Pharmacology & Therapeutics最新文献_第6页

Alternative splicing in aging and aging-related diseases: From pathogenesis to therapy 衰老和衰老相关疾病的选择性剪接：从发病机制到治疗。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-01 Epub Date: 2025-05-23 DOI: 10.1016/j.pharmthera.2025.108887

Mingrui Han , Peiru Han , Zihui Wang , Lingdong Kong , Qiang Xu , Qianqian Liu , Yang Sun

引用次数: 0

Corrigendum to “Immunomodulation and targeted drug delivery with high intensity focused ultrasound (HIFU): Principles and mechanisms” [Volume 244, April 2023, 108393] “高强度聚焦超声（HIFU）的免疫调节和靶向药物递送：原理和机制”的勘误表[第244卷，2023年4月，108393]

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-01 Epub Date: 2025-05-30 DOI: 10.1016/j.pharmthera.2025.108890

Harshini Ashar, Happy Agarwal, Ashish Ranjan

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Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing 神经肌肉和心脏类器官和组合体：先进的药物测试平台。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-01 Epub Date: 2025-05-14 DOI: 10.1016/j.pharmthera.2025.108876

Lorenzo Fontanelli , Noemi Nisini , Sergio Pirola , Fabio A. Recchia

{"title":"Neuromuscular and cardiac organoids and assembloids: Advanced platforms for drug testing","authors":"Lorenzo Fontanelli , Noemi Nisini , Sergio Pirola , Fabio A. Recchia","doi":"10.1016/j.pharmthera.2025.108876","DOIUrl":"10.1016/j.pharmthera.2025.108876","url":null,"abstract":"<div><div>The inherent technical difficulties, ethical/regulatory issues and costs of experimental studies in animal models is prompting investigators to replace as much as possible living organisms with <em>in vitro</em> physiological models named organoids and assembloids. Generated from induced pluripotent stem cells, these three-dimensional structures approximate the complexity of tissues and their interactions, enabling personalized disease modelling and drug testing. The integration of multiple components in assembloids further enhances their predictive value for multi-system interactions and toxicities. This review describes how neuromuscular organoids, incorporating functional neuromuscular junctions and contractile muscle tissue, have been used to replicate, <em>in vitro</em>, complex neuromuscular morpho-functional structures, offering very valuable platforms to study molecular mechanisms and drug effects in models of incurable diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. In the cardiological field, cardiac organoids and assembloids are proving reliable models for testing drug effects at molecular, morphological, electrophysiological and mechanical level. Recently, the integration of neuronal components into cardiac organoids has provided a potential approach to investigate autonomic function, a fundamental aspect of many neurological, neuromuscular and cardiac diseases. Challenges and limitations still remain, including the non-uniform differentiation protocols across studies, the incomplete maturation of cell phenotypes, and the lack of integrated pharmacokinetic modelling. We discussed some future developments aimed at overcoming such hurdles. Despite their current limitations, organoids and assembloids clearly hold great promises and will help advancing many fields of biomedicine.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108876"},"PeriodicalIF":12.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085592","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

The free fatty acid receptor 2 (FFA2): Mechanisms of action, biased signaling, and clinical prospects 游离脂肪酸受体2 (FFA2)：作用机制、偏倚信号和临床前景

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-01 Epub Date: 2025-05-16 DOI: 10.1016/j.pharmthera.2025.108878

Yang Li , Qiao Liu , Chuan-Ying Pan , Xian-Yong Lan

引用次数: 0

Characteristics and pharmacological responsiveness in hiPSC models of inherited cardiomyopathy 遗传性心肌病hiPSC模型的特点和药理反应性。

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-08-01 Epub Date: 2025-04-16 DOI: 10.1016/j.pharmthera.2025.108845

Merel Gerritse , Willem B. van Ham , Chris Denning , Toon A.B. van Veen , Renee G.C. Maas

{"title":"Characteristics and pharmacological responsiveness in hiPSC models of inherited cardiomyopathy","authors":"Merel Gerritse , Willem B. van Ham , Chris Denning , Toon A.B. van Veen , Renee G.C. Maas","doi":"10.1016/j.pharmthera.2025.108845","DOIUrl":"10.1016/j.pharmthera.2025.108845","url":null,"abstract":"<div><div>Inherited cardiomyopathies are a major cause of heart failure in all age groups, often with an onset in adolescence or early adult life. More than a thousand variants in approximately one hundred genes are associated with cardiomyopathies. Interestingly, many genetic cardiomyopathies display overlapping phenotypical defects in patients, despite the diversity of the initial pathogenic variants. Understanding how the underlying pathophysiology of genetic cardiomyopathies leads to these phenotypes will improve insights into a patient's disease course, and creates the opportunity for conceiving treatment strategies. Moreover, therapeutic strategies can be used to treat multiple cardiomyopathies based on shared phenotypes. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer reliable, high-throughput models for studying molecular and cellular characteristics of hereditary cardiomyopathies. hiPSC-CMs are produced relatively easily, either by directly originating them from patients, or by introducing patient-specific genetic variants in healthy lines. This review evaluates 90 studies on 24 cardiomyopathy-associated genes and systematically summarises the morphological and functional phenotypes observed in hiPSC-CMs. Additionally, treatment strategies applied in cardiomyopathic hiPSC-CMs are compiled and scored for effectiveness. Multiple overlapping phenotypic defects were identified in cardiomyocytes with different variants, whereas certain characteristics were only associated with specific genetic variants. Based on these findings, common mechanisms, therapeutic prospects, and considerations for future research are discussed with the aim to improve clinical translation from hiPSC-CMs to patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108845"},"PeriodicalIF":12.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951711","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

Retina-directed gene therapy: Achievements and remaining challenges 视网膜导向基因治疗：成就与挑战

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-07-01 Epub Date: 2025-04-21 DOI: 10.1016/j.pharmthera.2025.108862

Josef Biber , Catharina Gandor , Elvir Becirovic , Stylianos Michalakis

{"title":"Retina-directed gene therapy: Achievements and remaining challenges","authors":"Josef Biber , Catharina Gandor , Elvir Becirovic , Stylianos Michalakis","doi":"10.1016/j.pharmthera.2025.108862","DOIUrl":"10.1016/j.pharmthera.2025.108862","url":null,"abstract":"<div><div>Gene therapy is an innovative medical approach that offers new treatment options for congenital and acquired diseases by transferring, correcting, inactivating or regulating genes to supplement, replace or modify a gene function. The approval of voretigene neparvovec (Luxturna), a gene therapy for <em>RPE65</em>-associated retinopathy, has marked a milestone for the field of retinal gene therapy, but has also helped to accelerate the development of gene therapies for genetic diseases affecting other organs. Voretigene neparvovec is a vector based on adeno-associated virus (AAV) that delivers a functional copy of <em>RPE65</em> to supplement the missing function of this gene. The AAV-based gene delivery has proven to be versatile and safe for the transfer of genetic material to retinal cells. However, challenges remain in treating additional inherited as well as acquired retinopathies with this technology. Despite the high level of activity in this field, no other AAV gene therapy for retinal diseases has been approved since voretigene neparvovec. Ongoing research focuses on overcoming the current restraints through innovative strategies like AAV capsid engineering, dual-AAV vector systems, or CRISPR/Cas-mediated genome editing. Additionally, AAV gene therapy is being explored for the treatment of complex acquired diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) by targeting molecules involved in the pathobiology of the degenerative processes. This review outlines the current state of retinal gene therapy, highlighting ongoing challenges and future directions.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108862"},"PeriodicalIF":12.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899597","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

Therapeutic potential of natural flavonoids in atherosclerosis through endothelium-protective mechanisms: An update 天然类黄酮通过内皮保护机制治疗动脉粥样硬化的潜力：最新进展

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-07-01 Epub Date: 2025-04-22 DOI: 10.1016/j.pharmthera.2025.108864

Chao Zhong , Keke Deng , Xiaoya Lang , Dan Shan , Yanfei Xie , Wen Pan , Jun Yu

{"title":"Therapeutic potential of natural flavonoids in atherosclerosis through endothelium-protective mechanisms: An update","authors":"Chao Zhong , Keke Deng , Xiaoya Lang , Dan Shan , Yanfei Xie , Wen Pan , Jun Yu","doi":"10.1016/j.pharmthera.2025.108864","DOIUrl":"10.1016/j.pharmthera.2025.108864","url":null,"abstract":"<div><div>Atherosclerosis and its associated cardiovascular complications remain significant global public health challenges, underscoring the urgent need for effective therapeutic strategies. Endothelial cells are critical for maintaining vascular health and homeostasis, and their dysfunction is a key contributor to the initiation and progression of atherosclerosis. Targeting endothelial dysfunction has, therefore, emerged as a promising approach for the prevention and management of atherosclerosis. Among natural products, flavonoids, a diverse class of plant-derived phenolic compounds, have garnered significant attention for their anti-atherosclerotic properties. A growing body of evidence demonstrates that flavonoids can mitigate endothelial dysfunction, highlighting their potential as endothelial dysfunction-targeted therapeutics for atherosclerosis. In this review, we summarize current knowledge on the roles of natural flavonoids in modulating various aspects of endothelial dysfunction and their therapeutic effects on atherosclerosis, focusing on the underlying molecular mechanisms. We also discuss the challenges and future prospects of translating natural flavonoids into clinical applications for cardiovascular medicine. This review aims to provide critical insights to advance the development of novel endothelium-protective pharmacotherapies for atherosclerosis.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108864"},"PeriodicalIF":12.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879029","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

Management of drug-resistant hypertension as a heterogeneous disorder 作为异质性疾病的耐药高血压的管理

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-07-01 Epub Date: 2025-05-06 DOI: 10.1016/j.pharmthera.2025.108875

Reza Tabrizchi

{"title":"Management of drug-resistant hypertension as a heterogeneous disorder","authors":"Reza Tabrizchi","doi":"10.1016/j.pharmthera.2025.108875","DOIUrl":"10.1016/j.pharmthera.2025.108875","url":null,"abstract":"<div><div>Approximately 1.3 billion adults globally have hypertension, and are at higher risk of death associated with cardiovascular disease. Adjusted death rate primarily due to high blood pressure is 31.3 per 100,000. The prevalence of drug-resistant hypertension is estimated to be up to 20 % in hypertensive individuals, and is more common in those with chronic kidney disease and obstructive sleep apnea. It occurs in individuals on ≥3 antihypertensive drugs including a diuretic. The addition of spironolactone, as a fourth drug has been found at times to be effective in management of blood pressure. Other strategies include sequential nephron block (e.g., spironolactone + furosemide + amiloride), and use of drugs such as alpha<sub>2</sub> agonists, endothelin antagonists, and nonsteroidal mineralocorticoid antagonists. Use of positive airway pressure and pharmacotherapy have been found to be of value in individuals with sleep apnea in lowering blood pressure. In contrast, baroreceptor stimulation and/or renal denervation combined with pharmacotherapy seem to offer little in a way of consistent efficacy of optimally lowering blood pressures. Remarkably, evidence in the literature strongly supports the view that life style changes including regular exercise and appropriate diet combined with pharmacotherapy can lead to positive outcomes in helping to significantly reduce blood pressure. There is also ample data in literature suggesting the non-compliance to antihypertensive medications as a significant barrier to lowering blood pressure in this group. Accordingly, education regarding pharmacotherapy, and appropriate exercise regimen, including changes to diet should underpin any strategy in the management of high blood pressure in this population.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108875"},"PeriodicalIF":12.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935759","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

USP1 inhibition: A journey from target discovery to clinical translation USP1抑制：从靶点发现到临床转化的旅程

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-07-01 Epub Date: 2025-04-22 DOI: 10.1016/j.pharmthera.2025.108865

Carlos Torrado , Nicholas W. Ashton , Alan D. D'Andrea , Timothy A. Yap

{"title":"USP1 inhibition: A journey from target discovery to clinical translation","authors":"Carlos Torrado , Nicholas W. Ashton , Alan D. D'Andrea , Timothy A. Yap","doi":"10.1016/j.pharmthera.2025.108865","DOIUrl":"10.1016/j.pharmthera.2025.108865","url":null,"abstract":"<div><div>Ubiquitin-specific protease 1 (USP1) is a deubiquitinating enzyme involved in the DNA damage response. Upon DNA damage, USP1 stabilizes replication forks by removing monoubiquitin from PCNA and FANCD2-FANCI, thereby catalyzing critical final steps in translesion synthesis and interstrand crosslink (ICL) repair. This function is particularly crucial in <em>BRCA1</em> mutant cancers, where the homologous recombination pathway is compromised, leading tumors to rely on USP1 for effective repair. USP1 is also overexpressed in <em>BRCA1</em> mutant cancers, as well as other tumor types. Preclinical studies have demonstrated that knockout of USP1 is synthetically lethal in tumors with biallelic BRCA1 mutations, and this relationship is enhanced by combination with PARP inhibitors. Newly developed USP1 inhibitors have confirmed this synthetic lethality in BRCA1-deficient tumor cells. Moreover, these drugs have the potential for resensitizing platinum-resistant tumors. Currently, potent and specific USP1 inhibitors are undergoing evaluation in phase I clinical trials. RO7623066 (KSQ-4279) reported an acceptable safety profile during a phase I dose escalation study, with anemia being the most common side effect, and demonstrated robust pharmacokinetic, pharmacodynamic, and clinical activity. Other USP1 inhibitors, including SIM0501, XL309–101, and HSK39775, are currently in early clinical development. In this review, we provide an overview of the molecular function of USP1 and its importance as a therapeutic target in oncology, before focusing on the current state of preclinical and clinical development of USP1 inhibitors.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"271 ","pages":"Article 108865"},"PeriodicalIF":12.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873285","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

Effect of cannabinoids on the efficacy and side effects of anticancer therapeutic strategies – Current status of preclinical and clinical research 大麻素对抗癌治疗策略的疗效和副作用的影响——临床前和临床研究现状

IF 12 1区医学

Pharmacology & Therapeutics Pub Date : 2025-06-01 Epub Date: 2025-04-11 DOI: 10.1016/j.pharmthera.2025.108851

Robert Ramer, Burkhard Hinz

{"title":"Effect of cannabinoids on the efficacy and side effects of anticancer therapeutic strategies – Current status of preclinical and clinical research","authors":"Robert Ramer, Burkhard Hinz","doi":"10.1016/j.pharmthera.2025.108851","DOIUrl":"10.1016/j.pharmthera.2025.108851","url":null,"abstract":"<div><div>Cannabinoids have attracted increasing attention in cancer research in recent decades. A major focus of current preclinical and clinical studies is on the interactions and potential risks when combined with chemotherapeutic agents, targeted therapies and other anticancer strategies. Given the extensive preclinical data on additive, synergistic and, in some cases, antagonistic tumor cell killing effects of chemotherapeutic agents and cannabinoids when co-administered, a critical analysis of these data seems essential. The available data mainly relate to combination treatments for glioblastoma, hematological malignancies and breast cancer, but also for other cancer types. Such an analysis also appears necessary because cannabinoids are used as an option to treat nausea and vomiting caused by chemotherapy, as well as tumor-related pain, and cancer patients sometimes take cannabinoids without a medical prescription. In addition, numerous recent preclinical studies also suggest cannabinoid-mediated relief of other chemotherapy-related side effects such as peripheral neuropathy, nephrotoxicity, cardiotoxicity, cystitis, bladder complications and mucositis. To summarize, the data available to date raise the prospect that cannabinoids may increase the efficacy of chemotherapeutic agents while reducing their side effects. However, preclinical studies on anticancer interactions are mostly limited to cytotoxicity analyses. An equally thorough investigation of the effects of such combinations on the immune system and on the tumorigenic levels of angiogenesis, invasion and metastasis is still pending. On this basis, a comprehensive understanding for the evaluation of a targeted additional treatment of various cancers with cannabinoids could be established.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108851"},"PeriodicalIF":12.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868470","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