bims-kracam Biomed News
on K-Ras in cancer metabolism
Issue of 2022–05–01
102 papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development
  1. Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.
  2. Current status of cancer starvation therapy.
  3. Combining Fruquintinib and Doxorubicin in Size-Converted Nano-Drug Carriers for Tumor Therapy.
  4. Amalgamation of Nanotechnology for Delivery of Bioactive Constituents in Solid Tumors.
  5. Fluorescence-Reporting-Guided Tumor Acidic Environment-Activated Triple Photodynamic, Chemodynamic, and Chemotherapeutic Reactions for Efficient Hepatocellular Carcinoma Cell Ablation.
  6. Metal ions/nucleotide coordinated nanoparticles comprehensively suppress tumor by synergizing ferroptosis with energy metabolism interference.
  7. Non-metabolic functions of Pyruvate kinase M2: PKM2 in tumorigenesis and therapy resistance.
  8. Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy.
  9. Iron ion and sulfasalazine-loaded polydopamine nanoparticles for Fenton reaction and glutathione peroxidase 4 inactivation for enhanced cancer ferrotherapy.
  10. H2O2 self-providing synergistic chemodynamic/photothermal therapy using graphene oxide supported zero valence iron nanoparticles.
  11. Recent Advances in Stimuli-Sensitive Amphiphilic Polymer-Paclitaxel Prodrugs.
  12. Tumor acidity/redox hierarchical-activable nanoparticles for precise combination of X-ray-induced photodynamic therapy and hypoxia-activated chemotherapy.
  13. Reversing the HDAC-inhibitor mediated metabolic escape in MYCN-amplified neuroblastoma.
  14. Polymer encapsulated clinical ICG nanoparticles for enhanced photothermal therapy and NIR fluorescence imaging in cervical cancer.
  15. Combination of Curcumin and Photodynamic Therapy Based on the Use of Red Light or Near-Infrared Radiation in Cancer: a Systematic Review.
  16. Enhancement of Conventional and Photodynamic Therapy for Treatment of Cervical Cancer with Cannabidiol.
  17. Apoptosis Induction, Cell Cycle Arrest and Anti-Cancer Potential of Tamoxifen-Curcumin Loaded Niosomes Against MCF-7 Cancer Cells.
  18. Targeted delivery of doxorubicin by Thermo/pH-responsive magnetic nanoparticles in a rat model of breast cancer.
  19. Epigallocatechin gallate: Phytochemistry, bioavailability, utilization challenges, and strategies.
  20. Tumor Microenvironment Responsive Polypeptide-Based Supramolecular Nanoprodrugs for Combination Therapy.
  21. Therapeutic implications and clinical manifestations of thymoquinone.
  22. Synergistic blocking of RAS downstream signaling and epigenetic pathway in KRAS mutant pancreatic cancer.
  23. Liposome Loaded Ion/Temperature Dual Responsive Gellan Gum Hydrogel as Potential Nasal-To-Brain Delivery System.
  24. A nanotheranostic agent based on Nd3+-doped YVO4 with blood-brain-barrier permeability for NIR-II fluorescence imaging/magnetic resonance imaging and boosted sonodynamic therapy of orthotopic glioma.
  25. Oxygen-Independent Sulfate Radical for Stimuli-Responsive Tumor Nanotherapy.
  26. Metabolic cross-talk between ovarian cancer and the tumor microenvironment-providing potential targets for cancer therapy.
  27. Anti- and pro-oxidant potential of lettuce (Lactuca sativa L.) biofortified with iodine by KIO3, 5-iodo- and 3,5-diiodosalicylic acid in human gastrointestinal cancer cell lines.
  28. Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases.
  29. Exploring the effects of Chinese herbal ingredients on the signaling pathway of alopecia and the screening of effective Chinese herbal compounds.
  30. Recent advances in ZnO-based photosensitizers: Synthesis, modification, and applications in photodynamic cancer therapy.
  31. A Revolutionary Blueprint for Mitigation of Hypertension via Nanoemulsion.
  32. A Review of Multifunction Smart Nanoparticle based Drug Delivery Systems.
  33. pH/Redox/Lysozyme-Sensitive Hybrid Nanocarriers With Transformable Size for Multistage Drug Delivery.
  34. Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model.
  35. Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer.
  36. PEGylated ethyl cellulose micelles as a nanocarrier for drug delivery.
  37. Applications of Alginate-Based Nanomaterials in Enhancing the Therapeutic Effects of Bee Products.
  38. 5FU encapsulated polyglycerol sebacate nanoparticles as anti-cancer drug carriers.
  39. Conjugation of a smart polymer to doxorubicin through a pH-responsive bond for targeted drug delivery and improving drug loading on graphene oxide.
  40. Bioactive natural products from marine sponges belonging to family Hymedesmiidae.
  41. Eupaformosanin induces apoptosis and ferroptosis through ubiquitination of mutant p53 in triple-negative breast cancer.
  42. An Overview of Dihydroartemisinin as a Promising Lead Compound for Development of Anticancer Agents.
  43. Promising Role of Phytochemicals in the Prevention and Treatment of Cancer.
  44. Co-delivery of daunorubicin and homoharringtonine in folic acid modified-liposomes for enhancing therapeutic effect on acute myeloid leukemia.
  45. Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model.
  46. Design, synthesis and mechanistic study of new benzenesulfonamide derivatives as anticancer and antimicrobial agents via carbonic anhydrase IX inhibition.
  47. Medicinal Uses, Phytochemistry, Pharmacology, and Toxicology of Mentha spicata.
  48. Factors that influence singlet oxygen formation vs. ligand substitution for light-activated ruthenium anticancer compounds.
  49. Targeting allosteric regulation of cancer metabolism.
  50. Selective terpene based therapeutic deep eutectic systems against colorectal cancer.
  51. The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor.
  52. Application of Quercetin in the Treatment of Gastrointestinal Cancers.
  53. Metabolic regulation of intrasynovial flexor tendon repair:The effects of dichloroacetate administration on early tendon healing in a canine model.
  54. Medicinal chemistry inspired by ginger: exploring the chemical space around 6-gingerol.
  55. Piperlongumine combined with vitamin C as a new adjuvant therapy against gastric cancer regulates the ROS-STAT3 pathway.
  56. Unravelling Micro and Nano vesicular System in Intranasal Drug Delivery for Epilepsy.
  57. Oxygen therapy in traditional and immunotherapeutic treatment protocols of cancer patients: current reality and future prospects.
  58. RAFT polymerization mediated core-shell supramolecular assembly of PEGMA-co-stearic acid block co-polymer for efficient anticancer drug delivery.
  59. Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors.
  60. Target identification of anticancer natural products using a chemical proteomics approach.
  61. Polyphenols from Chinese Herbal Medicine: Molecular Mechanisms and Therapeutic Targets in Pulmonary Fibrosis.
  62. The phytochemistry, pharmacology and traditional medicinal use of Glechomae Herba - a systematic review.
  63. Application of computational screening tools and nanotechnology for enhanced drug synergism in cancer therapy.
  64. Advocation and advancements of EPR effect theory in drug delivery science: A commentary.
  65. Systemic Therapy in Thyroid Cancer.
  66. Nanomaterials enabling clinical translation of antimicrobial photodynamic therapy.
  67. Editorial: Design, Synthesis, and Preclinical Testing of Innovative Anti-Cancer Compounds With a High Level of Selectivity of Action and Low Toxicity.
  68. LS-HB-Mediated Photodynamic Therapy Inhibits Proliferation and Induces Cell Apoptosis in Melanoma.
  69. Rational Fabrication of Folate-Conjugated Zein/Soy Lecithin/Carboxymethyl Chitosan Core-Shell Nanoparticles for Delivery of Docetaxel.
  70. Amino Acids and Doxorubicin as Building Blocks for Metal Ions-Driven Self-Assembly of Biodegradable Polyprodrugs for Tumor Theranostics.
  71. Chemistry of trisindolines: natural occurrence, synthesis and bioactivity.
  72. Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging.
  73. Synthesis and efficacy of norfloxacin loaded onto magnetic hydrogel nanocomposites.
  74. Metabolism in tumor-associated macrophages.
  75. Advances in biopolymeric active films incorporated with emulsified lipophilic compounds: a review.
  76. Small molecule NSAID derivatives for impairing powerhouse in cancer cells.
  77. A Therapeutic Sheep in Metastatic Wolf's Clothing: Trojan Horse Approach for Cancer Brain Metastases Treatment.
  78. Pharmacological effects of cannabidiol by transient receptor potential channels.
  79. Toxic reactive oxygen species enhanced chemodynamic therapy by copper metal-nanocellulose based nanocatalysts.
  80. Silymarin-Encapsulated Xanthan Gum-Stabilized Selenium Nanocarriers for Enhanced Activity Against Amyloid Fibril Cytotoxicity.
  81. Non-Invasive Thermal Therapy for Tissue Engineering and Regenerative Medicine.
  82. Antidepressant Potential of Quercetin and its Glycoside Derivatives: A Comprehensive Review and Update.
  83. Nanocarrier-based co-delivery approaches of chemotherapeutics with natural P-glycoprotein inhibitors in the improvement of multidrug resistance cancer therapy.
  84. An unexpected strategy to alleviate hypoxia limitation of photodynamic therapy by biotinylation of photosensitizers.
  85. NIR-triggered upconversion nanoparticles@thermo-sensitive liposome hybrid theranostic nanoplatform for controlled drug delivery.
  86. Drotaverine Hydrochloride Superporous Hydrogel Hybrid System: a Gastroretentive Approach for Sustained Drug Delivery and Enhanced Viscoelasticity.
  87. Paramylon hydrogel: A bioactive polysaccharides hydrogel that scavenges ROS and promotes angiogenesis for wound repair.
  88. Sea Cucumber Compounds Targeting NF-κB in Cancer Treatment.
  89. Design and Development of Naringin Loaded Proposomal Gel for Wound Healing.
  90. Kaempferol: A flavonoid with wider biological activities and its applications.
  91. Vascular Protective Effect and Its Possible Mechanism of Action on Selected Active Phytocompounds: A Review.
  92. A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy.
  93. Tumor Microenvironment-Responsive Nanodrug for Clear-Cell Renal Cell Carcinoma Therapy via Triggering Waterfall-Like Cascade Ferroptosis.
  94. Green synthesis of gold nanoparticles using an antiepileptic plant extract: in vitro biological and photo-catalytic activities.
  95. The future of functional food: Emerging technologies application on prebiotics, probiotics and postbiotics.
  96. Combined exposure to nanoplastics and metal oxide nanoparticles inhibits efflux pumps and causes oxidative stress in zebrafish embryos.
  97. Self-assembly of diclofenac prodrug into nanomicelles for enhancing the anti-inflammatory activity.
  98. Development of stealth liposomal formulation of celecoxib: In vitro and in vivo evaluation.
  99. Dual Vinorelbine bitartrate and Resveratrol Loaded Polymeric Aqueous core Nanocapsules for Synergistic Efficacy in Breast Cancer.
  100. Potential epigenetic modifications implicated in triple- to quadruple-negative breast cancer transition: a review.
  101. Topical nanostructured lipid carriers of alpha-mangostin and resveratrol for synergistic antioxidant activity.
  102. An osmium-peroxo complex for photoactive therapy of hypoxic tumors.
  1. Acta Biomater. 2022 Apr 20. pii: S1742-7061(22)00231-8. [Epub ahead of print]
    Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.
    Xiangyu Meng, Zhuoxuan Lu, Qingyu Lv, Yongqiang Jiang, Liming Zhang, Zhifei Wang.
      Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met-based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met-based or GOx-mediated monotherapy.
    Keywords:  Metformin; glycolysis inhibition; modified zeolitic imidazolate framework-8; starvation therapy; tumor metabolism
    DOI:  https://doi.org/10.1016/j.actbio.2022.04.022
  2. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Jan 25. 50(7): 1-11
    Current status of cancer starvation therapy.
    Jianyi Li, Dandan Tong, Junsheng Lin.
      Conventional therapies for malignant tumors have limitations and disadvantages. In recent years, the cancer starvation therapy has emerged which intends to deprive cancer cells of nutritional supply. There are several approaches to"starve" cancer cells: to intervene tumor angiogenesis by targeted inhibition of angiogenic factors or their receptors and integrins; to block the blood supply of cancer cells by embolizing or compressing blood vessels; to intervene metabolic process of cancer cells by inhibition of the signal pathways of mitochondrial serine-glycine-one earbon metabolism, glycolysis and amino acid metabolism; cancer starvation therapy can be employed with oxidation therapy, chemotherapy, sonodynamic therapy, anti-autophagy therapy or other therapies to achieve synergistic effects. This article reviews the research progress of cancer starvation therapy in recent years and discusses the existing problems.
    Keywords:  Anti-angiogenesis; Neoplasms; Review; Starvation therapy; Synergistic therapy; Tumor metabolism
    DOI:  https://doi.org/10.3724/zdxbyxb-2021-0297
  3. ACS Biomater Sci Eng. 2022 Apr 28.
    Combining Fruquintinib and Doxorubicin in Size-Converted Nano-Drug Carriers for Tumor Therapy.
    Nan Zhang, Xiangying Xin, Nannan Feng, Deqiao Wu, Junwei Zhang, Tong Yu, Qianqian Jiang, Ming Gao, Hui Yang, Siyuan Zhao, Qingfeng Tian, Zhenzhong Zhang.
      Single-modality tumor therapy confronts many challenges, such as incomplete tumor ablation, tumor metastasis, and limited tumor tissue penetration. Combination therapy simultaneously achieves deep drug delivery to fully exert synergistic effects and has received increasing attention. Herein, based on the excellent efficacy of anti-angiogenesis therapy combined with chemotherapy and the specific size of the poly-amidoamine dendrimer (PAMAM), we developed a pH-triggered size-converted nano-drug delivery system to co-deliver fruquintinib (FRU) and doxorubicin (DOX). This study used cyclic Arg-Gly-Asp (cRGD) as the target, pH-responsive liposomes (PRLs), and PAMAM as the drug carrier. The FRU and DOX-loaded small-particle-size complex polyamide-amine-doxorubicin (PD) was encapsulated into PRLs with the target to construct a size-converted nano-drug delivery system, PRL-PD/FRU-cRGD. This nanoparticle (∼120 nm) actively targeted tumor tissues and used the acidic microenvironment outside tumor cells to release FRU and small-particle-size complex PD (∼15 nm), enabling the conversion of large-size nanoparticles to small-size nanoparticles and resulting in efficient tumor accumulation. In addition, the released PD could realize the deep delivery of DOX, showing efficient deep tumor penetration and further enhancing the tumor-suppressing effect. The results of in vivo and in vitro experiments showed that PRL-PD/FRU-cRGD exhibited the excellent synergistic effects of anti-angiogenesis therapy combined with chemotherapy and effectively inhibited tumor cell proliferation and metastasis, thereby achieving efficient tumor therapy. Thus, PRL-PD/FRU-cRGD shows great potential for combined tumor therapy.
    Keywords:  PAMAM; fruquintinib; fruquintinib-combined chemotherapy; size-converted; tumor tissue penetration
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c01606
  4. Curr Drug Deliv. 2022 Apr 25.
    Amalgamation of Nanotechnology for Delivery of Bioactive Constituents in Solid Tumors.
    Rabea Parveen, Sradhanjali Mohapatra, Sayeed Ahmad, Syed Akhtar Husain.
      Solid tumor is one of the highly prevalent cancers among humans and the treatment is often restricted by drug resistance to chemotherapeutics. One of the main reasons might attribute to limited penetration ability of drugs through tumor tissues due to heterogeneity within the tumor microenvironment. Over the recent years, so much of research has been carried out in developing phytochemicals as cancer therapeutic agents. These are well-established as potential candidates for preventing and treating cancer, especially solid tumors, but have limited clinical applications due to their large molecular size, low bioavailability, stability, and target specificity, along with other side effects when used at high concentrations. There has been widely proposed nano delivery system of bioactive constituents to overcome these obstacles. This nanostructured system might be able to potentiate the action of plant constituents, by reducing the side effects at a lesser dose with improved efficacy. Indeed, nanosystems can deliver the bioactive constituents at a specific site in the desired concentration and avoid undesired drug exposure to normal tissues. Furthermore, these nanoparticles demonstrate high differential absorption efficiency in the target cells over normal cells by preventing them from interacting prematurely with the biological environment, enhancing the cellular uptake and retention effect in disease tissues, while decreasing the toxicity. This review discusses various treatment stratagems used for the management of solid tumors with special emphasis on nanocarrier systems as a potential treatment strategy for herbal drugs. This also covers a wide list of plants that are used for the treatment of solid tumors and cancers along with their mechanisms of action and enlists various nanocarrier systems used for different phytoconstituents. This review gives a brief idea about different plants and their constituents exploited for their anticancer/antitumor potential along with several nanocarrier systems employed for the same and gives future directions to stress the nanotechnology platform as a valuable approach for the prevention and treatment of solid tumors.
    Keywords:  Bioactive constituents; Cancer; Nanodelivery; Nanotechnology; Phytomedicine; Solid tumor
    DOI:  https://doi.org/10.2174/1567201819666220425093102
  5. Langmuir. 2022 Apr 25.
    Fluorescence-Reporting-Guided Tumor Acidic Environment-Activated Triple Photodynamic, Chemodynamic, and Chemotherapeutic Reactions for Efficient Hepatocellular Carcinoma Cell Ablation.
    Mengyu Yao, Xiaojie Wang, Kunshan Huang, Xiao Jia, Jinping Xue, Bing Guo, Juanjuan Chen.
      Tumor acidic environment-activated combination therapy holds great promise to significantly decrease side effects, circumvent multiple drug resistance, and improve therapeutic outcomes for cancer treatment. Herein, Sorafenib/ZnPc(PS)4@FeIII-TA nanoparticles (SPFT) are designed with acid-environment turned-on fluorescence to report the activation of triple therapy including photodynamic, chemodynamic, and chemotherapy on hepatocellular carcinoma. The SPFT are composed of SP cores formulated via self-assembly of sorafenib and ZnPc(PS)4, with high drug loading efficiency, and FeIII-TA shells containing FeCl3 and tannic acid. Importantly, the nanoparticles suppress reactive oxygen species (ROS) generation of ZnPc(PS)4 due to their formation in nanoparticles, while assisting simultaneous uptake of the uploaded drugs in cancer cells. The tumor acidic environment initiates FeIII-TA decomposition and accelerates a chemodynamic reaction between FeII and H2O2 to generate toxic •OH. Then, the SP core is decomposed to separate ZnPc(PS)4 and sorafenib, which leads to fluorescence turning-on of ZnPc(PS)4, expedited photodynamic reactions, and burst release of sorafenib. Notably, SPFT shows low dark cytotoxicity to normal cells but exerts high potency on hepatocellular carcinoma cells under near-infrared light irradiation, which is much more potent than either sorafenib or ZnPc(PS)4 alone. This research offers a facile nanomedicine design strategy for cancer therapy.
    DOI:  https://doi.org/10.1021/acs.langmuir.1c03211
  6. J Nanobiotechnology. 2022 Apr 26. 20(1): 199
    Metal ions/nucleotide coordinated nanoparticles comprehensively suppress tumor by synergizing ferroptosis with energy metabolism interference.
    Yanqiu Wang, Jie Chen, Jianxiu Lu, Juqun Xi, Zhilong Xu, Lei Fan, Hua Dai, Lizeng Gao.
       BACKGROUND: Ferroptosis holds promise as a potential tumor therapy by programming cell death with a hallmark of reactive oxygen species (ROS)-induced lipid peroxidation. However, vigorous energy metabolism may assist tumors to resist oxidative damage and thus weaken the effects of ferroptosis in tumor treatment.
    RESULTS: Herein, a bifunctional antitumor platform was constructed via coordinated interactions between metal ions and nucleotides to synergistically activate ferroptosis and interrupt energy metabolism for tumor therapy. The designed nanoparticles were composed of Fe2+/small interfering RNA (siRNA) as the core and polydopamine as the cloak, which responded to the tumor microenvironment with structural dissociation, thereby permitting tumor-specific Fe2+ and siRNA release. The over-loaded Fe2+ ions in the tumor cells then triggered ferroptosis, with hallmarks of lipid peroxidation and cellular glutathione peroxidase 4 (GPX4) down-regulation. Simultaneously, the released siRNA targeted and down-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in the tumor to inhibit glycolytic pathway, which interfered with tumor energy metabolism and enhanced Fe2+-induced ferroptosis to kill tumor cells.
    CONCLUSIONS: This study presents a concise fabrication of a metal ion/nucleotide-based platform to integrate ferroptosis and energy metabolism intervention in one vehicle, thereby providing a promising combination modality for anticancer therapy.
    Keywords:  Cancer synergistic therapy; Energy metabolic interference; GAPDH siRNA; Metal ion–nucleotide interaction; Nano ferroptosis inducers
    DOI:  https://doi.org/10.1186/s12951-022-01405-w
  7. Neoplasma. 2022 Apr 26. pii: 220119N77. [Epub ahead of print]
    Non-metabolic functions of Pyruvate kinase M2: PKM2 in tumorigenesis and therapy resistance.
    Mustafa İlhan.
      Cancer is the disease of uncontrollably dividing cells in the body. As cancer cells proliferate at higher rates, they need more energy in a short time necessitating deregulation of energy-generating pathways for their benefit. Although oxidative phosphorylation generates more energy from a glucose molecule, cancer cells have a tendency to enhance aerobic glycolysis by consuming more glucose and producing lactate as a by-product even if oxygen is present. In addition to the generation of rapid energy to fulfill their increasing demands, this strategy also provides the use of glucose metabolites such as lactate as a source for the synthesis of anabolic molecules, such as nucleotides, amino acids, and lipids during the rapid phase of the proliferation. Pyruvate kinase M2 (PKM2) is an isoform of pyruvate kinase, which mediates the balancing of energy generation mechanisms during the anabolic and catabolic events. Due to its vital role in glycolysis, PKM2 has been investigated to target cancer cell metabolism for several years. However, recent studies demonstrate that PKM2 may also promote cancer progression by regulating core steps in metastasis such as migration, angiogenesis, and stemness. Of note, it is estimated that 90% of cancer-related deaths are due to metastasis. This review is intended to summarize the recent advances in the non-metabolic roles of PKM2 in cancer progression and to indicate its potential uses for the development of new treatment strategies.
    DOI:  https://doi.org/10.4149/neo_2022_220119N77
  8. J Drug Target. 2022 Apr 28. 1-28
    Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy.
    Gang Wang, Wang Jun-Jie, Xiao-Na Xu, Feng Shi, Fu Xing-Li.
      Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumor microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumor cells and even enhance their aggressive phenotype. This review summarizes the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumor ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumor cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumor cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumor therapies for colorectal cancer.
    Keywords:  Colorectal cancers; energy metabolism; small molecule compounds; tumor ferroptosis
    DOI:  https://doi.org/10.1080/1061186X.2022.2071909
  9. Acta Biomater. 2022 Apr 22. pii: S1742-7061(22)00233-1. [Epub ahead of print]
    Iron ion and sulfasalazine-loaded polydopamine nanoparticles for Fenton reaction and glutathione peroxidase 4 inactivation for enhanced cancer ferrotherapy.
    Xiaokang Zhu, Qifang Chen, Li Xie, Wenjie Chen, Yang Jiang, Erqun Song, Yang Song.
      Ferroptosis shows promising potential in tumor treatment; however, factors that compromise the efficiency of the Fenton catalyst have limited its therapeutic effectiveness. We developed a polydopamine-based nanoplatform constructed with ferric ion and sulfasalazine-loaded nanoparticles (Fe(III)PP@SAS NPs) for dual-functional ferrotherapy strategy of "sword and shield" through enhanced Fenton reaction and inactivation of glutathione peroxidase 4 (GPX4), respectively. Both the Fenton reaction-based hydroxyl radical (•OH) production and sulfasalazine-driven GPX4 inhibition induced ferroptotic cell death, thus achieving synergistic cancer therapy. Near-infrared light irradiation and acidic tumor microenvironment enhanced the release of ferric ions and sulfasalazine from the Fe(III)PP@SAS NPs. In addition, the released iron ions underwent valence state change due to Fenton reaction and thus provided a supplementary T1-weighted signal for in situ visualization of the tumor based on magnetic resonance imaging. The Fe(III)PP@SAS NPs exhibited high pro-ferroptosis performance by utilizing •OH radicals as a "sword" to attack cancer cells and the GPX4 inhibitor to break down the "shield" of cancer cells, thus showing potential for cancer treatment. STATEMENT OF SIGNIFICANCE: Several strategies of cancer therapy based on ferroptosis have emerged in recent years, which have provided new insights into designing materials for therapeutic applications. The antitumor efficacy of ferroptosis is, however, still unsatisfactory, mainly because of insufficient intracellular pro-ferroptotic stimuli. In the current study, we report a multifunctional theranostic nanoplatform, namely Fe(Ⅲ)PP@SAS, with three-fold synergistic effect; this nanoplatform has excellent theranostic potential with multifunctional ferrotherapy.
    Keywords:  GPX4; ferroptosis; photo-ferrotherapy; polydopamine; sulfasalazine
    DOI:  https://doi.org/10.1016/j.actbio.2022.04.024
  10. RSC Adv. 2021 Aug 23. 11(46): 28973-28987
    H2O2 self-providing synergistic chemodynamic/photothermal therapy using graphene oxide supported zero valence iron nanoparticles.
    Miao Xu, Qin Li, Yi Xiang, Shanshan Yuan, Yihan Wu, Jing Zhang, Jinliang Liu, Xiaohui Zhu, Yong Zhang.
      Chemodynamic therapy (CDT) represents an emerging modality that treats cancer and other malignant diseases by using Fenton or Fenton-like catalysts to decompose hydrogen peroxide (H2O2) into toxic hydroxyl radicals (·OH). Despite its great promise, chemodynamic therapy is still limited by low endogenous H2O2 levels and lack of highly efficient nanocatalysts. In this study, we have developed multi-functional therapeutic nanocomposites GO-ZVI-GOx (GO = graphene oxide, ZVI = zero valence iron nanoparticles and GOx = glucose oxidase), where the GOx can catalyze the intracellular glucose and self-produce H2O2 for enhanced CDT therapy, and the GO is used as a template to avoid the aggregation of ZVI nanoparticles and also as an excellent photo-thermal converter for photothermal therapy under near-infrared (NIR) light. Our results show that this H2O2 self-generating nanoplatform can produce substantial amounts of reactive radicals under 808 nm NIR light due to the combinational effect of dual chemodynamic and photothermal therapy, which eventually leads to a significant decrease in cancer cell viability. It is believed that the methodology developed in this study enables conventional chemodynamic therapy to be efficiently improved, and holds great potential for overcoming challenges in many other H2O2-dependent cancer therapies.
    DOI:  https://doi.org/10.1039/d1ra04528h
  11. Front Bioeng Biotechnol. 2022 ;10 875034
    Recent Advances in Stimuli-Sensitive Amphiphilic Polymer-Paclitaxel Prodrugs.
    Man Zhou, Lijuan Wen, Cui Wang, Qiao Lei, Yongxiu Li, Xiaoqing Yi.
      Paclitaxel (PTX) is a broad-spectrum chemotherapy drug employed in the treatment of a variety of tumors. However, the clinical applications of PTX are limited by its poor water solubility. Adjuvants are widely used to overcome this issue. However, these adjuvants often have side effects and poor biodistribution. The smart drug delivery system is a promising strategy for the improvement of solubility, permeability, and stability of drugs, and can promote sustained controlled release, increasing therapeutic efficacy and reducing side effects. Polymeric prodrugs show great advantages for drug delivery due to their high drug loading and stability. There has been some groundbreaking work in the development of PTX-based stimulus-sensitive polymeric prodrug micelles, which is summarized in this study. We consider these in terms of the four main types of stimulus (pH, reduction, enzyme, and reactive oxygen species (ROS)). The design, synthesis, and biomedical applications of stimulus-responsive polymeric prodrugs of PTX are reviewed, and the current research results and future directions of the field are summarized.
    Keywords:  cancer; drug delivery; paclitaxel; polymer prodrug; stimuli-sensitive
    DOI:  https://doi.org/10.3389/fbioe.2022.875034
  12. J Mater Chem B. 2022 Apr 26.
    Tumor acidity/redox hierarchical-activable nanoparticles for precise combination of X-ray-induced photodynamic therapy and hypoxia-activated chemotherapy.
    Beibei Zhang, Rui Xue, Jisheng Lyu, An Gao, Chunyang Sun.
      With the advantages of deep tissue penetration and controllability, external X-ray-induced photodynamic therapy (X-PDT) is highly promising for combined cancer therapy. In addition to the low efficiency of photosensitizer (PS) delivery to tumor sites, however, the radiation- and drug-resistance of hypoxic cells inside the tumor after X-PDT also limit its benefits. Herein, we develop a combined therapeutic modality based on an intelligent nanosized platform (DATAT-NPVT) with tumor acidity-activated TAT presenting and redox-boosted release of tirapazamine (TPZ) for more precise and synchronous X-PDT and selective hypoxia-motivated chemotherapy. After DATAT-NPVT has accumulated in tumor tissues via decreased blood clearance by masking of the TAT ligand, its targeting ability is reactivated by tumor pH (∼6.8), which enhances tumoral cellular uptake. Upon low-dose X-ray irradiation, the encapsulated verteporfin (VP) generates reactive oxygen species (ROS) to carry out X-PDT against MDA-MB-231 breast tumors. As a result of the abundant GSH-triggered degradation of ditelluride bridged bonds, the cascaded TPZ release and activation in the hypoxic environment following X-PDT would produce highly cytotoxic radicals to serve as antitumor agents to kill the remaining hypoxic tumor cells. This concept provides new avenues for the design of hierarchical-responsive drug delivery systems and represents a proof-of-concept combinatorial tumor treatment.
    DOI:  https://doi.org/10.1039/d2tb00303a
  13. Biomed Pharmacother. 2022 Apr 26. pii: S0753-3322(22)00421-8. [Epub ahead of print]150 113032
    Reversing the HDAC-inhibitor mediated metabolic escape in MYCN-amplified neuroblastoma.
    Kausik Bishayee, Uddin Md Nazim, Vijay Kumar, Jieun Kang, Jaebong Kim, Sung-Oh Huh, Ali Sadra.
      In MYCN-amplified neuroblastoma (NB), we noticed that the single compound treatment with the HDAC inhibitor vorinostat led to a reprogramming of the glycolytic pathway in these cells. This reprogramming was upregulation of fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), allowing the cells to generate ATP, albeit at a reduced rate. This behavior was dependent on reduced levels of MYCN and a corresponding increase in the levels of PPARD transcription factors. By integrating metabolic and functional studies in NB cells and mouse xenografts, we demonstrate a compensatory upregulation of FAO/OXPHOS metabolism that promotes resistance to HDAC inhibitors. From the additional compounds that could reverse this metabolic reprogramming, the mTORC1 inhibitor sirolimus was selected. Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level. This combination was seen with no overall toxicity in treated mice in terms of weight loss or liver/kidney function.
    Keywords:  Glycolysis; Neuroblastoma; Sirolimus; Vorinostat; Warburg effect
    DOI:  https://doi.org/10.1016/j.biopha.2022.113032
  14. RSC Adv. 2021 Jun 09. 11(34): 20850-20858
    Polymer encapsulated clinical ICG nanoparticles for enhanced photothermal therapy and NIR fluorescence imaging in cervical cancer.
    Shuang Chen, Lijun Zhu, Zhong Du, Rong Ma, Ting Yan, Gulinigaer Alimu, Xueliang Zhang, Nuernisha Alifu, Cailing Ma.
      Photothermal therapy (PTT) is a popular tumor therapy method, which is based on efficient photothermal nanoagents (PTNs). Clinical Indocyanine Green (ICG), as a Food and Drug Administration (FDA) approved agent, is an often-used PTN, meanwhile it is also a good near-infrared (NIR) fluorescence contrast agent. However, the further applications of ICG in biomedical fields are limited due to its poor stability. In this study, ICG was encapsulated by the amphiphilic polymer poly(styrene-co-maleic anhydride) (PSMA) to form ICG@PSMA nanoparticles. Furthermore, optical and thermal characteristics of ICG@PSMA nanoparticles were studied in detail. Strong NIR fluorescence and excellent photothermal properties of ICG@PSMA nanoparticles under 808 nm laser irradiation were measured. Besides, favorable biocompatibility of ICG@PSMA nanoparticles was demonstrated on a human cervical cancer cell line (HeLa) via cell viability studies. Hence, ICG@PSMA nanoparticles were further applied to enhanced PTT of living HeLa cells under 808 nm excitation, and a high PTT efficiency of ∼70% was obtained. The novel ICG nanoparticles as a promising PTT nanoplatform could offer an opportunity for further tumour treatments.
    DOI:  https://doi.org/10.1039/d1ra02875h
  15. Anticancer Agents Med Chem. 2022 Apr 25.
    Combination of Curcumin and Photodynamic Therapy Based on the Use of Red Light or Near-Infrared Radiation in Cancer: a Systematic Review.
    Marcelo Augusto Germani Marinho, Magno da Silva Marques, Marcos Freitas Cordeiro, Daza de Moraes Vaz Batista Filgueira, Ana Paula Horn.
       BACKGROUND: Photodynamic therapy (PDT) is a therapeutic intervention that can be applied to the treatment of cancer. The interaction between a photosensitizer (PS), ideal wavelength radiation and tissue molecular oxygen, triggers a series of photochemical reactions that are responsible for the production of reactive oxygen species. These highly reactive species can decrease proliferation and induce tumor cell death. The search for PS of natural origin extracted from plants becomes relevant, as they have photoactivation capacity, preferentially targeting tumor cells and because they do not present any or little toxicity to healthy cells.
    OBJECTIVE: Our work aimed to carry out a qualitative systematic review to investigate the effects of curcumin (CUR), a molecule considered as PS of natural origin, on PDT, using red light or near infrared radiation, in tumor models.
    METHODS: A systematic search was performed in three databases (PubMed, Scopus, and Web of Science) using the PICOT method, retrieving a total of 1,373 occurrences. At the end of the peer screening, using inclusion, exclusion, and eligibility criteria, 25 eligible articles were included in this systematic review.
    RESULTS: CUR, whether in its free state, associated with metal complexes or other PS, and in a nanocarrier system, was considered a relevant PS for PDT using red light or near-infrared against tumoral models in vitro and in vivo, acting by increasing cytotoxicity, inhibiting proliferation, inducing cell death mainly by apoptosis, and changing oxidative parameters.
    CONCLUSION: The results found in this systematic review suggest the potential use of CUR as a PS of natural origin to be applied in PDT against many neoplasms, encouraging further search in the field of PDT against cancer and serving as an investigative basis for upcoming pre-clinical and clinical applications.
    Keywords:  Curcuma longa; natural photosensitizer; neoplasm; phototoxicity; qualitative synthesis; turmeric.
    DOI:  https://doi.org/10.2174/1871520622666220425093657
  16. Integr Cancer Ther. 2022 Jan-Dec;21:21 15347354221092706
    Enhancement of Conventional and Photodynamic Therapy for Treatment of Cervical Cancer with Cannabidiol.
    Radmila Razlog, Cherie Ann Kruger, Heidi Abrahamse.
      Cervical cancer (CC) is the fourth most diagnosed cancer in women worldwide. Conventional treatments include surgery, chemo- and radiotherapy, however these are invasive and may cause severe side effects. Furthermore, approximately 70% of late-stage CC patients experience metastasis, due to treatment resistance and limitations. Thus, there is a dire need to investigate alternative therapeutic combination therapies. Photodynamic therapy (PDT) is an alternative CC treatment modality that has been clinically proven to treat primary CC, as well as to limit secondary metastasis. Since PDT is a non-invasive localized treatment, with fewer side effects and lessened resistance to dose repeats, it is considered far more advantageous. However, more clinical trials are required to refine its delivery and dosing, as well as improve its ability to activate specific immune responses to eradicate secondary CC spread. Cannabidiol (CBD) isolates have been shown to exert in vitro CC anticancer effects, causing apoptosis post treatment, as well as inducing specific immune responses, which obstruct tumor invasion and angiogenesis, and so hinder CC metastatic spread. This review paper discusses the current conventional and alternative PDT treatment modalities for CC, as well as their limitations over the last 10 years. It has a particular focus on the combinative administration of CBD with these treatments in order to prevent CC secondary migration and so possibly encourage future research studies to focus on this synergistic effect to eradicate CC.
    Keywords:  cancer treatment; cannabidiol; cannabis; cervical cancer; photodynamic therapy
    DOI:  https://doi.org/10.1177/15347354221092706
  17. Iran J Pathol. 2022 ;17(2): 183-190
    Apoptosis Induction, Cell Cycle Arrest and Anti-Cancer Potential of Tamoxifen-Curcumin Loaded Niosomes Against MCF-7 Cancer Cells.
    Mahdi Fatemizadeh, Farzaneh Tafvizi, Farzaneh Shamsi, Sahar Amiri, Afsaneh Farajzadeh, Iman Akbarzadeh.
       Background & Objective: Breast cancer is the most common cancer among women. One of the most effective treatments for breast cancer is chemotherapy, in which specific drugs destroy the mass and its proliferation is inhibited. Chemotherapy is the most effective adjunctive therapy when multiple medications are used concurrently. Also, combining the drugs with nanocarrier has become an important strategy in targeted therapy. This study is designed to assess the apoptosis induction, cell cycle arrest, and anti-cancer potential of Tamoxifen-Curcumin-loaded niosomes against MCF-7 Cancer Cells.
    Methods: A novel niosomal formulation of tamoxifen-curcumin with Span 80 and lipid to drug ratio of 20 was employed. The MCF-7 cells were cultured and then treated with IC50 value of tamoxifen-curcumin-loaded niosomes, the combination of tamoxifen and curcumin, tamoxifen, and curcumin alone. Flow cytometry, Real-Time PCR, and cell cycle analysis tests were conducted to evaluate the induction of apoptosis.
    Results: Drug-loaded niosomes caused up-regulation of bax and p53 genes and down-regulation of bcl2 gene. Flow cytometry studies showed that niosomes containing tamoxifen-curcumin increased apoptosis rate in MCF-7 cells compared to the combination of tamoxifen and curcumin owing to the synergistic effect between the two drugs along with higher cell uptake by formulation niosomal. These results were also confirmed by cell cycle analysis.
    Conclusion: Co-delivery of curcumin and tamoxifen using optimized niosomal formulation revealed that at acidic pH of MCF-7 cancer cells, released drugs from niosomal carriers would be more effective than physiological pH. This feature of niosomal nanoparticles can reduce the side effects of drugs in normal cells. Niosomal nanoparticles might be used as a biological anti-cancer factor in treatment of breast cancer.
    Keywords:  Breast cancer; Curcumin; Drug delivery; Niosome; Tamoxifen
    DOI:  https://doi.org/10.30699/IJP.2022.124340.2356
  18. Toxicol Appl Pharmacol. 2022 Apr 26. pii: S0041-008X(22)00181-8. [Epub ahead of print] 116036
    Targeted delivery of doxorubicin by Thermo/pH-responsive magnetic nanoparticles in a rat model of breast cancer.
    Nasibeh Mohammad Ali Pourradi, Hossein Babaei, Hamed Hamishehkar, Behzad Baradaran, Behrooz Shokouhi-Gogani, Dariush Shanehbandi, Marjan Ghorbani, Yadollah Azarmi.
      The novel folate conjugated Thermo/pH-responsive magnetic nanoparticles (folate-poly-MNPs) have been developed as a potential nanocarrier for improving site-specific drug delivery, tumor drug accumulation, and therapeutic effects while reducing the adverse effects of conventional drug delivery systems. To evaluate the anticancer efficacy of developed tumor-targeted drug delivery system, forty rat models of breast cancer received saline as control, DOX, DOX-poly-MNPs, and DOX-folate-poly-MNPs at a dose of 2 mg/kg/48 h. The DOX-folate-poly-MNPs showed a significant increase in protein expression of BAX and C-caspase-3 with concomitant downregulation of Bcl-2 expression and ki67 proliferation index compared to the DOX group. The synergistic antitumor efficacy of passive and active drug targeting led to enhanced drug uptake, increased tumor cell apoptosis, decreased tumor volume, and a prolonged survival rate in animals, suggesting that DOX-folate-poly-MNPs may prove to be a promising nanomedicine for the smart treatment of breast cancer in the future.
    Keywords:  Breast cancer; Doxorubicin; Folate targeting; Nanoparticles; Tumor-targeted drug delivery systems
    DOI:  https://doi.org/10.1016/j.taap.2022.116036
  19. J Food Biochem. 2022 Apr 26. e14189
    Epigallocatechin gallate: Phytochemistry, bioavailability, utilization challenges, and strategies.
    Shomaila Mehmood, Maria Maqsood, Nazia Mahtab, Muhammad Issa Khan, Amna Sahar, Sania Zaib, Shehla Gul.
      Epigallocatechin gallate (EGCG), a green tea catechin, has gained the attention of current study due to its excellent health-promoting effects. It possesses anti-obesity, antimicrobial, anticancer, anti-inflammatory activities, and is under extensive investigation in functional foods for improvement. It is susceptible to lower stability, lesser bioavailability, and lower absorption rate due to various environmental, processing, formulations, and gastrointestinal conditions of the human body. Therefore, it is the foremost concern for the researchers to enhance its bioactivity and make it the most suitable therapeutic compound for its clinical applications. In the current review, factors affecting the bioavailability of EGCG and the possible strategies to overcome these issues are reviewed and discussed. This review summarizes structural modifications and delivery through nanoparticle-based approaches including nano-emulsions, encapsulations, and silica-based nanoparticles for effective use of EGCG in functional foods. Moreover, recent advances to enhance EGCG therapeutic efficacy by specifically targeting its molecules to increase its bioavailability and stability are also described. PRACTICAL APPLICATIONS: The main green tea constituent EGCG possesses several health-promoting effects making EGCG a potential therapeutic compound to cure ailments. However, its low stability and bioavailability render its uses in many disorders. Synthesizing EGCG prodrugs by structural modifications helps against its low bioavailability and stability by overcoming premature degradation and lower absorption rate. This review paper summarizes various strategies that benefit EGCG under different physiological conditions. The esterification, nanoparticle approaches, silica-based EGCG-NPs, and EGCG formulations serve as ideal EGCG modification strategies to deliver superior concentrations with lesser toxicity for its efficient penetration and absorption across cells both in vitro and in vivo. As a result of EGCG modifications, its bioactivities would be highly improved at lower doses. The protected or modified EGCG molecule would have enhanced potential effects and stability that would contribute to the clinical applications and expand its use in various food and cosmetic industries.
    Keywords:  EGCG; bio-accessibility; bioactivity; glycosylation; nano-chemoprevention; prodrugs
    DOI:  https://doi.org/10.1111/jfbc.14189
  20. Acta Biomater. 2022 Apr 22. pii: S1742-7061(22)00236-7. [Epub ahead of print]
    Tumor Microenvironment Responsive Polypeptide-Based Supramolecular Nanoprodrugs for Combination Therapy.
    Yue Ding, Chenwei Wang, Yuxuan Ma, Lvming Zhu, Bing Lu, Yang Wang, Jin Wang, Chang-Ming Dong, Yong Yao.
      Tumor microenvironment responsive nanomedicine has drawn considerable attention for combination therapy, but still remains a significant challenge for less side effects and enhanced anti-tumor efficiency. Herein, we develop a pH/ROS dual-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) by using pillar[5]arene-based host-guest strategy for combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT). The PFW-DOX/GOD consists of a pH-responsive ferrocene/pillar[5]arene-containing polypeptide, a ROS-responsive polyprodrug, and encapsulated glucose oxidase (GOD). Upon into intracellular acidic environment, PFW-DOX/GOD exhibits rapid pH-triggered disassembly behavior. Simultaneously, the released GOD can catalyze intratumoral glucose into massive H2O2, which are further converted into highly toxic hydroxyl radicals (•OH) by the catalysis of ferrocene via the Fenton reaction. Thereafter, induced by the ROS-responsive cleavage of thioketal linkage, the conjugated DOX prodrug was released and activated. The combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT) of PFW-DOX/GOD present anti-tumor effect with 96% of tumor inhibitory rate (TIR). Therefore, such tumor microenvironment-responsive supramolecular polypeptide nanoprodrugs represent a potential candidate for combination therapy with minimal side effects. STATEMENT OF SIGNIFICANCE: In this work, a tumor microenvironment-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) was prepared via pillar[5]arene-based host-guest interactions, and presented low side effects and high tumor accumulation owing to the diameters of about 200 nm and surface PEG segment. After pH-responsive release of GOD in the intracellular acidic environment, the cascade catalytic reactions including GOD-catalyzed degradation of intratumoral glucose and Fenton reaction, effectively happened to generate •OH for chemodynamic therapy (CDT), which subsequently induced the cleavage of thioketal linkage to activate free DOX for chemotherapy (CT). Collectively, this supramolecular polypeptide nanoprodrugs provide a promising strategy for combination therapy with synergetic anti-tumor effect.
    Keywords:  anti-tumor therapy; ferrocene-containing nanoprodrug; host-guest interactions; supramolecular prodrug; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.actbio.2022.04.027
  21. Phytochemistry. 2022 Apr 23. pii: S0031-9422(22)00129-7. [Epub ahead of print] 113213
    Therapeutic implications and clinical manifestations of thymoquinone.
    Manzar Alam, Gulam Mustafa Hasan, Md Meraj Ansari, Rishi Sharma, Dharmendra Kumar Yadav, Md Imtaiyaz Hassan.
      Thymoquinone (TQ), a natural phytochemical predominantly found in Nigella sativa, has been investigated for its numerous health benefits. TQ showed anti-cancer, anti-oxidant, and anti-inflammatory properties, validated in various disease models. The anti-cancer potential of TQ is stimulated through anti-proliferation, cell cycle arrest, apoptosis induction, ROS production, anti-metastasis and anti-angiogenesis, inhibition of cell migration and an invasion. Additionally, TQ exhibited antitumor activity via the modulation of multiple pathways and molecular targets, including Akt, ERK1/2, STAT3, and NF-κB. The present review emphasized highlighting the potential of TQ in anti-cancer therapy. We summarize the anti-cancer, anti-oxidant, and anti-inflammatory properties of TQ, focusing on its molecular targets and its promising action in cancer therapy. We further described the molecular mechanisms by which TQ prevents signaling pathways that mediate cancer progression, invasion, and metastasis.
    Keywords:  Anti-cancer; Anti-inflammatory; Anti-oxidant; Apoptosis; Cancer therapy; Signaling pathways; Thymoquinone
    DOI:  https://doi.org/10.1016/j.phytochem.2022.113213
  22. Aging (Albany NY). 2022 Apr 25. 14(undefined):
    Synergistic blocking of RAS downstream signaling and epigenetic pathway in KRAS mutant pancreatic cancer.
    Xiaofei Zhang, Tiebo Mao, Haiyan Xu, Shumin Li, Ming Yue, Jingyu Ma, Jiayu Yao, Yongchao Wang, Xiao Zhang, Weiyu Ge, Yanling Wang, Daiyuan Shentu, Liwei Wang.
       BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy and lacks effective therapeutic targets. Trametinib is considered to be a promising potential indirectly targeted KRAS inhibitor in PDAC. However, the clinical outcomes were poor. JQ1 displayed a significant synergistic effect when combined with chemotherapy or potential targeted therapy in pancreatic cancer. The impact of Trametinib and JQ1 combination treatment in PDAC remains to be fully elucidated.
    METHODS: The efficacy of trametinib and JQ1 on cell proliferation and cytotoxicity was assayed in 7 KRAS mutant pancreatic cancer cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using a luminescent cell viability assay. Immunoblot analysis was carried out to investigate changes in p62 and autophagy.
    RESULTS: We found that either trametinib or JQ1 alone inhibited the proliferation of some pancreatic cancer cell lines with KRAS alterations, irrespective of the mutational loci of KRAS and the aberrant status of the other driver genes. The synergistic effects of combination treatment of trametinib and JQ1 were observed in both trametinib-resistant and trametinib-sensitive cells. In trametinib-sensitive PDAC cells, the combined treatment definitely inhibited p62 expression compared with trametinib alone, while LC3 expression at high levels changed little. In trametinib-resistant PDAC cells, the combination of MEK/BET inhibitor dramatically decreased p62 expression compared with single agent, while p62 expression increased after anti-autophagic therapy was added.
    CONCLUSIONS: Blocking RAS downstream signaling and epigenetic pathway synergistically increases the antiproliferative activity in KRAS mutant PDAC cells. Combination therapeutic synergism may induce different cell death modes in different pancreatic cancer subtypes.
    Keywords:  BET inhibitor; MEK inhibitor; autophagy; pancreatic ductal adenocarcinoma; synergistic effect
    DOI:  https://doi.org/10.18632/aging.204031
  23. J Biomed Nanotechnol. 2022 Feb 01. 18(2): 571-580
    Liposome Loaded Ion/Temperature Dual Responsive Gellan Gum Hydrogel as Potential Nasal-To-Brain Delivery System.
    Shuwen Zhou, Xinmeng Zheng, Jun Chen, Yiyang Xu, Xuancheng Du, Cheng Wang, Pengfei Cui, Lin Qiu, Pengju Jiang, Xinye Ni, Jianhao Wang.
      Intranasal administration, which can bypass the blood-brain barrier (BBB), is widely recognized as a promising strategy for high-efficiency drug delivery to the brain. Herein, for the purpose of effectively delivering drugs to the brain via intranasal administration, glutathione (GSH)-modified gellan gum (GSH-GG) with ion/temperature dual responsive properties was synthesized and encapsulated on galanthamine hydrobromide (GH)-loaded liposomes (GH-Lipo) for effective GH delivery to the brain (GH-Lipo@GSH-GG). Our results demonstrated that GSH-GG greatly decreased the gelation temperature of GG from 44.0 °C to 22.1 °C without compromising its ion responsiveness. Moreover, GSH-GG had a good protection ability for GH-loaded liposomes without affecting its drug release. Most importantly, the finally obtained GH-Lipo@GSHGG showed acceptable targeted delivery of GH to the brain upon in vivo administration. Therefore, this formulation can be employed as a potential delivery system in nasal-to-brain delivery.
    DOI:  https://doi.org/10.1166/jbn.2022.3253
  24. Light Sci Appl. 2022 Apr 29. 11(1): 116
    A nanotheranostic agent based on Nd3+-doped YVO4 with blood-brain-barrier permeability for NIR-II fluorescence imaging/magnetic resonance imaging and boosted sonodynamic therapy of orthotopic glioma.
    Zhijia Lv, Longhai Jin, Yue Cao, Hao Zhang, Dongzhi Xue, Na Yin, Tianqi Zhang, Yinghui Wang, Jianhua Liu, Xiaogang Liu, Hongjie Zhang.
      The specific diagnosis and treatment of gliomas is a primary challenge in clinic due to their high invasiveness and blood-brain barrier (BBB) obstruction. It is highly desirable to find a multifunctional agent with good BBB penetration for precise theranostics. Herein, we design and construct a core-shell structured nanotheranostic agent (YVO4:Nd3+-HMME@MnO2-LF, marked as YHM) with YVO4:Nd3+ particles as the core and MnO2 nanosheets as the shell. Sonosensitizer hematoporphyrinmonomethyl ether (HMME) and lactoferrin (LF) were further loaded and modified on the surface, giving it a good ability to cross the BBB, near-infrared fluorescence imaging in the second window (NIR-II)/magnetic resonance imaging (MRI) bimodality, and highly efficient sonodynamic therapy (SDT) of orthotopic gliomas. The YVO4:Nd3+ (25%) core exhibited good NIR-II fluorescence properties, enabling YHM to act as promising probes for NIR-II fluorescence imaging of vessels and orthotopic gliomas. MnO2 shell can not only provide O2 in the tumor microenvironments (TME) to significantly improve the healing efficacy of SDT, but also release Mn2+ ions to achieve T1-weight MRI in situ. Non-invasive SDT can effectively restrain tumor growth. This work not only demonstrates that multifunctional YHM is promising for diagnosis and treatment of orthotopic glioma, but also provides insights into exploring the theranostic agents based on rare earth-doped yttrium vanadate nanoparticles.
    DOI:  https://doi.org/10.1038/s41377-022-00794-9
  25. Adv Sci (Weinh). 2022 Apr 30. e2200974
    Oxygen-Independent Sulfate Radical for Stimuli-Responsive Tumor Nanotherapy.
    Dandan Ding, Zihan Mei, Hui Huang, Wei Feng, Liang Chen, Yu Chen, Jianqiao Zhou.
      Variant modalities are quested and merged into the tumor nanotherapy by leveraging the excitation from external or intratumoral incentives. However, the ubiquitous hypoxia and the insufficient content of hydrogen peroxide (H2 O2 ) in tumor microenvironments inevitably hinder the effective production of reactive oxygen species (ROS). To radically extricate from the shackles, peroxymonosulfate (PMS: HSO5 - )-loaded hollow mesoporous copper sulfide (CuS) nanoparticles (NPs) are prepared as the distinct ROS donors for sulfate radical (•SO4 - )-mediated and stimuli-responsive tumor nanotherapy in an oxygen-independent manner. In this therapeutic modality, the second near-infrared laser irradiation, together with the released copper ions as well as the heat produced by CuS after illumination, work together to activate PMS thus triply ensuring the copious production of •SO4 - . Different from conventional ROS, the emergence of •SO4 - , possessing a longer half-life and more rapid reaction, is independent of the oxygen (O2 ) and H2 O2 content within the tumor. In addition, this engineered nanosystem also exerts the function of photoacoustic imaging and skin restoration on the corresponding animal models. This study reveals the enormous potential of sulfate radical in oncotherapy and broadens pave for exploring the application of multifunctional and stimuli-responsive nanosystems in biomedicine.
    Keywords:  melanoma; reactive oxygen species (ROS); skin tissue healing; stimuli-responsive; ulfate radical
    DOI:  https://doi.org/10.1002/advs.202200974
  26. Front Biosci (Landmark Ed). 2022 Apr 20. 27(4): 139
    Metabolic cross-talk between ovarian cancer and the tumor microenvironment-providing potential targets for cancer therapy.
    Yi Lin, Xiao Liang, Xijie Zhang, Yanghong Ni, Xiaoting Zhou, Xia Zhao.
      Conventional treatments for ovarian cancer, including debulking cytoreductive surgery combined with carboplatin/paclitaxel-based chemotherapy, are insufficient, as evidenced by the high mortality rate, which ranks first among gynecological tumors. Therefore, there is an urgent need to develop new and effective treatment strategies. Recent evidence has shown that metabolic processes and cell behaviors in ovarian cancer are regulated by intracellular factors as well as metabolites in the tumor microenvironment (TME), which determine occurrence, proliferation, and metastasis. In this review, we describe the comprehensive landscape of metabolic cross-talk between ovarian cancer and its TME with a focus on the following four aspects: (1) intracellular metabolism based on the Warburg effect, (2) metabolism in non-tumor cells in the ovarian TME, (3) metabolic communication between tumor cells and non-tumor cells in the TME, and (4) metabolism-related therapeutic targets and agents for ovarian cancer. The metabolic cross-talk between ovarian cancer and its microenvironment involves a complex network of interactions, and interrupting these interactions by metabolic interventions is a promising therapeutic strategy.
    Keywords:  cancer therapies; metabolites; ovarian cancer; review; tumor microenvironment
    DOI:  https://doi.org/10.31083/j.fbl2704139
  27. RSC Adv. 2021 Aug 09. 11(44): 27547-27560
    Anti- and pro-oxidant potential of lettuce (Lactuca sativa L.) biofortified with iodine by KIO3, 5-iodo- and 3,5-diiodosalicylic acid in human gastrointestinal cancer cell lines.
    Olga Sularz, Aneta Koronowicz, Sylwester Smoleń, Iwona Kowalska, Łukasz Skoczylas, Marta Liszka-Skoczylas, Małgorzata Tabaszewska, Joanna Pitala.
      Vegetables are particularly rich sources of micronutrients and phytochemicals such as polyphenols and vitamins. These plant-derived bioactive compounds provide antitumor and antioxidant properties due to their capacity to interact with reactive oxygen species (ROS). The objective of this study was to determine the effect of iodine biofortification (potassium iodate/KIO3/, 5-iodosalicylic acid/5-ISA/, and 3,5-diiodosalicylic acid/3,5-diISA/) on the antioxidant activity of lettuce (Lactuca sativa L. capitata) cv. 'Melodion'. In this work, HPLC analysis was used to identify polyphenolic compounds while the antioxidant activity of iodine-enriched vegetables was determined by using DPPH, ABTS and FRAP methods. The content of the water-soluble vitamins was analyzed by using the LC-MS/MS technique. The impact of extracts from iodine-biofortified lettuce on production of reactive oxygen species (ROS) in gastrointestinal cancer cells was also evaluated. The results from this research indicate that application of iodine compounds improves the antioxidant potential of lettuce by increasing the concentration of some vitamins, antioxidant enzymes and polyphenolic compounds in the enriched plants. Moreover, the study has shown that iodine-biofortified lettuce induces production of ROS in cancer cells, resulting in an anticancer effect by the induction of programmed cancer cell death.
    DOI:  https://doi.org/10.1039/d1ra04679a
  28. Microb Pathog. 2022 Apr 22. pii: S0882-4010(22)00165-6. [Epub ahead of print] 105552
    Curcumin: A therapeutic strategy for targeting the Helicobacter pylori-related diseases.
    Asadollah Mohammadi, Hashem Khanbabaei, Farid Zandi, Abbas Ahmadi, Saeed Mohammadian Haftcheshmeh, Thomas P Johnston, Amirhossein Sahebkar.
      Helicobacter pylori is a significant human pathogen of the stomach's epithelial lining. This type of carcinogen is associated with gastric cancer, indigestion, peptic ulcers, and upper digestive diseases. Therefore, successful treatment and eradication of this bacterium are required to reduce the prevalence of these diseases, especially in high-risk individuals. Moreover, some concerns exist regarding the extensive use of elimination therapy, such as anti-microbial resistance and rising H. pylori-associated diseases. Since there is still no effective vaccine, finding alternative therapies would appear to be a worthwhile pursuit. In this regard, curcumin exhibits anti-inflammatory, anti-carcinogenic, anti-oxidant properties and is widely used as a natural product-derived medicine or nutraceutical. Furthermore, curcumin has been reported to have anti-bacterial activity. Therefore, curcumin might be an effective herbal-based medicine for preventing, managing, or treating H. pylori infection. This review discusses the anti-inflammatory, anti-cancer, and anti-bacterial properties of curcumin as it pertains to gastric cancer and H. pylori-associated diseases.
    Keywords:  Gastric cancer; Helicobacter pylori; Herbal medicine; Turmeric
    DOI:  https://doi.org/10.1016/j.micpath.2022.105552
  29. J Ethnopharmacol. 2022 Apr 25. pii: S0378-8741(22)00359-2. [Epub ahead of print] 115320
    Exploring the effects of Chinese herbal ingredients on the signaling pathway of alopecia and the screening of effective Chinese herbal compounds.
    Dou Jinjin, Zhang Zhiming, Xu Xianrong, Zhang Xiwu.
       ETHNOPHARMACOLOGICAL RELEVANCE: alopecia is a hair disorder that can add a significant medical and psychological burden to patients. Currently, the FDA-approved drugs for the treatment of androgenetic alopecia (AGA) are minoxidil and finasteride and immunosuppressives are therapeutic options for alopecia areata (AA), but the objective adverse effects and high cost of these treatments reduce patient compliance and thus the effectiveness of the drugs. Traditional Chinese medicine (TCM) has good efficacy, a high safety profile and low treatment costs, but its mechanism of action is still not fully understood. The use of signaling pathways to modulate hair loss is a major direction in the study of the pathogenesis and pharmacology of alopecia.
    AIM OF THE STUDY: This review aims to collect the results of experimental studies related to alopecia, to screen previously documented combinations of herbs claimed to be effective based on the herbs and their constituent compounds used in the identified studies, and to uncover other useful information that we hope will better guide the clinical application and scientific research of drug combinations or individual herbs for the treatment of alopecia.
    MATERIALS AND METHODS: We have reviewed experimental studies to determine the methods used and the mechanisms of action of the herbs and constituent compounds. The following keywords were searched in databases, including PubMed, EMBASE, CNKI and CSTJ." Medicinal plants" "Chinese herbal medicine", "hair loss", " alopecia", "androgenetic alopecia" and " alopecia areata ". We also collected combinations of drugs from books approved by various schools for screening.
    RESULTS: Using known combinations of compounds within herbal medicine to match the documented combinations, 34 topical combinations and 74 oral combinations were identified, and among the 108 herbal combinations screened Angelica, Rehmannia glutinosaLigusticum chuanxiong hort, Radix Rehmanniae, etc. The number of occurrences was very high, and the association with vascular drugs was also found to be very close.
    CONCLUSIONS: This review further elucidates the therapeutic mechanisms of the compounds within the herbal components associated with alopecia and screens for other combinations that may be dominated by this component for the treatment of alopecia, uncovering compounds from other drugs that may be key factors in the treatment of alopecia. This improvement will provide a better quality of evidence for the effectiveness of herbs and compounds used to treat alopecia.
    Keywords:  Active ingredients; Alopecia; Herbal medicine; Review; Signaling pathways
    DOI:  https://doi.org/10.1016/j.jep.2022.115320
  30. J Colloid Interface Sci. 2022 Apr 20. pii: S0021-9797(22)00649-X. [Epub ahead of print]621 440-463
    Recent advances in ZnO-based photosensitizers: Synthesis, modification, and applications in photodynamic cancer therapy.
    Hira Fatima, Zheng Yang Jin, Zongping Shao, Xiang Jian Chen.
      Zinc oxide nanoparticles (ZnO NPs) are important semiconductor materials with interesting photo-responsive properties. During the past, ZnO-based NPs have received considerable attention for photodynamic therapy (PDT) due to their biocompatibility and excellent potential of generating tumor-killing reactive oxygen species (ROS) through gentle photodynamic activation. This article provides a comprehensive review of the recent developments and improvements in optical properties of ZnO NPs as photosensitizers for PDT. The optical properties of ZnO-based photosensitizers are significantly dependent on their charge separation, absorption potential, band gap engineering, and surface area, which can be adjusted/tuned by doping, compositing, and morphology control. Here, we first summarize the recent progress in the charge separation capability, absorption potential, band gap engineering, and surface area of nanosized ZnO-based photosensitizers. Then, morphology control that is closely related to their synthesis method is discussed. Following on, the state-of-art for the ZnO-based NPs in the treatment of hypoxic tumors is comprehensively reviewed. Finally, we provide some outlooks on common targeted therapy methods for more effective tumor killing, including the attachment of small molecules, antibodies, ligands molecules, and receptors to NPs which further improve their selective distribution and targeting, hence improving the therapeutic effectiveness. The current review may provide useful guidance for the researchers who are interested in this promising dynamic cancer treatment technology.
    Keywords:  Hypoxic tumor; Photodynamic therapy; Photosensitizer; Targeted therapy; ZnO nanoparticles
    DOI:  https://doi.org/10.1016/j.jcis.2022.04.087
  31. Biomed Res Int. 2022 ;2022 4109874
    A Revolutionary Blueprint for Mitigation of Hypertension via Nanoemulsion.
    Girish Kumar, Tarun Virmani, Kamla Pathak, Abdulsalam Alhalmi.
      Hypertension is one of the most important causes of mortality, affecting the health status of the patient. At the same time, hypertension causes a huge health and economic burden on the whole world. The incidence and prevalence of hypertension are rising even among young people in both urban as well as rural communities. Although various conventional therapeutic moieties are available for the management of hypertension, they have serious flaws such as hepatic metabolism, reduced dose frequency, poor aqueous solubility, reduced bioavailability, and increased adverse effects, making the drug therapy ineffective. Therefore, it is required to design a novel drug delivery system having the capability to solve the constraints associated with conventional treatment of hypertension. Nanotechnology is a new way of using and manipulating the matter at the molecular level, whose functional organization is measured in nanometers. The applications of nanotechnology in the field of medicine provide an alternative and novel direction for the treatment of cardiovascular diseases and show excellent performance in the field of targeted drug therapy. Various nanotechnologies based drug delivery systems, such as solid lipid nanoparticles, nanosuspension, nanoemulsion, liposome, self-emulsifying systems, and polymeric nanoparticles, are available. Among them, nanoemulsion has provided a niche to supplement currently available therapeutic choices due to numerous benefits like stability, ease of preparation, enhanced drug absorption, reduced hepatic metabolism, increased dose frequency, enhanced bioavailability, and encapsulation of hydrophilic as well as hydrophobic drugs. This present review provides an in-depth idea about progression in treatment of hypertension, constraints for antihypertensive drug therapy, need of nanoemulsions to overcome these constraints, comparative analysis of nanoemulsions over other nanostructure drug delivery systems, pharmacodynamics studies of nanoemulsions for treatment of hypertension, recent patents for drug-loaded nanoemulsions meant for hypertension, and marketed formulations of nanoemulsions for hypertension.
    DOI:  https://doi.org/10.1155/2022/4109874
  32. Curr Pharm Des. 2022 Apr 22.
    A Review of Multifunction Smart Nanoparticle based Drug Delivery Systems.
    Hareem Fatima, Muhammad Yasin Naz, Shazia Shukrullah, Hira Aslam, Sami Ullah, Mohammed Ali Assiri.
      Cancer nano-therapeutics are rapidly evolving and are often used to overcome a number of concerns with traditional drug delivery methods, including non-specific drug targeting and distribution, low oral bioavailability and poor hydrophilicity. Modern nano-based targeting techniques have been developed as a result of advances in nano vehicle engineering and materials science, which may bring people with cancer a new hope. Clinical trials have been authorized for a number of medicinal nanocarriers. To optimize biodistribution and enhance circulation duration in the blood, nanocarriers have been created for the best possible size and surface properties. Nanotherapeutics can carry preloaded active medicine towards cancerous cells by preferentially leveraging the specific physiopathology of malignancies. In contrast to passive targeting, active targeting strategies involving antigens or ligands, developed against specific tumor sites, boost the selectivity of these curative nano-vehicles. Another barrier that nanoparticles may resolve or lessen is drug resistance. Multi-functional and complex nanoparticles are currently being researched and are expected to be the next era of nanoparticles, allowing for more individualized and customized cancer therapy. The potential prospects as well as opportunities of stimuli-triggered nano systems in therapeutic trials are also explored in this review.
    Keywords:  Smart nanoparticles; active targeting tactics; drug delivery systems; drug resistance; nanotherapeutics; physiopathology of malignancies
    DOI:  https://doi.org/10.2174/1381612828666220422085702
  33. Front Bioeng Biotechnol. 2022 ;10 882308
    pH/Redox/Lysozyme-Sensitive Hybrid Nanocarriers With Transformable Size for Multistage Drug Delivery.
    Zhe Liu, Dong Zhou, Lan Liao.
      The majority of current nanocarriers in cancer treatment fail to deliver encapsulated cargos to their final targets at therapeutic levels, which decreases the ultimate efficacy. In this work, a novel core-shell nanocarrier with a biodegradable property was synthesized for efficient drug release and subcellular organelle delivery. Initially, silver nanoparticles (AgNPs) were grafted with terminal double bonds originating from N, N'-bisacrylamide cystamine (BAC). Then, the outer coatings consisting of chitosan (CTS) and polyvinyl alcohol (PVA) were deposited on the surface of modified AgNPs using an emulsion method. To improve the stability, disulfide-containing BAC was simultaneously reintroduced to cross-link CTS. The as-prepared nanoparticles (CAB) possessed the desired colloidal stability and exhibited a high drug loading efficiency of cationic anticancer agent doxorubicin (DOX). Furthermore, CAB was tailored to transform their size into ultrasmall nanovehicles responding to weak acidity, high glutathione (GSH) levels, and overexpressed enzymes. The process of transformation was accompanied by sufficient DOX release from CAB. Due to the triple sensitivity, CAB enabled DOX to accumulate in the nucleus, leading to a great effect against malignant cells. In vivo assays demonstrated CAB loading DOX held excellent biosafety and superior antitumor capacity. Incorporating all the benefits, this proposed nanoplatform may provide valuable strategies for efficient drug delivery.
    Keywords:  antitumor; multistage drug delivery; nanocarrier; transformable size; triple sensitivity
    DOI:  https://doi.org/10.3389/fbioe.2022.882308
  34. ACS Appl Mater Interfaces. 2022 Apr 27.
    Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model.
    Min Lu, Xu Huang, Xiaohui Cai, Jiajia Sun, Xuemeng Liu, Lingyan Weng, Li Zhu, Qianqian Luo, Zhongping Chen.
      Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(d,l-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.
    Keywords:  breast cancer; drug delivery; hypoxia-responsiveness; polymeric micelles; stereocomplex; tumor metastasis
    DOI:  https://doi.org/10.1021/acsami.1c23737
  35. Oncologist. 2022 Apr 26. pii: oyac077. [Epub ahead of print]
    Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer.
    Marwan Fakih, Huakang Tu, Hil Hsu, Shivani Aggarwal, Emily Chan, Marko Rehn, Victoria Chia, Scott Kopetz.
       BACKGROUND: The KRAS p.G12C mutation has recently become an actionable drug target. To further understand KRAS p.G12C disease, we describe clinicopathologic characteristics, treatment patterns, overall survival (OS), and real-world progression-free survival (rwPFS) in patients with metastatic colorectal cancer (mCRC), KRAS p.G12C mutations (KRAS G12C), and other KRAS mutations (KRAS non-G12C) using a de-identified database.
    PATIENTS AND METHODS: Clinical and tumor characteristics, including treatments received, genomic profile, and clinical outcomes were assessed for patients from a US clinical genomic database with mCRC diagnosed between January 1, 2011, and March 31, 2020, with genomic sequencing data available.
    RESULTS: Of 6477 patients with mCRC (mCRC cohort), 238 (3.7%) had KRAS G12C and 2947 (45.5%) had KRAS non-G12C mutations. Treatment patterns were generally comparable across lines of therapy (LOT) in KRAS G12C versus KRAS non-G12C cohorts. Median (95% CI) OS after the first LOT was 16.1 (13.0-19.0) months for the KRAS G12C cohort versus 18.3 (17.2-19.3) months for the KRAS non-G12C cohort, and 19.2 (18.5-19.8) months for the mCRC overall cohort; median (95% CI) rwPFS was 7.4 (6.3-9.5), 9.0 (8.2-9.7), and 9.2 (8.6-9.7) months, respectively. The different KRAS non-G12C mutations examined did not affect clinical outcomes. Median OS and rwPFS for all cohorts declined with each subsequent LOT.
    CONCLUSIONS: Patients with KRAS p.G12C-mutant mCRC have poor treatment outcomes, and outcomes appear numerically worse than for those without this mutation, indicating potential prognostic implications for KRAS p.G12C mutations and an unmet medical need in this population.
    Keywords:   KRAS p.G12C; metastatic colorectal cancer; retrospective
    DOI:  https://doi.org/10.1093/oncolo/oyac077
  36. RSC Adv. 2021 Sep 14. 11(49): 30532-30543
    PEGylated ethyl cellulose micelles as a nanocarrier for drug delivery.
    Amarnath Singam, Naresh Killi, Pratikshkumar R Patel, Rathna V N Gundloori.
      Natural polymers provide a better alternative to synthetic polymers in the domain of drug delivery systems (DDSs) because of their renewability, biocompatibility, and low immunogenicity; therefore, they are being studied for the development of bulk/nanoformulations. Likewise, current methods for engineering natural polymers into micelles are in their infancy, and in-depth studies are required using natural polymers as controlled DDSs. Accordingly, in our present study, a new micellar DDS was synthesized using ethyl cellulose (EC) grafted with polyethylene glycol (PEG); it was characterized, its properties, cell toxicity, and hemocompatibility were evaluated, and its drug release kinetics were demonstrated using doxorubicin (DOX) as a model drug. Briefly, EC was grafted with PEG to form the amphiphilic copolymers EC-PEG1 and EC-PEG2 with varying PEG concentrations, and nano-micelles were prepared with and without the drug (DOX) via a dialysis method; the critical micelle concentrations (CMCs) were recorded to be 0.03 mg mL-1 and 0.00193 mg mL-1 for EC-PEG1 and EC-PEG2, respectively. The physicochemical properties of the respective nano-micelles were evaluated via various characterization techniques. The morphologies of the nano-micelles were analyzed via transmission electron microscopy (TEM), and the average size of the nano-micelles was recorded to be ∼80 nm. In vitro, drug release studies were done for 48 h, where 100% DOX release was recorded at pH 5.5 and 52% DOX release was recorded at pH 7.4 from the micelles. In addition, cytotoxicity studies suggested that DOX-loaded micelles were potent in killing MDA-MB-231 and MCF-7 cancer cells, and the blank micelles were non-toxic toward cancerous and normal cells. A cellular uptake study via fluorescence microscopy indicated the internalization of DOX-loaded micelles by cancer cells, delivering the DOX into the cellular compartments. Based on these studies, we concluded that the developed material should be studied further via in vivo studies to understand its potential as a controlled DDS to treat cancer.
    DOI:  https://doi.org/10.1039/d1ra04242d
  37. Front Mol Biosci. 2022 ;9 865833
    Applications of Alginate-Based Nanomaterials in Enhancing the Therapeutic Effects of Bee Products.
    Mohammad A I Al-Hatamleh, Walhan Alshaer, Ma'mon M Hatmal, Lidawani Lambuk, Naveed Ahmed, Mohd Zulkifli Mustafa, Siew Chun Low, Juhana Jaafar, Khalid Ferji, Jean-Luc Six, Vuk Uskoković, Rohimah Mohamud.
      Since the ancient times, bee products (i.e., honey, propolis, pollen, bee venom, bee bread, and royal jelly) have been considered as natural remedies with therapeutic effects against a number of diseases. The therapeutic pleiotropy of bee products is due to their diverse composition and chemical properties, which is independent on the bee species. This has encouraged researchers to extensively study the therapeutic potentials of these products, especially honey. On the other hand, amid the unprecedented growth in nanotechnology research and applications, nanomaterials with various characteristics have been utilized to improve the therapeutic efficiency of these products. Towards keeping the bee products as natural and non-toxic therapeutics, the green synthesis of nanocarriers loaded with these products or their extracts has received a special attention. Alginate is a naturally produced biopolymer derived from brown algae, the desirable properties of which include biodegradability, biocompatibility, non-toxicity and non-immunogenicity. This review presents an overview of alginates, including their properties, nanoformulations, and pharmaceutical applications, placing a particular emphasis on their applications for the enhancement of the therapeutic effects of bee products. Despite the paucity of studies on fabrication of alginate-based nanomaterials loaded with bee products or their extracts, recent advances in the area of utilizing alginate-based nanomaterials and other types of materials to enhance the therapeutic potentials of bee products are summarized in this work. As the most widespread and well-studied bee products, honey and propolis have garnered a special interest; combining them with alginate-based nanomaterials has led to promising findings, especially for wound healing and skin tissue engineering. Furthermore, future directions are proposed and discussed to encourage researchers to develop alginate-based stingless bee product nanomedicines, and to help in selecting suitable methods for devising nanoformulations based on multi-criteria decision making models. Also, the commercialization prospects of nanocomposites based on alginates and bee products are discussed. In conclusion, preserving original characteristics of the bee products is a critical challenge in developing nano-carrier systems. Alginate-based nanomaterials are well suited for this task because they can be fabricated without the use of harsh conditions, such as shear force and freeze-drying, which are often used for other nano-carriers. Further, conjunction of alginates with natural polymers such as honey does not only combine the medicinal properties of alginates and honey, but it could also enhance the mechanical properties and cell adhesion capacity of alginates.
    Keywords:  alginates; alginic acid; green synthesis; honey; nanobiotechnology; nanomedicine; propolis; regenerative medicine
    DOI:  https://doi.org/10.3389/fmolb.2022.865833
  38. RSC Adv. 2021 May 24. 11(31): 18984-18993
    5FU encapsulated polyglycerol sebacate nanoparticles as anti-cancer drug carriers.
    Divya Sivanesan, Rama S Verma, Edamana Prasad.
      The majority of anti-cancer drugs fail to reach clinical trials due to their low water solubility. A biocompatible drug delivery system that encapsulates and efficiently delivers hydrophobic drugs to the target site is the need of the hour. This study addresses the issue by focusing on a polymeric polyglycerol sebacate (PGS) nanoparticles loaded with 5-fluorouracil (5FU), a primary line chemotherapy drug for many types of cancers. The generated nanoparticle (PGS-NP) was biocompatible and had minimal cytotoxicity against the MDA-MB-231 and A549 cell lines, even at a high concentration of 100 μg mL-1. The cell viability post treatment with PGS nanoparticles encapsulated with 5FU (PGS-5FU) decreased to as low as around 40% whereas, in the case of treatment with 5FU, the viability percentage increased. The nanoparticles also showed controlled drug release when encapsulated with 5FU. This striking observation suggested that these nanoparticles can improve the efficacy of drug delivery to tumor sites. Apoptosis assay and caspase-3 activity quantification supported these data wherein PGS-5FU treatment showed almost three times caspase-3 activity as compared to control cells. Additionally, throughout all the experiments, MDA-MB-231 cells were more sensitive to PGS-5FU than A549 cells, indicating that these nanoparticles are ideal for breast cancer treatment. In summary, 5FU encapsulated PGS nanoparticles are a potential drug carrier to deliver 5FU efficiently to cancer cells.
    DOI:  https://doi.org/10.1039/d1ra01722e
  39. RSC Adv. 2021 May 24. 11(31): 18809-18817
    Conjugation of a smart polymer to doxorubicin through a pH-responsive bond for targeted drug delivery and improving drug loading on graphene oxide.
    Ali Bina, Heidar Raissi, Hassan Hashemzadeh, Farzaneh Farzad.
      Polymeric nanoparticles have emerged as efficient carriers for anticancer drug delivery because they can improve the solubility of hydrophobic drugs and also can increase the bio-distribution of drugs throughout the bloodstream. In this work, a computational study is performed on a set of new pH-sensitive polymer-drug compounds based on an intelligent polymer called poly(β-malic acid) (PMLA). The molecular dynamics (MD) simulation is used to explore the adsorption and dynamic properties of PMLA-doxorubicin (PMLA-DOX) interaction with the graphene oxide (GOX) surface in acidic and neutral environments. The PMLA is bonded to DOX through an amide bond (PMLA-ami-DOX) and a hydrazone bond (PMLA-hz-DOX) and their adsorption behavior is compared with free DOX. Our results confirm that the polymer-drug prodrug shows unique properties. Analysis of the adsorption behavior reveals that this process is spontaneous and the most stable complex with a binding energy of -1210.262 kJ mol-1 is the GOX/PMLA-hz-DOX complex at normal pH. On the other hand, this system has a great sensitivity to pH so that in an acidic environment, its interaction with GOX became weaker while such behavior is not observed for the PMLA-ami-DOX complex. The results obtained from this study provide accurate information about the interaction of the polymer-drug compounds and nanocarriers at the atomic level, which can be useful in the design of smart drug delivery systems.
    DOI:  https://doi.org/10.1039/d1ra02361f
  40. RSC Adv. 2021 Apr 30. 11(27): 16179-16191
    Bioactive natural products from marine sponges belonging to family Hymedesmiidae.
    Asmaa Abo Elgoud Said, Basma Khalaf Mahmoud, Eman Zekry Attia, Usama Ramadan Abdelmohsen, Mostafa Ahmed Fouad.
      Natural products of marine origin exhibit extensive biological activities, and display a vital role in the exploration of new compounds for drug development. Marine sponges have been reported at the top with respect to the discovery of biologically active metabolites that have potential pharmaceutical applications. The family Hymedesmiidae belonging to the Demospongiae class includes ten accepted genera, of which four genera were explored for their bioactive metabolites, namely Phorbas, Hamigera, Hemimycale, and Kirkpatrickia. Genus Phorbas has received more attention due to the isolation of various classes of compounds with unique structures mainly diterpenes, alkaloids, sesterterpenes, and steroids that exhibited diverse biological activities including: antiviral, antimicrobial, and anti-inflammatory, whereas anticancer compounds predominated. This review focuses on the isolated secondary metabolites from family Hymedesmiidae with their biological potential and covers the literature from 1989 to 2020.
    DOI:  https://doi.org/10.1039/d1ra00228g
  41. Eur J Pharmacol. 2022 Apr 22. pii: S0014-2999(22)00231-X. [Epub ahead of print]924 174970
    Eupaformosanin induces apoptosis and ferroptosis through ubiquitination of mutant p53 in triple-negative breast cancer.
    Yingying Wei, Zhihui Zhu, Hongtao Hu, Jiaqi Guan, Bo Yang, Huajun Zhao.
      The mutant p53 plays a vital role in the control of cell survival and division under various stresses, including apoptosis and ferroptosis. Here, we showed that eupaformosanin (Eup), a natural compound isolated from Eupatorium cannabinum Linn., significantly inhibited the viability of triple-negative breast cancer (TNBC) cells. Meanwhile, mitochondrial apoptosis contributed to the apoptosis induced by Eup, followed by the disruption of mitochondrial membrane potential (MMP; Δψm) and accumulation of mitochondrial ROS (mt ROS). Apoptosis inhibitor Z-VAD rescued Eup-induced cell death. Afterward, ferroptosis-induced cell death was demonstrated after treatment with Eup, accompanied by lipid reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and iron increase. These events were blocked by ferroptosis inhibitors ferrostatin-1 (Fer-1), deferoxamine (DFO), and liproxstatin-1 (lip-1), indicating that ferroptosis facilitated Eup-induced cell death. Furthermore, Eup regulated mutant p53 ubiquitination. Mutant p53 signaling pathway participated in Eup-induced apoptosis and ferroptosis, which were rescued when mutant p53 was silent in TNBC cells. Also, Eup exerted an anti-TNBC effect by inducing apoptosis and ferroptosis in vivo. Taken together, the data demonstrate that the natural compound Eup is a potential TNBC therapeutic agent that induces apoptosis and ferroptosis through ubiquitination of mutant p53.
    Keywords:  Apoptosis; Ferroptosis; Mutant p53; Triple-negative breast cancer; eupaformosanin
    DOI:  https://doi.org/10.1016/j.ejphar.2022.174970
  42. Mini Rev Med Chem. 2022 Apr 25.
    An Overview of Dihydroartemisinin as a Promising Lead Compound for Development of Anticancer Agents.
    Olagoke Zacchaeus Olatunde, Jianping Yong, Canzhong Lu.
      Dihydroartemisinin(DHA) is a derivative of artemisinin, which firstly showed higher antimalarial activity. Over the years, DHA has also been discovered to exhibit higher anticancer efficacy without adverse side effects. Although some shortcomings have been discovered during biological evaluation (such as poor aqueous solubility, short half-life, and initial burst release effect), several attempts have been developed to overcome these shortcomings. For example, appropriate delivery techniques were used to improve its anticancer efficacy. In this minireview, we focused on summarizing the anticancer mechanisms, anticancer efficacy of free DHA and in combination therapies, hybrids, and nanoparticle formulations, which will provide adequate insights for its clinical use as anticancer agents, and on the design and synthesis of DHA derivatives for development of anticancer agents.
    Keywords:  Dihydroartemisinin; anticancer mechanisms; derivatives; hybrids; nanoparticles; shortcomings
    DOI:  https://doi.org/10.2174/1389557522666220425124923
  43. Anticancer Agents Med Chem. 2022 Apr 25.
    Promising Role of Phytochemicals in the Prevention and Treatment of Cancer.
    Aziz Unnisa, Ananda Kumar Chettupalli.
      Cancer has a significant social consequence all around the globe. In 2020, approximately 193 lakh new cases of cancer were diagnosed worldwide, with about 100 lakhs cancer deaths. In the next two decades, suspected cases are anticipated to increase by roughly 47%. The rising number of cancer patients, as well as the inadequacy of traditional chemotherapeutic agents, radiation, and invasive surgical procedures, all rely on massive cell death with hardly any selectivity, causing severe toxicities. In comparison to synthetic medications, there has subsequently been a surge in international importance in non-synthetic and alternative remedies, owing to improved adaptability and reduced side effects of drug responses. Several people with cancer prefer alternative and complementary therapy treatments, and natural remedies play a crucial role in cancer chemoprevention as they are thought to be harmless, offer fewer negative effects, and become less sufficient to evoke addiction by the wider population. Chemopreventive, anti-metastatic, cytotoxic, and anti-angiogenic actions are among the promising clinical advantages, which have been established in vitro research and certain clinical trials; nevertheless, additional clinical trials are needed. This review examines several phytochemicals that may have anti-cancer and chemopreventive properties.
    Keywords:  Cancer; flavonoid; phytochemicals; polyphenol; steroid; tannin.
    DOI:  https://doi.org/10.2174/1871520622666220425133936
  44. J Pharm Sci. 2022 Apr 22. pii: S0022-3549(22)00166-6. [Epub ahead of print]
    Co-delivery of daunorubicin and homoharringtonine in folic acid modified-liposomes for enhancing therapeutic effect on acute myeloid leukemia.
    Qi Liu, Lijun Luo, Xiaofeng Gao, Di Zhang, Xinqian Feng, Peng Yang, Hui Li, Shengjun Mao.
      Acute myeloid leukemia (AML) remains a threatening disease due to severe complications, drug resistance, and high recurrence rates. Many drug combinations have demonstrated enhanced therapeutic effects in clinical practice. However, it requires complicated dosing regimens and is accompanied by increased toxicity. This study explored the combined effect of two therapeutic agents, daunorubicin (DNR) and homoharringtonine (HHT) in cell viability, apoptosis, and cell cycle in vitro and verified their synergistic effect. We encapsulated the two drugs into liposomes to construct a folic acid-modified co-delivery system (FA-DH-LP) to achieve an effective and safe therapeutic strategy. The FA-DH-LP was prepared by film hydration method. The resultant FA-DH-LP was homogeneously spherical and showed good blood compatibility with high encapsulation efficiency for DNR and HHT. The FA-DH-LP exhibited higher cellular uptake in HL60 and K562 cells and enhanced cytotoxicity than DNR/HHT co-delivery liposomes without folic acid modification (DH-LP) in vitro. In the HL60 subcutaneous xenotransplantation model, FA-DH-LP showed improved tumor targeting ability, anti-leukemia activity and safety profile superior to free combinational drugs and DH-LP after 18-day treatment. The results demonstrated that FA-DH-LP might present a promising delivery strategy to improve the efficacy of the two combinational chemotherapeutics while reducing toxicity.
    Keywords:  Cancer chemotherapy; Drug delivery system; Drug targeting; Liposome
    DOI:  https://doi.org/10.1016/j.xphs.2022.04.014
  45. Korean J Physiol Pharmacol. 2022 May 01. 26(3): 145-155
    Chemosensitizing effect and mechanism of imperatorin on the anti-tumor activity of doxorubicin in tumor cells and transplantation tumor model.
    Xin-Li Liang, Miao-Miao Ji, Zheng-Gen Liao, Guo-Wei Zhao, Xi-Lan Tang, Wei Dong.
      Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined in vivo and in vitro. Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.
    Keywords:  Doxorubicin; Imperatorin; Leukemia; Multidrug resistance; P-glycoprotein
    DOI:  https://doi.org/10.4196/kjpp.2022.26.3.145
  46. RSC Adv. 2021 Jul 27. 11(42): 26241-26257
    Design, synthesis and mechanistic study of new benzenesulfonamide derivatives as anticancer and antimicrobial agents via carbonic anhydrase IX inhibition.
    Mohamed T M Nemr, Asmaa M AboulMagd, Hossam M Hassan, Ahmed A Hamed, Mohamed I A Hamed, Mohamed T Elsaadi.
      Changes in gene expression cause uncontrolled cell proliferation and consequently tumor hypoxia. The tumor cells shift their metabolism to anaerobic glycolysis with a significant modification in pH. Therefore, an over expression of carbonic anhydrase IX (CA IX) genes was detected in many solid tumors. Accordingly, selective inhibition of CA IX can be a useful target for discovering novel antiproliferative agents. The present study described the synthesis of new aryl thiazolone-benzenesulfonamides 4a-j as well as their carbonic anhydrase IX inhibitory effect. All the designed derivatives were evaluated for their anti-proliferative activity against triple-negative breast cancer cell line (as MDA-MB-231) and another breast cancer cell line (MCF-7) in addition to normal breast cell line MCF-10A. Compounds 4b-c, 4e, 4g-h showed significant inhibitory effect against both cancer cell lines at concentration ranges from 1.52-6.31 μM, with a high selectivity against breast cancer cell lines ranges from 5.5 to 17.5 times. Moreover, three sulfonamides derivatives 4e, 4g and 4h showed excellent enzyme inhibition against CA IX with IC50 10.93-25.06 nM and against CA II with IC50 1.55-3.92 μM that revealed their remarkable selectivity for CA IX over CA II. Additionally, 4e was able to induce apoptosis in MDA-MB-231 with a significant increase in the annexin V-FITC percent by 22 fold as compared with control. Cellular uptake on MDA-MB-231 cell lines were carried out using HPLC method on the three active compounds (4e, 4g and 4h). On the other hand inhibition of one or more CAs present in bacteria was reported to interfere with bacterial growth. So, the new benzenesulfonamides were evaluated against their antibacterial and anti-biofilm activities. Analogues 4e, 4g and 4h exhibited significant inhibition at 50 μg mL-1 concentration with 80.69%, 69.74% and 68.30% against S. aureus compared to the positive control CIP which was 99.2%, while compounds 4g and 4h showed potential anti-biofilm inhibition 79.46% and 77.52% against K. pneumonia. Furthermore, the designed compounds were docked into CA IX (human) protein (PDB ID: 5FL6) and molecular modeling studies revealed favorable binding interactions for the active inhibitors. Finally, the predictive ADMET studies showed that, compounds 4e, 4g and 4h possessed promising pharmacokinetic properties.
    DOI:  https://doi.org/10.1039/d1ra05277b
  47. Evid Based Complement Alternat Med. 2022 ;2022 7990508
    Medicinal Uses, Phytochemistry, Pharmacology, and Toxicology of Mentha spicata.
    Naoual El Menyiy, Hanae Naceiri Mrabti, Nasreddine El Omari, Afaf Ei Bakili, Saad Bakrim, Mouna Mekkaoui, Abdelaali Balahbib, Ehsan Amiri-Ardekani, Riaz Ullah, Ali S Alqahtani, Abdelaaty A Shahat, Abdelhakim Bouyahya.
      Mentha spicata, also called Mentha viridis, is a medicinal plant of the Lamiaceae family characterized by its potency to synthesize and secret secondary metabolites, essentially essential oils. Different populations use the aerial parts of this plant for tea preparation, and this tisane has shown several effects, according to ethnopharmacological surveys carried out in different areas around the world. These effects are attributed to different compounds of M. spicata, in which their biological effects were recently proved experimentally. Pharmacological properties of M. spicata extracts and essential oils were investigated for different health benefits such as antioxidant, anticancer, antiparasitic, antimicrobial, and antidiabetic effects. In vitro and in vivo studies showed positives effects that could be certainly related to different bioactive compounds identified in M. spicata. Indeed, volatile compounds seem to be efficient in inhibiting different microbial agents such as bacteria, fungi, and parasites through several mechanisms. Moreover, M. spicata exhibited, according to some studies, promising antioxidant, antidiabetic, anti-inflammatory, and anticancer effects, which show its potential to be used as a source for identifying natural drugs against cellular oxidative stress and its related diseases. Importantly, toxicological investigations of M. spicata show the safety of this species at different doses and several periods of use which justify its use in traditional medicines as tisane with tea. Here, we report, explore, and highlight the data published on M. spicata concerning its botanical description and geographical distribution, its phytochemical compounds, its pharmacological properties, and its toxicological investigations of M. spicata.
    DOI:  https://doi.org/10.1155/2022/7990508
  48. Curr Opin Chem Biol. 2022 Apr 25. pii: S1367-5931(22)00028-X. [Epub ahead of print]68 102143
    Factors that influence singlet oxygen formation vs. ligand substitution for light-activated ruthenium anticancer compounds.
    Elizabeth T Papish, Olaitan E Oladipupo.
      This review focuses on light-activated ruthenium anticancer compounds and the factors that influence which pathway is favored. Photodynamic therapy (PDT) is favored by π expansion and the presence of low-lying triplet excited states (e.g. 3MLCT, 3IL). Photoactivated chemotherapy (PACT) refers to light-driven ligand dissociation to give a toxic metal complex or a toxic ligand upon photo substitution. This process is driven by steric bulk near the metal center and weak metal-ligand bonds to create a low-energy 3MC state with antibonding character. With protic dihydroxybipyridine ligands, ligand charge can play a key role in these processes, with a more electron-rich deprotonated ligand favoring PDT and an electron-poor protonated ligand favoring PACT in several cases.
    Keywords:  Anticancer; Diimine ligands; Photoactivated chemotherapy; Photochemistry; Photodissociation; Photodynamic therapy; Photosubstitution; Protic ligands; Ruthenium; pH responsive
    DOI:  https://doi.org/10.1016/j.cbpa.2022.102143
  49. Nat Chem Biol. 2022 May;18(5): 441-450
    Targeting allosteric regulation of cancer metabolism.
    Daniel M Kremer, Costas A Lyssiotis.
      Metabolic reprogramming is observed across all cancer types. Indeed, the success of many classic chemotherapies stems from their targeting of cancer metabolism. Contemporary research in this area has refined our understanding of tumor-specific metabolic mechanisms and has revealed strategies for exploiting these vulnerabilities selectively. Based on this growing understanding, new small-molecule tools and drugs have been developed to study and target tumor metabolism. Here, we highlight allosteric modulation of metabolic enzymes as an attractive mechanism of action for small molecules that target metabolic enzymes. We then discuss the mechanistic insights garnered from their application in cancer studies and highlight the achievements of this approach in targeting cancer metabolism. Finally, we discuss technological advances in drug discovery for allosteric modulators of enzyme activity.
    DOI:  https://doi.org/10.1038/s41589-022-00997-6
  50. Eur J Pharm Biopharm. 2022 Apr 25. pii: S0939-6411(22)00080-7. [Epub ahead of print]
    Selective terpene based therapeutic deep eutectic systems against colorectal cancer.
    Joana Pereira, Maria Miguel Castro, Filipa Santos, Ana Rita Jesus, Alexandre Paiva, Filipe Oliveira, Ana Rita C Duarte.
      Cancer remains a major health problem worldwide, with colorectal cancer (CRC) being the third most incident and the second most lethal. Inflammation, on the other hand, has been highly associated with cancer development and maintenance, therefore, the reduction of the inflammatory microenvironment represents a promising therapeutic strategy. Deep eutectic systems (DES) are based on the combination of different components which together, at a certain molar ratio, present a deep decrease in their melting point compared with the individual compounds. When an active pharmaceutical ingredient is part of a DES it is designated by therapeutic deep eutectic system (THEDES). New THEDES combining terpenes with anticancer properties, such as safranal, menthol and linalool, with nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, ketoprofen and flurbiprofen were produced. To evaluate THEDES anti-CRC therapeutic potential, their physico-chemical properties, bioavailability and bioactivity, were explored. Our results show that safranal:ibuprofen (3:1), safranal:ibuprofen (4:1) and menthol:ibuprofen (3:1) present promising therapeutic activity towards CRC cells due to a selective cytotoxic action towards cancer cells. menthol:ibuprofen (3:1) anti-proliferative action seems to be related with cell membrane disruption, reduction of the inflammation through the reduction of reactive oxygen species (ROS) production, and induction of apoptosis via caspase-3. On the other hand, safranal:ibuprofen (3:1) and safafranal:ibuprofen (4:1) seem to prevent tumour expansion only through the induction of apoptosis via caspase-3. Besides, these systems present an increase in ibuprofen permeability, with menthol:ibuprofen (3:1) increasing also ibuprofen's solubility thus its overall bioavailability. Knowing that cancer is a huge problematic situation that requires alternative therapies with less side effects, improved efficacy, associated with less costs and environmentally friendly, a new opportunity emerges for DES to be part of the pharmaceutical industry.
    Keywords:  Colorectal cancer; Deep eutectic systems; Natural compounds; Nonsteroidal anti-inflammatory drugs; Terpenes; Therapeutic deep eutectic systems
    DOI:  https://doi.org/10.1016/j.ejpb.2022.04.008
  51. Cancer Metastasis Rev. 2022 Apr 25.
    The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor.
    Kendall C Case, Michael W Schmidtke, Miriam L Greenberg.
      Inositol is an essential nutrient, obtained either by uptake from the environment or by de novo synthesis from glucose. Inositol and its derivatives exhibit tumor-suppressive effects, potentially mediated by inhibition of the ERK-MAPK or PI3K-Akt pathways. Accordingly, many cancers have been documented to silence expression of the ISYNA1 gene, which encodes the rate-limiting enzyme of inositol synthesis. Paradoxically, recent studies have also reported upregulation of ISYNA1 in some cancers. Upregulation may reflect a compensatory response brought about by defective inositol uptake or oncogenic mutations that preclude its tumor-suppressive effects. In these scenarios, de novo synthesis of inositol may be upregulated to promote cell proliferation. The role of inositol in cancer is further complicated by its ability to inhibit the master metabolic regulator AMPK, which upon activation can either decrease cell proliferation and metastasis or promote cell survival. Due to its potential dual role in cancer, inositol homeostasis must be tightly regulated in tumor cells. Thus, whether inositol acts to suppress or promote tumor progression is determined by the metabolic profile and oncogenic background of the cancer.
    Keywords:  AMPK; Cancer; ISYNA1; Inositol; Metabolism; PI3K-Akt
    DOI:  https://doi.org/10.1007/s10555-022-10032-8
  52. Front Pharmacol. 2022 ;13 860209
    Application of Quercetin in the Treatment of Gastrointestinal Cancers.
    Seyed Mohammad Ali Mirazimi, Fatemeh Dashti, Mohammad Tobeiha, Ali Shahini, Raha Jafari, Mehrad Khoddami, Amir Hossein Sheida, Parastoo EsnaAshari, Amir Hossein Aflatoonian, Fateme Elikaii, Melika Sadat Zakeri, Michael R Hamblin, Mohammad Aghajani, Minoodokht Bavarsadkarimi, Hamed Mirzaei.
      Many cellular signaling pathways contribute to the regulation of cell proliferation, division, motility, and apoptosis. Deregulation of these pathways contributes to tumor cell initiation and tumor progression. Lately, significant attention has been focused on the use of natural products as a promising strategy in cancer treatment. Quercetin is a natural flavonol compound widely present in commonly consumed foods. Quercetin has shown significant inhibitory effects on tumor progression via various mechanisms of action. These include stimulating cell cycle arrest or/and apoptosis as well as its antioxidant properties. Herein, we summarize the therapeutic effects of quercetin in gastrointestinal cancers (pancreatic, gastric, colorectal, esophageal, hepatocellular, and oral).
    Keywords:  bioactive compounds; gastrointestinal cancers; natural compounds; quercetin; therapy
    DOI:  https://doi.org/10.3389/fphar.2022.860209
  53. J Orthop Res. 2022 Apr 30.
    Metabolic regulation of intrasynovial flexor tendon repair:The effects of dichloroacetate administration on early tendon healing in a canine model.
    Richard H Gelberman, Ryan A Lane, Shelly E Sakiyama-Elbert, Stavros Thomopoulos, Hua Shen.
      Enriched in glycolytic enzymes, paucicellular and hypovascular intrasynovial flexor tendons fail to mount an effective healing response after injury and repair. In contrast, well-vascularized extrasynovial flexor tendons possess high levels of oxidative phosphorylation (OXPHOS) enzymes and have a markedly improved healing capacity. This study was designed to compare the metabolic profiles of the two types of tendons and to evaluate the impact of metabolic reprogramming on early intrasynovial tendon healing in a clinically relevant canine model. Results showed that healthy intrasynovial tendons expressed higher levels of PDK1 and GAPDH and lower levels of SCX and IGF1 than did extrasynovial tendons. PDK1 encodes a subtype of pyruvate dehydrogenase kinase (PDK) that inhibits OXPHOS. Consistently, ATP production via glycolysis was favored in intrasynovial tendon cells whereas OXPHOS was the preferred pathway in extrasynovial tendon cells. Inhibition of glycolysis in vitro increased SCX expression in intrasynovial tendon cells. Therefore, dichloroacetate (DCA), a PDK1 inhibitor, was used in vivo to shift intrasynovial tendon ATP production from glycolysis to OXPHOS. Oral DCA administration reduced serum lactate concentration and increased acetyl-CoA content in repaired intrasynovial tendons and led to reduced TLR4 and IL1B and increased IGF1, SCX, and TGFB3 expressions in treated intrasynovial tendons compared to controls. Immunohistochemistry staining with anti-Ki67 and anti-CD31 antibodies revealed marked increases in cellularity and neovascularization in treated intrasynovial tendons. Clinical significance: The findings of this experiment indicate that improved gene expression and histological outcomes can be achieved by regulating glucose metabolism in the early stages following intrasynovial tendon repair. This article is protected by copyright. All rights reserved.
    Keywords:  dichloroacetate; glucose metabolism; glycolysis; intrasynovial flexor tendon repair; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/jor.25354
  54. RSC Adv. 2021 Aug 02. 11(43): 26687-26699
    Medicinal chemistry inspired by ginger: exploring the chemical space around 6-gingerol.
    Sara Hassan Hassan Ahmed, Tímea Gonda, Attila Hunyadi.
      Ginger (Zingiber officinale Roscoe) has been used as a spice and as a traditional remedy since ancient times, especially in traditional Chinese medicine. It has been applied as a treatment for many diseases either alone or in combination with other remedies. Many studies were conducted on ginger and its constituents and a wide array of bioactivities were reported, e.g., antioxidant, anti-inflammatory, antiemetic, and anticancer activity. Most of these had been correlated to gingerols and shogaols, the most abundant secondary metabolites in ginger. This inspired several research groups to explore the biomedical value of the chemical space around these compounds, and many of their synthetic or semi-synthetic analogues have been prepared and studied for various bioactivities. Thanks to this, many valuable structure activity relationships have been revealed for such compounds. Herein, we provide a brief summary on the synthetic derivatization efforts that had so far been implemented on 6-gingerol, the main constituent of fresh ginger. This review covers 160 natural, semisynthetic, or synthetic 6-gingerol derivatives and their reported bioactivities.
    DOI:  https://doi.org/10.1039/d1ra04227k
  55. J Int Med Res. 2022 Apr;50(4): 3000605221093308
    Piperlongumine combined with vitamin C as a new adjuvant therapy against gastric cancer regulates the ROS-STAT3 pathway.
    Di Chen, Xinyue Wei, Ke Yang, Xinyue Liu, Yujin Song, Futing Bai, Yi Jiang, Yuhang Guo, Rajiv Kumar Jha.
       OBJECTIVE: To investigate the effects of piperlongumine (PL) and vitamin C (VC) on signal transducer and activator of transcription 3 (STAT3) signalling in gastric cancer cell lines.
    METHODS: In vivo tumour xenograft anticancer assays were undertaken to confirm the anticancer activity of PL. Cell viability, flow cytometry and Western blot assays were undertaken to evaluate the anticancer effects of PL, VC and combinations of PL and VC in AGS and KATO III cells.
    RESULTS: Both PL and VC induced apoptosis and inhibited cell proliferation in AGS and KATO III cells. These effects were dependent on reactive oxygen species (ROS). PL effectively suppressed STAT3 activation while VC caused abnormal activation of STAT3. The combination of PL and VC exhibited a stronger apoptotic effect compared with either agent alone. PL reversed the abnormal activation of STAT3 by VC, which could be a key to their synergistic effect.
    CONCLUSIONS: PL combined with VC exhibited a stronger anticancer effect by regulating the ROS-STAT3 pathway, suggesting that this combination might be a potential adjuvant therapy for gastric cancer.
    Keywords:  Gastric cancer; apoptosis; piperlongumine; reactive oxygen species; signal transducer and activator of transcription 3; vitamin C
    DOI:  https://doi.org/10.1177/03000605221093308
  56. Pharm Nanotechnol. 2022 Apr 26.
    Unravelling Micro and Nano vesicular System in Intranasal Drug Delivery for Epilepsy.
    Sagar Salave, Dhwani Rana, Rupali Pardhe, Prajakta Bule, Derajram Benival.
       BACKGROUND: Epilepsy is one of the major neurological disorders, affecting about 50 million people globally. Oral, intravenous, and rectal delivery systems are available for the management of epileptic seizures. However, intranasal delivery serves beneficial for delivering anti-epileptic drugs owing to the advantages it offers.
    OBJECTIVE: Various approaches have been developed over the years aiming to attain either a safer or faster brain delivery; a nasal delivery system proposes significant outcomes. The non-invasiveness and high vascularity contribute to the high permeability of the nasal mucosa, allowing rapid drug absorption. This review highlights some of the promising novel approaches delivering antiepileptic drugs efficiently employing the nasal route.
    METHODS: The method includes a collection of data from different search engines like PubMed, ScienceDirect, SciFinder for obtaining appropriate and relevant literature regarding epilepsy, intranasal delivery of antiepileptic agents, and novel therapeutics.
    RESULTS: The present review underlines the majority of work related to intranasal delivery in the treatment of epilepsy, aiming to draw the attention of the researchers towards the easiest and efficient ways of formulation for the delivery of antiepileptics during seizures.
    CONCLUSION: This review intends to provide understanding about the delivery aspects of anti-epileptic drugs, the benefits of intranasal delivery, and the novel approaches employed for the treatment of epilepsy.
    Keywords:  Epilepsy; drug delivery; intranasal; nanomedicines; nanoparticles; nasal route.
    DOI:  https://doi.org/10.2174/2211738510666220426115340
  57. Expert Rev Anticancer Ther. 2022 Apr 29. 1-7
    Oxygen therapy in traditional and immunotherapeutic treatment protocols of cancer patients: current reality and future prospects.
    Victor Ivanovich Seledtsov, Alexei A von Delwig.
       INTRODUCTION: The metabolic environment in ischemic and hypoxic tumors is known to contribute to cancer progression. Importantly, peculiar metabolic changes occurring in malignant cells (the increased glycolysis and the hampered Krebs cycle) may contribute to decreased antioxidant-dependent defense in ischemic and hypoxic tumors.
    AREAS COVERED: In the clinic, oxygen saturation of tumors is usually achieved by the application of water-soluble ozone and hyperbaric oxygen therapy. Tumor oxygenation has been shown to inhibit tumor growth and potentiate anti-tumor effects of chemoradiotherapy in animal experiments and the clinical setting. Tumor oxygenation could enhance anti-tumor effects achieved by tumor blood vessel occlusion or angiostatic therapy.
    EXPERT OPINION: Owing to a profound influence of ROS on both the innate and adaptive immunity, oxygen therapy, when combined simultaneously or sequentially with immunotherapeutic interventions (such as immune checkpoint inhibition, drug-induced immunostimulation, adoptive cell therapy, hyperthermia, etc.), could be considered as a novel highly-effective clinical biological approach to cancer treatment.
    Keywords:  Reactive oxygen species; cancer; chemoradiotherapy; hyperthermia; immunotherapy; oxidative stress
    DOI:  https://doi.org/10.1080/14737140.2022.2070153
  58. RSC Adv. 2021 May 06. 11(28): 16913-16923
    RAFT polymerization mediated core-shell supramolecular assembly of PEGMA-co-stearic acid block co-polymer for efficient anticancer drug delivery.
    Priyatosh Sarkar, Santanu Ghosh, Rima Saha, Kishor Sarkar.
      In this work, core-shell supramolecular assembly polymeric nano-architectures containing hydrophilic and hydrophobic segments were synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization. Herein, polyethylene glycol methyl ether methacrylate (PEGMA), and stearic acid were used to synthesize the poly(PEGMA) homopolymer and stearyl ethyl methacrylate (SEMA), respectively. Then, PEGMA and SEMA were polymerized through controlled RAFT polymerization to obtain the final diblock copolymer, poly(PEGMA-co-SEMA) (BCP). Model anticancer drug, doxorubicin (DOX) was loaded on BCPs. Interestingly, efficient DOX release was observed at acidic pH, similar to the cancerous environment pH level. Significant cellular uptake of DOX loaded BCP50 (BCP50-DOX) was observed in MDA-MB-231 triple negative breast cancer cells and resulted in a 35 fold increase in anticancer activity against MDA MB-231 cells compared to free DOX. Scanning electron microscopy (SEM) imaging confirmed the apoptosis mediated cellular death. These core-shell supramolecular assembly polymeric nano-architectures may be an efficient anti-cancer drug delivery system in the future.
    DOI:  https://doi.org/10.1039/d1ra01660a
  59. PLoS Comput Biol. 2022 Apr;18(4): e1009962
    Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors.
    Mansour Poorebrahim, Mohammad Foad Abazari, Leila Moradi, Behzad Shahbazi, Reza Mahmoudi, Hourieh Kalhor, Hassan Askari, Ladan Teimoori-Toolabi.
      K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-RasG12D and K-RasG12C mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009962
  60. RSC Adv. 2021 Aug 16. 11(45): 27950-27964
    Target identification of anticancer natural products using a chemical proteomics approach.
    Swadhapriya Bhukta, Pushparathinam Gopinath, Rambabu Dandela.
      In recent years, there has been a strong demand worldwide for the identification and development of potential anticancer drugs based on natural products. Natural products have been explored for their diverse biological and therapeutic applications from ancient time. In order to enhance the efficacy and selectivity and to minimize the undesired side effects of anti cancer natural products (ANPs), it is essential to understand their target proteins and their mechanistic pathway. Chemical proteomics is one of the most powerful tools to connect ANP target identification and quantification where labeling and non-labeling based approaches have been used. Herein, we have discussed the various strategies to systemically develop selective ANP based chemical probes to characterise their specific and non-specific target proteins using a chemical proteomic approach in various cancer cell lysates.
    DOI:  https://doi.org/10.1039/d1ra04283a
  61. Am J Chin Med. 2022 Apr 26. 1-32
    Polyphenols from Chinese Herbal Medicine: Molecular Mechanisms and Therapeutic Targets in Pulmonary Fibrosis.
    Lei Wang, Ting Zhu, Deqin Feng, Renshi Li, Chaofeng Zhang.
      Pulmonary fibrosis (PF) is a highly confounding and fatal pathological process with finite treatment options. Multiple factors such as oxidative and immune/inflammation involve key pathological processes in chronic lung disease, and their intimate interactions mediate chronic lung damage, denudation of the alveolar epithelium, hyperproliferation of type II alveolar epithelial cells (AECIIs), proliferation and differentiation of fibroblasts, and the permeability of microvessels. We reviewed the classic mechanism of PF and highlighted a few emerging mechanisms for studying complex networks in lung disease pathology. Polyphenols, as a multi-target drug, has excellent potential in the treatment of pulmonary fibrosis. We then reviewed recent advances in discovering phenolic compounds from fruits, tea, and medical herbs with the bioactivities of simultaneously regulating multiple factors (e.g., oxidative stress, inflammation, autophagy, apoptosis, pyroptosis) for minimizing pulmonary fibrosis injury. These compounds include resveratrol, curcumin, salvianolic acid B, epigallocatechin-3-gallate, gallic acid, corilagin. Each phenolic compound can exert its anti-PF effect through various mechanisms, and the signaling pathways involved in different phenolic compounds are not the same. This review summarized the available evidence on phenolic compounds' effectiveness in pulmonary diseases and explored the molecular mechanisms and therapeutic targets of phenolic compounds from Chinese herbal medicine with the properties of inhibition of ongoing fibrogenesis and resolution of existing fibrosis.
    Keywords:  Chemokines; EndMT/EMT; Mechanism; Polyphenols; Pulmonary Fibrosis; Review; Traditional Chinese Medicine
    DOI:  https://doi.org/10.1142/S0192415X22500434
  62. RSC Adv. 2021 May 24. 11(31): 19221-19237
    The phytochemistry, pharmacology and traditional medicinal use of Glechomae Herba - a systematic review.
    Liu Yang, Jiaxu Zhang, Senwang Zheng, Ajiao Hou, Song Wang, Huan Yu, Xuejiao Wang, Yingjie Xu, Haixue Kuang, Hai Jiang.
      Glechomae Herba is a Chinese herb, which has been used in China for thousands of years, mainly for the treatment of nephrolithiasis. This paper summarizes the modern research progress on Glechomae Herba from the aspects of botany, traditional medicinal use, phytochemistry, pharmacology, pharmacokinetics, analytical methods and quality control. In addition, it also points out the deficiencies of current research on this herb and provides possible directions for its development. So far, more than 190 chemical components have been isolated and identified from Glechomae Herba, including organic acids and their esters, volatile oils, flavonoids and their glycosides, terpenes and other chemical components. Its extracts and compounds have a wide range of pharmacological effects, including anti-stone, anti-inflammatory, bacteriostatic, cholagogic and diuretic, effect on ileum smooth muscle, anti-tumor effect on tumor and hypoglycemic effects. However, future studies should focus on drug metabolism, clarify its pharmacodynamic mechanism, and establish a reasonable quality control standards for Glechomae Herba.
    DOI:  https://doi.org/10.1039/d1ra01366a
  63. Curr Drug Deliv. 2022 Apr 26.
    Application of computational screening tools and nanotechnology for enhanced drug synergism in cancer therapy.
    Thu Thi Kim Ninh, Tuan Hiep Tran, Chi Ying F-Huang, Chien Ngoc Nguyen.
       BACKGROUND: Chemoresistance continues to limit the recovery of patients with cancer. New strategies, such as combination therapy or nanotechnology can be further improved.
    OBJECTIVE: In this study, we applied the computational strategy by exploiting two databases (CellMiner and Prism) to sort out the cell lines sensitive to both anti-cancer drugs, paclitaxel (PTX) and dihydroartemisinin (DHA); both of which are potentially synergistic in several cell lines.
    METHODS: The combination of PTX and DHA was screened at different ratios to select the optimal ratio that could inhibit lung adenocarcinoma NCI-H23 the most. To further enhance therapeutic efficacy, these combinations of drugs were incorporated into a nanosystem.
    RESULTS: At a PTX:DHA ratio of 1:2 (w/w), the combined drugs obtained the best combination index (0.84), indicating a synergistic effect. The drug-loaded nanoparticles sized at 135 nm with the drug loading capacity of 15.5 ± 1.34 and 13.8 ± 0.56 corresponding to DHA and PTX, respectively were used. The nano-sized particles improved drug internalization into the cells, resulting in the significant inhibition of cell growth at all tested concentrations (p < 0.001). Additionally, α-tubulin aggregation, DNA damage suggested the molecular mechanism behind cell death upon PTX-DHA-loaded nanoparticle treatment. Moreover, the rate of apoptosis increased from approximately 5% to more than 20%, and the expression of apoptotic proteins changed 4 and 3 folds corresponding to p-53 and Bcl-2, respectively.
    CONCLUSION: This study was designed thoroughly by screening cell lines for the optimization of formulations. This novel approach could pave the way for the selection of combined drugs for precise cancer treatment.
    Keywords:  bio-computational tool; cancer; chemoresistance; combination therapy; nanoparticles; synergistic effect
    DOI:  https://doi.org/10.2174/1567201819666220426092538
  64. J Control Release. 2022 Apr 25. pii: S0168-3659(22)00227-9. [Epub ahead of print]
    Advocation and advancements of EPR effect theory in drug delivery science: A commentary.
    Mitsuru Hashida.
      To honor the contributions of Professor Hiroshi Maeda to the progress of targeted drug delivery research, a brief review of enhanced permeability and retention (EPR) effect theory proposed by him as the physiology-based principal mechanism of intra-tumoral accumulation of large molecules and small particles is presented. Under historical and practical backgrounds in developments of various drug delivery systems including macromolecular conjugates, the concept of EPR effect was advocated in mid1980s and has cultivated new cancer chemotherapeutic modalities until recently. Namely, nanoplatforms such as polymer conjugates, liposomes, polymeric micelles, and nanoparticles have been studied as a promising fusion area for nanotechnology and medicine. Modulation of EPR effect by chemical and/or mechanical approaches to achieve tumor vascular and tissue modification would further lead to sophistication of cancer chemotherapy employing nanomedicines.
    Keywords:  Cancer chemotherapy; Enhanced permeability and retention (EPR) effect theory; Macromolecule-drug conjugate; Nanomedicine; Tumor targeting
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.031
  65. Indian J Surg Oncol. 2022 Mar;13(1): 68-80
    Systemic Therapy in Thyroid Cancer.
    Amit Kumar Agrawal, Vanita Noronha, Vijay Patil, Nandini Menon, Akhil Kapoor, Anuradha Chougule, Pratik Chandrani, Kumar Prabhash.
      Thyroid cancer is the most common endocrine malignancy. While surgery remains the mainstay of the treatment of all different histologies, for differentiated thyroid cancers, radioactive iodine also plays an important role in management. Once tumor becomes radio-iodine refractory, it needs systemic therapy. Earlier, these tumors had very dismal prognosis. However, with the advancement of technology and research, it has become clear now that thyroid cancer cells are driven by various mutations. Targeting these oncogenic drivers by various molecules have proven to be effective therapeutic strategy in thyroid cancer. Besides, as in other solid tumors, immunotherapy is also being evaluated in thyroid cancer. While these new therapeutic approaches have revolutionized the treatment on advanced/metastatic thyroid cancer, there are definite challenges which limit their use in common clinical practice. These challenges include higher treatment cost and lack of testing to identify the driver mutations. Moreover, there is still need for further research in thyroid cancers to identify oncogenic targets and agent to act upon them.
    Keywords:  Immunotherapy; Radioactive iodine refractory; Systemic therapy; Thyroid cancer; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1007/s13193-021-01398-2
  66. J Control Release. 2022 Apr 25. pii: S0168-3659(22)00231-0. [Epub ahead of print]
    Nanomaterials enabling clinical translation of antimicrobial photodynamic therapy.
    Muhammed Awad, Nicky Thomas, Timothy J Barnes, Clive A Prestidge.
      Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach to aid the fight against looming antibiotic resistance. aPDT harnesses the energy of light through photosenstizers to generate highly reactive oxygen species that can inactivate bacteria and fungi with no resistance. To date aPDT has shown great efficacy against microbes causing localized infections in the skin and the oral cavity. However, its wide application in clinical settings has been limited due to both physicochemical and biological challenges. Over the past decade nanomaterials have contributed to promoting photosensitizer performance and aPDT efficiency, yet further developments are required to establish accredited treatment options. In this review we discuss the challenges facing the clinical application of aPDT and the opportunities that nanotechnology may offer to promote the safety and efficiency of aPDT.
    Keywords:  Antimicrobial photodynamic therapy; Antimicrobial resistance; Delivery system; Nanocarriers; Nanomaterials photosensitizers
    DOI:  https://doi.org/10.1016/j.jconrel.2022.04.035
  67. Front Mol Biosci. 2022 ;9 859821
    Editorial: Design, Synthesis, and Preclinical Testing of Innovative Anti-Cancer Compounds With a High Level of Selectivity of Action and Low Toxicity.
    Ana Maria Da Costa Ferreira, Regine Schneider-Stock, Francesca Aiello.
      
    Keywords:  anti-cancer (anticancer) drugs; innovative compounds; metabolomics; selectivity; strategies to improve biological activity
    DOI:  https://doi.org/10.3389/fmolb.2022.859821
  68. Mol Pharm. 2022 Apr 29.
    LS-HB-Mediated Photodynamic Therapy Inhibits Proliferation and Induces Cell Apoptosis in Melanoma.
    Lanlan Wang, Li Wang, Yang Zhang, Zhiyu Zhao, Cong Liu, Mengqi Li, Jiajing Liu, Shengyu Wang, Dong Yang, Fanghong Luo, Jianghua Yan.
      Chlorin e6-C-15-ethyl ester (LS-HB), a newly identified photosensitizer, was isolated from chlorin e6. The mechanism of tumor cell death induced by photodynamic therapy with LS-HB (LS-HB-PDT) is still unknown. Here, we investigated the photophysical properties of LS-HB, evaluated the antitumor effect on melanoma in vitro and in vivo, and explored its possible mechanisms. LS-HB not only has an optimal spectral band of red wavelength (660 nm) for photosensitization but also has favorable photostability. More importantly, LS-HB-PDT elicited a potent dose-dependent phototoxic effect in vitro. We discovered that LS-HB located in the mitochondria of B16F10 cells was able to generate excess reactive oxygen species, which subsequently resulted in mitochondrial membrane potential loss and induced apoptosis via caspase-9 and caspase-3 pathways. Moreover, PDT with LS-HB markedly inhibited the growth of melanoma in vivo. Therefore, LS-HB is expected to be an effective potential photosensitizer in antitumor therapy.
    Keywords:  apoptosis; melanoma; mitochondria; photodynamic therapy; photosensitizers; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.2c00302
  69. ACS Omega. 2022 Apr 19. 7(15): 13371-13381
    Rational Fabrication of Folate-Conjugated Zein/Soy Lecithin/Carboxymethyl Chitosan Core-Shell Nanoparticles for Delivery of Docetaxel.
    Zhenyao Wu, Jie Li, Xin Zhang, Yangjia Li, Dongwei Wei, Lichang Tang, Shiming Deng, Guijin Liu.
      The objective of this work is to design and fabricate a natural zein-based nanocomposite with core-shell structure for the delivery of anticancer drugs. As for the design, folate-conjugated zein (Fa-zein) was synthesized as the inner hydrophobic core; soy lecithin (SL) and carboxymethyl chitosan (CMC) were selected as coating components to form an outer shell. As for fabrication, a novel and appropriate atomizing/antisolvent precipitation process was established. The results indicated that Fa-zein/SL/CMC core-shell nanoparticles (FZLC NPs) were successfully produced at a suitable mass ratio of Fa-zein/SL/CMC (100:30:10) and the freeze-dried FZLC powder showed a perfect redispersibility and stability in water. After that, docetaxel (DTX) as a model drug was encapsulated into FZLC NPs at different mass ratios of DTX to FZLC (MR). When MR = 1:15, DTX/FZLC NPs were obtained with high encapsulation efficiency (79.22 ± 0.37%), small particle size (206.9 ± 48.73 nm), and high zeta potential (-41.8 ± 3.97 mV). DTX was dispersed in the inner core of the FZLC matrix in an amorphous state. The results proved that DTX/FZLC NPs could increase the DTX dissolution, sustain the DTX release, and enhance the DTX cytotoxicity significantly. The present study provides insight into the formation of zein-based complex nanocarriers for the delivery of anticancer drugs.
    DOI:  https://doi.org/10.1021/acsomega.2c01270
  70. Acta Biomater. 2022 Apr 26. pii: S1742-7061(22)00243-4. [Epub ahead of print]
    Amino Acids and Doxorubicin as Building Blocks for Metal Ions-Driven Self-Assembly of Biodegradable Polyprodrugs for Tumor Theranostics.
    Daquan Wang, Ning Zhang, Tingting Yang, Yun Zhang, Xunan Jing, Yu Zhou, Jiangang Long, Lingjie Meng.
      On-demand designed theranostics nanoagents show promising applications for next-generation precision-and-personalized oncotherapy. Researchers have since aimed to develop nanoplatforms that can efficiently deliver drugs and contrast medium to tumor and release active ingredients in response to tumor microenvironment (TME) conditions. Herein, we propose a modular strategy, and develop a series of nanoplatforms based on metal-coordinated-polyprodrugs for cancer theranostics. The polyprodrugs were synthesized through a click-reaction between amino acid and doxorubicin (DOX) with dipropiolate. The backbones of the polyprodrugs had intrinsic sensitivities to pH and/or GSH, and provided abundant -COOH, -NH2, or -S-S- to chelate with functional metal ions and further self-assembled to form different morphologies. Dicysteine, which contains disulfide bond (-S-S-), was chosen to copolymerize with DOX and triethylene glycol dipropiolate (TEP) to prepare the pH/GSH dual-responsive polyprodrug poly(dicysteine-co-TEP-co-DOX) (pDTD), then separately coordinated with Gd3+, Fe3+, and Mn2+ to construct nanoplatforms pDTD@M (M representing the metal ions). In vitro and in vivo investigations suggest the metal-coordinated-polyprodrug nanoplatforms have good magnetic resonance imaging (MRI) ability and efficient tumor-growth inhibition with high safety. The design strategy of nanoplatforms based on metal-coordinated-polyprodrugs provides a new idea for on-demand construction of promising theranostics agents. STATEMENT OF SIGNIFICANCE: :Compared to small molecule antitumor drugs, polymeric drugs have high drug loading ratio and are easily enriched at the tumor site to achieve improved therapy efficacy. This work utilizes click reactions to link amino acids with anticancer drugs to produce polymeric drugs that are degraded in response to tumor microenvironment and released small molecule antitumor drugs mainly in tumor sites, and subtly utilizes the coordination of amino acid to chelate MRI functional metal ion to realize enhanced MRI imaging mediated tumor therapy. This strategy provides a new idea for the convenient construction of polymeric drugs for tumor theranostics.
    Keywords:  Click reactions; Ion-driven Self-assembly; Modular Nanoplatforms; Polyprodrugs; Theranostics
    DOI:  https://doi.org/10.1016/j.actbio.2022.04.034
  71. RSC Adv. 2021 Jul 19. 11(41): 25381-25421
    Chemistry of trisindolines: natural occurrence, synthesis and bioactivity.
    First Ambar Wati, Mardi Santoso, Ziad Moussa, Sri Fatmawati, Arif Fadlan, Zaher M A Judeh.
      Heterocyclic nitrogen compounds are privileged structures with many applications in the pharmaceutical and nutraceutical industries since they possess wide bioactivities. Trisindolines are heterocyclic nitrogen compounds consisting of an isatin core bearing two indole moieties. Trisindolines have been synthesized by reacting isatins with indoles using various routes and the yield greatly depends on the catalyst used, reaction conditions, and the substituents on both the isatin and indole moieties. Amongst the synthetic routes, acid-catalyzed condensation reaction between isatins and indoles are the most useful due to high yield, wide scope and short reaction times. Trisindolines are biologically active compounds and show anticancer, antimicrobial, antitubercular, antifungal, anticonvulsant, spermicidal, and antioxidant activities, among others. Trisindolines have not previously been reviewed. Therefore, this review aims to provide a comprehensive account of trisindolines including their natural occurrence, routes of synthesis, and biological activities. It aims to inspire the discovery of lead trisindoline drug candidates for further development.
    DOI:  https://doi.org/10.1039/d1ra03091d
  72. Annu Rev Cancer Biol. 2021 Mar;5 161-179
    Nutritional Preconditioning in Cancer Treatment in Relation to DNA Damage and Aging.
    Winnie M C van den Boogaard, Marry M van den Heuvel-Eibrink, Jan H J Hoeijmakers, Wilbert P Vermeij.
      Dietary restriction (DR) is the most successful nutritional intervention for extending lifespan and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life- and health span and decrease DNA damage in DNA repair-deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment.
    Keywords:  DNA damage repair; aging; cancer; chemotherapy; dietary restriction; fasting
    DOI:  https://doi.org/10.1146/annurev-cancerbio-060820-090737
  73. RSC Adv. 2021 Sep 06. 11(48): 30183-30194
    Synthesis and efficacy of norfloxacin loaded onto magnetic hydrogel nanocomposites.
    Nehal Salahuddin, Ahmed Rehab, Sahar Emad.
      A targeted drug delivery system based on biocompatible magnetic hydrogel nanocomposites consisting of poly[oligo(oxyethylene methacrylate)] anchored Fe3O4 nanoparticles was synthesized. The characteristics, thermal properties, morphology and magnetic properties were studied by XRD, FT-IR, TGA, SEM, TEM and VSM. A norfloxacin (NOR) anti-bacterial agent with a potential antitumor activity was immobilized into hydrogels, Fe3O4 nanoparticles and their magnetic hydrogel nanocomposites. The in vitro drug release manner of NOR was explored at different temperatures and pH values. The behavior of the drug release has been studied via different kinetic models. The antibacterial efficacy was tested against Streptococcus, Staphylococcus aureus, Kelebsella pneumonia and Escherichia coli via well diffusion method, and showed significant activity compared to the unloaded drug. Furthermore, an antitumor efficacy against HCT-116, HepG-2, PC3 and MCF-7 cancer cells revealed the highest cytotoxic efficacy with no influence on healthy cells. These nanodrugs, retaining both antibacterial and anticancer efficacy, have a talented therapeutic potential because of their selective cytotoxicity, connected with the ability to minimize the risk of bacterial infection in a cancer patient who is frequently immunocompromised.
    DOI:  https://doi.org/10.1039/d1ra04230k
  74. Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00004-1. [Epub ahead of print]367 65-100
    Metabolism in tumor-associated macrophages.
    Jie Li, Gina M DeNicola, Brian Ruffell.
      Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.
    Keywords:  Immunometabolism; Metabolic reprogramming; Metabolism; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/bs.ircmb.2022.01.004
  75. RSC Adv. 2021 Aug 16. 11(45): 28148-28168
    Advances in biopolymeric active films incorporated with emulsified lipophilic compounds: a review.
    Ilyes Dammak, Carla Giovana Luciano, Luis Jaime Pérez-Córdoba, Maria Lúcia Monteiro, Carlos Adam Conte-Junior, Paulo José do Amaral Sobral.
      The attention towards active films has increased due to consumer demand for high-quality foods without chemical additives. Active biopolymer-based films have shown great potential for active films by impacting food safety, acting as the carriers of various natural antioxidant and antimicrobial compounds, and decreasing environmental pollution from petrol-derived packaging materials. However, there is a wide range of challenges concerning the different characteristics of biopolymers and plasticizers, often hygroscopic/hydrophilic, compared to numerous lipophilic bioactive compounds. Therefore, recent studies have focused on applying oil-in-water emulsion-based systems to enhance the lipophilic bioactive compounds' dispersibility into the film matrix, improving their performance. It is worth emphasizing that resulting complex systems give rise to new challenges such as (i) dispersion technology of the bioactive compounds with minimum adverse effects on its bioactivities, (ii) interactions between different components of the active films, giving rise to new physicochemical properties, and (iii) the change of the diffusion properties of bioactive compounds into the active films, resulting in different release properties. These challenges are profound and critically discussed in this review, as well as the encapsulation techniques employed in preparing emulsions loaded with lipophilic bioactive compounds for the active film development. An outlook of future directions in the research, development, and application of these active films are given.
    DOI:  https://doi.org/10.1039/d1ra04888k
  76. Bioorg Med Chem. 2022 Apr 20. pii: S0968-0896(22)00151-1. [Epub ahead of print]64 116759
    Small molecule NSAID derivatives for impairing powerhouse in cancer cells.
    Aman Bajpai, Deepshikha, Dimple Chhabria, Tripti Mishra, Sivapriya Kirubakaran, Sudipta Basu.
      Mitochondrion emerged as an important therapeutic target for anti-cancer strategy due to its involvement in cancer progression and development. However, progress of novel small molecules for selective targeting of mitochondria in cancer cells remained a major challenge. To address this, herein, through a concise synthetic strategy, we have synthesized a small molecule library of indomethacin and ibuprofen (non-steroidal anti-inflammatory drugs, NSAIDs) derivatives having triarylphosphonium moiety for mitochondria localization. Two of the library members were identified to induce mitochondrial damage through outer membrane permeabilization (MOMP) followed by generation of reactive oxygen species (ROS) leading to the remarkable MCF7 breast cancer cell death through apoptosis. These novel mitochondria targeted NSAID derivatives could open a new direction in understanding mitochondrial biology towards anti-cancer therapeutics in future.
    Keywords:  Cancer; Ibuprofen; Indomethacin; Mitochondria
    DOI:  https://doi.org/10.1016/j.bmc.2022.116759
  77. Nanomicro Lett. 2022 Apr 28. 14(1): 114
    A Therapeutic Sheep in Metastatic Wolf's Clothing: Trojan Horse Approach for Cancer Brain Metastases Treatment.
    Hai-Jun Liu, Mingming Wang, Shanshan Shi, Xiangxiang Hu, Peisheng Xu.
      Early-stage brain metastasis of breast cancer (BMBC), due to the existence of an intact blood-brain barrier (BBB), is one of the deadliest neurologic complications. To improve the efficacy of chemotherapy for BMBC, a Trojan horse strategy-based nanocarrier has been developed by integrating the cell membrane of a brain-homing cancer cell and a polymeric drug depot. With the camouflage of a MDA-MB-231/Br cell membrane, doxorubicin-loaded poly (D, L-lactic-co-glycolic acid) nanoparticle (DOX-PLGA@CM) shows enhanced cellular uptake and boosted killing potency for MDA-MB-231/Br cells. Furthermore, DOX-PLGA@CM is equipped with naturally selected molecules for BBB penetration, as evidenced by its boosted capacity in entering the brain of both healthy and early-stage BMBC mouse models. Consequently, DOX-PLGA@CM effectively reaches the metastatic tumor lesions in the brain, slows down cancer progression, reduces tumor burden, and extends the survival time for the BMBC animal. Furthermore, the simplicity and easy scale-up of the design opens a new window for the treatment of BMBC and other brain metastatic cancers.
    Keywords:  Blood–brain barrier; Brain metastasis; Cell membrane; Nanomedicine; Trojan horse
    DOI:  https://doi.org/10.1007/s40820-022-00861-1
  78. Life Sci. 2022 Apr 25. pii: S0024-3205(22)00282-X. [Epub ahead of print] 120582
    Pharmacological effects of cannabidiol by transient receptor potential channels.
    Leila Etemad, Gholamreza Karimi, Mohaddeseh Sadat Alavi, Ali Roohbakhsh.
      Cannabidiol (CBD), as a major phytocannabinoid of Cannabis sativa, has emerged as a promising natural compound in the treatment of diseases. Its diverse pharmacological effects with limited side effects have promoted researchers to pursue new therapeutic applications. It has little affinity for classical cannabinoid receptors (CB1 and CB2). Considering this and its diverse pharmacological effects, it is logical to set up studies for finding its putative potential targets other than CB1 and CB2. A class of ion channels, namely transient potential channels (TRP), has been identified during two recent decades. More than 30 members of this family have been studied, so far. They mediate diverse physiological functions and are associated with various pathological conditions. Some have been recognized as key targets for natural compounds such as capsaicin, menthol, and CBD. Studies show that CBD has agonistic effects for TRPV1-4 and TRPA1 channels with antagonistic effects on the TRPM8 channel. In this article, we reviewed the recent findings considering the interaction of CBD with these channels. The review indicated that TRP channels mediate, at least in part, the effects of CBD on seizure, inflammation, cancer, pain, acne, and vasorelaxation. This highlights the role of TRP channels in CBD-mediated effects, and binding to these channels may justify part of its paradoxical effects in comparison to classical phytocannabinoids.
    Keywords:  Cancer; Cannabidiol; Cannabis sativa; Inflammation; Pain; TRPA1; TRPM8; TRPV1; TRPV2; Tetrahydrocannabinol
    DOI:  https://doi.org/10.1016/j.lfs.2022.120582
  79. Carbohydr Polym. 2022 Aug 01. pii: S0144-8617(22)00337-X. [Epub ahead of print]289 119432
    Toxic reactive oxygen species enhanced chemodynamic therapy by copper metal-nanocellulose based nanocatalysts.
    Chaoqun You, Like Ning, Zhen Zhang, Hongshuai Wu, Qingli Qu, Fei Wang, Ranhua Xiong, Chaobo Huang.
      When compared with traditional petroleum-based materials, bio-based materials show greater application potential in the field of biomedicine owing to the good biocompatibility, in specifical, the application of natural macromolecular polymers in chemotherapeutics has become a hot topic in anticancer treatment. In this study, cellulose nanocrystals (CNCs) were selected as carriers, and Au nanoparticles (NPs) were directly conjugated on their surface, with the highly reactive Cu2+ ions serving as an ion-ligand bridge, to construct a multifunctional nanocatalyst. These findings suggest that the nanosystem delivers a large amount of highly reactive Cu2+ ions (3.75 wt%) and DOX (7.71 wt%) by the surface loading of cellulose nanocrystals, which greatly improves ROS yield and promotes the application of the Fenton reaction system in cancer therapy.
    Keywords:  Bio-based materials; Cellulose; Chemodynamic therapy; Drug carrier; Reactive oxygen species; Synergistic therapy
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119432
  80. AAPS PharmSciTech. 2022 Apr 26. 23(5): 125
    Silymarin-Encapsulated Xanthan Gum-Stabilized Selenium Nanocarriers for Enhanced Activity Against Amyloid Fibril Cytotoxicity.
    Vanshul Saini, Ajit Singh, Rahul Shukla, Keerti Jain, A K Yadav.
      The accumulation of amyloid-beta at the neuronal sites is a major pathological hallmark involved in the etiology of Alzheimer's disease. To reduce the Aβ-induced neuronal cytotoxicity, selenium nanoparticles and silymarin were fabricated in a single polysaccharide matrix for dual antioxidant and Aβ fibril disaggregation activity. These nanoparticles were further stabilized by an exopolysaccharide xanthan gum. The nanoparticles were fabricated to reduce the amyloid-induced cytotoxicity in SH-SY5Y cells. A three-step method employing redox reaction of sodium selenite and ascorbic acid has been adopted for the synthesis of selenium nanoparticles. Consequently, xanthan gum powder was added to impart stability to the nanocarriers. The nanoparticles exhibited a particle size of 119.2 ± 2.8 nm, zeta potential of - 35.4 ± 3.8 mV, and % EE of 87.7 ± 2.23. HR-TEM with EDX analysis confirmed the presence of spherical nanoparticles. An in vitro drug release study exhibited 89.33 ± 5.4% release of silymarin from nanocarriers and was able to scavenge 90% free radicals of DPPH reagent. The thioflavin T (ThT) fibrillation kinetics study showed that the nanoparticles elicited maximum disaggregation of Aβ fibrils that was depicted by the quenched fluorescence intensity signal. The cell viability results revealed that the highest neuroprotection activity was observed in the cell group treated with SLY-XG-Se against Aβ 1-42-induced toxicity. The nanoparticles were able to internalize in SH-SY5Y cells. Our findings showed that the nanocarrier elicited anti-aggregation efficacy in neuronal cell lines and mitigated the Aβ-induced cytotoxicity, which represents the prospects of neuroprotection involved in the therapeutics of AD.
    Keywords:  alzheimer’s disease; amyloid beta fibril; neuroprotection; selenium nanoparticles; silymarin
    DOI:  https://doi.org/10.1208/s12249-022-02274-0
  81. Small. 2022 Apr 27. e2107705
    Non-Invasive Thermal Therapy for Tissue Engineering and Regenerative Medicine.
    Longfei Li, Xiaodi Zhang, Jun Zhou, Liqun Zhang, Jiajia Xue, Wei Tao.
      Owing to the development of nanotechnology and noninvasive treatment, thermal therapy in combination with external stimuli has been applied for tissue engineering and regenerative medicine (TERM), which has attracted more and more attention in recent years. In this review, the recent progress of applying a variety of non-invasive thermal therapeutic modalities for TERM, including photothermal therapy, magnetic thermotherapy, and ultrasound thermotherapy, as well as other thermal therapeutics are discussed. The parameters and conditions that need to be considered and regulated to realize a well-controlled thermal therapy for tissue regeneration are also discussed. Afterwards, the current concerns and challenges of putting thermal therapy into clinical applications are pointed out. At last, perspectives are provided for the future development directions, aiming to providing opportunities and a novel pathway for TERM.
    Keywords:  magnetic thermotherapy; photothermal therapy; thermal therapy; tissue engineering; ultrasound thermotherapy
    DOI:  https://doi.org/10.1002/smll.202107705
  82. Front Pharmacol. 2022 ;13 865376
    Antidepressant Potential of Quercetin and its Glycoside Derivatives: A Comprehensive Review and Update.
    Shen Chen, Yueheng Tang, Yang Gao, Kexin Nie, Hongzhan Wang, Hao Su, Zhi Wang, Fuer Lu, Wenya Huang, Hui Dong.
      Depression is a global health problem with growing prevalence rates and serious impacts on the daily life of patients. However, the side effects of currently used antidepressants greatly reduce the compliance of patients. Quercetin is a flavonol present in fruits, vegetables, and Traditional Chinese medicine (TCM) that has been proved to have various pharmacological effects such as anti-depressant, anti-cancer, antibacterial, antioxidant, anti-inflammatory, and neuroprotective. This review summarizes the evidence for the pharmacological application of quercetin to treat depression. We clarified the mechanisms of quercetin regulating the levels of neurotransmitters, promoting the regeneration of hippocampal neurons, improving hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and reducing inflammatory states and anti-oxidative stress. We also summarized the antidepressant effects of some quercetin glycoside derivatives to provide a reference for further research and clinical application.
    Keywords:  antidepressant; avicularin; glycoside derivatives; hyperin; isoquercetin; quercetin; quercetin 4′-O-glucoside; rutin
    DOI:  https://doi.org/10.3389/fphar.2022.865376
  83. J Drug Target. 2022 Apr 25. 1-52
    Nanocarrier-based co-delivery approaches of chemotherapeutics with natural P-glycoprotein inhibitors in the improvement of multidrug resistance cancer therapy.
    Shadab Md, Nabil A Alhakamy, Priyanka Sharma, Mohammad Shahnawaze Ansari, Bapi Gorain.
      Chemotherapy is the mainstay in cancer treatment; however, its application is clinically limited to patients with multidrug resistance (MDR). MDR reverses the role of chemotherapy through significant attribution to pharmacokinetic characteristics, where ATP-binding cassette transporter proteins, P-glycoprotein (P-gp), pump out the intracellularly transported chemotherapeutics from the cancer cells. Therefore, overexpression of such receptors on MDR cancer cell surfaces tends to decrease the efficacy of a large number of existing chemotherapeutics. P-gp inhibitors, especially from natural origin, play a vital role in enhancing the cellular concentration of clinically applicable chemotherapeutics. Therefore, co-administration of these natural P-gp inhibitors with chemotherapeutics could improve chemotherapeutic efficacy against MDR cancer, which has been evidenced in the literature. Co-delivery of these therapeutic components can effectively be made using the emerging nanotechnology platform, which could facilitate controlled delivery of the incorporated components to the cancerous microenvironment, through passive and active targeting. Thereby, cellular retention of chemotherapeutic agents by the P-gp mediated inhibitory effect on efflux pump using the nanocarrier co-delivery platform could improve the anticancer potential of the chemotherapeutics. This review has presented the advancement of naturally occurring P-gp inhibitors as promising adjuvant in chemotherapy to modulate the pharmacokinetic properties of chemotherapeutic agents using the nanotechnology platform.
    Keywords:  P- glycoprotein inhibitors; enhanced cancer management; multidrug resistance; pharmacokinetic modulation; reversal of resistance
    DOI:  https://doi.org/10.1080/1061186X.2022.2069782
  84. Nat Commun. 2022 Apr 25. 13(1): 2225
    An unexpected strategy to alleviate hypoxia limitation of photodynamic therapy by biotinylation of photosensitizers.
    Jing An, Shanliang Tang, Gaobo Hong, Wenlong Chen, Miaomiao Chen, Jitao Song, Zhiliang Li, Xiaojun Peng, Fengling Song, Wen-Heng Zheng.
      The most common working mechanism of photodynamic therapy is based on high-toxicity singlet oxygen, which is called Type II photodynamic therapy. But it is highly dependent on oxygen consumption. Recently, Type I photodynamic therapy has been found to have better hypoxia tolerance to ease this restriction. However, few strategies are available on the design of Type I photosensitizers. We herein report an unexpected strategy to alleviate the limitation of traditional photodynamic therapy by biotinylation of three photosensitizers (two fluorescein-based photosensitizers and the commercially available Protoporphyrin). The three biotiylated photosensitizers named as compound 1, 2 and 3, exhibit impressive ability in generating both superoxide anion radicals and singlet oxygen. Moreover, compound 1 can be activated upon low-power white light irradiation with stronger ability of anion radicals generation than the other two. The excellent combinational Type I / Type II photodynamic therapy performance has been demonstrated with the photosensitizers 1. This work presents a universal protocol to provide tumor-targeting ability and enhance or trigger the generation of anion radicals by biotinylation of Type II photosensitizers against tumor hypoxia.
    DOI:  https://doi.org/10.1038/s41467-022-29862-9
  85. RSC Adv. 2021 Aug 23. 11(46): 29065-29072
    NIR-triggered upconversion nanoparticles@thermo-sensitive liposome hybrid theranostic nanoplatform for controlled drug delivery.
    Yibin Yu, Yida Huang, Wanqian Feng, Mei Yang, Baiqi Shao, Jingjing Li, Fangfu Ye.
      Posterior segment ocular diseases are highly prevalent worldwide due to the lack of suitable noninvasive diagnostic and therapeutic tactics. Herein, concerning this predicament, we designed a hybrid retina-targeted photothermal theranostic nanoplatform (UCNPs@Bi@SiO2@GE HP-lips), based on the unique upconversion luminescence (UCL) imaging of upconversion nanoparticles (UCNPs), efficient photothermal conversion ability of Bi nanoparticles, and thermal-induced phase transition properties of the liposomes (lips). The nanoplatform was functionalized with penetratin (PNT) and hyaluronic acid (HA), to obtain retina-targeted liposomes (HP-lips). Lipophilic genistein (GE) was entrapped into the liposomes (GE HP-lips). An in vitro release study showed NIR irradiation could photothermally trigger controlled release of GE from the liposomal platform. Moreover, cellular uptake evaluation via UCL imaging demonstrated UCNPs@Bi@SiO2@GE HP-lips represented the brightest UCL, compared with other formulations, which is beneficial for the accurate evaluation of the prognosis and severity of angiogenesis-related posterior segment disorders. Therefore, UCNPs@Bi@SiO2@GE HP-lips exhibit promising potential as a theranostic nanoplatform for posterior segment ocular diseases.
    DOI:  https://doi.org/10.1039/d1ra04431a
  86. AAPS PharmSciTech. 2022 Apr 26. 23(5): 124
    Drotaverine Hydrochloride Superporous Hydrogel Hybrid System: a Gastroretentive Approach for Sustained Drug Delivery and Enhanced Viscoelasticity.
    Michael M Farag, Mina M Louis, Alia A Badawy, Demiana I Nessem, Nevine S Abd Elmalak.
      This study aims to prepare drotaverine hydrochloride superporous hydrogel hybrid systems (DSHH systems) to prolong its residence time in the stomach, provide extended release and reduce its frequency of administration. Drotaverine hydrochloride (DRH) is a spasmolytic drug that suffers from brief residence due to intestinal hypermotility during diarrheal episodes associated with gastrointestinal colics resulting in low bioavailability and repeated dosing. Eight DSHH systems were prepared using gas blowing technique. The prepared DSHH systems were evaluated regarding their morphology, incorporation efficiency, density, porosity, swelling ratio, viscoelastic property, erosion percentage and release kinetics. The FH8 formula containing equal proportion of chitosan (3%) /polyvinyl alcohol (3%) as strengthener and crosslinked with tripolyphosphate showed the highest incorporation efficiency (91.83 ± 1.33%), good swelling ratio (28.32 ± 3.15% after 24 h), optimum viscoelastic properties (60.19 ± 3.82 kPa) and sustained release profile (88.03 ± 2.15% after 24 h). A bioequivalence study was done to compare the bioavailability of the candidate formula versus Spasmocure®. Statistical analysis showed significant (P < 0.05) increase in bioavailability 2.7 folds with doubled Tmax (4 h) compared to the marketed product (2 h). These results declared that the superporous hydrogel hybrid systems could be a potential gastroretentive approach for the sustained delivery of drugs with short residence time with enhanced viscoelasticity.
    Keywords:  drotaverine hydrochloride; gastroretentive; hydrogel; superporous; sustained drug delivery
    DOI:  https://doi.org/10.1208/s12249-022-02280-2
  87. Carbohydr Polym. 2022 Aug 01. pii: S0144-8617(22)00372-1. [Epub ahead of print]289 119467
    Paramylon hydrogel: A bioactive polysaccharides hydrogel that scavenges ROS and promotes angiogenesis for wound repair.
    Huan Lei, Jing Zhao, Hang Li, Daidi Fan.
      The excessive inflammation, oxidative stress, and impaired angiogenesis are major factors leading to difficulties in chronic wound healing. To develop bioactive materials with intrinsic antioxidant and anti-inflammatory properties, we prepared hydrogels for the first time using paramylon secreted by Euglena gracilis which is a polysaccharide has been approved by FDA as food additive. Results showed that the paramylon hydrogel has favourable anti-inflammatory effects and the ability to scavenge reactive oxygen species (ROS) through free radical destruction, deoxygenation, and singlet oxygen quenching, and inhibit ROS production by chelating the metal ions required for the formation of ROS. We found that the paramylon hydrogel could effectively reduce wound inflammation and promote angiogenesis to facilitate wound repair. Furthermore, for the first time, we found that paramylon hydrogel could promote the formation of blood vessels via the HIF-1α-VEGF pathway. These results indicated that the highly bioactive paramylon could be the preferred material for wound healing.
    Keywords:  1,4-Butanediol diepoxyglycerol ether (PubChem CID: 9581357); Anti-inflammatory; Antioxidant; Paramylon (PubChem SID: 405237933); Paramylon hydrogel; Pro-angiogenesis; Wound repair
    DOI:  https://doi.org/10.1016/j.carbpol.2022.119467
  88. Bioinform Biol Insights. 2022 ;16 11779322221091740
    Sea Cucumber Compounds Targeting NF-κB in Cancer Treatment.
    Teresa Liliana Wargasetia, Hana Ratnawati, Nashi Widodo.
      Cancer is a major health problem worldwide and the leading cause of death in many countries. It remains challenging to find anticancer treatments that work efficiently for varying types of cancer cells. Several studies revealed that nuclear factor kappa B (NF-κB) is a family of dimeric transcription factors that induce tumor promotion, progression, and therapeutic resistance, providing evidence that NF-kB may be a promising target for cancer drugs. Some research has found that sea cucumber biocompounds have anticancer properties, but further research is essential to confirm anticancer targets. This manuscript discusses the mechanisms of anticancer targeting the NF-κB signaling pathway induced by sea cucumber-derived compounds. Additional database analysis showed the protein targeted by the compounds involved in several pathways related to the NF-κB network. Moreover, SwissADME predicted druglikeliness properties of the active compounds of sea cucumber. The discussion is expected to provide new insight into the promising potential of these marine natural products for the treatment of many different types of cancers.
    Keywords:  Drug discovery; nuclear factor kappa B; pharmacokinetics; physicochemical; sea cucumbers
    DOI:  https://doi.org/10.1177/11779322221091740
  89. J Cosmet Dermatol. 2022 Apr 29.
    Design and Development of Naringin Loaded Proposomal Gel for Wound Healing.
    Shifali D Kumari, Naga Thirumalesh Chevala, Srinivas Reddy Jitta, Lalit Kumar, Ruchi Verma, Jobin Jose.
       BACKGROUND: The injuries or wounds caused by various means will impact human lives severely. An increase in the demand for wounds or burns was observed. For better wound healing and to combat the free radical effect on the healing process, wounds must be treated with multifunctional or multipurpose dressing or gel or any other type of biomaterial.
    OBJECTIVES: The study aims to develop, optimize, and evaluate the naringin-loaded proposomal gel (PPG) for quick wound healing.
    METHODS: The central composite design was employed for the optimization of proposomes. Naringin-loaded proposomes were evaluated for percentage entrapment efficiency (EE), the particle size of proposomes (PsP), and the zeta potential of proposomes (ZpP). The change in drug release profile was studied by dissolution. Furthermore, naringin and naringin-loaded proposomes, antioxidant activity was determined by 2,2- diphenyl-1-picrylhydrazyl hydrate (DPPH) reagent and ascorbic acid as a reference standard. Different gel bases were prepared, and based on various parameters, the G2 (0.6 % Carbopol 974) gel base was selected for naringin proposomes loading. The naringin-loaded PPG was evaluated for various in vitro and in vivo wound healing properties.
    RESULTS: The optimized naringin-loaded proposomes showed extended drug release (90.78 ± 2.19%) for 72 h. The naringin-loaded PPG improved the permeability of naringin, which showed 28.91 ± 2.81% of drug release after 96 h, and the drug solution showed 9.05 ± 0.92%. IC50 values of antioxidant activity of naringin and naringin proposomes were found to be 337.31 μg/ mL and 201.86 μg/ mL, respectively. The naringin-loaded PPG showed better-wound closure on the 15th day (3.32%) compared to proposomal solution (4.75%) or naringin topical gel (4.2%).
    CONCLUSION: Based on the obtained results, we conclude naringin-loaded PPG can be an alternative strategic approach to deliver the naringin for quick wound healing.
    Keywords:  Naringin; antioxidant activity; proposomes; topical gel; wound-healing activity
    DOI:  https://doi.org/10.1111/jocd.15029
  90. Crit Rev Food Sci Nutr. 2022 Apr 25. 1-25
    Kaempferol: A flavonoid with wider biological activities and its applications.
    Sneh Punia Bangar, Vandana Chaudhary, Nitya Sharma, Vasudha Bansal, Fatih Ozogul, Jose M Lorenzo.
      Kaempferol and its derivatives are naturally occurring phytochemicals with promising bioactivities. This flavonol can reduce the lipid oxidation in the human body, prevent the organs and cell structure from deterioration and protect their functional integrity. This review has extensively highlighted the antioxidant, antimicrobial, anticancer, neuroprotective, and hepatoprotective activity of kaempferol. However, poor water solubility and low bioavailability of kaempferol greatly limit its applications. The utilization of advanced delivery systems can improve its stability, efficacy, and bioavailability. This is the first review that aimed to comprehensively collate some of the vital information published on biosynthesis, mechanism of action, bioactivities, bioavailability, and toxicological potential of kaempferol. Besides, it provides insights into the future direction on the improvement of bioavailability of kaempferol for wide applications.
    Keywords:  Flavonoids; bioactivities; bioavailability; biosynthesis; flavonols
    DOI:  https://doi.org/10.1080/10408398.2022.2067121
  91. Evid Based Complement Alternat Med. 2022 ;2022 3311228
    Vascular Protective Effect and Its Possible Mechanism of Action on Selected Active Phytocompounds: A Review.
    Nur Aqilah Kamaruddin, Muhammad Nazrul Hakim Abdullah, Jun Jie Tan, Vuanghao Lim, Lai Yen Fong, Siti Aisyah Abd Ghafar, Yoke Keong Yong.
      Vascular endothelial dysfunction is characterized by an imbalance of vasodilation and vasoconstriction, deficiency of nitric oxide (NO) bioavailability and elevated reactive oxygen species (ROS), and proinflammatory factors. This dysfunction is a key to the early pathological development of major cardiovascular diseases including hypertension, atherosclerosis, and diabetes. Therefore, modulation of the vascular endothelium is considered an important therapeutic strategy to maintain the health of the cardiovascular system. Epidemiological studies have shown that regular consumption of medicinal plants, fruits, and vegetables promotes vascular health, lowering the risk of cardiovascular diseases. This is mainly attributed to the phytochemical compounds contained in these resources. Various databases, including Google Scholar, MEDLINE, PubMed, and the Directory of Open Access Journals, were searched to identify studies demonstrating the vascular protective effects of phytochemical compounds. The literature had revealed abundant data on phytochemical compounds protecting and improving the vascular system. Of the numerous compounds reported, curcumin, resveratrol, cyanidin-3-glucoside, berberine, epigallocatechin-3-gallate, and quercetin are discussed in this review to provide recent information on their vascular protective mechanisms in vivo and in vitro. Phytochemical compounds are promising therapeutic agents for vascular dysfunction due to their antioxidative mechanisms. However, future human studies will be necessary to confirm the clinical effects of these vascular protective mechanisms.
    DOI:  https://doi.org/10.1155/2022/3311228
  92. Biomaterials. 2022 Apr 18. pii: S0142-9612(22)00173-9. [Epub ahead of print]284 121533
    A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy.
    Zan Dai, Qiaoyun Wang, Jie Tang, Rui Qu, Min Wu, Haoze Li, Yannan Yang, Xu Zhen, Chengzhong Yu.
      Adenosine and lactate accumulated in tumor microenvironment are two major causes of immunosuppression, their concurrent downregulation holds promise in effective cancer immunotherapy, but remains challenging. Here, a sub-6 nm MnFe2O4 conjugated with dichloroacetic acid (DCA) nanoparticle is developed to modulate tumor glucose metabolism and ATP catabolism for reversing the tumor immunosuppressive microenvironment. The ultrasmall MnFe2O4-DCA nanoparticle can efficiently enter mitochondria and supply oxygen, improving the bioactivity of DCA to regulate glucose metabolism and reduce lactate production ca. 100 times higher than free DCA itself. Moreover, this design significantly downregulates CD39 and CD73 expression than DCA or MnFe2O4 alone, which consequently decreases the extracellular ATP catabolism. The concurrent regulation of glucose metabolism and ATP catabolism leads to increased immunostimulatory ATP level and decreased immunosuppressive adenosine and lactate levels in tumor microenvironment, eventually amplified dendritic cells maturation, enhanced cytotoxic T lymphocyte response, and improved cancer immunotherapy efficacy.
    Keywords:  ATP catabolism; Glucose metabolism; Mitochondrial entry; Tumor immunosuppressive microenvironment; Ultrasmall nanocomposite
    DOI:  https://doi.org/10.1016/j.biomaterials.2022.121533
  93. J Biomed Nanotechnol. 2022 Feb 01. 18(2): 327-342
    Tumor Microenvironment-Responsive Nanodrug for Clear-Cell Renal Cell Carcinoma Therapy via Triggering Waterfall-Like Cascade Ferroptosis.
    Wenjun Ni, Yongxiang Li, Lingxia Liang, Shuyue Yang, Meixiao Zhan, Cuixia Lu, Ligong Lu, Liewei Wen.
      The most common type of kidney tumor, clear-cell renal cell carcinoma (ccRCC) with relatively insidious development and easily metastatic characteristics is generally insensitive to cytotoxic chemotherapy. The abundant polyunsaturated fatty acids (PUFAs) content in advanced ccRCC allows it to be intrinsically vulnerable to ferroptosis-based therapeutic strategies. Nevertheless, the strategy to cause the "iron overload" by administration with iron-based nanomaterials has limited therapeutic efficacy. And the classic ferroptosis agonist (RSL3) with low specificity for tumors, short half-life in the blood, poor water solubility and deficient accumulation at the tumor site prevents its reliable application in vivo. In this study, iron-based metal-organic framework nanoparticles (MIL-101(Fe) NPs) delivered RSL3 to ccRCC tumors, and then released the iron ions and RSL3 accompanied by the degradation of MIL-101(Fe) NPs in the acidic tumor microenvironment. The MIL-101(Fe)@RSL3 as a pH-responsive nanodrug causes cellular iron overload and promotes the hydroxyl radical (•OH) generation by Fenton reaction to attack PUFAs, leading to the aberrant accumulation of lipid peroxides (L-OOH). Additionally, RSL3 directly inhibits glutathione peroxidase 4 (GPX4) to detoxify L-OOH, and ferrous ions further catalyze the irreversible conversion of highly reactive lipid alkoxyl radicals (L-O•) from L-OOH to triggering waterfall-like cascade ferroptosis. In contrast to the limited antitumor efficiency of free RSL3, MIL-101(Fe)@RSL3 with high encapsulation efficiency (88.7%) shows a significant ccRCC-specific antitumor effect and negligible side effects. Taken together, MIL-101(Fe)@RSL3 could aggravate ferroptosis and be expected to be a promising nanodrug for ccRCC systemic therapy due to the targeted delivery and responsive release of RSL3 and iron ions.
    DOI:  https://doi.org/10.1166/jbn.2022.3250
  94. RSC Adv. 2021 Aug 16. 11(45): 28029-28041
    Green synthesis of gold nanoparticles using an antiepileptic plant extract: in vitro biological and photo-catalytic activities.
    Jayanta S Boruah, Chayanika Devi, Upasana Hazarika, P Vijaya Bhaskar Reddy, Devasish Chowdhury, Manash Barthakur, Pankaj Kalita.
      Gold nanoparticles are one of the widely used metallic nanoparticle having unique surface plasmon characteristic, offers major utility in biomedical and therapeutic fields. However, chemically synthesized nanoparticle creates toxicity in the living organisms and contradicts the eco-friendly and cost-effective nature. So, developing greener synthetic route for synthesis of gold nanoparticle using natural materials is an enthralling field of research for its effectiveness in synthesizing eco-friendly, non-toxic materials. Moreover, biological components attached as stabilizing agent can exert its own effect along with the advantages of nanoparticle conjugation. In this work, we used for the first time methanolic leaf extract of Moringa oleifera as this fraction of M. oleifera exerts a neuroactive modulation against seizure as evidenced by earlier literature. The green gold nanoparticles synthesized were characterized by different characterization tools, dynamic light scattering and transmission electron microscopy techniques etc. Prepared nanoparticles were biologically (antioxidant, antimicrobial and blood cytotoxicity) characterized to screen their further utility in therapeutic strategies. Characteristics and activities of green gold nanoparticles were compared with conventional citrate stabilized gold nanoparticles. It was observed that green gold nanoparticles prepared using M. oleifera show less cytotoxicity and helps in regeneration of neuronal cells in animal model study. It establishes the fact that conjugation of different plant extract fraction for stabilization of gold nanoparticle may be responsible factor for enhancement of bioactive nature of green gold nanoparticle. In addition, the green gold nanoparticle show efficient photo-catalytic efficiency. Development of such bioactive gold nanoparticles will lead to functional materials for biomedical and therapeutic applications.
    DOI:  https://doi.org/10.1039/d1ra02669k
  95. Compr Rev Food Sci Food Saf. 2022 Apr 26.
    The future of functional food: Emerging technologies application on prebiotics, probiotics and postbiotics.
    Celso F Balthazar, Jonas F Guimarães, Nathália M Coutinho, Tatiana C Pimentel, C Senaka Ranadheera, Antonella Santillo, Marzia Albenzio, Adriano G Cruz, Anderson S Sant'Ana.
      This review was the first to gather literature about the effect of emerging technologies on probiotic, prebiotic, and postbiotic products. Applying emerging technologies to probiotic products can increase probiotic survival and improve probiotic properties (cholesterol attachment, adhesion to Caco-2 cells, increase angiotensin-converting enzyme (ACE) inhibitory, antioxidant, and antimicrobial activities, and decrease systolic blood pressure). Furthermore, it can optimize the fermentation process, produce or maintain compounds of interest (bacteriocin, oligosaccharides, peptides, phenolic compounds, flavonoids), improve bioactivity (vitamin, aglycones, calcium), and sensory characteristics. Applying emerging technologies to prebiotic products did not result in prebiotic degradation. Still, it contributed to higher concentrations of bioactive compounds (citric and ascorbic acids, anthocyanin, polyphenols, flavonoids) and health properties (antioxidant activity and inhibition of ACE, α-amylase, and α-glucosidase). Emerging technologies may also be applied to obtain postbiotics with increased health effects. In this way, current studies suggest that emerging food processing technologies enhance the efficiency of probiotics and prebiotics in food. The information provided may help food industries to choose a more suitable technology to process their products and provide a basis for the most used process parameters. Furthermore, the current gaps are discussed. Emerging technologies may be used to process food products resulting in increased probiotic functionality, prebiotic stability, and higher concentrations of bioactive compounds. In addition, they can be used to obtain postbiotic products with improved health effects compared to the conventional heat treatment.
    Keywords:  beneficial microbes; ecofriendly processing; food safety; functional food; innovative food processing; new food products
    DOI:  https://doi.org/10.1111/1541-4337.12962
  96. Sci Total Environ. 2022 Apr 21. pii: S0048-9697(22)02530-X. [Epub ahead of print] 155436
    Combined exposure to nanoplastics and metal oxide nanoparticles inhibits efflux pumps and causes oxidative stress in zebrafish embryos.
    Jacky Bhagat, Liqing Zang, Satoshi Kaneco, Norihiro Nishimura, Yasuhito Shimada.
      The ubiquity of microplastic/nanoplastics (MP/NPs) provides an opportunity for their interaction with other widely spread environmental contaminants. MP/NP and nanoparticles share a similar transport route from sources, production, and disposal. Metal oxide nanoparticles (nMOx) have varied industrial applications, and limited knowledge is available on their interaction with MP/NPs. The present study investigated the effect of NPs (1 mg/L) on the efflux of two nMOx, aluminium oxide nanoparticles (nAl2O3, 1 mg/L) and cerium oxide nanoparticles (nCeO2, 1 mg/L), and their combined toxicity to zebrafish embryos. The results illustrated increased accumulation of aluminium and cerium in the combined exposure group compared to the nMOx alone treatment. The presence of NPs exacerbated the oxidative stress caused by nAl2O3 and nCeO2, as evidenced by an increase in the concentration of reactive oxygen species (ROS), alteration of antioxidants, and lipid peroxidation. The integrated biomarker response (IBRv2) values showed the induction of an antioxidative response in NP + nAl2O3, whereas a decline in IBRv2 values was observed in NP + nCeO2. Our results indicate that NPs aggravated the accumulation of nMOx and their toxicity. The present work highlights that more attention should be paid to the discharge of these contaminants into the natural environment.
    Keywords:  ABC efflux transporter; DNA repair; Integrated biomarker response; Polystyrene nanoparticle; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.scitotenv.2022.155436
  97. RSC Adv. 2021 Jun 21. 11(36): 22433-22438
    Self-assembly of diclofenac prodrug into nanomicelles for enhancing the anti-inflammatory activity.
    Mohyeddin Assali, Ramzi Shawahna, Raeda Alhawareen, Haifa Najajreh, Oraib Rabaya, Maryam Faroun, Ahed Zyoud, Hikmat Hilal.
      Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the treatment of various types of inflammatory conditions. Diclofenac is a very common NSAID that is utilized to relieve pain and reduce fever and, most importantly, inflammation. However, it suffers from low water solubility and a low dissolution profile. Therefore, we aim to develop a new drug delivery system based on the synthesis of amphiphilic structures that are capable of self assembling into nano-micelles which will be a water-soluble delivery system for the diclofenac. The amphiphilic structure consists of a hydrophilic moiety of triethylene glycol (TEG), polyethylene glycol PEG 400, or PEG 600 linked with the hydrophobic drug diclofenac through an ester linkage. The diclofenac derivatives were successfully synthesized as confirmed by nuclear magnetic resonance. Moreover, the formation of the micellar structure of the synthesized amphiphilic derivatives was confirmed by atomic force microscopy obtaining a spherical shape of the micelles with average diameters of 200 nm for Dic-PEG400-Dic, and 110 nm for Dic-PEG600-Dic. The critical micelle concentration has been determined as 2.7 × 10-3 mg mL-1 for Dic-PEG400-Dic, and 1 × 10-4 mg mL-1 for Dic-PEG600-Dic. The in vitro diclofenac release profile by esterase enzyme was conducted and showed almost complete conversion to free diclofenac within 35 h in the case of Dic-PEG400-Dic micelles and more than 85% of Dic-PEG600-Dic micelles. Then the anti-inflammatory activity was determined by testing the TNF-α production in LPS-stimulated Balb/c mice. Diclofenac micelles significantly suppressed TNF-α production after a 5 mg kg-1 dose was given. The developed micelles showed TNF-α inhibition up to 87.4% and 84% after 48 hours of treatment in the case of Dic-PEG400-Dic and Dic-PEG600-Dic micelles respectively in comparison to 42.3% in the case of diclofenac alone. Dic-PEG400-Dic micelles showed the most potent anti-inflammatory activity with improved TNF-α suppression through time progress. Therefore, the developed nano-micelles provide a facile synthetic approach to enhance diclofenac water solubility, improve the anti-inflammatory effect and achieve a sustained release profile to get better patient compliance.
    DOI:  https://doi.org/10.1039/d1ra03804d
  98. PLoS One. 2022 ;17(4): e0264518
    Development of stealth liposomal formulation of celecoxib: In vitro and in vivo evaluation.
    M Yasmin Begum, Riyaz Ali M Osmani, Ali Alqahtani, Mohammed Ghazwani, Umme Hani, Hissana Ather, Akhtar Atiya, Mohamed Rahamathulla, Ayesha Siddiqua.
      Celecoxib (CLB) is a highly hydrophobic selective cyclo-oxygenase inhibitor with high plasma protein binding and undergoes extensive hepatic metabolism. CLB is highly effective in the treatment of osteo and rheumatoid arthritis as first line therapy but produces severe gastro-intestinal toxicities and cardiovascular side effects. In this research, stealth liposomes of CLB were developed with the intention to reduce the side effects and increase the accumulation of drug in the sites of inflammation. Stealth liposomes were prepared by thin film hydration technique using distearoylphosphatidylcholine and PE-PEG 2000 with variable amounts of cholesterol and characterized. The effects of various lipids such as hydrogenated soy phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoylphosphatidylcholine and cholesterol content on % drug encapsulation was investigated. The optimized stealth liposomes were characterized by FT-IR and DSC for possible drug excipients interaction. Pharmacokinetics, pharmacodynamics and biodistribution studies were carried out for the stealth liposomes. The results revealed that the stealth liposomes reduced the inflammation to the larger magnitude and have also sustained the magnitude when compared to free drug along with maximum analgesic response. Higher elimination half-life, AUC, MRT and lowered clearance rate denotes the extended bioavailability of the drug in blood. Biodistribution studies revealed that stealth liposomes extend the circulation time of liposomes in blood by decreasing opsonisation and be less concentrated in kidney, thereby reducing the toxicities to RES and renal organs and facilitate the drug accumulation in the area of inflammation. Our results indicated that CLB, without the requirement of modifications to enhance solubilisation, can be encapsulated and released from liposomal formulations. This new-fangled drug delivery approach may be used to circumvent the low bioavailability and toxic side effects of oral CLB formulations.
    DOI:  https://doi.org/10.1371/journal.pone.0264518
  99. J Microencapsul. 2022 Apr 26. 1-39
    Dual Vinorelbine bitartrate and Resveratrol Loaded Polymeric Aqueous core Nanocapsules for Synergistic Efficacy in Breast Cancer.
    Lakshmi Maurya, Sanjay Singh, Kamal Shah, Hitesh Kumar Dewangan.
       AIM: The current study focused on the development and evaluation of aqueous core nanocapsules (ACNs) as an effective carrier to deliver an optimal synergistic combination of a highly water soluble Vinorelbine bitartrate (VRL) and a poorly water-soluble Resveratrol (RES) for treatment of breast cancer.
    METHODS: Various molar ratios of VRL to RES were screened against MCF-7 cell lines to determine the synergistic effects using Chou-Talalay method. Synergistic ratio of therapeutic agents was then incorporated into aqueous core nanocapsules utilizing a double emulsion solvent evaporation technique to yield dual drug loaded nanocapsules (dd-ACNs). The dd-ACNs were optimized using Box-Behnken design and characterized for physicochemical parameters such as particle size, zeta potential, polydispersity index, total drug content and encapsulation efficiency, surface morphology, drug excipient compatibility by FTIR and DSC, release kinetics, toxicity studies and anticancer efficacy (in-vitro and in-vivo).
    RESULTS: Results demonstrated that the combination exhibited maximum synergy when higher doses of VRL were combined with smaller doses of RES (1:1, 5:1, and 10:1). The dual drug loaded ACNs were found to be stable and depicted a core-shell structure, narrow size range (150.2 ± 3.2 nm) with enhanced encapsulation (80% for VRL and 99% for RES). Moreover, the dd-ACNs were 5 times more efficacious in-vitro than a combination of free drugs, while reducing systemic toxicity. Also, pre-clinical evaluation of dd-ACNs also depicted drastic reduction of tumor volume as compared tp pristine VRL and physical combination of drugs.
    CONCLUSION: The developed dd-ACNs can be applied as potential carrier for delivery of combination of chemotherapeutics at a synergistic ratio at tumor site.
    Keywords:  Aqueous core nanocapsules; Box Behnken design; Combination therapy; Resveratrol; Vinorelbine bitartrate
    DOI:  https://doi.org/10.1080/02652048.2022.2070679
  100. Epigenomics. 2022 Apr 27.
    Potential epigenetic modifications implicated in triple- to quadruple-negative breast cancer transition: a review.
    Aliyu Muhammad, Gilead Ebiegberi Forcados, Babangida Sanusi Katsayal, Rabiatu Suleiman Bako, Suleiman Aminu, Idris Zubairu Sadiq, Murtala Bello Abubakar, Abdurrahman Pharmacy Yusuf, Ibrahim Malami, Mohammed Faruk, Sani Ibrahim, Peter Abur Pase, Saad Ahmed, Ibrahim Babangida Abubakar, Murtala Abubakar, Clayton Yates.
      Current research on triple-negative breast cancer (TNBC) has resulted in delineation into the quadruple-negative breast cancer (QNBC) subgroup. Epigenetic modifications such as DNA methylation, histone posttranslational modifications and associated changes in chromatin architecture have been implicated in breast cancer pathogenesis. Herein, the authors highlight genes with observed epigenetic modifications that are associated with more aggressive TNBC/QNBC pathogenesis and possible interventions. Advanced literature searches were done on PubMed/MEDLINE, Scopus and Google Scholar. The results suggest that nine epigenetically altered genes/differentially expressed proteins in addition to the downregulated androgen receptor are associated with TNBC aggressiveness and could be implicated in the TNBC to QNBC transition. Thus, restoring the normal expression of these genes via epigenetic reprogramming could be therapeutically beneficial to TNBC and QNBC patients.
    Keywords:  epigenetic modifications; genes; quadruple-negative breast cancer; therapeutic targets; triple-negative breast cancer
    DOI:  https://doi.org/10.2217/epi-2022-0033
  101. Pharm Nanotechnol. 2022 Apr 26.
    Topical nanostructured lipid carriers of alpha-mangostin and resveratrol for synergistic antioxidant activity.
    Wipada Samprasit, Chitralada Vasarach, Praneet Opanasopit, Pornsak Sriamornsak, Benchawan Chamsai.
       BACKGROUND: Nanostructured lipid carriers (NLCs) are interesting lipid-based carrier systems for enhancing the penetration of drugs through the skin after topical administration.
    OBJECTIVE: Dual drug-loaded NLCs of alpha-mangostin (M) and resveratrol (R) to enhance antioxidant activity were developed for topical delivery.
    METHODS: The efficacy of a combination of M and R was evaluated in terms of the antioxidant activity. M and R were loaded into the NLCs using a high shear homogenization and ultrasonication process. The particle size, zeta potential, and physical properties of the NLCs were observed. The M and R loading efficiency as well as release patterns were examined using Franz diffusion cells. Moreover, the antioxidant efficacy and in vitro cytotoxicity in the normal human fibroblast (NHF) of the NLCs were evaluated as well.
    RESULTS: The results found that the combination of M and R offered synergistic antioxidant activity and was successfully loaded into the NLCs with the size of a nanometer and negative zeta potential. The drugs were loaded in the NLCs as molecular dispersions and slowly released from the NLCs. Interestingly, both drugs maintained their antioxidant activity after being loaded into the NLCs and provided a higher antioxidant activity than those in the single loading of M and R, thus demonstrating that the incorporation of M and R into the NLCs allowed an enhanced antioxidant activity. Moreover, a cytotoxicity study showed that the NLCs were safe and had low cytotoxicity on the NHF cells.
    CONCLUSION: The M and R loaded NLCs were attractive systems for synergistic antioxidant activity for topical application.
    Keywords:  alpha-mangostin; antioxidant activity; nanostructured lipid carriers; resveratrol; synergy; topical application
    DOI:  https://doi.org/10.2174/2211738510666220426112508
  102. Nat Commun. 2022 Apr 26. 13(1): 2245
    An osmium-peroxo complex for photoactive therapy of hypoxic tumors.
    Nong Lu, Zhihong Deng, Jing Gao, Chao Liang, Haiping Xia, Pingyu Zhang.
      The limited therapeutic effect on hypoxic and refractory solid tumors has hindered the practical application of photodynamic therapy. Herein, we report our investigation of an osmium-peroxo complex (Os2), which is inactive in the dark, but can release a peroxo ligand O2•- upon light irradiation even in the absence of oxygen, and is transformed into a cytotoxic osmium complex (Os1). Os1 is cytotoxic in the presence or absence of irradiation in hypoxic tumors, behaving as a chemotherapeutic drug. At the same time, the light-activated Os2 induces photocatalytic oxidation of endogenous 1,4-dihydronicotinamide adenine dinucleotide in living cancer cells, leading to ferroptosis, which is mediated by glutathione degradation, lipid peroxide accumulation and down-regulation of glutathione peroxidase 4. In vivo studies have confirmed that the Os2 can effectively inhibit the growth of solid hypoxic tumors in mice. A promising strategy is proposed for the treatment of hypoxic tumors with metal-based drugs.
    DOI:  https://doi.org/10.1038/s41467-022-29969-z
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