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Beyond the blood-brain barrier: the fate of transcytosed therapeutics. 超越血脑屏障：转酶疗法的命运。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-10-01 Epub Date: 2025-09-19 DOI: 10.1016/j.tips.2025.08.006
Habib Baghirov
{"title":"Beyond the blood-brain barrier: the fate of transcytosed therapeutics.","authors":"Habib Baghirov","doi":"10.1016/j.tips.2025.08.006","DOIUrl":"10.1016/j.tips.2025.08.006","url":null,"abstract":"<p><p>Transcytosis across the blood-brain barrier (BBB) enables systemically administered large therapeutics to reach the brain parenchyma, but their fate in the parenchyma ultimately governs their therapeutic effect. Recent studies show that brain parenchymal cell uptake, internalization kinetics, reuptake at the BBB, and diffusion in the brain parenchyma shape the distribution and retention of therapeutics. Target engagement further influences their behavior beyond the BBB. These insights have prompted new strategies to enhance their distribution, retention, and target engagement. These include the selection of transport targets with favorable trafficking properties, the use of anchoring proteins, and modeling-based optimization. This opinion highlights emerging understanding of the fate of therapeutics in the brain parenchyma and outlines strategies to optimize this fate.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"946-957"},"PeriodicalIF":19.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102960","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}
引用次数: 0
Beyond G protein and arrestin: GRK2-biased β₂AR signaling. 超越G蛋白和阻滞蛋白：grk2偏倚的β 2 AR信号。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-10-01 Epub Date: 2025-08-01 DOI: 10.1016/j.tips.2025.07.010
Ren-Lei Ji, Zhe Wang, Jean J Zhao
{"title":"Beyond G protein and arrestin: GRK2-biased β₂AR signaling.","authors":"Ren-Lei Ji, Zhe Wang, Jean J Zhao","doi":"10.1016/j.tips.2025.07.010","DOIUrl":"10.1016/j.tips.2025.07.010","url":null,"abstract":"<p><p>Biased G-protein-coupled receptor (GPCR) signaling is reshaping drug discovery by enabling pathway-selective drug action. Recent work by Motso et al. identified GPCR kinase 2 (GRK2) as a non-canonical transducer, independent of G proteins or β-arrestins, redefining the biased signaling landscape and highlighting GRK2 as a novel therapeutic target for selective modulation of GPCR-driven metabolic responses.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"928-930"},"PeriodicalIF":19.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12321243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769124","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}
引用次数: 0
Tackling microbial iron homeostasis: novel antimicrobial strategies. 处理微生物铁稳态：新的抗菌策略。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-10-01 Epub Date: 2025-09-06 DOI: 10.1016/j.tips.2025.08.003
Alexander Hoffmann, Philipp Grubwieser, Dirk Bumann, David Haschka, Günter Weiss
{"title":"Tackling microbial iron homeostasis: novel antimicrobial strategies.","authors":"Alexander Hoffmann, Philipp Grubwieser, Dirk Bumann, David Haschka, Günter Weiss","doi":"10.1016/j.tips.2025.08.003","DOIUrl":"10.1016/j.tips.2025.08.003","url":null,"abstract":"<p><p>The escalating threat of antimicrobial resistance demands innovative therapeutic strategies beyond classical targets. Recent insights into the mechanisms of bacterial iron acquisition - ranging from siderophores and heme uptake to ferrous iron transport - have enabled new approaches to impair pathogen growth and virulence. These pathways are increasingly being harnessed for therapeutic gain. Emerging strategies include next-generation iron chelators with improved specificity and reduced toxicity, gallium-based iron mimics that disrupt redox metabolism, and siderophore-drug conjugates that hijack bacterial uptake systems for targeted delivery. In parallel, antivirulence agents such as hemolysin inhibitors are promising resistance-sparing alternatives by targeting iron-driven pathogenesis. In this review we highlight these advances and emphasize the potential of host-mediated iron sequestration and bio-inspired nanotechnologies to strengthen nutritional immunity and guide future antimicrobial strategies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"1004-1017"},"PeriodicalIF":19.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008457","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}
引用次数: 0
Be CLEAR to ensure methodological and data transparency. 明确确保方法和数据的透明度。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-29 DOI: 10.1016/j.tips.2025.09.001
Christopher H George, Simon T Bate, S Clare Stanford, Amrita Ahluwalia, Michael J Curtis, Farhad Dehkhoda, John Kolassa, Vanessa Minervini, Vandana Nikam, Taiwo O Omotoso, Michael Spedding, Debbie L Hay
{"title":"Be CLEAR to ensure methodological and data transparency.","authors":"Christopher H George, Simon T Bate, S Clare Stanford, Amrita Ahluwalia, Michael J Curtis, Farhad Dehkhoda, John Kolassa, Vanessa Minervini, Vandana Nikam, Taiwo O Omotoso, Michael Spedding, Debbie L Hay","doi":"10.1016/j.tips.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.tips.2025.09.001","url":null,"abstract":"<p><p>A central tenet of research articles is that they should accurately describe the experiments performed. Yet important aspects of experimental design and methods are sometimes omitted, precluding proper interpretation and follow-on studies. To remedy this, we urge researchers to adopt the CLEAR principle (Clarity, Evaluation, Assessment, Rigour) when reporting research.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":19.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201390","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}
引用次数: 0
Can GLP-1RAs redefine transplantation standard of care? GLP-1RAs能否重新定义移植治疗标准？
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-18 DOI: 10.1016/j.tips.2025.08.013
Bassem A Almalki
{"title":"Can GLP-1RAs redefine transplantation standard of care?","authors":"Bassem A Almalki","doi":"10.1016/j.tips.2025.08.013","DOIUrl":"https://doi.org/10.1016/j.tips.2025.08.013","url":null,"abstract":"<p><p>Metabolic derangements, particularly obesity and post-transplant diabetes mellitus, remain major challenges in solid organ transplantation, contributing to graft dysfunction and increased morbidity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents due to their glucose-lowering, weight-reducing, and cardiorenal protective effects. Accumulating evidence supports their efficacy in improving glycemic control, reducing body weight, and potentially enhancing graft and patient survival across diverse transplant populations. Notably, GLP-1RAs exhibit a favorable safety profile, with minimal risk of drug interactions or rejection. Early data also suggest immunomodulatory and anti-inflammatory benefits. Moreover, newer dual and triple incretin agonists offer enhanced metabolic efficacy, potentially extending these benefits further. While long-term outcomes remain under investigation, GLP-1RAs represent a compelling therapeutic option that may reshape metabolic management paradigms in both pre- and post-transplant care.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":19.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092573","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}
引用次数: 0
Emerging mechanisms of psilocybin-induced neuroplasticity. 裸盖菇素诱导神经可塑性的新机制。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-15 DOI: 10.1016/j.tips.2025.08.012
Sonia Sonda, Diana Pendin, Stefano Comai, Sara De Martin, Paolo Manfredi, Andrea Mattarei
{"title":"Emerging mechanisms of psilocybin-induced neuroplasticity.","authors":"Sonia Sonda, Diana Pendin, Stefano Comai, Sara De Martin, Paolo Manfredi, Andrea Mattarei","doi":"10.1016/j.tips.2025.08.012","DOIUrl":"https://doi.org/10.1016/j.tips.2025.08.012","url":null,"abstract":"<p><p>Psilocybin, a serotonergic psychedelic, is gaining attention for its rapid and sustained therapeutic effects in depression and other hard-to-treat neuropsychiatric conditions, potentially through its capacity to enhance neuronal plasticity. While its neuroplastic and therapeutic effects are commonly attributed to serotonin 2A (5-HT<sub>2A</sub>) receptor activation, emerging evidence reveals a more nuanced pharmacological profile involving multiple serotonin receptor subtypes and nonserotonergic targets such as TrkB. This review integrates current findings on the molecular interactome of psilocin (psilocybin active metabolite), emphasizing receptor selectivity, biased agonism, and intracellular receptor localization. Together, these insights offer a refined framework for understanding psilocybin's enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":19.9,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076108","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}
引用次数: 0
Deubiquitinating enzymes as therapeutic targets in diabetic nephropathy. 去泛素酶作为糖尿病肾病的治疗靶点。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-11 DOI: 10.1016/j.tips.2025.07.015
Jing Liu, Xiaozhen Tan, Xia Fang, Xinxu Ge, Linghao Xu, Yang Long, Xiaobing Mao, Yong Xu
{"title":"Deubiquitinating enzymes as therapeutic targets in diabetic nephropathy.","authors":"Jing Liu, Xiaozhen Tan, Xia Fang, Xinxu Ge, Linghao Xu, Yang Long, Xiaobing Mao, Yong Xu","doi":"10.1016/j.tips.2025.07.015","DOIUrl":"https://doi.org/10.1016/j.tips.2025.07.015","url":null,"abstract":"<p><p>Diabetic nephropathy (DN), a leading cause of chronic kidney disease and end-stage renal disease, remains a major clinical challenge. Current therapeutic strategies primarily delay rather than prevent disease progression, highlighting the urgent need for novel interventions. Emerging evidence implicates deubiquitinating enzymes (DUBs) in the dysregulation of key pathological processes in DN, including glycolipid metabolism, oxidative stress, inflammation, and fibrosis. By modulating the stability and activity of critical substrates, DUBs exert context-dependent dual roles in DN pathogenesis. This review summarizes current insights into the regulatory roles of DUBs in DN pathogenesis and discusses their potential as promising therapeutic targets for future clinical intervention.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":19.9,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145055868","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}
引用次数: 0
Targeting Tregs in T1DM: bridging heterogeneity, mechanisms, and clinical progress. 靶向Tregs治疗T1DM：桥接异质性、机制和临床进展
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-06 DOI: 10.1016/j.tips.2025.08.004
Yutong Li, Eyad Elkord
{"title":"Targeting Tregs in T1DM: bridging heterogeneity, mechanisms, and clinical progress.","authors":"Yutong Li, Eyad Elkord","doi":"10.1016/j.tips.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.tips.2025.08.004","url":null,"abstract":"<p><p>Regulatory T cells (Tregs) play a pivotal role in maintaining immune tolerance and sustaining immunological homeostasis. Emerging evidence indicates that Treg characteristics and functional alterations can significantly contribute to the pathogenesis of autoimmune diseases including type 1 diabetes mellitus (T1DM). Notably, recent studies have established a positive correlation between diminished numbers of Tregs and the onset of T1DM. Although targeting Tregs has emerged as an attractive therapeutic strategy for T1DM, the heterogeneity and mechanistic complexities of Tregs remain largely unexplored and limit clinical success. We explore the dynamic alterations of Treg frequencies and phenotypes, and discuss their regulatory mechanisms throughout T1DM progression. Furthermore, we provide an overview of preclinical studies and clinical trials targeting Tregs in T1DM. By addressing translational challenges and current limitations in clinical efficacy, the ultimate aim is to develop innovative immunotherapeutic interventions for T1DM.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":19.9,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016242","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}
引用次数: 0
Mutated G proteins as drug targets. 突变的G蛋白作为药物靶点。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-01 Epub Date: 2025-08-09 DOI: 10.1016/j.tips.2025.07.003
Kian Noorman van der Dussen, Willem Jespers
{"title":"Mutated G proteins as drug targets.","authors":"Kian Noorman van der Dussen, Willem Jespers","doi":"10.1016/j.tips.2025.07.003","DOIUrl":"10.1016/j.tips.2025.07.003","url":null,"abstract":"<p><p>G proteins, members of the GTPase superfamily, are central mediators of signal transduction downstream of G protein-coupled receptors (GPCRs). Despite their critical roles in normal physiology and the high intrinsic affinity for endogenous ligands, G proteins have traditionally been considered 'undruggable'. Recent advances have led to the development of small molecules and peptides targeting wild-type (WT) G proteins; however, none have yet progressed to clinical application. By contrast, somatic and germline mutations in G proteins have been increasingly implicated in oncogenesis and neurodevelopmental disorders. Thus, targeting mutant G proteins represents a promising therapeutic strategy, offering the potential for selective intervention while sparing normal signaling. In this review, we provide an overview of known G protein modulators and pathogenic mutations recently reported in the literature, and discuss emerging opportunities for therapeutic targeting of mutant G proteins.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"891-906"},"PeriodicalIF":19.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144817487","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}
引用次数: 0
Recycling gone wrong: how inflammation promotes neuronal stress. 循环出了问题：炎症如何促进神经元压力。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2025-09-01 Epub Date: 2025-07-25 DOI: 10.1016/j.tips.2025.07.005
Yifei Dong, V Wee Yong
{"title":"Recycling gone wrong: how inflammation promotes neuronal stress.","authors":"Yifei Dong, V Wee Yong","doi":"10.1016/j.tips.2025.07.005","DOIUrl":"10.1016/j.tips.2025.07.005","url":null,"abstract":"<p><p>Neuroinflammation and neurodegeneration are key pathological features of chronic neurological diseases. In a recent study, Woo and colleagues highlight that interferon (IFN)-γ signaling promotes an immunoproteosome-mediated shift of metabolism within neurons that elevates their susceptibility to oxidative injury. The results add to mechanisms of neurodegeneration in multiple sclerosis (MS) and introduce new therapeutic targets.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"817-819"},"PeriodicalIF":19.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144718735","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}
引用次数: 0
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