Medicinal Research Reviews最新文献

{"title":"Advances in Traditional Chinese Medicine for Diabetic Glaucoma: A Systematic Review From Holistic Pathogenesis to Multi-Target Interventions.","authors":"Jinshen Liu, Yujia Yu, Chen Hu, Feng Cheng, Chunhan Feng, Jie Bao, Xiangqu Yu, Zhao Xia, Rao Ding, Zhonghui Li, Jiaqi Chen, Jiamin Zhou, Hui Zhang, Xiang Li","doi":"10.1002/med.70085","DOIUrl":"10.1002/med.70085","url":null,"abstract":"<p><p>Diabetic glaucoma, a severe microvascular and neurodegenerative complication of diabetes, involves complex pathological mechanisms including chronic hyperglycemia‑induced oxidative stress, inflammatory responses, microcirculatory disturbances, and retinal ganglion cell (RGC) apoptosis. While conventional Western medicine has achieved significant success in intraocular pressure (IOP) control, it faces challenges in providing long‑term neuroprotection and delaying disease progression. Traditional Chinese Medicine (TCM), guided by its holistic concept and treatment based on syndrome differentiation, demonstrates unique advantages through multi-component, multi‑target, and multi‑pathway synergistic regulation. This review systematically elucidates the TCM pathogenesis evolution pattern of \"deficiency leading to stasis, ocular collateral damage\" in diabetic glaucoma and establishes correlation networks between TCM syndrome types and modern pathological mechanisms. Integrating epidemiological evidence, we analyze the core mechanisms of representative Chinese herbs and formulas-including Ginkgo biloba extract, indirubin‑related components, and the Si‑Hua formula-in exerting antioxidant, anti‑inflammatory, microcirculation‑improving, and direct neuroprotective effects through regulation of key signaling pathways such as PI3K/AKT, Nrf2, and NF‑κB. Importantly, this article employs network pharmacology methods to visually present the synergistic \"component‑target‑pathway\" interaction network of the Si‑Hua formula, and introduces a quantitative comparison of the regulatory intensity of key herbal components on signaling pathways. We also discuss the chemical structures of major secondary metabolites from these herbs and the principles of reverse pharmacology that connect TCM to modern drug discovery. By quantitatively evaluating the regulatory intensity of key herbal components on signaling pathways and exploring the interventional potential of TCM in emerging mechanisms like ferroptosis (Figure 9), this review aims to establish a comprehensive scientific framework for TCM prevention and treatment of diabetic glaucoma, providing solid academic support for the modernization and internationalization of TCM.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":"1990-2012"},"PeriodicalIF":13.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond Bioenergetics: Moonlighting Functions of F₁F_O-ATPase From ATP Synthesis to an ATP-Wasting Death Switch.","authors":"Salvatore Nesci","doi":"10.1002/med.70088","DOIUrl":"10.1002/med.70088","url":null,"abstract":"<p><p>Mitochondrial F₁F_O-ATPase is classically viewed as the \"splendid\" rotary nanomachine that sustains life by converting the proton-motive force (pmf) into ATP. Yet this same complex can adopt a second, context-dependent function that links bioenergetics to cell fate. When oxygen becomes limiting during ischemia, stroke, hypoxia, or anoxia, respiratory chain activity declines, pmf collapses, and the enzyme reverses direction: ATP hydrolysis drives rotor turnover and pumps H⁺ across the inner mitochondrial membrane to partially restore pmf. This reverse mode can be protective by preserving membrane potential and basic mitochondrial homeostasis, but it also imposes a severe energetic burden on the cell. A key determinant of whether F₁F_O-ATPase acts as an energy-conserving or energy-dissipating machine is the identity of the catalytic divalent cation. Under physiological conditions, Mg²⁺ supports efficient, reversible ATP synthesis/hydrolysis. In pathology, mitochondrial Ca²⁺ overload may replace Mg²⁺ at catalytic sites, shifting catalysis toward ATP hydrolysis and promoting an ATP-wasting state that triggers mitochondrial permeability transition pore (mPTP) formation and regulated cell death. Thus, ATP hydrolysis by F₁F_O-ATPase beyond regulation by pmf and inhibitory proteins such as IF1, cation cofactor selection emerges as a decisive switch that repurposes the enzyme from \"enzyme of life\" to \"enzyme of death.\" Here, this cofactor-dependent reversibility is framed as a moonlighting role of F₁F_O-ATPase, integrating energy conversion with death signaling. Conceptual questions are outlined to resolve current debate and to exploit this switch for therapeutic insight.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":"2013-2016"},"PeriodicalIF":13.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focus on Azole-Based and Other N-Containing Heterocycles Within the Landscape of Current Structural Classes as Feline McDonough Sarcoma-Like Tyrosine Kinase 3 (FLT3) Inhibitors for Acute Myeloid Leukemia.","authors":"Giovanna Panzeca, Nicola Tardiolo, Stefania Butini, Sandra Gemma, Gabriele Carullo, Giuseppe Campiani","doi":"10.1002/med.70113","DOIUrl":"https://doi.org/10.1002/med.70113","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is the most common form of acute leukemia. It is characterized by unfavorable prognosis, elevated rates of recurrence, short overall survival and high mortality rates. Genetic and epigenetic aberrations contribute to its initiation and progression, presenting a considerable clinical challenge. Genomic investigations revealed that FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase regulating the proliferation and differentiation of hematopoietic cells, is overexpressed in AML leukemic blasts. To date, FDA has approved only three FLT3 inhibitors for targeted AML therapy (midostaurin, gilteritinib, quizartinib). These molecules feature several nitrogen atoms; in particular quizartinib contains an oxazole and a urea group that are involved in interactions with FLT3 kinase domain. Similarly, different N-containing heterocycles have proven to play a key role in other FLT3 inhibitors. Though small-molecule FLT3 inhibitors encompass various chemical classes, N-containing heterocycles and particularly the azole core represent the most common scaffold. The electron-rich properties of the azoles allow them to easily bind with enzymes and receptors. Based on this, we will provide a general overview of FLT3 inhibitor classes in AML, along with a comprehensive report on azole-based structures, reviewing recent contributions to the field.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Gut Microbiota-Metabolism Axis: Novel Pharmacological Mechanisms and Translational Application Strategies for Oral Antidiabetic Drugs.","authors":"Ruodi Yang, Shichao Zhang, Zishan Fu, Yufeng Yang, Qingfeng Wang, Ying Zhou, Jiaxin Li, Ruisi Yang, Shunyu Ning, Yan Shi, Juntong Liu","doi":"10.1002/med.70117","DOIUrl":"https://doi.org/10.1002/med.70117","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is a highly prevalent chronic metabolic disease worldwide, and the clinical prevention and control situation is severe. Although the various antidiabetic drugs currently in clinical use can lower blood glucose levels through different mechanisms, there are significant differences in efficacy among individuals. Existing evidence suggests that differences in gut microbiota (GM) composition and metabolic function may be one of the key factors contributing to the heterogeneity in drug efficacy. Based on this, this review describes the physiological and pathological mechanisms of the GM-metabolism axis and systematically reviews the modulatory effects of different classes of antidiabetic drugs on this axis and their underlying mechanisms. Available studies suggest that metformin, α-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), thiazolidinediones (TZDs), and oral glucagon-like peptide-1 receptor agonists (GLP-1RAs) may differentially affect GM composition and/or microbial metabolites, including short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), and bile acids. These alterations may be associated with glucose homeostasis and insulin resistance through pathways involving GPR41/43, HDACs, AMPK, mTORC1/S6K1, FXR-FGF15/19, and TGR5-GLP-1 signaling. By integrating clinical and mechanistic evidence, this review highlights the potential contribution of the GM-metabolism axis to the glucose-lowering effects of antidiabetic drugs. However, the quantity and confidence of evidence vary substantially across drug classes, and causal and clinical relevance requires further validation. These findings provide a basis for future research on personalized interventions for T2DM characterized by SCFA-producing bacterial deficiency, BCAA overload, or dysregulated bile acid metabolism.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aptamer-Based Targeted Protein Degradation: Mechanistic Principles, Delivery Strategies, and Translational Opportunities.","authors":"Ambrin Malik, Suyeon Son, Jaesung Lee, Ki Soo Park","doi":"10.1002/med.70110","DOIUrl":"https://doi.org/10.1002/med.70110","url":null,"abstract":"<p><p>Targeted elimination of pathogenic proteins remains a fundamental challenge in therapeutic intervention, particularly for proteins considered \"undruggable\" by conventional inhibition-based approaches. Aptamer-based targeted protein degradation (TPD) has emerged as a versatile strategy that leverages the high specificity, structural programmability, and chemical tunability of nucleic acid aptamers to redirect disease-relevant proteins toward endogenous degradation pathways. Intracellular platforms, exemplified by aptamer-conjugated proteolysis-targeting chimeras (PROTACs), induce ubiquitination and proteasomal degradation of cytosolic and nuclear targets. In parallel, extracellular and membrane-targeting modalities, including aptamer-conjugated lysosome-targeting chimeras (LYTACs) and related lysosomal degradation systems, enable clearance of secreted and membrane-bound proteins that are inaccessible to proteasome-based strategies. Collectively, these approaches broaden the potentially degradable proteome and offer opportunities to improve target selectivity and therapeutic safety. However, most aptamer-based TPD systems remain at the proof-of-concept or early preclinical stage, with limited standardization of degradation potency, kinetics, selectivity, and in vivo efficacy. Additional challenges include the discovery of functionally active aptamers, preservation of affinity and activity after chemical modification or conjugation, efficient delivery, chemical stability, controlled biodistribution, and mitigation of innate immune activation. This review provides a mechanistic and comparative framework for intracellular and extracellular aptamer-based TPD strategies, with emphasis on quantitative performance, delivery considerations, technical bottlenecks, and their translational potential for precision protein-targeted therapeutics.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Structural Modification to Diverse Pharmacological Activities: Recent Advances and Future Perspectives of Bile Acids.","authors":"Hongxia Zhu, Heming Chen, Qi Gong, Zhe-Sheng Chen, Chuan Zhang, Jinyi Xu, Tingfang Wang","doi":"10.1002/med.70116","DOIUrl":"https://doi.org/10.1002/med.70116","url":null,"abstract":"<p><p>Bile acids (BAs) are amphiphilic steroid acids that exert a broad range of physiological effects-including the regulation of metabolism, immune responses, and inflammatory processes-through activation of specific receptors such as the farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5). The gut microbiota plays a critical role in BA metabolism, and alterations in the BA pool have been closely linked to various metabolic disorders, including nonalcoholic fatty liver disease and type 2 diabetes. Consequently, targeting BA signaling pathways offers a novel mechanistic perspective for the prevention and treatment of these metabolic and inflammatory diseases. With growing insight into the biological functions of BAs, the development of BA-based therapeutics and their structural derivatives is emerging as a promising strategy for the management of metabolic diseases.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Primetime for the Gasdermins Seesaw in Intestinal Homeostasis and Digestive Disorders.","authors":"Qiong Liu, Huihong Liu, Ye Liu, Chunhui Wang","doi":"10.1002/med.70114","DOIUrl":"https://doi.org/10.1002/med.70114","url":null,"abstract":"<p><p>The five pore-forming gasdermins (GSDMs, namely GSDMA-E) are best known for executing pyroptosis, a lytic and highly inflammatory form of programmed cell death. Accumulating evidence over the past decade has unveiled diverse nonlytic functions of GSDMs in digestive homeostasis and disease. GSDMs preserve intestinal barrier integrity and mucosal immunity under physiological conditions, whereas their dysregulated activation fuels tissue injury across a spectrum of digestive diseases, including inflammatory bowel disease, acute intestinal injury, radiation enteritis, acute pancreatitis, and liver disorders. Notably, the functional outcome of GSDM activation is highly context-dependent: the same protein can be either protective or injurious. This duality extends to digestive oncology, where GSDM-mediated pyroptosis can stimulate or suppress antitumor immunity. GSDM-targeted drugs, including GSDMD agonists, GSDMD inhibitors, and GSDME inhibitors, have shown encouraging efficacy in preclinical models, although none have yet reached the clinic. Here, we review the dual roles of GSDMs across the digestive system, outline the mechanistic basis of their form-, cell-, and tissue-specific functions, and discuss the progress and remaining challenges in GSDM-targeted therapy.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Covalent Recruitment of E3 Ligases: A New Path for Rational Design of Protein Degraders.","authors":"Ziyan Yu, Jianqiang Zhang, Man Tong, Lanlan Zang, Jie Sun, Xiaoyun Lu","doi":"10.1002/med.70111","DOIUrl":"https://doi.org/10.1002/med.70111","url":null,"abstract":"<p><p>The covalent recruitment of E3 ubiquitin ligases is a rapidly advancing strategy in targeted protein degradation (TPD). While traditional non-covalent PROTACs and molecular glues operate through transient binding equilibria that can limit catalytic efficiency, covalent degraders form irreversible bonds with E3 ligases, thereby stabilizing ternary complexes, enhancing degradation kinetics, and enabling a \"pre-assembly\" mechanism in which the degrader remains bound to the E3 ligase after each degradation event to facilitate multi-turnover catalysis. Recent advances in chemoproteomic platforms have enabled the systematic identification of ligandable amino acid residues across the E3 ligase landscape, transforming degrader discovery from serendipitous observation to rational structure-guided design. This technological revolution has dramatically expanded the repertoire of recruitable E3 ligases beyond traditional candidates such as CRBN and VHL, thereby overcoming resistance mechanisms and enabling access to historically undruggable targets. This review systematically outlines the design principles of covalent E3-targeting PROTACs and contrasts them with covalent E3-targeting molecular glues. The latter achieve potent degradation through either template-assisted covalent modification or the incorporation of transplantable electrophilic handles. We summarize representative covalent E3-recruiting degraders, focusing on their design principles, mechanistic insights, and therapeutic potential. We further discuss key challenges and future directions, particularly the imperative to broaden E3 ligase coverage and diversify warhead chemistry, aiming to provide valuable insights for the development of covalent protein degraders.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Comprehensive Insight of Mechanisms of Drugs Targeting Ion Channels: Exemplified by Marine Natural Products and Their Analogues","authors":"Dashuai Zhang,&nbsp;Shugeng Cao,&nbsp;Shan He,&nbsp;Shengjun Mao,&nbsp;Sulan Luo,&nbsp;Lijian Ding","doi":"10.1002/med.70067","DOIUrl":"10.1002/med.70067","url":null,"abstract":"<div>\u0000 \u0000 <p>Ion channels represent a significant class of drug targets implicated in the development of various diseases. In recent years, there has been a significant increase in research on the structure and function of ion channels, thereby promoting the study of drug targeting mechanisms involving these channels. The ocean serves as a rich reservoir of lead compounds for drug development, undeniably providing a valuable source for ion channel-targeting drugs. However, various factors contribute to the superficial nature of many studies on drug action mechanisms and there is ongoing confusion surrounding related concepts. This review systematically reviews the mechanisms of action of marine natural products and synthetic derivatives studied from 2000 to 2025, with the goal to establish reference standards relevant to this field of study. Additionally, we systematically review the structure-activity relationship studies and summarize drug optimization strategies in subsequent sections. The primary objective of this review is to promote deeper investigations into drug action mechanisms, providing insights for drug development and fostering the emergence of more precise pharmacological terminology to clarify these complex mechanisms.</p>\u0000 </div>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 6","pages":"1672-1716"},"PeriodicalIF":13.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small-Molecule Kinase Inhibitors Modulating Circadian Rhythms","authors":"Irene Castellino,&nbsp;Manuela Bartolini,&nbsp;Rudolf Andrys,&nbsp;Kamil Musilek","doi":"10.1002/med.70071","DOIUrl":"10.1002/med.70071","url":null,"abstract":"<p>The circadian clock mechanism generates 24-h rhythms crucial for regulating various physiological processes, and its dysregulation has been implicated in numerous diseases. In cells, the circadian clock operates through a transcriptional-translational feedback loop, where phosphorylation plays a pivotal role in maintaining accurate circadian rhythms. Consequently, kinase inhibitors have emerged as promising targets for modulating the circadian clock and potentially treating circadian-related diseases. This review aims to provide an overview of the current state-of-the-art of kinase inhibitors with effects on the mammalian circadian clock. By highlighting promising targets and addressing the limitations of existing inhibitors, this review intends to provide a guide for future research efforts towards the development of novel compounds for the treatment of circadian-related disorders. Furthermore, it highlights the critical discrepancy between <i>in vitro</i> activity and <i>in vivo</i> effectiveness, emphasizing the critical need for rigorous <i>in vivo</i> validation to translate the therapeutic potential of kinase inhibitors into effective treatments for these disorders.</p>","PeriodicalId":207,"journal":{"name":"Medicinal Research Reviews","volume":"46 6","pages":"1735-1752"},"PeriodicalIF":13.6,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/med.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}