bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–11–20
76 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. The single-atom iron nanozyme mimicking peroxidase remodels energy metabolism and tumor immune landscape for synergistic chemodynamic therapy and photothermal therapy of triple-negative breast cancer.
  2. Light-Activated Phytochemicals in Photodynamic Therapy for Cancer: A Mini Review.
  3. The role of nanomaterials in enhancing natural product translational potential and modulating endoplasmic reticulum stress in the treatment of ovarian cancer.
  4. Docetaxel prodrug and hematoporphyrin co-assembled nanoparticles for anti-tumor combination of chemotherapy and photodynamic therapy.
  5. Biomedical engineered nanomaterials to alleviate tumor hypoxia for enhanced photodynamic therapy.
  6. Disorders of cancer metabolism: The therapeutic potential of cannabinoids.
  7. Bone-Targeted Dual Functional Lipid-coated Drug Delivery System for Osteosarcoma Therapy.
  8. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics.
  9. Induction of ferroptosis using functionalized iron-based nanoparticles for anti-cancer therapy.
  10. [Adequate and clinically effective levels of curcumin consumption].
  11. The role of KRAS splice variants in cancer biology.
  12. Natural products targeting glycolysis in cancer.
  13. Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy.
  14. Targeting the Cancer Stem Cells with Phytochemicals in Endocrine Cancers.
  15. A novel strategy against hepatitis B virus: Glycyrrhetnic acid conjugated multi-component synergistic nano-drug delivery system for targeted therapy.
  16. Targeting lipid metabolism for ferroptotic cancer therapy.
  17. Ferroptosis-based nano delivery systems targeted therapy for colorectal cancer: Insights and future perspectives.
  18. Challenges and emerging strategies for next generation liposomal based drug delivery: An account of the breast cancer conundrum.
  19. Smart drug delivery systems for precise cancer therapy.
  20. Curcumin in human osteosarcoma: From analogs to carriers.
  21. Nanofibrillar peptide hydrogels for self-delivery of lonidamine and synergistic photodynamic therapy.
  22. Nanoparticles for Chemoimmunotherapy Against Triple-Negative Breast Cancer.
  23. Photodynamic Therapy Initiated Ferrotherapy of Self-Delivery Nanomedicine to Amplify Lipid Peroxidation via GPX4 Inactivation.
  24. Strategies to overcome/penetrate the BBB for systemic nanoparticle delivery to the brain/brain tumor.
  25. Pharmaceutical liposomal delivery-specific considerations of innovation and challenges.
  26. Dual-Responsive Curcumin-Loaded Nanoparticles for the Treatment of Cisplatin-Induced Acute Kidney Injury.
  27. Efforts Towards Repurposing of Antioxidant Drugs and Active Compounds for Multiple Sclerosis Control.
  28. Applications of mannose-binding lectins and mannan glycoconjugates in nanomedicine.
  29. Therapeutic potential of Curcuma oil and its terpenoids in gynecological cancers.
  30. Vitamin D metabolism and extraskeletal outcomes: an update.
  31. Recent advances in dual- and multi-responsive nanomedicines for precision cancer therapy.
  32. The anticancer effects of curcumin and clinical research progress on its effects on esophageal cancer.
  33. Silibinin-Loaded Nanostructured Lipid Carriers for Growth Inhibition of Cisplatin-Resistant Ovarian Cancer Cells.
  34. Artemisinin inhibits the development of esophageal cancer by targeting HIF-1α to reduce glycolysis levels.
  35. Ginsenosides: Allies of gastrointestinal tumor immunotherapy.
  36. Boswellic acids as promising agents for the management of brain diseases.
  37. Curcuma as an anti-inflammatory component in treating osteoarthritis.
  38. Hepatic-Targeted Nano-enzyme with Resveratrol Loading for Precise Relief of Nonalcoholic Steatohepatitis.
  39. Prodrug nanoparticles potentiate tumor chemo-immunometabolic therapy by disturbing oxidative stress.
  40. A Preliminary Pharmacodynamic Study for the Management of Alzheimer's Disease Using Memantine-Loaded PLGA Nanoparticles.
  41. Metabolic reprogramming of immune cells in pancreatic cancer progression.
  42. Dual "unlocking" strategy to overcome inefficient nanomedicine delivery and tumor hypoxia for enhanced photodynamic-immunotherapy.
  43. Metformin: Activation of 5' AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action.
  44. Biological function and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: promises and challenges.
  45. Dietary polyphenols link extracellular histones and nonhistone proteins.
  46. Hybrid nanoparticulate system of Fluvastatin loaded phospholipid, alpha lipoic acid and melittin for the management of colon cancer.
  47. Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress.
  48. Apoptosis induction of essential oils from Artemisia arborescens L. in human prostate cancer cells.
  49. A comprehensive review on lactoferrin: a natural multifunctional glycoprotein.
  50. Ultrasound nanotheranostics: Toward precision medicine.
  51. Promises of Molecular Pharmaceutics in the Development of Novel Drug Delivery Formulations.
  52. Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis.
  53. Cannabinoids as Prospective Anti-Cancer Drugs: Mechanism of Action in Healthy and Cancer Cells.
  54. Epigenetic regulation by metabolites from the gut microbiome.
  55. An esterase-activatable curcumin prodrug for tumor-targeting therapy.
  56. A liposomal formulation of simvastatin and doxorubicin for improved cardioprotective and anti-cancer effect.
  57. Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy.
  58. Zinc Oxide Nanoparticles as Diagnostic Tool for Cancer Cells.
  59. Curcumin Suppresses the Progression of Colorectal Cancer by Improving Immunogenic Cell Death Caused by Irinotecan.
  60. Melatonin: A Potential Antineoplastic Agent in Breast Cancer.
  61. Nanostructured lipid carrier-loaded metformin hydrochloride: Design, optimization, characterization, assessment of cytotoxicity and ROS evaluation.
  62. Epigenetic alterations fuel brain metastasis via regulating inflammatory cascade.
  63. Toward Precise Antitumoral Photodynamic Therapy Using a Dual Receptor-Mediated Bioorthogonal Activation Approach.
  64. Formulation and Evaluation of Azithromycin-Loaded Niosomal Gel: Optimization, In Vitro Studies, Rheological Characterization, and Cytotoxicity Study.
  65. A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.
  66. Intermittent fasting and time-restricted eating role in dietary interventions and precision nutrition.
  67. Fucoidan-ferulic acid nanoparticles alleviate cisplatin-induced acute kidney injury by inhibiting the cGAS-STING pathway.
  68. Preparation of pectin-chitosan hydrogels based on bioadhesive-design micelle to prompt bacterial infection wound healing.
  69. A review of the mechanism of succinylation in cancer.
  70. SuperNatural 3.0-a database of natural products and natural product-based derivatives.
  71. Flash drug release from nanoparticles accumulated in the targeted blood vessels facilitates the tumour treatment.
  72. Ivermectin inhibits tumor metastasis by regulating the Wnt/β-catenin/integrin β1/FAK signaling pathway.
  73. Cannabidiol for neurodegenerative disorders: A comprehensive review.
  74. Metabolic reprogramming in the immunosuppression of tumor-associated macrophages.
  75. Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer.
  76. Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer.
  1. Front Bioeng Biotechnol. 2022 ;10 1026761
    The single-atom iron nanozyme mimicking peroxidase remodels energy metabolism and tumor immune landscape for synergistic chemodynamic therapy and photothermal therapy of triple-negative breast cancer.
    Xiaojun Qian, Ronghua Shi, Jian Chen, Yong Wang, Xinghua Han, Yubei Sun, Cong Ling, Gang Wang, An-Wu Xu, Yueyin Pan.
      Chemotherapy, as one main strategy to relieve tumor progression, has a weak effect on triple-negative breast cancer (TNBC) chest wall metastasis. The development of near-infrared (NIR) light-responsive nanomaterials for chemodynamic therapy (CDT) and photothermal therapy (PTT) is a promising platform but still challenging in biomedicine. This study reports a peroxidase mimicking nanozyme (Fe-N-C SAzyme) against TNBC by CDT and PTT. Fe-N-C SAzyme generated reactive oxygen species (ROS) by decomposing H2O2 into hydroxyl radicals (•OH) and also induced light-to-heat conversion under the exposure of 808 nm laser irradiation. With these biological characteristics, the obtained Fe-N-C SAzymes displayed enhanced cell cytotoxicity and inhibition of cancer cell proliferation both in vitro and in vivo at a low dose of nanoagent and a moderate NIR laser power density. Besides, Fe-N-C nanoagent with its excellent ROS generation brought metabolic reprogramming of elevated glycolysis in tumor cells. In vivo experiments, when combined with PTT, the enhanced antitumor effect was found by the elimination of M-MDSC in tumor microenvironment. Fe-N-C SAzymes can serve as a new synergistic CDT and PTT nanoagent to simultaneously reprogram tumor metabolism and tumor microenvironment. It will provide prospects for chemodynamic/photothermal combined cancer therapy for TNBC chest wall metastasis based on the use of a single nanosystem.
    Keywords:  CDT; Fe-N-C single atom nanozymes; M-MDSC; PTT; TNBC; energy metabolism
    DOI:  https://doi.org/10.3389/fbioe.2022.1026761
  2. Photobiomodul Photomed Laser Surg. 2022 Nov;40(11): 734-741
    Light-Activated Phytochemicals in Photodynamic Therapy for Cancer: A Mini Review.
    Blassan P George, Heidi Abrahamse.
      Background: Cancer is a serious life-threatening disease often thought of as a deadly and painful disease with no permanent cure. With the advancement of medical science, there have been several clinically approved treatment options developed over the past decade. Photodynamic therapy (PDT) is one such approved minimally invasive light-based therapeutic option for many cancers. Selection of a suitable photosensitizer (PS) is an important step in PDT for improved therapeutic outcomes. Efforts to discover more efficient PSs continue for optimal PDT. Objective: This review discusses the available natural PS of plant origin, the role of phytochemicals in the application of PDT of cancer, specific localization of PS in various cell organelles, and photochemical reactions. Materials and methods: Owing to the substantial side effects, many biomedical research fields are currently focusing on natural compounds with chemotherapeutic potential with environmentally sustainable green approaches. Medicinal plant extracts have been used since ancient times for the treatment of various ailments. Plants are a natural source of many bioactive compounds with pharmaceutical potential and there have been some efforts made to discover potential new compounds from plants with photosensitizing properties for effective PDT outcomes. Results and conclusions: The PDT application in the current scenario raises some questions, such as most effective PS, its administration, the time of irradiation, light source, sensitivity of cells toward PS, and so forth. PDT effects can be direct or indirect. Owing to the direct effect of the PDT, most of the tumoral mass is destroyed. In the cancer cells that were not directly affected, secondary effects such as vascular effects, apoptosis induction, inflammation, and generation of an immune response may occur; however, the complex nature of PDT tissue response is not fully established.
    Keywords:  cancer; photochemical reactions; photodynamic therapy; photosensitizers; phytochemicals; subcellular localization
    DOI:  https://doi.org/10.1089/photob.2022.0094
  3. Front Pharmacol. 2022 ;13 987088
    The role of nanomaterials in enhancing natural product translational potential and modulating endoplasmic reticulum stress in the treatment of ovarian cancer.
    Rajeev K Singla, Pooja Sharma, Dinesh Kumar, Rupesh K Gautam, Rajat Goyal, Christos Tsagkaris, Ankit Kumar Dubey, Himangini Bansal, Rohit Sharma, Bairong Shen.
      Ovarian cancer, and particularly its most frequent type, epithelial ovarian carcinoma, constitutes one of the most dangerous malignant tumors among females. Substantial evidence has described the potential of phytochemicals against ovarian cancer. The effect of natural compounds on endoplasmic reticulum (ER) stress is of great relevance in this regard. In ovarian cancer, the accumulation of misfolded proteins in the ER lumen results in decompensated ER stress. This leads to deregulation in the physiological processes for the posttranslational modification of proteins, jeopardizes cellular homeostasis, and increases apoptotic signaling. Several metabolites and metabolite extracts of phytochemical origin have been studied in the context of ER stress in ovarian cancer. Resveratrol, quercetin, curcumin, fucosterol, cleistopholine, fucoidan, and epicatechin gallate, among others, have shown inhibitory potential against ER stress. The chemical structure of each compound plays an important role concerning its pharmacodynamics, pharmacokinetics, and overall effectiveness. Studying and cross-comparing the chemical features that render different phytochemicals effective in eliciting particular anti-ER stress actions can help improve drug design or develop multipotent combination regimens. Many studies have also investigated the properties of formulations such as nanoparticles, niosomes, liposomes, and intravenous hydrogel based on curcumin and quercetin along with some other phytomolecules in ovarian cancer. Overall, the potential of phytochemicals in targeting genetic mechanisms of ovarian cancer warrants further translational and clinical investigation.
    Keywords:  ER stress; nanomaterial; nanotechnology; natural compounds; ovarian neoplasms; ovaries; phytomedicine; secondary metabolites
    DOI:  https://doi.org/10.3389/fphar.2022.987088
  4. Drug Deliv. 2022 Dec;29(1): 3358-3369
    Docetaxel prodrug and hematoporphyrin co-assembled nanoparticles for anti-tumor combination of chemotherapy and photodynamic therapy.
    Guolian Ren, Yujie Li, Canqi Ping, Danyu Duan, Ning Li, Jiaqi Tang, Rongrong Wang, Wenju Guo, Xiaomin Niu, Qiuyue Ji, Guoshun Zhang, Ruili Wang, Shuqiu Zhang.
      To realize the synergistic anti-tumor effect of chemotherapy and photodynamic therapy, the mono sulfide-modified docetaxel (DTX) prodrugs (DSD) provided by our laboratory and hematoporphyrin (HP) were used to physically prepare co-assembled nanoparticles (DSD/HP NPs) by nano-precipitation. For the first time, this study showed its characteristics, in vitro anti-tumor activity, pharmacokinetic behavior in rats, in vivo distribution, and pharmacodynamic effects on 4T1 tumor-bearing Bal b/c mice. DSD/HP NPs optimized by single-factor and response surface optimization had several distinct characteristics. First, it had dark purple appearance with particle size of 105.16 ± 1.24 nm, PDI of 0.168 ± 0.15, entrapment efficiency and drug loading of DSD and HP in DSD/HP NPs of 96.27 ± 1.03% and 97.70 ± 0.20%, 69.22 ± 1.03% and 20.03 ± 3.12%, respectively. Second, it had good stability and could release DTX and HP slowly in the media of pH 7.4 PBS with 10 mM DTT (H2O2). Moreover, DSD/HP NPs along with NiR treatment significantly inhibited 4T1 cells proliferation, and induced more reactive oxygen species and cells apoptosis. In vivo pharmacokinetic and pharmacodynamic studies showed that DSD/HP NPs could prolong the drug circulation time in rats, increase drug distribution in tumor site, obviously inhibit tumor growth, and decrease the exposure of drug to normal tissues. Therefore, DSD/HP NPs as a promising co-assembled nano-drug delivery system could potentially improve the therapeutic efficiency of chemotherapeutic drug and achieve better anti-tumor effects due to the combination of chemotherapy and photodynamic therapy.
    Keywords:  Docetaxel prodrug; chemotherapy; co-assembled nanoparticles; hematoporphyrin; photodynamic therapy
    DOI:  https://doi.org/10.1080/10717544.2022.2147280
  5. Pharmacol Res. 2022 Nov 09. pii: S1043-6618(22)00497-2. [Epub ahead of print] 106551
    Biomedical engineered nanomaterials to alleviate tumor hypoxia for enhanced photodynamic therapy.
    Chunmei Lai, Bangyue Luo, Jiangwen Shen, Jingwei Shao.
      Photodynamic therapy (PDT), as a highly selective, widely applicable, and non-invasive therapeutic modality that is an alternative to radiotherapy and chemotherapy, is extensively applied to cancer therapy. Practically, the efficiency of PDT is severely hindered by the existence of hypoxia in tumor tissue. Hypoxia is a typical hallmark of malignant solid tumors, which remains an essential impediment to many current treatments, thereby leading to poor clinical prognosis after therapy. To address this issue, studies have been focused on modulating tumor hypoxia to augment the therapeutic efficacy. Although nanomaterials to relieve tumor hypoxia for enhanced PDT have been demonstrated in many research articles, a systematical summary of the role of nanomaterials in alleviating tumor hypoxia is scarce. In this review, we introduced the mechanism of PDT, and the involved therapeutic modality of PDT for ablation of tumor cells was specifically summarized. Moreover, current advances in nanomaterials-mediated tumor oxygenation via oxygen-carrying or oxygen-generation tactics to alleviate tumor hypoxia are emphasized. Based on these considerable summaries and analyses, we proposed some feasible perspectives on nanoparticle-based tumor oxygenation to ameliorate the therapeutic outcomes, which may provide some detailed information in designing new oxygenation nanomaterials in this burgeneous field.
    Keywords:  Nanomaterials; Oxygenation; Photodynamic therapy; Tumor hypoxia
    DOI:  https://doi.org/10.1016/j.phrs.2022.106551
  6. Biomed Pharmacother. 2022 Nov 12. pii: S0753-3322(22)01382-8. [Epub ahead of print]157 113993
    Disorders of cancer metabolism: The therapeutic potential of cannabinoids.
    Dingya Sun, Xin Li, Shengdan Nie, Jiajia Liu, Shan Wang.
      Abnormal energy metabolism, as one of the important hallmarks of cancer, was induced by multiple carcinogenic factors and tumor-specific microenvironments. It comprises aerobic glycolysis, de novo lipid biosynthesis, and glutamine-dependent anaplerosis. Considering that metabolic reprogramming provides various nutrients for tumor survival and development, it has been considered a potential target for cancer therapy. Cannabinoids have been shown to exhibit a variety of anticancer activities by unclear mechanisms. This paper first reviews the recent progress of related signaling pathways (reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1α), and p53) mediating the reprogramming of cancer metabolism (including glucose metabolism, lipid metabolism, and amino acid metabolism). Then we comprehensively explore the latest discoveries and possible mechanisms of the anticancer effects of cannabinoids through the regulation of the above-mentioned related signaling pathways, to provide new targets and insights for cancer prevention and treatment.
    Keywords:  Cancer; Cancer metabolism; Cannabinoids; Drug targets; Glycolysis; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.biopha.2022.113993
  7. Pharm Res. 2022 Nov 15.
    Bone-Targeted Dual Functional Lipid-coated Drug Delivery System for Osteosarcoma Therapy.
    Jie Zhong, Weiye Wen, Jinjin Wang, Mengyu Zhang, Yijiang Jia, Xiaowei Ma, Yu-Xiong Su, Yuji Wang, Xinmiao Lan.
       PURPOSE OR OBJECTIVE: Osteosarcoma is well-known for its high incidence in children and adolescents and long-term bone pain, which seriously reduces the life quality of patients. Cisplatin (CDDP), as the first-line anti-osteosarcoma drug, has been used in many anticancer treatments. At the same time, the serious side effects of platinum (Pt) drugs have also attracted widespread attention. To accurately deliver Pt drugs to the lesion site and realize controlled release of Pt drugs, certain modified delivery systems have been extensively studied.
    METHODS: Among them, liposomes have been approved for clinical cancer treatment due to their highly biocompatibility and superior modifiability. Here, we developed a bone-targeted dual functional lipid-coated drug delivery system, lipid-coated CDDP alendronate nanoparticles (LCA NPs) to target the bone and precisely deliver the drugs to the tumor site. Cell toxicity, apoptosis and cellular uptake were detected to evaluate the anticancer effect for LCA NPs. Furthermore, transwell assay and wound healing assay were conducted to estimate the osteosarcoma cell migration and invasion. Hemolysis assay was utilized to assess the biocapitibility of the kind of NPs.
    RESULTS: With the aim of bone-targeted unit alendronate (ALD), LCA NPs serve as a rich bone homing Pt delivery system to exert efficient anticancer effects and synergistically reduce bone resorption and bone loss potentially.
    CONCLUSIONS: By providing a highly biocompatible platform for osteosarcoma therapy, LCA NPs may help to significantly enhance the anticancer effect of Pt and greatly reduce the systemic toxicity and side effects of Pt towards osteosarcoma.
    Keywords:  bone target; cisplatin; drug delivery; nanoparticle; osteosarcoma
    DOI:  https://doi.org/10.1007/s11095-022-03430-8
  8. Semin Cancer Biol. 2022 Nov 09. pii: S1044-579X(22)00229-2. [Epub ahead of print]
    Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics.
    Dolly Sharma, Mamta Singh, Reshma Rani.
      Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most cancer cells are characterized by an enhanced rate of tumor glycolysis to ensure the energy demand of fast-growing cancer cells leading to increased lactate production. Excess lactate creates extracellular acidosis which facilitates invasion, angiogenesis, and metastasis and affects the immune response. Lactate shuttle and lactate symbiosis is established in cancer cells, which may further increase the poor prognosis. Several genetic and phenotypic studies established the potential role of lactate dehydrogenase A (LDHA) or LDH5, the one homo-tetramer of subunit A, in cancer development and metastasis. The LDHA is considered a viable target for drug design and discovery. Several small molecules have been discovered to date exhibiting significant LDHA inhibitory activities and anticancer activities, therefore the starvation of cancer cells by targeting tumor glycolysis through LDHA inhibition with improved selectivity can generate alternative anticancer therapeutics. This review provides an overview of the role of LDHA in metabolic reprogramming and its association with proto-oncogenes and oncogenes. This review also aims to deliver an update on significant LDHA inhibitors with anticancer properties and future direction in this area.
    Keywords:  LDH inhibitors; Lactate dehydrogenase A; Tumor glycolysis; cancer cell metabolism; lactate shuttle
    DOI:  https://doi.org/10.1016/j.semcancer.2022.11.007
  9. Mater Today Bio. 2022 Dec 15. 17 100457
    Induction of ferroptosis using functionalized iron-based nanoparticles for anti-cancer therapy.
    Chaewon Bae, Hyerim Kim, Yun-Min Kook, Chaedong Lee, Changheon Kim, Chungmo Yang, Min Hee Park, Yuanzhe Piao, Won-Gun Koh, Kangwon Lee.
      Ferroptosis, a cell death pathway that is induced in response to iron, has recently attracted remarkable attention given its emerging therapeutic potential in cancer cells. The need for a promising modality to improve chemotherapy's efficacy through this pathway has been urgent in recent years, and this non-apoptotic cell death pathway accumulates reactive oxygen species (ROS) and is subsequently involved in lipid peroxidation. Here, we report cancer-targeting nanoparticles that possess highly efficient cancer-targeting ability and minimal systemic toxicity, thereby leading to ferroptosis. To overcome the limit of actual clinical application, which is the ultimate goal due to safety issues, we designed safe nanoparticles that can be applied clinically. Nanoparticles containing ferroptosis-dependent iron and FDA-approved hyaluronic acid (FHA NPs) are fabricated by controlling physicochemical properties, and the FHA NPs specifically induce ROS production and lipid peroxidation in cancer cells without affecting normal cells. The excellent in vivo anti-tumor therapeutic effect of FHA NPs was confirmed in the A549 tumor-bearing mice model, indicating that the induction of FHA NP-mediated cell death via the ferroptosis pathway could serve as a powerful platform in anticancer therapy. We believe that this newly proposed FHA NP-induced ferroptosis strategy is a promising system that offers the potential for efficient cancer treatment and provides insight into the safe design of nanomedicines for clinical applications.
    Keywords:  Biomaterials; Cancer nanomedicine; Fenton reaction; Ferroptosis; Iron-based nanoparticles; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.mtbio.2022.100457
  10. Vopr Pitan. 2022 ;91(5): 6-15
    [Adequate and clinically effective levels of curcumin consumption].
    V M Kodentsova, D V Risnik, V A Sarkisyan, Yu V Frolova.
      Despite the existence of sufficiently effective drug therapy, interest in additional dietary interventions that improve the clinical condition of patients with the most common alimentary diseases is constantly growing; as well as the inclusion of biologically active compounds (BAC) of plant origin as functional ingredients in foods for special dietary uses (FSDU) and dietary supplements is intensively developing. The purpose of the review is comparison of curcumin doses allowed for use in dietary supplements and FSDU with doses that provide a clinical effect, as well as an analysis of ways to increase curcumin bioavailability. Material and methods. A review of the existing literature on the problem in recent years was carried out using the databases of the Russian Science Citation Index, PubMed, ResearchGate. Results. The amount of BAC added to the FSDU in the daily portion has been established by domestic regulatory documents. The allowed maximum level in FSDU for curcumin is 150 mg per day. Literature analysis has shown that effective doses of turmeric are 320- 1670 mg per day when consumed for 10-12 weeks. The main barriers for using curcumin at lower doses are its low water solubility, rapid metabolism and elimination from the body, and therefore poor bioavailability. Curcumin bioavailability can be increased by including it in liposomes, phospholipid complexes, emulsions, oleogels, hydrogels, etc. Conclusion. Curcumin content in FSDU in an amount that does not reach doses with efficacy proven in a certain pathology, and the inclusion of such FSDU in the diet for a short period does not allow to achieve the expected result. A promising approach to achieve a clinical effect at lower doses of curcumin is the use of new technological methods to increase bioavailability.
    Keywords:  bioavailability; clinical efficacy; curcumin; dietary supplements; foods for special dietary uses; oleogels
    DOI:  https://doi.org/10.33029/0042-8833-2022-91-5-6-15
  11. Front Cell Dev Biol. 2022 ;10 1033348
    The role of KRAS splice variants in cancer biology.
    Cristina Nuevo-Tapioles, Mark R Philips.
      The three mammalian RAS genes (HRAS, NRAS and KRAS) encode four proteins that play central roles in cancer biology. Among them, KRAS is mutated more frequently in human cancer than any other oncogene. The pre-mRNA of KRAS is alternatively spliced to give rise to two products, KRAS4A and KRAS4B, which differ in the membrane targeting sequences at their respective C-termini. Notably, both KRAS4A and KRAS4B are oncogenic when KRAS is constitutively activated by mutation in exon 2 or 3. Whereas KRAS4B is the most studied oncoprotein, KRAS4A is understudied and until recently considered relatively unimportant. Emerging work has confirmed expression of KRAS4A in cancer and found non-overlapping functions of the splice variants. The most clearly demonstrated of these is direct regulation of hexokinase 1 by KRAS4A, suggesting that the metabolic vulnerabilities of KRAS-mutant tumors may be determined in part by the relative expression of the splice variants. The aim of this review is to address the most relevant characteristics and differential functions of the KRAS splice variants as they relate to cancer onset and progression.
    Keywords:  KRAS; KRAS4A; KRAS4B; alternative splicing; glycolysis; oncogene; oncoprotein
    DOI:  https://doi.org/10.3389/fcell.2022.1033348
  12. Front Pharmacol. 2022 ;13 1036502
    Natural products targeting glycolysis in cancer.
    Yuanyuan Zhao, Louisa S Chard Dunmall, Zhenguo Cheng, Yaohe Wang, Lingling Si.
      Many energy metabolism pathways exist in cancer, including glycolysis, amino acid metabolism, fatty acid oxidation, and mitochondrial respiration. Tumor cells mainly generate energy through glycolysis to maintain growth and biosynthesis of tumor cells under aerobic conditions. Natural products regulate many steps in glycolysis and targeting glycolysis using natural products is a promising approach to cancer treatment. In this review, we exemplify the relationship between glycolysis and tumors, demonstrate the natural products that have been discovered to target glycolysis for cancer treatment and clarify the mechanisms involved in their actions. Natural products, such as resveratrol mostly found in red grape skin, licochalcone A derived from root of Glycyrrhiza inflate, and brusatol found in Brucea javanica and Brucea mollis, largely derived from plant or animal material, can affect glycolysis pathways in cancer by targeting glycolytic enzymes and related proteins, oncogenes, and numerous glycolytic signal proteins. Knowledge of how natural products regulate aerobic glycolysis will help illuminate the mechanisms by which these products can be used as therapeutics to inhibit cancer cell growth and regulate cellular metabolism. Systematic Review Registration: https://pubmed.ncbi.nlm.nih.gov/, https://clinicaltrials.gov/, http://lib.zzu.edu.cn/.
    Keywords:  cancer; glycolysis; glycolysis signaling pathway; glycolytic enzymes; natural product; oncogene
    DOI:  https://doi.org/10.3389/fphar.2022.1036502
  13. Acta Pharm Sin B. 2022 Nov;12(11): 4204-4223
    Cascade two-stage tumor re-oxygenation and immune re-sensitization mediated by self-assembled albumin-sorafenib nanoparticles for enhanced photodynamic immunotherapy.
    Zaigang Zhou, Jiashe Chen, Yu Liu, Chunjuan Zheng, Wenjuan Luo, Lele Chen, Shen Zhou, Zhiming Li, Jianliang Shen.
      As a promising modality for cancer therapy, photodynamic therapy (PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin (BSA-MHI148) and multi-kinase inhibitor Sorafenib (SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms: (i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory. (ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows: (i) Enhanced immunogenic cell death (ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species (ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability. (ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSA-MHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.
    Keywords:  Hypoxia; Mitochondrial oxidative phosphorylation; Photodynamic immunotherapy; Programmed death ligand-1; Sorafenib; Tumor vessel normalization
    DOI:  https://doi.org/10.1016/j.apsb.2022.07.023
  14. Curr Top Med Chem. 2022 Nov 14.
    Targeting the Cancer Stem Cells with Phytochemicals in Endocrine Cancers.
    Ravi Gor, Ilangovan Ramachandran, Satish Ramalingam.
      Endocrine cancer is an uncontrolled growth of cells in the hormone-producing glands. Endocrine cancers include the adrenal, thyroid, parathyroid, pancreas, pituitary, and ovary malignancy. Recently, there has been an increase in the incidence of the most common endocrine cancer types, namely pancreatic and thyroid cancers. Cancer stem cells (CSCs) of endocrine tumors have received more attention due to their role in cancer progression, therapeutic resistance, and cancer relapse. Therefore, finding the natural phytochemicals that target the CSCs will help improve cancer patients' prognosis and life expectancy. Phytochemicals have also been shown to have anti-CSCs and are very effective in treating various cancer types. Curcumin is a common polyphenol found in turmeric, which has been shown to promote cellular drug accumulation and increase the effectiveness of chemotherapy. Moreover, various other phytochemicals such as resveratrol, genistein, and apigenin are effective against different endocrine cancers by regulating the CSCs. Therefore, phytochemicals have emerged as chemotherapeutics that may have significance in preventing and treating endocrine cancers.
    Keywords:  Cancer Stem Cells; Curcumin; Endocrine Cancer; Phytochemicals; Polyphenols; Resveratrol
    DOI:  https://doi.org/10.2174/1567205020666221114112814
  15. J Biomater Appl. 2022 Nov 12. 8853282221139132
    A novel strategy against hepatitis B virus: Glycyrrhetnic acid conjugated multi-component synergistic nano-drug delivery system for targeted therapy.
    QingXia Guan, XiaoYing Zhou, FangFang Yang, Xue Zhang, YanHong Wang, WeiNan Li, XiuYan Li.
      It is well known that Glycyrrhetnic acid (GA) has significant liver-targeting and anti-inflammatory effects. Syringopicroside (SYR) and Hydroxytyrosol (HT), the active components of the Chinese herb Syringa oblata Lindl, have earned great reputation for their potential in preventing or treating viral hepatitis type B. Therefore, we loaded SYR and HT into GA-conjugated PEG-PLGA, so that they could target the liver in additional to exerting their own pharmacological effects in a synergistic. However, the in vivo targeting and the low bioavailability of SYR and HT pose a huge challenge. Therefore, we synthesized GA-conjugated multi-component nano-drug delivery system (SH-GPP). SH-GPP had a regular spherical shape with a uniform size distribution of 110.5 ± 3.18 nm. We further evaluated the effects of SH-GPP in vitro and in vivo. In the in vivo experiment, we evaluated the following parameters: the serum ALT and AST values; liver tissue homogenate MDA and SOD; HE staining of the pathological liver sections; and the liver coefficient. In the in vitro studies, the following parameters were evaluated: cellular uptake of SH-GPP; wound healing/scratch assay; cellular apoptosis; cell cycle; HBsAg; and HBeAg content. SH-GPP had better anti-hepatitis B effect than Syringopicroside and hydroxytyrosol (SH) and NPP alone. The targeting ability of GA enabled HT and SYR in GPP to reach the liver accurately, and played a synergistic role to maximize their therapeutic effects. This study provides a novel strategy against hepatitis B virus, and also provides a feasible scheme for improving the low bioavailability of the active components of traditional Chinese medicine.
    Keywords:  SH-GPP; hepatitis B virus; multi-component; nano-drug delivery system; synergistic effect
    DOI:  https://doi.org/10.1177/08853282221139132
  16. Apoptosis. 2022 Nov 18.
    Targeting lipid metabolism for ferroptotic cancer therapy.
    Minhua Luo, Jiajing Yan, Xinyu Hu, Haolong Li, Hongsheng Li, Quentin Liu, Yibing Chen, Zhengzhi Zou.
      It has been 10 years since the concept of ferroptosis was put forward and research focusing on ferroptosis has been increasing continuously. Ferroptosis is driven by iron-dependent lipid peroxidation, which can be antagonized by glutathione peroxidase 4 (GPX4), ferroptosis inhibitory protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH) and Fas-associated factor 1 (FAF1). Various cellular metabolic events, including lipid metabolism, can modulate ferroptosis sensitivity. It is worth noting that the reprogramming of lipid metabolism in cancer cells can promote the occurrence and development of tumors. The metabolic flexibility of cancer cells opens the possibility for the coordinated targeting of multiple lipid metabolic pathways to trigger cancer cells ferroptosis. In addition, cancer cells must obtain immortality, escape from programmed cell death including ferroptosis, to promote cancer progression, which provides new perspectives for improving cancer therapy. Targeting the vulnerability of ferroptosis has received attention as one of the significant possible strategies to treat cancer given its role in regulating tumor cell survival. We review the impact of iron and lipid metabolism on ferroptosis and the potential role of the crosstalk of lipid metabolism reprogramming and ferroptosis in antitumor immunity and sum up agents targeting lipid metabolism and ferroptosis for cancer therapy.
    Keywords:  Anti-tumor immunity; Ferroptosis; Ferroptotic cancer therapy; Lipid metabolism
    DOI:  https://doi.org/10.1007/s10495-022-01795-0
  17. Asian J Pharm Sci. 2022 Aug;17(5): 613-629
    Ferroptosis-based nano delivery systems targeted therapy for colorectal cancer: Insights and future perspectives.
    Chu Qiao, Haiying Wang, Qiutong Guan, Minjie Wei, Zhenhua Li.
      There are limited options for patients who develop liver metastasis from colorectal cancer (CRC), the leading cause of cancer-related mortality worldwide. Emerging evidence has provided insights into iron deficiency and excess in CRC. Ferroptosis is an iron-dependent form of programmed cell death characterized by aberrant iron and lipid metabolism, which play crucial roles in tumorigenesis, tumor progression, and treatment options. A better understanding of the underlying molecular mechanism of ferroptosis has shed light on the current findings of ferroptosis-based nanodrug targeting strategies, such as driving ferroptosis in tumor cells and the tumor microenvironment, emerging combination therapy and against multidrug resistance. Furthermore, this review highlights the challenge and perspective of a ferroptosis-driven nanodrug delivery system for CRC-targeted therapy.
    Keywords:  Colorectal cancer; Ferroptosis; Immunotherapy; Iron metabolism; Lipid metabolism; Nano delivery system
    DOI:  https://doi.org/10.1016/j.ajps.2022.09.002
  18. Chem Phys Lipids. 2022 Nov 11. pii: S0009-3084(22)00086-X. [Epub ahead of print] 105258
    Challenges and emerging strategies for next generation liposomal based drug delivery: An account of the breast cancer conundrum.
    Aliesha Moudgil, Rajesh Salve, Virendra Gajbhiye, Bhushan P Chaudhari.
      The global cancer burden is witnessing an upsurge with breast cancer surpassing other cancers worldwide. Furthermore, an escalation in the breast cancer caseload is also expected in the coming years. The conventional therapeutic regimens practiced routinely are associated with many drawbacks to which nanotechnological interventions offer a great advantage. But how eminent could liposomes and their advantages be in superseding these existing therapeutic modalities? A solution is reflected in this review that draws attention to a decade-long journey embarked upon by researchers in this wake. This text is a comprehensive discussion of liposomes, the front runners of the drug delivery systems, and their active and passive targeting approaches for breast cancer management. Active targeting has been studied over the decade by many receptors overexpressed on the breast cancer cells and passive targeting with many drug combinations. The results converge on the fact that the actively targeted formulations exhibit a superior efficacy over their non-targeted counterparts and the all liposomal formulations are efficacious over the free drugs. This undoubtedly underlines the dominion of liposomal formulations over conventional chemotherapy. These investigations have led to the development of different liposomal formulations with active and passive targeting capacities that could be explored in depth. Acknowledging and getting a deeper insight into the liposomal evolution through time also unveiled many imperfections and unchartered territories that can be explored to deliver dexterous liposomal formulations against breast cancer and more in the clinical trial pipeline.
    Keywords:  Breast cancer; Liposomal metamorphosis; Receptor-Ligand dynamics; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.chemphyslip.2022.105258
  19. Acta Pharm Sin B. 2022 Nov;12(11): 4098-4121
    Smart drug delivery systems for precise cancer therapy.
    Xiaoyou Wang, Chong Li, Yiguang Wang, Huabing Chen, Xinxin Zhang, Cong Luo, Wenhu Zhou, Lili Li, Lesheng Teng, Haijun Yu, Jiancheng Wang.
      Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.
    Keywords:  Cancer; Nano-drug delivery systems; Pharmaceutics; Precise therapy; Receptor-ligand-based delivery; Smart drug delivery system; Stimuli-responsive; Toxicity
    DOI:  https://doi.org/10.1016/j.apsb.2022.08.013
  20. Drug Discov Today. 2022 Nov 11. pii: S1359-6446(22)00430-5. [Epub ahead of print] 103437
    Curcumin in human osteosarcoma: From analogs to carriers.
    Ko-Hsiu Lu, Peace Wun-Ang Lu, Chiao-Wen Lin, Shun-Fa Yang.
      Osteosarcoma (osteogenic sarcoma), the most prevalent primary malignant bone tumor in adolescents, confers low survival rates in patients with metastatic disease. Dietary curcumin has a number of anticancer properties but has poor bioavailability. To improve the clinical applications of curcumin, several potential curcumin analogs and nanobased curcumin delivery systems have been developed. In this critical review, we address the biological and pharmacological characteristics of curcumin and its analogs, with an emphasis on strategies to improve the bioactivity and bioavailability of curcumin analogs that may increase their application in the treatment of potent human metastatic osteosarcoma. We highlight promising current multifunctional nanoformulations and three-dimensional printed scaffold systems utilized for the targeting and delivery of curcumin in human osteosarcoma cells. Our purpose is to drive further research on curcumin analogs and carriers to improve their bioavailability and anti-osteosarcoma bioactivity.
    Keywords:  analog; carrier; curcumin; osteosarcoma
    DOI:  https://doi.org/10.1016/j.drudis.2022.103437
  21. Acta Biomater. 2022 Nov 09. pii: S1742-7061(22)00735-8. [Epub ahead of print]
    Nanofibrillar peptide hydrogels for self-delivery of lonidamine and synergistic photodynamic therapy.
    Can Wu, Qishu Jiao, Chunlu Wang, Yaxin Zheng, Xiaohui Pan, Wenying Zhong, Keming Xu.
      The use of lonidamine (LND) in photodynamic therapy (PDT) provides a viable approach to develop low-dose PDT modules with high efficacy, for LND potentiates cytotoxicity of photosensitizers through dysregulation of mitochondrial function. Yet, the efficacy of LND is restricted by its low accumulation in cancer cells, especially in the mitochondrial compartments. To address the problem, we design an LND-derived self-assembling peptide molecule (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. The targeted cellular delivery of LND-K gives higher efficacy in ablation of mitochondrial function in melanoma cells A375, as compared to free LND or the control molecule that lacks mitochondria-targeting moieties. To integrate LND-K in a typical PDT module, we develop a nanofibrillar hydrogel system through co-assembly of LND-K and TPPS4, an anionic photosensitizer that forms tight electrostatic interactions with cationic residues of LND-K. Notably, hydrogel formulation of LND-K/TPPS4 facilitates slow release of TPPS4 over 14 days in vitro, and displays a longer retention time than aqueous solution of TPPS4in vivo. By integrating a mitochondria-targeted molecule (LND-K) in a typical PDT module, we achieve synergistic killing of A375 cells with dual drugs, where LND-K not only serves as a chemotherapeutic drug, but also potentiates the cytotoxicities of TPPS4 toward A375 cells in vitro and in vivo. The peptide-based drug self-delivery system promises the development of efficacious combination treatments against cancer, that integrate cell sensitization with existing anticancer modules (e.g., chemotherapy and PDT) for enhanced therapeutic efficacy. STATEMENT OF SIGNIFICANCE: This study reports the design and synthesis of a lonidamine (LND)-derived self-assembling peptide (LND-K) that dually targets integrin receptors and mitochondria of cancer cells. Under the precision guidance of a mitochondria-targeting sequence, LND-K-containing nanofibers target mitochondria and ablate mitochondrial functions. On one hand, the targeted delivery of LND-K reduces cell viabilities through a chemotherapy route; on the other hand, LND-K sensitizes cancer cells for subsequent PDT treatment with enhanced efficacy, which is mediated by induction of ROS, loss of mitochondrial membrane potential, and decrease of cellular ATP level. We believe that the design of mitochondria-targeted drug delivery systems with a self-assembling molecule provides a new approach to potentiate cytotoxicity of photosensitizers in a low-dose PDT module.
    Keywords:  Peptide, Mitochondria; Photodynamic therapy; Self-assembly; Targeted delivery
    DOI:  https://doi.org/10.1016/j.actbio.2022.11.008
  22. Int J Nanomedicine. 2022 ;17 5209-5227
    Nanoparticles for Chemoimmunotherapy Against Triple-Negative Breast Cancer.
    Siyan Liu, Jing Li, Lin Gu, Kunzhe Wu, Hua Xing.
      Triple-negative breast cancer (TNBC) exhibits high recurrence and mortality rates because of the lack of effective treatment targets. Surgery and traditional chemotherapy are the primary treatment options. Immunotherapy shows high potential for treating various cancers but exhibits limited efficacy against TNBC as a monotherapy. Chemoimmunotherapy has broad prospects for applications for cancer treatment conferred through the synergistic immunomodulatory and anti-tumor effects of chemotherapy and immunotherapeutic strategies. However, improving the efficacy of synergistic therapy and reducing the side effects of multiple drugs remain to be the main challenges in chemoimmunotherapy against TNBC. Nanocarriers can target both cancer and immune cells, promote drug accumulation, and show minimal toxicity, making them ideal delivery systems for chemotherapeutic and immunotherapeutic agents. In this review, we introduce the immunomodulatory effects of chemotherapy and combined mechanisms of chemoimmunotherapy, followed by a summary of nanoparticle-mediated chemoimmunotherapeutic strategies used for treating TNBC. This up-to-date synthesis of relevant findings in the field merits contemplation, while considering avenues of investigation to enable advances in the field.
    Keywords:  chemotherapy; drug-delivery system; immunotherapy; mechanism; targeted delivery
    DOI:  https://doi.org/10.2147/IJN.S388075
  23. ACS Appl Mater Interfaces. 2022 Nov 18.
    Photodynamic Therapy Initiated Ferrotherapy of Self-Delivery Nanomedicine to Amplify Lipid Peroxidation via GPX4 Inactivation.
    Lin-Ping Zhao, Shao-Yi Chen, Rong-Rong Zheng, Xiao-Na Rao, Ren-Jiang Kong, Chu-Yu Huang, Yi-Bin Liu, Youzhi Tang, Hong Cheng, Shi-Ying Li.
      Lipid peroxide (LPO) is the hallmark of ferroptosis, which is a promising antitumor modality for its unique advantages. However, a cellular defense system would weaken the antitumor efficacy of ferrotherapy. Herein, a GPX4 inhibitor of ML162 and a photosensitizer of chlorine e6 (Ce6) are used to prepare the self-delivery nanomedicine (C-ML162) through hydrophobic and electrostatic interactions to enhance ferroptosis by photodynamic therapy (PDT). Specifically, carrier-free C-ML162 improves the solubility, stability, and cellular uptake of antitumor agents. Upon light irradiation, the internalized C-ML162 generates large amounts of reactive oxygen species (ROS) to oxidize cellular unsaturated lipid into LPO. More importantly, C-ML162 can directly inactivate GPX4 to enhance the accumulation of toxic LPO, inducing ferroptotic cell death. Additionally, C-ML162 is capable of accumulating at a tumor site for effective treatment. This self-delivery system to amplify lipid peroxidation via GPX4 inactivation for PDT initiated ferrotherapy might provide an appealing strategy against malignancies.
    Keywords:  GPX4 inactivation; carrier free; ferrotherapy; lipid peroxides; photodynamic therapy
    DOI:  https://doi.org/10.1021/acsami.2c15495
  24. Adv Drug Deliv Rev. 2022 Nov 10. pii: S0169-409X(22)00509-9. [Epub ahead of print] 114619
    Strategies to overcome/penetrate the BBB for systemic nanoparticle delivery to the brain/brain tumor.
    Hai-Jun Liu, Peisheng Xu.
      Despite its prevalence in the management of peripheral tumors, compared to surgery and radiation therapy, chemotherapy is still a suboptimal intervention in fighting against brain cancer and cancer brain metastases. This discrepancy is mainly derived from the complicatedly physiological characteristic of intracranial tumors, including the presence of blood-brain barrier (BBB) and limited enhanced permeability and retention (EPR) effect attributed to blood-brain tumor barrier (BBTB), which largely lead to insufficient therapeutics penetrating to tumor lesions to produce pharmacological effects. Therefore, dependable methodologies that can boost the efficacy of chemotherapy for brain tumors are urgently needed. Recently, nanomedicines have shown great therapeutic potential in brain tumors by employing various transcellular strategies, paracellular strategies, and their hybrids, such as adsorptive-mediated transcytosis, receptor-mediated transcytosis, BBB disruption technology, and so on. It is compulsory to comprehensively summarize these practices to shed light on future directions in developing therapeutic regimens for brain tumors. In this review, the biological and pathological characteristics of brain tumors, including BBB and BBTB, are illustrated. After that, the emerging delivery strategies for brain tumor management are summarized into different classifications and supported with detailed examples. Finally, the potential challenges and prospects for developing and clinical application of brain tumor-oriented nanomedicine are discussed.
    Keywords:  Blood-brain barrier; Brain tumor; Nanoparticle; Transcytosis; Transport
    DOI:  https://doi.org/10.1016/j.addr.2022.114619
  25. Biomater Sci. 2022 Nov 14.
    Pharmaceutical liposomal delivery-specific considerations of innovation and challenges.
    Taoxing Peng, Weihua Xu, Qianqian Li, Yang Ding, Yongzhuo Huang.
      Liposomal technology has been widely used in the pharmaceutical field for the preparation of nano-sized drug delivery systems based on natural or synthetic lipids. Liposomes possess many attractive properties, such as easy processing, high biocompatibility, adaptable drug loading, and improved PK profiles. In recent decades, great efforts have been made in this field, and dozens of liposomal medicines have been marketed worldwide and many more are under preclinical or clinical investigations. Liposomes can enhance the aqueous dissolution and stability of the encapsulated drugs and modulate the in vivo fate of the drugs (e.g., prolonged half-life and increased drug accumulation in the pathological sites). Therefore, liposomal technology can improve the druggability of the candidates, enhance treatment efficacy and reduce side effects. This review discusses the prospects of liposomal delivery, including the specific considerations of innovation and challenges.
    DOI:  https://doi.org/10.1039/d2bm01252a
  26. Biomacromolecules. 2022 Nov 16.
    Dual-Responsive Curcumin-Loaded Nanoparticles for the Treatment of Cisplatin-Induced Acute Kidney Injury.
    Tianyu Lan, Honglei Guo, Xin Lu, Kedui Geng, Lin Wu, Yongjun Luo, Jingfeng Zhu, Xiangchun Shen, Qianqian Guo, Shuizhu Wu.
      Acute kidney injury (AKI) has been a global public health concern leading to high patient morbidity and mortality in the world. Nanotechnology-mediated antioxidative therapy has facilitated the treatment of AKI. Herein, a hierarchical curcumin-loaded nanodrug delivery system (NPS@Cur) was fabricated for antioxidant therapy to ameliorate AKI. The nanoplatform could respond to subacidic and reactive oxygen species (ROS) microenvironments. The subacidic microenvironment led to a smaller size (from 140.9 to 99.36 nm) and positive charge (from -4.9 to 12.6 mV), contributing to the high accumulation of nanoparticles. An excessive ROS microenvironment led to nanoparticle degradation and drug release. In vitro assays showed that NPS@Cur could scavenge excessive ROS and relieve oxidative stress in H2O2-induced HK-2 cells through reduced apoptosis, activated autophagy, and decreased endoplasmic reticulum stress. Results from cisplatin-induced AKI models revealed that NPS@Cur could effectively alleviate mitochondria injury and protect kidneys via antioxidative protection, activated autophagy, decreased endoplasmic reticulum stress, and reduced apoptosis. NPS@Cur showed excellent biocompatibility and low toxicity to primary tissues in mice. These results revealed that NPS@Cur may be a potential therapeutic strategy for efficiently treating cisplatin or other cause-induced AKI.
    DOI:  https://doi.org/10.1021/acs.biomac.2c01083
  27. Neurochem Res. 2022 Nov 16.
    Efforts Towards Repurposing of Antioxidant Drugs and Active Compounds for Multiple Sclerosis Control.
    Panagiotis Theodosis-Nobelos, Eleni A Rekka.
      Multiple Sclerosis (MS) is a degenerative disorder of the central nervous system (CNS) with complicated etiology that has not been clearly analyzed until nowadays. Apart from anti-inflammatory, immune modulatory and symptomatic treatments, which are the main tools towards MS control, antioxidant molecules may be of interest. Oxidative stress is a key condition implicated in the disease progression. Reactive species production is associated with immune cell activation in the brain as well as in the periphery, accounting for demyelinating and axonal disruptive processes. This review refers to research articles, of the last decade. It describes biological evaluation of antioxidant drugs, and molecules with pharmaceutical interest, which are not designed for MS treatment, however they seem to have potency against MS. Their antioxidant effect is accompanied, in most of the cases, by anti-inflammatory, immune-modulatory and neuroprotective properties. Compounds with such characteristics are expected to be beneficial in the treatment of MS, alone or as complementary therapy, improving some clinical and mechanistic aspects of the disease. This review also summarizes some of the pathobiological characteristics of MS, as well as the role of oxidative stress and inflammation in the progression of neurodegeneration. It presents known drugs and bioactive compounds with antioxidant, and in many cases, pleiotropic activity that have been tested for their efficacy in MS progression or the experimentally induced MS. Antioxidants may offer reduction or prevention of the disease symptoms and progression. Thus, their results may, combined with already applied treatments, be beneficial for the development of new molecules or the repurposing of drugs and supplements that are used with other indication so far.
    Keywords:  Antioxidant bioactive compounds; Antioxidant drugs; Inflammation; Multiple sclerosis; Neurodegeneration; Oxidative stress
    DOI:  https://doi.org/10.1007/s11064-022-03821-8
  28. J Nanopart Res. 2022 ;24(11): 228
    Applications of mannose-binding lectins and mannan glycoconjugates in nanomedicine.
    Anita Gupta, G S Gupta.
      Glycosylated nanoparticles (NPs) have drawn a lot of attention in the biomedical field over the past few decades, particularly in applications like targeted drug delivery. Mannosylated NPs and mannan-binding lectins/proteins (MBL/MBP) are emerging as promising tools for delivery of drugs, medicines, and enzymes to targeted tissues and cells as nanocarriers, enhancing their therapeutic benefits while avoiding the adverse effects of the drug. The occurrence of plenty of lectin receptors and their mannan ligands on cell surfaces makes them multifaceted carriers appropriate for specific delivery of bioactive drug materials to their targeted sites. Thus, the present review describes the tethering of mannose (Man) to several nanostructures, like micelles, liposomes, and other NPs, applicable for drug delivery systems. Bioadhesion through MBL-like receptors on cells has involvements applicable to additional arenas of science, for example gene delivery, tissue engineering, biomaterials, and nanotechnology. This review also focuses on the role of various aspects of drug/antigen delivery using (i) mannosylated NPs, (ii) mannosylated lectins, (iii) amphiphilic glycopolymer NPs, and (iv) natural mannan-containing polysaccharides, with most significant applications of MBL-based NPs as multivalent scaffolds, using different strategies.
    Graphical abstract: Mannosylated NPs and/or MBL/MBP are coming up as viable and versatile tools as nanocarriers to deliver drugs and enzymes precisely to their target tissues or cells. The presence of abundant number of lectin receptors and their mannan ligands on cell surfaces makes them versatile carriers suitable for the targeted delivery of bioactive drugs.
    Keywords:  Biomaterials; Drug delivery systems; Lectin-mediated targeting; Mannans; Mannose-binding lectins; Nanomedicine; Nanoparticles; Nanostructures; Targeted drug delivery
    DOI:  https://doi.org/10.1007/s11051-022-05594-1
  29. Biomed Pharmacother. 2022 Nov 14. pii: S0753-3322(22)01405-6. [Epub ahead of print]157 114016
    Therapeutic potential of Curcuma oil and its terpenoids in gynecological cancers.
    Yuan Zhang, Fu Peng, Chenghao Yu.
       BACKGROUND: Gynecological cancers encompass all uncontrolled and aberrant cell growth in the female reproductive system, therapeutic interventions are constantly evolving, but there is still a high death rate, significant side effects and medication resistance, making the task of treatment challenging and complex. The essential oil extracted from the rhizome of Curcuma longa is a promising natural drug, which has excellent biological activity on cancer cells and is to be developed as a new type of anti-gynecological tumor therapeutic agent.
    PURPOSE: To systematically summarize the available evidence for the efficacy of Curcuma oil and its terpenoids (β-elemene, curcumol, furanodiene, and germacrone) in gynecological cancers, primarily malignancies of the reproductive system, involving ovarian, cervical, and endometrial cancers, explain the underlying mechanisms of preventing and treating gynecological cancers, and assess the shortcomings of existing work.
    RESULTS: Through several signaling channels, Curcuma oil and its terpenoids can not only stop the growth of ovarian cancer, cervical cancer, and endometrial cancer cells, limit the formation of tumors, but also raise the effectiveness of chemotherapy drugs and improve the quality of life for patients.
    CONCLUSION: It provides a preclinical basis for the efficacy of Curcuma oil as a broad-spectrum anti-tumor agent for the prevention and treatment of gynecological cancers. Even so, further efforts are still needed to improve the bioavailability of Curcuma oil and upgrade related experiments.
    Keywords:  Curcuma oil; Curcumol; Furanodiene; Germacrone; Gynecological cancer; β-elemene
    DOI:  https://doi.org/10.1016/j.biopha.2022.114016
  30. Arch Endocrinol Metab. 2022 Nov 11. pii: 2359-3997000000565. [Epub ahead of print]66(5): 748-755
    Vitamin D metabolism and extraskeletal outcomes: an update.
    Isabela Cristina Januário Silva, Marise Lazaretti-Castro.
      Vitamin D deficiency is a general health problem affecting individuals at all stages of life and on different continents. The musculoskeletal effects of vitamin D are well known. Its deficiency causes rickets, osteomalacia, and secondary hyperparathyroidism and increases the risk of fractures. Clinical and experimental evidence suggests that vitamin D performs multiple extraskeletal functions. Several tissues unrelated to calcium and phosphate metabolism express vitamin D receptor (VDR) and are directly or indirectly influenced by 1,25(OH)2D (calcitriol). Some also express the enzyme 1 alpha-hydroxylase (CYP27B1) and produce 1,25(OH)2D, inducing autocrine or paracrine effects. Among the pleiotropic effects of vitamin D are the regulation of cell proliferation and differentiation, hormone secretion, and immune function. In this review, we outline vitamin D physiology and the outcomes of recent large RCTs on its potential extraskeletal effects. Those studies exhibit a need for continued clinical analysis to elucidate whether vitamin D status can influence extraskeletal health. Longer longitudinal follow-up and standardized assays are crucial to better assess potential outcomes.
    Keywords:  Vitamin D; randomized controlled trial; vitamin D/metabolism; vitamin D/physiology; vitamin D/therapeutic use
    DOI:  https://doi.org/10.20945/2359-3997000000565
  31. Biomaterials. 2022 Nov 07. pii: S0142-9612(22)00546-4. [Epub ahead of print]291 121906
    Recent advances in dual- and multi-responsive nanomedicines for precision cancer therapy.
    Yijing Zhang, Jingchao Li, Kanyi Pu.
      Nanomedicines have been regarded as a potential approach in the field of cancer treatment due to their unique advantages. Although improved therapeutic efficacy can be achieved, the applications of most traditional nanomedicines are still limited by severe side effects resulting from unintended retention of therapeutic agents in non-diseased tissues. To increase the controllability of therapeutic agent accumulation in targeting sites (such as tumors), stimuli-responsive nanomedicines that realize drug release in response to exogenous or endogenous stimuli have been developed. In these stimuli-responsive nanomedicines, most of them are activated by mono type of stimulus, and therefore show unsatisfactory selectivity and specificity. In contrast, dual- and multi-responsive nanomedicines that integrate different responsive components into a signal nanoplatform can allow drug release in a more safe and effective manner, leading to both improved therapeutic efficacy and reduced systemic toxicity. Herein, we summarize recent advances in precision cancer therapy by using dual- and multi-responsive nanomedicines. The design strategies and working mechanisms of these dual- and multi-responsive nanomedicines and their applications in chemotherapy, phototherapy, and immunotherapy of cancer are introduced in detail. The existing challenges and future prospects are finally discussed in anticipation of accelerating the clinical translation of these nanomedicines.
    Keywords:  Cancer therapy; Immunotherapy; Nanomedicine; Stimuli-responsive; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121906
  32. Front Pharmacol. 2022 ;13 1058070
    The anticancer effects of curcumin and clinical research progress on its effects on esophageal cancer.
    Shimeng Wang, Xinliang Gao, Jialin Li, Shixiong Wei, Yifeng Shao, Yipeng Yin, Duo Zhang, Mingbo Tang.
      Esophageal cancer (EC) is a common tumor of the gastrointestinal system and a major threat to human health. The etiology and incidence of EC vary depending on the type of pathology. Owing to the unique physiological structure of the esophagus and the poor biological behavior of EC, the treatment modalities available are limited, and the prognosis of patients is relatively poor. Curcumin is a type of natural phytochemical belonging to the class of phenolic compounds. It exerts favorable anticancer effects on various cancers. A growing body of evidence indicates that curcumin suppresses tumor development and progression by inhibiting tumor cell proliferation, invasion, and migration, thus inducing apoptosis, regulating microRNA expression, reversing multidrug resistance, and inducing sensitivity to the therapeutic effect of chemoradiotherapy. Multiple cellular molecules, growth factors, and genes encoding proteins participating in different signaling pathways interact with each other to contribute to the complex and orderly anticancer effect. The efficacy and safety of curcumin have been established in preclinical studies for EC and clinical trials for other cancers. However, the low bioavailability of curcumin limits its clinical application. Therefore, the modification of curcumin analogs, the combination of curcumin with other drugs or therapies, and the use of novel nanocarriers have been widely investigated to improve the clinical effects of curcumin in EC.
    Keywords:  anticancer effect; bioavailability; curcumin; esophageal cancer; gastrointenstinal
    DOI:  https://doi.org/10.3389/fphar.2022.1058070
  33. Assay Drug Dev Technol. 2022 Nov 16.
    Silibinin-Loaded Nanostructured Lipid Carriers for Growth Inhibition of Cisplatin-Resistant Ovarian Cancer Cells.
    Sevda Jafari, Atabak Bakhshaei, Morteza Eskandani, Ommoleila Molavi.
      Cisplatin is the most often used chemotherapy in the treatment of ovarian cancer (OC), however long-term usage leads to drug resistance and treatment failure. Silibinin is a sparingly water-soluble natural compound with well-known anticancer effects. The use of lipid-based delivery systems is a potential approach for enhancing silibinin's water solubility. In this study, nanostructured lipid carriers (NLCs) containing silibinin were prepared and their inhibitory effects were tested in combination with cisplatin against sensitive/resistant A2780 OC cells. Silibinin-loaded NLCs (silibinin-NLCs) were prepared by the hot homogenization method, and their size, shape, zeta potential (ZP), and encapsulation efficiency (EE), as well as their inhibitory effects, were examined in combination with cisplatin against sensitive/resistant A2780 OC cells. Formulation of silibinin-NLCs using cocoa butter led to spherical-shaped NLCs with a size of 95 nm and EE of 98%. The ZP and the dispersion index of the silibinin-NLCs were -27.12 ± 0.13 mv and 0.12 ± 0.04, respectively. The release kinetics of silibinin-NLCs was best fitted with the zero-order model. The combination of cisplatin and silibinin-NLCs sensitized the cisplatin-resistant A2780 OC cells and exhibited a more synergistic inhibitory effect on A2780 cells as compared with the combination of cisplatin and plain silibinin. The optimized silibinin-NLCs can be considered a suitable drug delivery system for the inhibition of cisplatin-resistant OC cells.
    Keywords:  cisplatin; nanostructured lipid carrier; ovarian cancer; silibinin
    DOI:  https://doi.org/10.1089/adt.2022.060
  34. J Gastrointest Oncol. 2022 Oct;13(5): 2144-2153
    Artemisinin inhibits the development of esophageal cancer by targeting HIF-1α to reduce glycolysis levels.
    Miao Wang, Huan Chen, Xu He, Xiaopeng Zhao, Haoran Zhang, Yu Wang, Hongyan Wang.
       Background: China has a high incidence of esophageal cancer (EC), mainly squamous cell carcinoma, which is a serious threat to human life. Previous studies have shown that artemisinin can inhibit the proliferation and metastasis of cancer cells, thus inhibiting the progression of cancer. Aerobic glycolysis plays an important role in the uncontrolled growth of tumor cells. However, there are still different opinions on the anti-cancer mechanism, and there have been few studies involving EC. Our pre-experiment found that artemisinin can inhibit the progression of EC by directly regulating aerobic glycolysis.
    Methods: The EC cell lines KYSE-150 and KYSE-170 were used to detect the effects of artemisinin on cell viability, proliferation, metastasis, and aerobic glycolysis. Network pharmacology technology was used to explore the potential molecular mechanism of artemisinin inhibiting the development of EC through aerobic glycolysis and the findings were verified by molecular docking.
    Results: Artemisinin could inhibit the proliferation, metastasis, and glycolysis of esophageal squamous cell carcinoma (ESCC), and this was verified by the expression of key metastatic proteins (N-cadherin) and key enzymes of glycolysis [hypoxia-inducible factor-1α (HIF-1α), pyruvate kinase M2 (PKM2)]. Through network pharmacology, we found the potential therapeutic target of artemisinin, HIF-1α. The results of molecular docking showed that artemisinin could directly target HIF-1α and promote its degradation.
    Conclusions: Artemisinin can target HIF-1α to reduce the level of glycolysis and inhibit the development of EC, which may become a targeted drug for the treatment of EC.
    Keywords:  Esophageal squamous cell carcinoma (ESCC); aerobic glycolysis; artemisinin; hypoxia-inducible factor-1α (HIF-1α)
    DOI:  https://doi.org/10.21037/jgo-22-877
  35. Front Pharmacol. 2022 ;13 922029
    Ginsenosides: Allies of gastrointestinal tumor immunotherapy.
    Yutao Feng, Fen Ma, Enjiang Wu, Zewei Cheng, Zhengtao Wang, Li Yang, Jiwei Zhang.
      In the past decade, immunotherapy has been the most promising treatment for gastrointestinal tumors. But the low response rate and drug resistance remain major concerns. It is therefore imperative to develop adjuvant therapies to increase the effectiveness of immunotherapy and prevent drug resistance. Ginseng has been used in Traditional Chinese medicine as a natural immune booster for thousands of years. The active components of ginseng, ginsenosides, have played an essential role in tumor treatment for decades and are candidates for anti-tumor adjuvant therapy. They are hypothesized to cooperate with immunotherapy drugs to improve the curative effect and reduce tumor resistance and adverse reactions. This review summarizes the research into the use of ginsenosides in immunotherapy of gastrointestinal tumors and discusses potential future applications.
    Keywords:  gastrointestinal tumors; ginseng; ginsenosides; immunotherapy; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fphar.2022.922029
  36. Life Sci. 2022 Nov 15. pii: S0024-3205(22)00896-7. [Epub ahead of print] 121196
    Boswellic acids as promising agents for the management of brain diseases.
    Arezoo Rajabian, Mohammadreza Farzanehfar, Hossein Hosseini, Fahimeh Lavi Arab, Ali Nikkhah.
      Boswellic acid (BA)s are pentacyclic triterpenic acids present in gum resin of Boswellia species (such as B. serrata and B. carterii). They possess a variety of pharmacological effects such as anti-inflammatory, anti-oxidant, and anti-excitotoxic effects. These properties may have potential therapeutic implication in neurological disorders. Notably, the BAs-induced neuroprotection is proposed to be associated with the ability to reduce neurotoxic aggregates, decrease oxidative stress, and improve cognitive dysfunction. Recently, BAs have been suggested as potential agents for the treatment of brain tumors due to their potential to attenuate cell proliferation, migration, metastasis, angiogenesis, and promote apoptosis during both in vitro and in vivo studies. The present review aims to address these studies and highlights the possible underlying mechanisms of the observed effects. Besides, novel formulations and improving pharmacokinetic properties may enhance the therapeutic efficacy of BAs.
    Keywords:  Bioavailability; Boswellic acid; Brain tumor; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.lfs.2022.121196
  37. Rheumatol Int. 2022 Nov 17.
    Curcuma as an anti-inflammatory component in treating osteoarthritis.
    Zrinka Djukić Koroljević, Katarina Jordan, Jakov Ivković, Darija Vranešić Bender, Porin Perić.
      Osteoarthritis (OA) is nowadays the most common musculoskeletal progressive condition. In recent decades, incidence and prevalence of OA have increased significantly. It is estimated that the prevalence of OA among adults older than 60 is 12%, affecting about 240 million people globally. The cause has not been fully elucidated, and therefore, there is no cure at the moment. It is a multifactorial degenerative disease with an inflammatory component mediated by numerous proinflammatory and anti-inflammatory cytokines, chemokines, and growth factors. OA is not yet fully understood; therefore, therapeutic interventions are aimed primarily at reducing symptoms and slowing the progression of joint destruction. Of the therapeutic options available, the most often prescribed are nonsteroidal antirheumatic drugs, which have numerous side effects. Therefore, a need for a safe, effective substance is differentiated, which will be used in adjuvant treatment, but also in disease prevention, and which will comparatively have no or fewer side effects. One such substance is curcumin, a hydrophobic polyphenol that forms the active component of the rhizome of the Curcuma longa plant. Several studies have shown its potent antioxidant and anti-inflammatory effect, non-toxicity, and safety at high daily doses. In addition to blocking chondrocyte apoptosis, curcumin also blocks the expression of cyclooxygenase, prostaglandin E-2 and proinflammatory cytokines in chondrocytes, potentially alleviating symptomatic diseases. Although there are significant variations in quality, methodology, and research results conducted on curcumin efficiency in OA treatment, curcumin is primarily recommended as systematic short-term and medium-term adjuvant therapy that reduces inflammatory biochemical factors. Reducing inflammation leads to better pain regulation and improved joint function, significantly reducing standard prescribed doses of drugs. The most researched daily doses of curcumin intake are 1000-2000 mg/day, which would also be the doses that most of the authors recommend. Further research is needed to determine the preventive role of curcumin in the pathogenesis of OA, the effects of long-term usage of curcumin in preventive purposes and treatment of osteoarthritis, as well as to determine optimal therapeutic dosages.
    Keywords:  Curcuma; Curcumin; Food as medicine; Medicinal substance; Osteoarthritis
    DOI:  https://doi.org/10.1007/s00296-022-05244-8
  38. ChemMedChem. 2022 Nov 15.
    Hepatic-Targeted Nano-enzyme with Resveratrol Loading for Precise Relief of Nonalcoholic Steatohepatitis.
    Yili Tong, Xiaofeng Yu, Yiqin Huang, Ziyan Zhang, Lin Mi, Zhijun Bao.
      Nonalcoholic steatohepatitis (NASH) characterizes with massive lipid deposition in hepatocytes and it's often associated with hepatic inflammation and other severe metabolism syndromes. The intervention of NASH can prevent its further progression into hepatocarcinoma. Here, we have successfully constructed a liver-targeted Ce-based hollowed mesoporous nanocarries loaded with a bioactive drugs may offer a satisfactory and effective approach for eliminating NASH. The liver section precise targeting was realized by covalently linked galactose (Gal), which can specifically recognized by receptors in the membrane of hepatocytes. Meanwhile, NASH treated drugs, resveratrol (Res) molecules were efficiently loaded in the pores and cavity of CeO2 (Res@H-CeO2-Gal). In steatotic HepG2 cells (free fatty acid induction), the nanosystem enhanced the cellular Res internalization for improvement of anti-lipogenesis capability. In NASH mice, Res@H-CeO2-Gal increased Res delivery to liver sections for the reduction of lipid accumulation and enhanced anti-inflammation ability from the antioxidant ability of Ce based nanocarries that effectively recovered NASH mice into normal state. This finding proved that the hepatic targeting and Res delivery nanoplatform could potentially act as a biosafety and promising strategy for elimination of NASH and other liver diseases.
    Keywords:  Res delivery; ameliorate lipid accumulation; hepatic targeting; hollowed mesoporous CeO2; reduce inflammation
    DOI:  https://doi.org/10.1002/cmdc.202200468
  39. J Control Release. 2022 Nov 14. pii: S0168-3659(22)00755-6. [Epub ahead of print]352 909-919
    Prodrug nanoparticles potentiate tumor chemo-immunometabolic therapy by disturbing oxidative stress.
    Hongjuan Zhao, Yatong Li, Haiyu Shi, Mengya Niu, Dan Li, Zhenzhong Zhang, Qianhua Feng, Yi Zhang, Lei Wang.
      Constant oxidative stress and lactate accumulation are two main causes of tumor immunosuppression, their concurrent reduction plays a dominant role in effective antitumor immunity, but remains challenging. Herein, reactive oxygen species (ROS) responsive prodrug nanoparticles (designed as DHCRJ) are constructed for metabolic amplified chemo-immunotherapy against triple-negative breast cancer (TNBC) by modulating oxidative state and hyperglycolysis. Specifically, DHCRJ is prepared by the self-assembly of DOX prodrug-tethered ROS consuming bond-bridged copolymers with the loading of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Interestingly, the nanoparticle polymer network could reduce ROS to relieve tumor hypoxia and realize the dense-to-loose structure inversion arising from ROS-triggered network collapse, which favors JQ1 release and hyaluronidase (Hyal)-activatable DOX prodrugs generation. More importantly, disruption of oxidative stress decreases glucose uptake and assists JQ1 to down-regulate oncogene c-Myc driven tumor glycolysis for blocking the source of lactate and reshaping immunosuppressive tumor microenvironment (ITME). Meanwhile, benefiting from the synergistic effect of DOX prodrugs and JQ1, DHCRJ is able to facilitate tumor immunogenicity and potentiate systemic immune responses through antigen processing and presentation pathway. In this manner, DHCRJ significantly suppresses tumor growth and metastasis with prolonged survival. Collectively, this study represents a proof of concept antioxidant-enhanced chemo-immunometabolic therapy strategy using ROS-reducing nanoparticles for efficient synergistic therapeutic modality of TNBC.
    Keywords:  Chemo-immunometabolic therapy; Oxidative stress; Triple-negative breast cancer; Tumor immunogenicity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.011
  40. AAPS PharmSciTech. 2022 Nov 15. 23(8): 298
    A Preliminary Pharmacodynamic Study for the Management of Alzheimer's Disease Using Memantine-Loaded PLGA Nanoparticles.
    Atinderpal Kaur, Kuldeep Nigam, Amit Tyagi, Shweta Dang.
      Alzheimer's disease is becoming a common disorder of the elderly population due to shrinkage of the brain size with age and many other neurological complications. To provide an effective treatment option, memantine-encapsulated polymeric nanoparticles were prepared in the study. The nanoparticles were prepared by using nanoprecipitation followed by homogenization and ultrasonication methods, characterized on the basis of particle size, polydispersity index, and zeta potential. Further, in vitro release profile, cytotoxicity analysis, and Giemsa staining were conducted. To observe the efficacy of nanoparticles in scopolamine-induced Alzheimer models in vivo studies were also carried out. The results showed that nanoparticles were in the nano range with a particle size of 58.04 nm and - 23 mV zeta potential. The in vitro release was also sustained till 24 h with ~ 100% release in selected media phosphate buffer saline, simulated nasal fluid, and artificial cerebrospinal fluid. The cytotoxicity results with ~ 98 to 100% cell viability and no morphological changes through Giemsa staining indicated that nanoparticles were not leading to cell toxicity. The gamma scintigraphy studies showed higher uptake of the drug in the target site through the intranasal route and pharmacodynamic studies indicated that nanoparticles were able to inhibit the spatial memory impairment significantly as compared to the control group. The findings clearly indicated that the developed memantine nanoparticles could act as an alternative approach for the management of Alzheimer's disease.
    Keywords:  Alzheimer; Morris water maze; memantine; nanoparticles; scopolamine
    DOI:  https://doi.org/10.1208/s12249-022-02449-9
  41. Biomed Pharmacother. 2022 Nov 14. pii: S0753-3322(22)01381-6. [Epub ahead of print]157 113992
    Metabolic reprogramming of immune cells in pancreatic cancer progression.
    Hong Xiang, Runjuan Yang, Jiaxin Tu, Yan Xi, Shilei Yang, Linlin Lv, Xiaohan Zhai, Yanna Zhu, Deshi Dong, Xufeng Tao.
      Abnormal intracellular metabolism not only provides nutrition for tumor occurrence and development, but also sensitizes the function of various immune cells in the immune microenvironment to promote tumor immune escape. This review discusses the emerging role of immune cells in the progress of pancreatic cancer, acrossing metabolic reprogramming and key metabolic pathways present in different immune cell types. At present, the hotspots of metabolic reprogramming of immune cells in pancreatic cancer progression mainly focuses on glucose metabolism, lipid metabolism, tricarboxylic acid cycle and amino acid metabolism, which affect the function of anti-tumor immune cells and immunosuppressive cells in the microenvironment, such as macrophages, dendritic cells, T cells, myeloid-derived suppressor cells, neutrophils and B cells by a series of key metabolic signaling pathways, such as PI3K/AKT, mTOR, AMPK, HIF-1α, c-Myc and p53. Drugs that target the tumor metabolism pathways for clinical treatment of pancreatic cancer are also systematically elaborated, which may constitute food for others' projects involved in clinical anti-cancer research.
    Keywords:  Immune cells; Immunotherapy; Metabolic reprogramming; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.biopha.2022.113992
  42. Adv Healthc Mater. 2022 Nov 15. e2202467
    Dual "unlocking" strategy to overcome inefficient nanomedicine delivery and tumor hypoxia for enhanced photodynamic-immunotherapy.
    Xianglong Li, Cong Jiang, Xinlin Jia, Yuanyuan Cao, Yuanqing Mao, Ji-Na Hao, Yang Yang, Peng Zhang, Yongsheng Li.
      Lacking blood vessels is one of the main characteristics of most solid tumors due to their rapid and unrestricted growth, which thus remarkably causes the inefficient delivery efficiency of nanomedicine and tumor hypoxia. Herein, a dual "unlocking" strategy to overcome these obstacles is proposed by combining the engineered hybrid nanoparticles (named ZnPc@FOM-Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro-vessel density (delivery "unlocking") to enhance the tumor delivery efficiency of ZnPc@FOM-Pt and decrease HIF-1α expression. Correspondingly, more Pt can catalyze tumor-overexpressed H2 O2 to produce oxygen to further cause hypoxia "unlocking", ultimately achieving boosted ZnPc-based photodynamic therapy in vivo (Tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti-PD-L1-based immunotherapy is promoted by this newly designed nanomedicine. This dual "unlocking" strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy. This article is protected by copyright. All rights reserved.
    Keywords:  Immunotherapy; Nanomedicine delivery; Photodynamic therapy; Tumor micro-vessel density modulation; anti-programmed death-ligand 1
    DOI:  https://doi.org/10.1002/adhm.202202467
  43. Front Genet. 2022 ;13 1022739
    Metformin: Activation of 5' AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action.
    Sanjay Goel, Ravinder Singh, Varinder Singh, Harmanjit Singh, Pratima Kumari, Hitesh Chopra, Rohit Sharma, Eugenie Nepovimova, Martin Valis, Kamil Kuca, Talha Bin Emran.
      Metformin is a plant-based drug belonging to the class of biguanides and is known to treat type-2 diabetes mellitus (T2DM). The drug, combined with controlling blood glucose levels, improves the body's response to insulin. In addition, trials have identified the cardioprotective potential of metformin in the diabetic population receiving the drug. Activation of 5' AMP-activated protein kinase (AMPK) is the major pathway for these potential beneficial effects of metformin. Historically, much emphasis has been placed on the potential indications of metformin beyond its anti-diabetic use. This review aims to appraise other potential uses of metformin primarily mediated by the activation of AMPK. We also discuss various mechanisms, other than AMPK activation, by which metformin could produce beneficial effects for different conditions. Databases including PubMed/MEDLINE and Embase were searched for literature relevant to the review's objective. Reports from both research and review articles were considered. We found that metformin has diverse effects on the human body systems. It has been shown to exert anti-inflammatory, antioxidant, cardioprotective, metabolic, neuroprotective, anti-cancer, and antimicrobial effects and has now even been identified as effective against SARS-CoV-2. Above all, the AMPK pathway has been recognized as responsible for metformin's efficiency and effectiveness. Owing to its extensive potential, it has the capability to become a part of treatment regimens for diseases apart from T2DM.
    Keywords:  anticancer; cardioprotective; hyperglycemia; metformin; oxidative stress
    DOI:  https://doi.org/10.3389/fgene.2022.1022739
  44. Pharmacol Res. 2022 Nov 15. pii: S1043-6618(22)00499-6. [Epub ahead of print] 106553
    Biological function and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: promises and challenges.
    Mahshid Deldar Abad Paskeh, Fatemeh Ghadyani, Mehrdad Hashemi, Alireza Abbaspour, Amirhossein Zabolian, Salar Javanshir, Mehrnaz Razzazan, Sepideh Mirzaei, Maliheh Entezari, Mohammad Ali Shekhi Beig Goharrizi, Shokooh Salimimoghadam, Amir Reza Aref, Alireza Kalbasi, Romina Rajabi, Mohsen Rashidi, Afshin Taheriazam, Gautam Sethi.
      Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits apoptosis and pro-death autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules, can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can be used as a biomarker to predict patients' response to therapy.
    Keywords:  Biomarker; Cancer therapy; Hepatocellular carcinoma; PI3K/Akt; PTEN
    DOI:  https://doi.org/10.1016/j.phrs.2022.106553
  45. J Biol Chem. 2022 Oct 27. pii: S0021-9258(22)01094-8. [Epub ahead of print]298(12): 102651
    Dietary polyphenols link extracellular histones and nonhistone proteins.
    Jiuyang Liu, Tatiana G Kutateladze.
      Numerous studies have demonstrated antioxidant, anti-inflammatory, antimicrobial, anticancer, and cardio-protective activities of dietary polyphenols, but due to diverse structures and subclasses of polyphenols, little is known about their mechanisms of action. The study by Yamaguchi et al. published in JBC provides mechanistic insights into how dietary polyphenols confer histone-binding ability on certain proteins and motivates the research community to further explore health benefits of polyphenols.
    Keywords:  antioxidant; diet; histone; polyphenol; protein
    DOI:  https://doi.org/10.1016/j.jbc.2022.102651
  46. Sci Rep. 2022 Nov 14. 12(1): 19446
    Hybrid nanoparticulate system of Fluvastatin loaded phospholipid, alpha lipoic acid and melittin for the management of colon cancer.
    Mohamed A Alfaleh, Omar Fahmy, Mohammed W Al-Rabia, Mohammed A S Abourehab, Osama A A Ahmed, Usama A Fahmy, Helal H Alsulimani, Shaimaa M Badr-Eldin, Hibah M Aldawsari, Bander M Aldhabi, Awaad S Alharbi, Nabil A Alhakamy.
      As a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, Fluvastatin (FLV) is used for reducing low-density lipoprotein (LDL) cholesterol as well as to prevent cardiovascular problems. FLV showed cell line cytotoxicity and antitumor effect. Melittin (MEL) exhibits antineoplastic activity and is known to be promising as a therapeutic option for cancer patients. The aim of this work was to investigate the combination of FLV with MEL loaded hybrid formula of phospholipid (PL) with alpha lipoic acid (ALA) nanoparticles to maximize anticancer tendencies. This study examines the optimization of the prepared formulation in order to minimize nanoparticles size and maximize zeta potential to potentiate cytotoxic potentialities in colon cancer cells (Caco2), cell viability, cell cycle analysis and annexin V were tested. In addition to biological markers as P53, Bax, bcl2 and Caspase 3 evaluation The combination involving FLV PL ALA MEL showed enhanced cytotoxic potentiality (IC50 = 9.242 ± 0.35 µg/mL), about twofold lower, compared to the raw FLV (IC50 = 21.74 ± 0.82 µg/mL). According to studies analyzing cell cycle, optimized FLV PL ALA MEL was found to inhibit Caco2 colon cancer cells more significantly than other therapeutic treatments, wherein a higher number of cells were found to accumulate over G2/M and pre-G1 phases, whereas G0/G1/S phases witnessed the accumulation of a lower number of cells. The optimized formulation may pave the way for a novel and more efficacious treatment for colon cancer.
    DOI:  https://doi.org/10.1038/s41598-022-24151-3
  47. Cell Mol Biol Lett. 2022 Nov 18. 27(1): 100
    Acquired drug resistance interferes with the susceptibility of prostate cancer cells to metabolic stress.
    Jessica Catapano, Marcin Luty, Tomasz Wróbel, Maciej Pudełek, Katarzyna Piwowarczyk, Sylwia Kędracka-Krok, Maciej Siedlar, Zbigniew Madeja, Jarosław Czyż.
       BACKGROUND: Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed.
    METHODS: Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness.
    RESULTS: Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial-mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress.
    CONCLUSIONS: Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.
    Keywords:  Drug resistance; Metabolic adaptation; Metabolic stress; Metformin; Prostate cancer
    DOI:  https://doi.org/10.1186/s11658-022-00400-1
  48. J Ethnopharmacol. 2022 Nov 12. pii: S0378-8741(22)00968-0. [Epub ahead of print] 115929
    Apoptosis induction of essential oils from Artemisia arborescens L. in human prostate cancer cells.
    Alessandra Russo, Adriana Graziano, Maurizio Bruno, Venera Cardile, Daniela Rigano.
       ETHNOPHARMACOLOGICAL RELEVANCE: Prostate cancer originates from cells inside a gland, which begin to grow out of control. In the world, prostate cancer is the most common cancer in the male population. New therapeutic strategies are needed for this tumor which still has a high mortality. A. arborescens leaves and aerial parts have various ethnopharmacological uses such as anti-spasmodic, and their decoctions were used to resolve urticaria, neuralgia and several lung diseases. Often this species has been also used to treat different inflammatory-related diseases such as cancer.
    AIM OF THE STUDY: In a continuation of our research on essential oils from medicinal plants, we have selected, two essential oils from Artemisia arborescens L. (Compositae), an aromatic shrub widely used in traditional medicine. We evaluated their pro-apototic effect on androgen-sensitive (LNCaP) and androgen-insensitive (DU-145) human prostate cancer cells. In this study, we also evaluated the anti-Signal transducer and transcription factor 3 (STAT-3) activity of both essential oils in the human prostate cancer cell lines, and the treatment with Tumor necrosis factor (TNF)-Related Apoptosis (TRAIL).
    MATERIALS AND METHODS: The cells were exposed to essential oils for 72 h and cell viability and cell membrane integrity were evaluated. Genomic DNA and the activity of caspase-3 was tested to confirm the cell death for apoptosis. Western blot analysis was employed to evaluate the expression of Bcl-2, Bax, cleaved caspase-3, cleaved caspase-9, Hsp70, STAT-3 and SOD proteins. Assays to evaluate reactive oxygen species (ROS) and GSH levels were also performed.
    RESULTS: The results showed the capacity of two essential oils to activate an apoptotic process increasing the inhibition of Hsp70 and STAT-3 protein expression. In addition, our natural products sensitize LNCaP cells to Tumor necrosis factor (TNF)-Related Apoptosis (TRAIL)-induced apoptosis.
    CONCLUSIONS: In summary, our study provides a further contribution to the hypothesis of the use of essential oils, from traditional medicinal plants, for the treatment of tumors, and suggests that the combination of our samples with other anti-prostate cancer therapies could be used to affect prostate cancer.
    Keywords:  Apoptosis; Artemisia arborescens; Essential oils; Prostate cancer; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.jep.2022.115929
  49. Food Funct. 2022 Nov 16.
    A comprehensive review on lactoferrin: a natural multifunctional glycoprotein.
    V S Shini, Chinthu Tharayil Udayarajan, P Nisha.
      Lactoferrin (Lf) is a natural iron-binding globular glycoprotein, present mainly in milk. It maintains human health through its multifunctional activities, including immunomodulation, iron metabolism, and antioxidant and prebiotic efficacy. It also shows anti-microbial, anti-fungal, and anti-viral activities against a broad spectrum of viruses, including SARS-CoV-2 that causes COVID-19. In addition, several investigations established that Lf is involved in bone metabolism, neural development, and metabolic disorders. In this review, we summarize the in vitro and in vivo studies on the health benefits of Lf and its bioavailability. Furthermore, we briefly describe the production, industrial applications and future prospects of Lf.
    DOI:  https://doi.org/10.1039/d2fo02371g
  50. J Control Release. 2022 Nov 15. pii: S0168-3659(22)00766-0. [Epub ahead of print]
    Ultrasound nanotheranostics: Toward precision medicine.
    Yang Qin, Xiaorui Geng, Yue Sun, Yitong Zhao, Wenyu Chai, Xiaobing Wang, Pan Wang.
      Ultrasound (US) is a mechanical wave that can penetrate biological tissues and trigger complex bioeffects. The mechanisms of US in different diagnosis and treatment are different, and the functional application of commercial US is also expanding. In particular, recent developments in nanotechnology have led to a wider use of US in precision medicine. In this review, we focus on US in combination with versatile micro and nanoparticles (NPs)/nanovesicles for tumor theranostics. We first introduce US-assisted drug delivery as a stimulus-responsive approach that spatiotemporally regulates the deposit of nanomedicines in target tissues. Multiple functionalized NPs and their US-regulated drug-release curves are analyzed in detail. Moreover, as a typical representative of US therapy, sonodynamic antitumor strategy is attracting researchers' attention. The collaborative efficiency and mechanisms of US and various nano-sensitizers such as nano-porphyrins and organic/inorganic nanosized sensitizers are outlined in this paper. A series of physicochemical processes during ultrasonic cavitation and NPs activation are also discussed. Finally, the new applications of US and diagnostic NPs in tumor-monitoring and image-guided combined therapy are summarized. Diagnostic NPs contain substances with imaging properties that enhance US contrast and photoacoustic imaging. The development of such high-resolution, low-background US-based imaging methods has contributed to modern precision medicine. It is expected that the integration of non-invasive US and nanotechnology will lead to significant breakthroughs in future clinical applications.
    Keywords:  Drug delivery; Nanotechnology; Precision theranostics; Ultrasound
    DOI:  https://doi.org/10.1016/j.jconrel.2022.11.021
  51. Curr Drug Deliv. 2022 Nov 14.
    Promises of Molecular Pharmaceutics in the Development of Novel Drug Delivery Formulations.
    Parveen Kumar, Benu Chaudhary, Vivek Jain, Sanjula Baboota, Palanisamy Shivanandy, Khalid Saad Alharbi, Mohammed M Ghoneim, Sultan Alshehri, Syed Sarim Imam, Gaurav Gupta, Madan Mohan Gupta.
      Molecular pharmaceutics play a critical role in the drug delivery system, representing the direct interconnection of drug bioavailability with its molecular form. There is a diversity in the molecular structures by which it affects its properties, such as amorphous form, crystalline form, partialamorphous molecular dispersion, and disordered state. The active pharmaceutical ingredient (API) and the excipients utilized in the formulation process contain various divergent modes used in the formulation process. They include better formulations of any type to obtain good quality pharmaceutical products. This review reveals how the molecular states affect the API and are important in maintaining the quality of dosage forms. Furthermore, the physio-chemical properties of the components and various pharmaceutical approaches employed in the formulation of dosage forms are studied from the point of view of molecular pharmaceutics.
    Keywords:  Active Pharmaceutical Ingredients; Drug delivery; Formulation; Microparticles; Molecular pharmaceutics; Polymer
    DOI:  https://doi.org/10.2174/1567201820666221114113637
  52. Front Oncol. 2022 ;12 981406
    Trends in metabolic signaling pathways of tumor drug resistance: A scientometric analysis.
    Ruiqi Jiang, Mingnan Cao, Shenghui Mei, Shanshan Guo, Wei Zhang, Nan Ji, Zhigang Zhao.
       Background: Cancer chemotherapy resistance is one of the most critical obstacles in cancer therapy. Since Warburg O first observed alterations in cancer metabolism in the 1950s, people gradually found tumor metabolism pathways play a fundamental role in regulating the response to chemotherapeutic drugs, and the attempts of targeting tumor energetics have shown promising preclinical outcomes in recent years. This study aimed to summarize the knowledge structure and identify emerging trends and potential hotspots in metabolic signaling pathways of tumor drug resistance research.
    Methods: Publications related to metabolic signaling pathways of tumor drug resistance published from 1992 to 2022 were retrieved from the Web of Science Core Collection database. The document type was set to articles or reviews with language restriction to English. Two different scientometric software including Citespace and VOS viewer were used to conduct this scientometric analysis.
    Results: A total of 2,537 publications including 1,704 articles and 833 reviews were retrieved in the final analysis. The USA made the most contributions to this field. The leading institution was the University of Texas MD Anderson Cancer Center. Avan A was the most productive author, and Hanahan D was the key researcher with the most co-citations, but there is no leader in this field yet. Cancers was the most influential academic journal, and Oncology was the most popular research field. Based on keywords occurrence analysis, these selected keywords could be roughly divided into five main topics: cluster 1 (study of cancer cell apoptosis pathway); cluster 2 (study of resistance mechanisms of different cancer types); cluster 3 (study of cancer stem cells); cluster 4 (study of tumor oxidative stress and inflammation signaling pathways); and cluster 5 (study of autophagy). The keywords burst detection identified several keywords as new research hotspots, including "tumor microenvironment," "invasion," and "target".
    Conclusion: Tumor metabolic reprogramming of drug resistance research is advancing rapidly. This study serves as a starting point, providing a thorough overview, the development landscape, and future opportunities in this field.
    Keywords:  drug resistance; metabolism; scientometrics; signaling pathways; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.981406
  53. Adv Exp Med Biol. 2022 Nov 18.
    Cannabinoids as Prospective Anti-Cancer Drugs: Mechanism of Action in Healthy and Cancer Cells.
    Özge Boyacıoğlu, Petek Korkusuz.
      Endogenous and exogenous cannabinoids modulate many physiological and pathological processes by binding classical cannabinoid receptors 1 (CB1) or 2 (CB2) or non-cannabinoid receptors. Cannabinoids are known to exert antiproliferative, apoptotic, anti-migratory and anti-invasive effect on cancer cells by inducing or inhibiting various signaling cascades. In this chapter, we specifically emphasize the latest research works about the alterations in endocannabinoid system (ECS) components in malignancies and cancer cell proliferation, migration, invasion, angiogenesis, autophagy, and death by cannabinoid administration, emphasizing their mechanism of action, and give a future perspective for clinical use.
    Keywords:  Apoptosis; Autophagy; Cancer; Cannabinoid receptors; Cannabinoids; Cell cycle; Invasion; Migration; Proliferation
    DOI:  https://doi.org/10.1007/5584_2022_748
  54. Benef Microbes. 2022 Nov 15. 1-8
    Epigenetic regulation by metabolites from the gut microbiome.
    C Marín-Tello, P Jintaridth, F Sanchez, C González, L Zelada-Castillo, A Vásquez-Arqueros, A Guevara-Vásquez, A Vieira.
      The gut microbiome can metabolise food components, such as dietary fibres and various phytochemicals; and the microbiome can also synthesise some nutrients, for example B vitamins. The metabolites produced by bacteria and other micro-organisms in the colon can have implications for health and disease risk. Some of these metabolites are epigenetically active, and can contribute to changes in the chemical modification and structure of chromatin by affecting the activity and expression of epigenetically-active enzymes, for example histone deacetylases and DNA methyltransferases. The epigenetic activity of such gut microbiome metabolites is reviewed herein.
    Keywords:  diet; epigenetic; gut; microbiome; nutrition; plant metabolites
    DOI:  https://doi.org/10.3920/BM2022.0006
  55. Chem Commun (Camb). 2022 Nov 14.
    An esterase-activatable curcumin prodrug for tumor-targeting therapy.
    Li Liu, Lele Zhang, Menglin Tao, Minghui Wang, Ling Dong, Zijuan Hai.
      A tumor-targeting therapy strategy is urgently needed to increase the accumulation of drugs in tumors and reduce the side effects in normal tissues. Herein, we developed an esterase-activatable curcumin prodrug Cur-RGD for tumor-targeting therapy. Armed with the tumor-targeting RGD peptide and in situ esterase-triggered drug release, this prodrug Cur-RGD can efficiently improve the therapeutic effect of curcumin in tumors.
    DOI:  https://doi.org/10.1039/d2cc03952d
  56. Int J Pharm. 2022 Nov 09. pii: S0378-5173(22)00934-6. [Epub ahead of print]629 122379
    A liposomal formulation of simvastatin and doxorubicin for improved cardioprotective and anti-cancer effect.
    Ronja Bjørnstad, Ingeborg Nerbø Reiten, Kaja Skålnes Knudsen, Jan Schjøtt, Lars Herfindal.
      Anthracyclines such as doxorubicin (Dox) are the preferred chemotherapeutics for several cancers. However, Dox-induced cardiotoxicity limits its therapeutic potential. Liposomal encapsulation of Dox has been used for patients with risk to develop Dox induced cardiotoxicity but does not surpass the efficacy of the unencapsulated drug. Statins are widely used as cholesterol lowering drugs and have also demonstrated cardioprotective activity in cancer patients undergoing Dox therapy. We developed a liposome loaded with Dox and simvastatin (Sim) and investigated their effect on cardiomyocytes and zebrafish larvae. Furthermore, we investigated if the doses required for cardioprotection compromised the cytotoxicity of Dox in mammary and prostate cancer cells. Combination of Sim and Dox reduced ROS generation in cardiomyocytes, both given as free drugs, or co-encapsulated in liposomes. In contrast, Sim potentiated ROS-generation and cytotoxic activity of Dox towards cancer cells also when co-encapsulated in liposomes. In zebrafish larvae, Sim treatment reduced Dox-induced cardiac affection, and the liposomes did not induce any sign of Dox-induced cardiotoxicity. Our results show that liposomal co-encapsulation of Sim and Dox can be an efficient way of further reducing the risk of cardiotoxic events of liposomal Dox, while retaining, or even potentiating the anti-cancer effect of Dox.
    Keywords:  Cancer; Cardiotoxicity; Doxorubicin; Drug repurposing; Liposomes; Simvastatin
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.122379
  57. Exp Mol Med. 2022 Nov 16.
    Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagy.
    Jing Zhou, Ji Feng, Yong Wu, Hui-Qi Dai, Guang-Zhi Zhu, Pan-Hong Chen, Li-Ming Wang, Guang Lu, Xi-Wen Liao, Pei-Zhi Lu, Wen-Jing Su, Shing Chuan Hooi, Xin-Pin Ye, Han-Ming Shen, Tao Peng, Guo-Dong Lu.
      Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC.
    DOI:  https://doi.org/10.1038/s12276-022-00878-x
  58. Int J Biomater. 2022 ;2022 2807644
    Zinc Oxide Nanoparticles as Diagnostic Tool for Cancer Cells.
    Sumayah Ibraheem, Afraa Ali Kadhim, Kadhim Ali Kadhim, Ihssan A Kadhim, Majid Jabir.
      ZnO nanoparticles have various characteristics that make them attractive to be used in many medical applications like a cancer diagnosis. It can be used as a nanoprobe for targeting different types of cancer cells in vitro as a cancer cell recognition system. The present study aims to investigate the permeability of ZnO NPs through both normal and cancerous cell lines in humans. In vitro experiments for ZnO NPs inside the environment of living cells have been described, which would contribute to the visualization of nanoparticles as cancer diagnostic and scanning techniques. MCF7, AMJ13, and RD cancer cells, and also the normal breast cell line HBL, were used in in vitro imaging experiments. The findings revealed that ZnO NPs specifically incorporated within tumor cells while accumulating less inside normal cells. Our findings show that ZnO NPs may be identified inside cancer cells after 1 h of exposure and can endure up to 3 h, providing them appropriate for tumor cell imaging. The findings showed that ZnO NPs might be employed as an alternate fluorophore for diagnostic imaging in the early identification of solid cancers. Therefore, here we studied in vitro applications of ZnO NPs and their beneficial use as a diagnostic tool for cancer cell lines rather than normal cells. Taken together, ZnO NPs can be used as good targeting NPs for the development of imaging agents for early diagnosis of cancers.
    DOI:  https://doi.org/10.1155/2022/2807644
  59. Chemotherapy. 2022 Jul 27. 67(4): 211-222
    Curcumin Suppresses the Progression of Colorectal Cancer by Improving Immunogenic Cell Death Caused by Irinotecan.
    Cunliang Zhu, Zhaobi Fang, Lei Peng, Fan Gao, Wei Peng, Fengqian Song.
       BACKGROUND: Irinotecan (IRI) is a common chemotherapeutic drug for colorectal cancer; however, the mechanism underlying its immunomodulatory effect remains unclear. Curcumin (CUR), an adjuvant drug with anti-inflammatory and antitumor effects, has been studied extensively, although its synergistic antitumor effect remains unclear.
    METHODS: The effects of CUR and IRI on oxidative stress and their antitumor effects were detected by flow cytometry. Endoplasmic reticulum stress-related proteins including CHOP and BiP, and immunogenic cell death (ICD) proteins including calreticulin (CALR) and high mobility group box 1 (HMGB1), were detected by Western blotting. IFN-γ and TNF-α levels in the serum of mice were detected by ELISA.
    RESULTS: IRI in combination with CUR had synergistic antitumor effects in CT-26 colon carcinoma cells. Combination treatment with IRI and CUR was more effective than IRI or CUR alone. IRI and CUR combination treatment significantly upregulated ICD-related proteins including CALR and HMGB1 and had a greater antitumor effect than IRI or CUR single treatment in vivo. CUR may synergistically improve the antitumor effect of IRI by promoting the ICD effect.
    CONCLUSION: Combination therapy with IRI and CUR may be an option for first-line chemotherapy in some patients with advanced colorectal cancer.
    Keywords:  Colorectal cancer; Endoplasmic reticulum stress; Immunogenic cell death; Irinotecan; Synergistic antitumor effects
    DOI:  https://doi.org/10.1159/000518121
  60. J Environ Pathol Toxicol Oncol. 2022 ;41(4): 55-84
    Melatonin: A Potential Antineoplastic Agent in Breast Cancer.
    Saptadip Samanta.
      Melatonin is primarily synthesized in the pineal gland under the influence of noradrenergic stimulation at night. It regulates the sleep-wake cycle, gonadal activity, redox homeostasis, immune functions, and anticarcinogenic effects at the normal physiological state. The activity of melatonin is mediated by membrane-bound G protein-coupled receptors MT1 and MT2. Circadian deregulation, exposure to light-at-night, shift work, and jet lag disrupt the melatonin rhythm. A low level of circulatory melatonin concentration influences the development of many cancers, including breast cancer. Melatonin acts as an anticancer agent in breast tissue. It suppresses metabolic activity, regulates cell-signaling pathways, and subsequently blocks cell proliferation. This indolamine induces apoptosis, inhibits chronic inflammation and metastasis. Melatonin restricts the functions of estrogen receptor α and also inhibits aromatase activity. Melatonin is a potent antioxidant that reduces the chemoresistance capacity of breast cancer cells. At therapeutic levels, it potentially increases the efficacy of chemotherapeutic agents and decreases their adverse effects during the treatment of breast cancer. The present review focuses on the antineoplastic activity of melatonin against breast cancer. Emphasis has been given to the possible use of melatonin in the treatment of breast cancer.
    DOI:  https://doi.org/10.1615/JEnvironPatholToxicolOncol.2022041294
  61. Chem Phys Lipids. 2022 Nov 10. pii: S0009-3084(22)00084-6. [Epub ahead of print] 105256
    Nanostructured lipid carrier-loaded metformin hydrochloride: Design, optimization, characterization, assessment of cytotoxicity and ROS evaluation.
    Meghanath B Shete, Ashwini S Deshpande, Pravin K Shende.
      Metformin hydrochloride (MET) is commonly used in diabetes treatment. Recently, it has gained interest for its anticancer potential against a wide range of cancers. Owing to its hydrophilic nature, the delivery and clinical actions of MET are limited. Therefore, the present work aims to develop MET-encapsulated NLCs using the hot-melt emulsification and probe-sonication method. The optimization was accomplished by 33 BB design wherein lipid ratio, surfactant concentration, and sonication time were independent variables while the PS (nm), PDI, and EE (%) were dependent variables. The PS, PDI, % EE and ZP of optimized GMSMET-NLCs were found to be 114.9 ± 1.32nm, 0.268 ± 0.04, 60.10 ± 2.23%, and ZP -15.76mV, respectively. The morphological features, DSC and PXRD, and FTIR analyses suggested the confirmation of formation of the NLCs. Besides, optimized GMSMET-NLCs showed up to 88% MET release in 24h. Moreover, GMSMET-NLCs showed significant cell cytotoxicity against KB oral cancer cells compared with MET solution as shown by the reduction of IC50 values. Additionally, GMSMET-NLCs displayed significantly increased intracellular ROS levels suggesting the GMSMET-NLCs induced cell death in KB cells. GMSMET-NLCs can therefore be explored to deliver MET through different routes of administration for the effective treatment of oral cancer.
    Keywords:  KB cells; Metformin; Nanostructured lipid carrier; Oral cancer; apoptosis
    DOI:  https://doi.org/10.1016/j.chemphyslip.2022.105256
  62. Semin Cell Dev Biol. 2022 Nov 12. pii: S1084-9521(22)00293-2. [Epub ahead of print]
    Epigenetic alterations fuel brain metastasis via regulating inflammatory cascade.
    Shailendra Kumar Maurya, Asad Ur Rehman, Mohd Ali Abbas Zaidi, Parvez Khan, Shailendra K Gautam, Juan A Santamaria-Barria, Jawed Akhtar Siddiqui, Surinder K Batra, Mohd Wasim Nasser.
      Brain metastasis (BrM) is a major threat to the survival of melanoma, breast, and lung cancer patients. Circulating tumor cells (CTCs) cross the blood-brain barrier (BBB) and sustain in the brain microenvironment. Genetic mutations and epigenetic modifications have been found to be critical in controlling key aspects of cancer metastasis. Metastasizing cells confront inflammation and gradually adapt in the unique brain microenvironment. Currently, it is one of the major areas that has gained momentum. Researchers are interested in the factors that modulate neuroinflammation during BrM. We review here various epigenetic factors and mechanisms modulating neuroinflammation and how this helps CTCs to adapt and survive in the brain microenvironment. Since epigenetic changes could be modulated by targeting enzymes such as histone/DNA methyltransferase, deacetylases, acetyltransferases, and demethylases, we also summarize our current understanding of potential drugs targeting various aspects of epigenetic regulation in BrM.
    Keywords:  Brain metastasis; Brain microenvironment; Epigenetics regulation; Inflammation; Inflammatory cascade
    DOI:  https://doi.org/10.1016/j.semcdb.2022.11.001
  63. Angew Chem Int Ed Engl. 2022 Nov 14.
    Toward Precise Antitumoral Photodynamic Therapy Using a Dual Receptor-Mediated Bioorthogonal Activation Approach.
    Jacky C H Chu, Clarence T T Wong, Dennis K P Ng.
      Targeted delivery and specific activation of photosensitizers can greatly improve the treatment outcome of photodynamic therapy. To this end, we report herein a novel dual receptor-mediated bioorthogonal activation approach to enhance the tumor specificity of the photodynamic action. It involves the targeted delivery of a biotinylated boron dipyrromethene (BODIPY)-based photosensitizer, which is quenched in the native form by the attached 1,2,4,5-tetrazine unit, and an epidermal growth factor receptor (EGFR)-targeting cyclic peptide conjugated with a bicyclo[6.1.0]non-4-yne moiety. Only for cancer cells that overexpress both the biotin receptor and EGFR, the two components can be internalized preferentially where they undergo an inverse electron-demand Diels-Alder reaction, leading to restoration of the photodynamic activity of the BODIPY core. By using a range of cell lines with different expression levels of these two receptors, we have demonstrated that this stepwise "deliver-and-click" approach can confine the photodynamic action on a specific type of cancer cells.
    Keywords:  bioorthogonal chemistry * boron dipyrromethene * dual receptor * inverse electron-demand Diels-Alder reaction * photodynamic therapy
    DOI:  https://doi.org/10.1002/anie.202214473
  64. ACS Omega. 2022 Nov 08. 7(44): 39782-39793
    Formulation and Evaluation of Azithromycin-Loaded Niosomal Gel: Optimization, In Vitro Studies, Rheological Characterization, and Cytotoxicity Study.
    Ahlam Zaid Alkilani, Rania Hamed, Hajer Abdo, Lubna Swellmeen, Haneen A Basheer, Walaa Wahdan, Amani D Abu Kwiak.
      Several novel, innovative approaches for improving transdermal delivery of BCS class III drugs have been proposed. Despite their great aqueous solubility, BCS class III drugs have the drawback of limited permeability. The objective of the current work was to screen the suitability of niosomes as a nanocarrier in permeation enhancement of azithromycin (AZM) transdermal delivery. Niosomes were prepared by an ether injection method using a nonionic surfactant (Span 60) and cholesterol at different concentrations. The ζ potential (ZP), polydispersity index (PDI), and particle size (PS) of AZM-loaded niosomes were evaluated. The size of the niosomes was found to vary between 288 and 394 nm. The results revealed that the niosomes prepared in a ratio of 2:1 (Span 60: cholesterol) had larger vesicle sizes, but all of them were characterized by narrow size distributions (PDI <0.95). Niosomal gel was successfully prepared using different polymers. The appearance, pH, viscosity, and ex vivo drug release of niosomal gel formulations were all examined. The flow curves showed that the niosomal gel displayed lower viscosity values than its corresponding conventional gels. Niosomal and conventional gels exhibited a domination of the elastic modulus (G') over the viscous modulus (G″) (G'>G″) in the investigated frequency range (0.1-100 rad/s), indicating stable gels with more solid-like properties. Ex vivo skin permeation studies for the niosomal gel show 90.83 ± 3.19% of drug release in 24 h as compared with the conventional gel showing significantly lower (P < 0.001) drug release in the same duration (1.25 ± 0.12%). Overall, these results indicate that niosomal gel could be an effective transdermal nanocarrier for enhancing the permeability of AZM, a BCS class III drug. In conclusion, this study suggests that transdermal formulations of AZM in the niosomal gel were successfully developed and could be used as an alternative route of administration.
    DOI:  https://doi.org/10.1021/acsomega.2c03762
  65. Cancer Res Commun. 2022 Sep;2(9): 951-965
    A ketogenic diet in combination with gemcitabine increases survival in pancreatic cancer KPC mice.
    Natalia E Cortez, Cecilia Rodriguez Lanzi, Brian V Hong, Jihao Xu, Fangyi Wang, Shuai Chen, Jon J Ramsey, Matthew G Pontifex, Michael Müller, David Vauzour, Payam Vahmani, Chang-Il Hwang, Karen Matsukuma, Gerardo G Mackenzie.
      Pancreatic ductal adenocarcinoma (PDAC) continues to be a major health problem. A ketogenic diet (KD), characterized by a very low carbohydrate and high fat composition, has gained attention for its anti-tumor potential. We evaluated the effect and mechanisms of feeding a strict KD alone or in combination with gemcitabine in the autochthonous LSL-KrasG12D/+; LSL-Trp53 R172H/+; Pdx1-Cre (KPC) mouse model. For this purpose, both male and female pancreatic tumor-bearing KPC mice were allocated to a control diet (CD; %kcal: 70% carb, 14% protein, 16% fat), a KD (%kcal: 14% protein, 1% carb, 85% fat), a CD + gemcitabine (CG), or a KD + gemcitabine (KG) group. Mice fed a KD alone or in combination with gemcitabine showed significantly increased blood β-hydroxybutyrate levels compared to mice fed a CD or CG. KPC mice fed a KG had a significant increase in overall median survival compared to KPC mice fed a CD (increased overall median survival by 42%). Interestingly, when the data was disaggregated by sex, the effect of a KG was significant in female KPC mice (60% increase in median overall survival), but not in male KPC mice (28% increase in median overall survival). Mechanistically, the enhanced survival response to a KD combined with gemcitabine was multifactorial, including inhibition of ERK and AKT pathways, regulation of fatty acid metabolism and the modulation of the gut microbiota. In summary, a KD in combination with gemcitabine appears beneficial as a treatment strategy in PDAC in KPC mice, deserving further clinical evaluation.
    Keywords:  ERK and AKT signaling pathways; Ketogenic diet; Lipid metabolism; gemcitabine; microbiome; pancreatic cancer; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1158/2767-9764.crc-22-0256
  66. Front Public Health. 2022 ;10 1017254
    Intermittent fasting and time-restricted eating role in dietary interventions and precision nutrition.
    Ghada A Soliman.
      Intermittent fasting (IF), time-restricted eating (TRE) and fasting-mimicking diets (FMD) are gaining popularity as weight loss programs. As such, the timing and frequency of meals have been recognized as essential contributors to improving cardiometabolic health and a role as adjuvant therapy in cancer. Randomized controlled trials suggested that the weight loss associated with IF is due to a reduced energy intake due to time restriction. Although the supervised TRE clinical trials documented the dietary caloric intake, many free-living studies focused on the timing of meals without a complete characterization of the dietary intake, caloric density, or macronutrient composition. It is possible that both caloric-restriction diets and time-restriction protocols could work synergistically or additively to improve metabolic health outcomes. Like personalized medicine, achieving precision nutrition mandates the provision of the right nutrients to the right patient at the right time. To accomplish this goal, future studies need to evaluate the benefits of IF and TRE. Randomized controlled trials were conducted in different populations, ethnic groups, ages, geographic distribution, physical activity levels, body composition and in patients with obesity, diabetes, and cardiovascular diseases. Also, it is crucial to analyze the dietary composition and caloric density as related to circadian rhythm and timing of meals. It is conceivable that IF and TRE may contribute to precision nutrition strategies to achieve optimal health. However, more research is needed to evaluate IF and TRE effects on health outcomes and any side effects.
    Keywords:  alternative day modified fasting (ADMF); fasting-mimicking diets (FMD); intermittent fasting (IF); precision nutrition; time-restricted eating (TRE)
    DOI:  https://doi.org/10.3389/fpubh.2022.1017254
  67. Int J Biol Macromol. 2022 Nov 10. pii: S0141-8130(22)02620-4. [Epub ahead of print]
    Fucoidan-ferulic acid nanoparticles alleviate cisplatin-induced acute kidney injury by inhibiting the cGAS-STING pathway.
    Xintao Gao, Jing Wang, Yaqi Wang, Shuai Liu, Kehong Dong, Jing Wu, Xiaochen Wu, Dayong Shi, Fanye Wang, Chuanlong Guo.
      Fucoidan (FU) is a natural sulfated polysaccharide with certain biological activity and has been shown to be an excellent nano-delivery material. In this study, ferulic acid (FA)-loaded FU nanoparticles (FA/FU NPs) were prepared and their nephroprotective mechanism was investigated. With a particle size of 158.6 ± 4.5 nm, FA/FU NPs increased the antioxidant activity of FA in vitro, possibly related to the increased dispersity of FA. In vitro results demonstrated that FA/FU NPs significantly protected human renal proximal tubule (HK-2) cells from cisplatin-induced damage, possibly by suppressing cisplatin-induced DNA damage and activating the cGAS-STING pathway. Furthermore, in vivo experiments confirmed that FA/FU NPs protected mice from cisplatin-induced acute kidney injury (AKI). Mechanistic studies confirmed that FA/FU NPs exerted nephroprotective effects by reducing MDA activity and increasing GSH and SOD activity. Our results demonstrated the potential of FU for delivering poorly soluble drug FA and protecting against cisplatin-induced AKI.
    Keywords:  Acute kidney injury; Drug delivery; Ferulic acid; Fucoidan; cGAS-STING
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.11.062
  68. Carbohydr Polym. 2023 Jan 15. pii: S0144-8617(22)01177-8. [Epub ahead of print]300 120272
    Preparation of pectin-chitosan hydrogels based on bioadhesive-design micelle to prompt bacterial infection wound healing.
    Kaichao Song, Yumei Hao, Yi Liu, Ruifeng Cao, Xiuli Zhang, Shuwang He, Jin Wen, Wensheng Zheng, Lulu Wang, Yujia Zhang.
      The aim of this study was to design a pectin-chitosan (PEC-CS) hydrogel loaded with a bioadhesive-design micelle containing large amount of ciprofloxacin for antibacterial and healing wound applications. Pectin and chitosan are crosslinked in a safe and convenient way, and the PEC-CS hydrogel have high water content (>95 %), strong water absorption (15,000 %), good water retention (>10,000 % at 30 % RH for 12 h), and the PEC-CS hydrogels showed no cytotoxicity and hemolysis, thus providing a humid microenvironment suitable for wound. Additionally, the dopamine modified carrier can greatly improve the solubility and retention time in the wound of ciprofloxacin, effectively increase the efficiency of drug loading into the PEC-CS hydrogels and exert antibacterial activity in the wound for a long time. In vitro and in vivo pharmacodynamics experiments have shown that PEC-CS#CIP@DPDMCs hydrogels can resist bacteria and promote wound healing. Thus，The PEC-CS#CIP@DPDMCs hydrogels can be a potential anti-infective hydrogel excipient.
    Keywords:  Bacterial-infected wound healing; Bioadhesive hydrogel; Chitosan; Ciprofloxacin; Dopamine; Pectin
    DOI:  https://doi.org/10.1016/j.carbpol.2022.120272
  69. Medicine (Baltimore). 2022 Nov 11. 101(45): e31493
    A review of the mechanism of succinylation in cancer.
    Keer Lu, Dongwei Han.
      Lysine succinylation is a novel, broad-spectrum, dynamic, non-enzymatic protein post-translational modification (PTM). Succinylation is essential for the regulation of protein function and control of various signaling and regulatory pathways. It is involved in several life activities, including glucose metabolism, amino acid metabolism, fatty acid metabolism, ketone body synthesis, and reactive oxygen species clearance, by regulating protease activity and gene expression. The level of succinylation is mainly regulated by succinyl donor, succinyltransferase, and desuccinylase. Many studies have confirmed that succinylation plays a role in tumorigenesis by creating tissue heterogeneity, and can promote or inhibit various cancers via the regulation of different substrate targets or signaling pathways. The mechanism of action of some antineoplastic drugs is related to succinylation. To better understand the role of succinylation modification in cancer development and treatment, the present study reviewed the current research content and latest progress of succinylation modification in cancer, which might provide a new direction and target for the prevention and treatment of cancer.
    DOI:  https://doi.org/10.1097/MD.0000000000031493
  70. Nucleic Acids Res. 2022 Nov 18. pii: gkac1008. [Epub ahead of print]
    SuperNatural 3.0-a database of natural products and natural product-based derivatives.
    Kathleen Gallo, Emanuel Kemmler, Andrean Goede, Finnja Becker, Mathias Dunkel, Robert Preissner, Priyanka Banerjee.
      Natural products (NPs) are single chemical compounds, substances or mixtures produced by a living organism - found in nature. Evolutionarily, NPs have been used as healing agents since thousands of years and still today continue to be the most important source of new potential therapeutic preparations. Natural products have played a key role in modern drug discovery for several diseases. Furthermore, following consumers' increasing demand for natural food ingredients, many efforts have been made to discover natural low-calorie sweeteners in recent years. SuperNatural 3.0 is a freely available database of natural products and derivatives. The updated version contains 449 058 natural compounds along with their structural and physicochemical information. Additionally, information on pathways, mechanism of action, toxicity, vendor information if available, drug-like chemical space prediction for several diseases as antiviral, antibacterial, antimalarial, anticancer, and target specific cells like the central nervous system (CNS) are also provided for the natural compounds. The updated version of the database also provides a valuable pool of natural compounds in which potential highly sweet compounds are expected to be found. The possible taste profile of the natural compounds was predicted using our published VirtualTaste models. The SuperNatural 3.0 database is freely available via http://bioinf-applied.charite.de/supernatural_3, without any login or registration.
    DOI:  https://doi.org/10.1093/nar/gkac1008
  71. Nat Commun. 2022 Nov 14. 13(1): 6910
    Flash drug release from nanoparticles accumulated in the targeted blood vessels facilitates the tumour treatment.
    Ivan V Zelepukin, Olga Yu Griaznova, Konstantin G Shevchenko, Andrey V Ivanov, Ekaterina V Baidyuk, Natalia B Serejnikova, Artur B Volovetskiy, Sergey M Deyev, Andrei V Zvyagin.
      Tumour microenvironment hinders nanoparticle transport deep into the tissue precluding thorough treatment of solid tumours and metastatic nodes. We introduce an anticancer drug delivery concept termed FlaRE (Flash Release in Endothelium), which represents alternative to the existing approaches based on enhanced permeability and retention effect. This approach relies on enhanced drug-loaded nanocarrier accumulation in vessels of the target tumour or metastasised organ, followed by a rapid release of encapsulated drug within tens of minutes. It leads to a gradient-driven permeation of the drug to the target tissue. This pharmaceutical delivery approach is predicted by theoretical modelling and validated experimentally using rationally designed MIL-101(Fe) metal-organic frameworks. Doxorubicin-loaded MIL-101 nanoparticles get swiftly trapped in the vasculature of the metastasised lungs, disassemble in the blood vessels within 15 minutes and release drug, which rapidly impregnates the organ. A significant improvement of the therapeutic outcome is demonstrated in animal models of early and late-stage B16-F1 melanoma metastases with 11-fold and 4.3-fold decrease of pulmonary melanoma nodes, respectively.
    DOI:  https://doi.org/10.1038/s41467-022-34718-3
  72. Am J Cancer Res. 2022 ;12(10): 4502-4519
    Ivermectin inhibits tumor metastasis by regulating the Wnt/β-catenin/integrin β1/FAK signaling pathway.
    Lu Jiang, Ying-Jian Sun, Xiao-Hua Song, Yan-Yan Sun, Wen-Yao Yang, Jing Li, Yi-Jun Wu.
      Tumor metastasis is the major cause of cancer mortality; therefore, it is imperative to discover effective therapeutic drugs for anti-metastasis therapy. In the current study, we investigated whether ivermectin (IVM), an FDA-approved antiparasitic drug, could prevent cancer metastasis. Colorectal and breast cancer cell lines and a cancer cell-derived xenograft tumor metastasis model were used to investigate the anti-metastasis effect of IVM. Our results showed that IVM significantly inhibited the motility of cancer cells in vitro and tumor metastasis in vivo. Mechanistically, IVM suppressed the expressions of the migration-related proteins via inhibiting the activation of Wnt/β-catenin/integrin β1/FAK and the downstream signaling cascades. Our findings indicated that IVM was capable of suppressing tumor metastasis, which provided the rationale on exploring the potential clinical application of IVM in the prevention and treatment of cancer metastasis.
    Keywords:  Cancer metastasis; HCT-8; Wnt/β-catenin/integrin β1/FAK; anti-metastasis; avermectin; breast cancer; colorectal cancer; xenograft model
  73. Front Pharmacol. 2022 ;13 989717
    Cannabidiol for neurodegenerative disorders: A comprehensive review.
    Sukanya Bhunia, Nagesh Kolishetti, Adriana Yndart Arias, Arti Vashist, Madhavan Nair.
      Despite the significant advances in neurology, the cure for neurodegenerative conditions remains a formidable task to date. Among various factors arising from the complex etiology of neurodegenerative diseases, neuroinflammation and oxidative stress play a major role in pathogenesis. To this end, some phytocannabinoids isolated from Cannabis sativa (widely known as marijuana) have attracted significant attention as potential neurotherapeutics. The profound effect of ∆9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, has led to the discovery of the endocannabinoid system as a molecular target in the central nervous system (CNS). Cannabidiol (CBD), the major non-psychoactive component of cannabis, has recently emerged as a potential prototype for neuroprotective drug development due to its antioxidant and anti-inflammatory properties and its well-tolerated pharmacological behavior. This review briefly discusses the role of inflammation and oxidative stress in neurodegeneration and demonstrates the neuroprotective effect of cannabidiol, highlighting its general mechanism of action and disease-specific pathways in Parkinson's disease (PD) and Alzheimer's disease (AD). Furthermore, we have summarized the preclinical and clinical findings on the therapeutic promise of CBD in PD and AD, shed light on the importance of determining its therapeutic window, and provide insights into identifying promising new research directions.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; cannabidiol; neurodegenerative diseases; neuroinflammation; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2022.989717
  74. Chin Med J (Engl). 2022 Nov 17.
    Metabolic reprogramming in the immunosuppression of tumor-associated macrophages.
    Ying Wang, Dan Wang, Li Yang, Yi Zhang.
       ABSTRACT: Tumor-associated macrophages (TAMs) are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment (TME) and have immunosuppressive functions. The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression, and suppress antineoplastic responses. Due to the uncontrolled proliferation of tumor cells, metabolism homeostasis is regulated, leading to a series of alterations in the metabolite profiles in the TME, which have a commensurate influence on immune cells. Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs, and can alter their metabolic profiles. TAMs undergo a series of metabolic reprogramming processes, involving glucose, lipid, and amino acid metabolism, and other metabolic pathways, which terminally promote the development of the immunosuppressive phenotype. TAMs express a pro-tumor phenotype by increasing glycolysis, fatty acid oxidation, cholesterol efflux, and arginine, tryptophan, glutamate, and glutamine metabolism. Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves. Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs. Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways. In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods. In this review, we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.
    DOI:  https://doi.org/10.1097/CM9.0000000000002426
  75. Sci Rep. 2022 Nov 12. 12(1): 19396
    Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer.
    Konjeti R Sekhar, David N Hanna, Sriram Cyr, Jordan J Baechle, Sudhakiranmayi Kuravi, Ramesh Balusu, Kimryn Rathmell, Naira Baregamian.
      Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers.
    DOI:  https://doi.org/10.1038/s41598-022-23906-2
  76. Phytomedicine. 2022 Oct 31. pii: S0944-7113(22)00612-2. [Epub ahead of print]108 154524
    Targeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer.
    Wenhao Liao, Lanlan Zhang, Xian Chen, Juyi Xiang, Qiao Zheng, Nianzhi Chen, Maoyuan Zhao, Gang Zhang, Xiaolin Xiao, Gang Zhou, Jinhao Zeng, Jianyuan Tang.
       BACKGROUND: Cancer stem cells (CSCs) are strongly associated with high tumourigenicity, chemotherapy or radiotherapy resistance, and metastasis and recurrence, particularly in colorectal cancer (CRC). Therefore, targeting CSCs may be a promising approach. Recently, discovery and research on phytochemicals that effectively target colorectal CSCs have been gaining popularity because of their broad safety profile and multi-target and multi-pathway modes of action.
    PURPOSE: This review aimed to elucidate and summarise the effects and mechanisms of phytochemicals with potential anti-CSC agents that could contribute to the better management of CRC.
    METHODS: We reviewed PubMed, EMBASE, Web of Science, Ovid, ScienceDirect and China National Knowledge Infrastructure databases from the original publication date to March 2022 to review the mechanisms by which phytochemicals inhibit CRC progression by targeting CSCs and their key signalling pathways. Phytochemicals were classified and summarised based on the mechanisms of action.
    RESULTS: We observed that phytochemicals could affect the biological properties of colorectal CSCs. Phytochemicals significantly inhibit self-renewal, migration, invasion, colony formation, and chemoresistance and induce apoptosis and differentiation of CSCs by regulating the Wnt/β-catenin pathway (e.g., diallyl trisulfide and genistein), the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin pathway (e.g., caffeic acid and piperlongumine), the neurogenic locus notch homolog protein pathway (e.g., honokiol, quercetin, and α-mangostin), the Janus kinase-signal transducer and activator of transcription pathway (e.g., curcumin, morin, and ursolic acid), and other key signalling pathways. It is worth noting that several phytochemicals, such as resveratrol, silibinin, evodiamine, and thymoquinone, highlight multi-target and multi-pathway effects in restraining the malignant biological behaviour of CSCs.
    CONCLUSIONS: This review demonstrates the potential of targeted therapies for colorectal CSCs using phytochemicals. Phytochemicals could serve as novel therapeutic agents for CRC and aid in drug development.
    Keywords:  Cancer stem cells; Colorectal cancer; Phytochemicals
    DOI:  https://doi.org/10.1016/j.phymed.2022.154524
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