTA; SH-SY5Y cells
    DOI:  https://doi.org/10.1016/j.fct.2022.113164
  105. Phytomedicine. 2022 May 13. pii: S0944-7113(22)00197-0. [Epub ahead of print]102 154119
    A comprehensive system review of pharmacological effects and relative mechanisms of Ginsenoside Re: Recent advances and future perspectives.
    Jiasong Cai, Kunlong Huang, Shengnan Han, Ruichan Chen, Zhijun Li, Yan Chen, Bing Chen, Shaoguang Li, Lin Xinhua, Hong Yao.
       BACKGROUND: Ginsenoside Re (Re) belongs to protopanaxatriol saponins and exists in Panax ginseng, Panax quinquefolium, Panax notoginseng, and other plants in the Araliaceae family. Re has recently become a research focus owing to its pharmacological activities and benefits to human bodies.
    PURPOSE: To summarize recent findings regarding the pharmacological effects and mechanisms of Re and highlight and predict the potential therapeutic effects and systematic mechanism of Re.
    METHODS: Recent studies (2011-2021) on the pharmacological effects and mechanisms of Re were retrieved from Web of Science, PubMed, Google Scholar, Scopus, and Embase up to December 2021 using relevant keywords. Network pharmacology and bioinformatics analysis were used to predict the therapeutic effects and mechanisms of Re against potential diseases.
    RESULTS: Re presented a wide range of therapeutic and biological activities, including neuroprotective, cardiovascular, antidepressant, antitumorigenic, and others effects. The related pharmacological mechanisms of Re include the regulation of cholinergic and antioxidant systems in the brain; the induction of tumor cell apoptosis; the inhibition of tau protein hyperphosphorylation and oxidative stress; the activation of p38MAPK, ERK1/2, and JNK signals; the improvement of lipid metabolism; and the reduction of endothelial cell dysfunction.
    CONCLUSION: This paper summarizes comprehensively the current research progress of Re and provides new research insights into the therapeutic effects and mechanisms of Re against potential diseases.
    Keywords:  ginsenoside Re; mechanisms; network pharmacology; pharmacological effects; targets
    DOI:  https://doi.org/10.1016/j.phymed.2022.154119
  106. Photodiagnosis Photodyn Ther. 2022 May 20. pii: S1572-1000(22)00209-5. [Epub ahead of print] 102923
    Critical PDT Theory II: Current Concepts and Indications.
    David Kessel, Girgis Obaid, Imran Rizvi.
      While photodynamic therapy (PDT) is effective for the eradication of neoplasia and certain other pathologic conditions, it has yet to achieve wide acceptance in clinical medicine. A variety of factors contribute to this situation: Relations with the pharmaceutical industry have often been problematic. Some current studies relating to photodynamic effects are 'phenomenological', i.e., they describe phenomena that only reiterate what is already known. The net result has been a tendency of granting agencies to become disillusioned with support for PDT research. This report is intended to provide some thoughts on current research efforts that improve clinical relevance and those that do not.
    Keywords:  Apoptosis; Photodynamic therapy; Photosensitization; Reactive Oxygen Species viability
    DOI:  https://doi.org/10.1016/j.pdpdt.2022.102923
  107. Pharmaceuticals (Basel). 2022 Apr 26. pii: 535. [Epub ahead of print]15(5):
    Enhanced Anticancer Activity of Hymenocardia acida Stem Bark Extract Loaded into PLGA Nanoparticles.
    Oluwasegun Adedokun, Epole N Ntungwe, Cláudia Viegas, Bunyamin Adesina Ayinde, Luciano Barboni, Filippo Maggi, Lucilia Saraiva, Patrícia Rijo, Pedro Fonte.
      Hymenocardia acida (H. acida) is an African well-known shrub recognized for numerous medicinal properties, including its cancer management potential. The advent of nanotechnology in delivering bioactive medicinal plant extract with poor solubility has improved the drug delivery system, for a better therapeutic value of several drugs from natural origins. This study aimed to evaluate the anticancer properties of H. acida using human lung (H460), breast (MCF-7), and colon (HCT 116) cancer cell lines as well as the production, characterization, and cytotoxicity study of H. acida loaded into PLGA nanoparticles. Benchtop models of Saccharomyces cerevisiae and Raniceps ranninus were used for preliminary toxicity evaluation. Notable cytotoxic activity in benchtop models and human cancer cell lines was observed for H. acida crude extract. The PLGA nanoparticles loading H. acida had a size of about 200 nm and an association efficiency of above 60%, making them suitable to be delivered by different routes. The outcomes from this research showed that H. acida has anticancer activity as claimed from an ethnomedical point of view; however, a loss in activity was noted upon encapsulation, due to the sustained release of the drug.
    Keywords:  Hymenocardia acida; PLGA; anticancer activity; cytotoxicity; nanoencapsulation; nanoparticle; plant extract
    DOI:  https://doi.org/10.3390/ph15050535
  108. Curr Drug Deliv. 2022 May 19.
    Enhanced Brain Delivery via Intranasal Administration of Carbamazepine Loaded Solid Lipid Nanoparticles: Optimization, Pharmacokinetic analysis, In-vitro and In-vivo Drug Release Study.
    Rajeshwar Kamal Kant Arya, Juyal Vijay, Dheeraj Bisht, Mohammad Rashid, Abdulmalik Saleh Alfawaz Altamimi, Obaid Afzal, Neeraj Kumar Sethiya.
      Background Carbamazepine (Cbz) is a first line drug for epileptic seizures, but exhibit fluctuation at plasma level and side effects after oral administration. To overcome these problems Cbz should be targeted directly into the brain. Therefore, the current experimental design was aimed to formulate and optimize the Cbz containing solid lipid nanoparticles (SLNs) for brain delivery via intranasal administration to get rid from oral complications associated with Cbz. Method To achieve this, a factorial design was performed to evaluate the effect of variables (X1 lipid concentration, X2 surfactant concentration, and X3 sonication time) on the response variables (size of nanoparticles, entrapment efficiency, and drug release). Herewith, a 2 level 3 factor design was employed and eight formulations were developed. Further, the formation of Cbz containing SLNs was characterized for compatibility, particle size, entrapment efficiency, and drug release with the support of Fourier Transform Infra-Red (FTIR), Zeta sizer, Transmission Electron Microscopy (TEM), Ultra-violet (UV) and High Performance Liquid Chromatography (HPLC). Results All the eight formulations were characterized through particle size, entrapment efficiency and in-vitro drug release performance. Out of eight characterized formulations, SN1 was shown most promising result including particle size of 210 ± 2.14 nm, entrapment efficiency of 42.1 ± 1.09%, and drug release of 61.3 ± 2.02% and considered as optimized batch. Additionally, the optimized batch SN1was further evaluated for an in-vivo study on male Wistar Rats. Conclusion The study revealed that a high amount of drug was reached into the brain through intranasal administration when compared with the intravenous route. Therefore, it can be used to minimize the unwanted side effects of the Cbz associated with oral administration. The formulation SN1 possesses an excellent drug targeting efficiency of 3.014. Finally, from the current experimental work, it was concluded that there is a direct pathway from the intranasal route to the brain, and this delivery system can be beneficial for directly delivering CNS active drugs into the brain.
    Keywords:  Carbamazepine; Entrapment efficiency; FTIR; Factorial design; Pharmacokinetics analysis.; SLNs; TEM
    DOI:  https://doi.org/10.2174/1567201819666220519120837
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