Pharmacology & Therapeutics最新文献

{"title":"Characteristics and pharmacological responsiveness in hiPSC models of inherited cardiomyopathy","authors":"Merel Gerritse ,&nbsp;Willem B. van Ham ,&nbsp;Chris Denning ,&nbsp;Toon A.B. van Veen ,&nbsp;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":"2025-04-16","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}

{"title":"Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure","authors":"Matteo Armillotta ,&nbsp;Francesco Angeli ,&nbsp;Pasquale Paolisso ,&nbsp;Marta Belmonte ,&nbsp;Emanuel Raschi ,&nbsp;Guido Di Dalmazi ,&nbsp;Sara Amicone ,&nbsp;Lisa Canton ,&nbsp;Damiano Fedele ,&nbsp;Nicole Suma ,&nbsp;Alberto Foà ,&nbsp;Luca Bergamaschi ,&nbsp;Carmine Pizzi","doi":"10.1016/j.pharmthera.2025.108861","DOIUrl":"10.1016/j.pharmthera.2025.108861","url":null,"abstract":"<div><div>Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral antidiabetic agents that have shown significant improvements in cardiovascular and renal outcomes among patients with heart failure (HF), regardless of diabetic status, establishing them as a cornerstone therapy.</div><div>In addition to glycemic control and the osmotic diuretic effect, the inhibition of SGLT2 improves endothelial function and vasodilation, optimizing myocardial energy metabolism and preserving cardiac contractility. Moreover, SGLT2 inhibitors may exhibit anti-inflammatory properties and attenuate acute myocardial ischemia/reperfusion injury, thereby reducing cardiac infarct size, enhancing left ventricular function, and mitigating arrhythmias. These pleiotropic effects have demonstrated efficacy across various cardiovascular conditions, ranging from acute to chronic coronary syndromes and extending to arrhythmias, valvular heart disease, cardiomyopathies, cardio-oncology, and cerebrovascular disease.</div><div>This review provides an overview of the current literature on the potential mechanisms underlying the effectiveness of SGLT2 inhibitors across a wide range of cardiovascular diseases beyond HF.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108861"},"PeriodicalIF":12.0,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847843","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":"Effect of cannabinoids on the efficacy and side effects of anticancer therapeutic strategies – Current status of preclinical and clinical research","authors":"Robert Ramer,&nbsp;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":"2025-04-11","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}

{"title":"Resetting the aging clock through epigenetic reprogramming: Insights from natural products","authors":"Xin Liu ,&nbsp;Jing Feng ,&nbsp;Madi Guo ,&nbsp;Chen Chen ,&nbsp;Tong Zhao ,&nbsp;Xiuxiu Sun ,&nbsp;Yong Zhang","doi":"10.1016/j.pharmthera.2025.108850","DOIUrl":"10.1016/j.pharmthera.2025.108850","url":null,"abstract":"<div><div>Epigenetic modifications play a critical role in regulating gene expression under various physiological and pathological conditions. Epigenetic modifications reprogramming is a recognized hallmark of aging and a key component of the aging clock used to differentiate between chronological and biological age. The potential for prospective diagnosis and regulatory capabilities position epigenetic modifications as an emerging drug target to extend longevity and alleviate age-related organ dysfunctions. In the past few decades, numerous preclinical studies have demonstrated the therapeutic potential of natural products in various human diseases, including aging, with some advancing to clinical trials and clinical application. This review highlights the discovery and recent advancements in the aging clock, as well as the potential use of natural products as anti-aging therapeutics by correcting disordered epigenetic reprogramming. Specifically, the focus is on the imbalance of histone modifications, alterations in DNA methylation patterns, disrupted ATP-dependent chromatin remodeling, and changes in RNA modifications. By exploring these areas, new insights can be gained into aging prediction and anti-aging interventions.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108850"},"PeriodicalIF":12.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143845023","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":"The multifaceted role of agents counteracting metabolic syndrome: A new hope for gastrointestinal cancer therapy","authors":"Elena Crecca ,&nbsp;Gianfranco Di Giuseppe ,&nbsp;Claudia Camplone ,&nbsp;Virginia Vigiano Benedetti ,&nbsp;Ombretta Melaiu ,&nbsp;Teresa Mezza ,&nbsp;Chiara Cencioni ,&nbsp;Francesco Spallotta","doi":"10.1016/j.pharmthera.2025.108847","DOIUrl":"10.1016/j.pharmthera.2025.108847","url":null,"abstract":"<div><div>Metabolic syndrome (MetS) is defined by the presence of at least three of five clinical parameters including abdominal obesity, insulin resistance, elevated triglycerides, reduced high-density lipoprotein (HDL) and hypertension. Major features describing MetS have been recognized risk factors for cancer onset, with an alarming impact on gastrointestinal (GI) tumors. Intriguingly, therapeutic administration of drugs to improve glycemic control and dyslipidemia (including metformin, statins) has been shown to have a preventive role in the development and in prognosis improvement of several cancer types. Overall, these observations highlight the key role of altered metabolism prevalently in cancer risk development and unveil anti-MetS agent repurposing potential beyond their conventional pharmacological action. The objective of this review is to summarize the current knowledge about the antitumor activity of anti-diabetic and anti-lipemic agents in GI cancer onset and progression. Here, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed. Possible clinical outcomes of these novel therapeutic combined protocols specifically dedicated to GI cancer patients will be put under the spotlight. In the future, these novel therapeutic options should be considered to improve conventional chemotherapy response and prognosis of this group of patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108847"},"PeriodicalIF":12.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855172","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":"Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics","authors":"Zoe Tasma ,&nbsp;Michael L. Garelja ,&nbsp;Aqfan Jamaluddin ,&nbsp;Tyla I. Alexander ,&nbsp;Tayla A. Rees","doi":"10.1016/j.pharmthera.2025.108846","DOIUrl":"10.1016/j.pharmthera.2025.108846","url":null,"abstract":"<div><div>Class B G protein-coupled receptors (GPCRs) are a subfamily of 15 peptide hormone receptors with diverse roles in physiological functions and disease pathogenesis. Over the past decade, several novel therapeutics targeting these receptors have been approved for conditions like migraine, diabetes, and obesity, many of which are ground-breaking and first-in-class. Most of these therapeutics are agonist analogues with modified endogenous peptide sequences to enhance receptor activation or stability. Several small molecule and monoclonal antibody antagonists have also been approved or are in late-stage development. Differences in the sequence and structure of these therapeutic ligands lead to distinct signalling profiles, including biased behaviour or inhibition of specific pathways. Understanding this biased pharmacology offers unique development opportunities for improving therapeutic efficacy and reducing adverse effects. This review summarises current knowledge on the ligand bias of approved class B GPCR drugs, highlights strategies to refine and exploit their pharmacological profiles, and discusses key considerations related to receptor structure, localisation, and regulation for developing new therapies.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108846"},"PeriodicalIF":12.0,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838373","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":"G-protein coupled receptors in metabolic reprogramming and cancer","authors":"Songyeon Ahn ,&nbsp;Benny Abraham Kaipparettu","doi":"10.1016/j.pharmthera.2025.108849","DOIUrl":"10.1016/j.pharmthera.2025.108849","url":null,"abstract":"<div><div>G-protein coupled receptors (GPCR) are one of the frequently investigated drug targets. GPCRs are involved in many human pathophysiologies that lead to various disease conditions, such as cancer, diabetes, and obesity. GPCR receptor activates multiple signaling pathways depending on the ligand and tissue type. However, this review will be limited to the GPCR-mediated metabolic modulations and the activation of relevant signaling pathways in cancer therapy. Cancer cells often have reprogrammed cell metabolism to support tumor growth and metastatic plasticity. Many aggressive cancer cells maintain a hybrid metabolic status, using both glycolysis and mitochondrial metabolism for better metabolic plasticity. In addition to glucose and glutamine pathways, fatty acid is a key mitochondrial energy source in some cancer subtypes. Recently, targeting alternative energy pathways like fatty acid beta-oxidation (FAO) has attracted great interest in cancer therapy. Several <em>in vitro</em> and <em>in vivo</em> experiments in different cancer models reported encouraging responses to FAO inhibitors. However, due to the potential liver toxicity of FAO inhibitors in clinical trials, new approaches to indirectly target metabolic reprogramming are necessary for <em>in vivo</em> targeting of cancer cells. This review specifically focused on free fatty acid receptors (FFAR) and β-adrenergic receptors (β-AR) because of their reported significance in mitochondrial metabolism and cancer. Further understanding the pharmacology of GPCRs and their role in cancer metabolism will help repurpose GPCR-targeting drugs for cancer therapy and develop novel drug discovery strategies to combine them with standard cancer therapy to increase anticancer potential and overcome drug resistance.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108849"},"PeriodicalIF":12.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820425","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":"Investigation into biased signaling, glycosylation, and drug vulnerability of acute myeloid leukemia","authors":"Tomasz Pienkowski ,&nbsp;Aleksandra Golonko ,&nbsp;Lukasz Bolkun ,&nbsp;Katarzyna Wawrzak-Pienkowska ,&nbsp;Lukasz Szczerbinski ,&nbsp;Adam Kretowski ,&nbsp;Michal Ciborowski ,&nbsp;Wlodzimierz Lewandowski ,&nbsp;Waldemar Priebe ,&nbsp;Renata Swislocka","doi":"10.1016/j.pharmthera.2025.108848","DOIUrl":"10.1016/j.pharmthera.2025.108848","url":null,"abstract":"<div><div>Understanding and harnessing biased signaling offers significant potential for developing novel therapeutic strategies or enhancing existing treatments. By managing biased signaling, it is possible to minimize adverse effects, including toxicity, and to optimize therapeutic outcomes by selectively targeting beneficial pathways. In the context of acute myeloid leukemia (AML), a highly aggressive blood cancer characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow and blood, the dysregulation of these signaling pathways, particularly those involving G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), significantly contributes to disease progression and therapeutic resistance. Traditional therapies for AML often struggle with resistance and toxicity, leading to poor patient outcomes. However, by exploiting the concept of biased signaling, researchers may be able to design drugs that selectively activate pathways that inhibit cancer cell growth while avoiding those that contribute to resistance or toxicity. Glycosylation, a key post-translational modification (PTM), plays a crucial role in biased signaling by altering receptor conformation and ligand-binding affinity, thereby affecting the outcome of biased signaling. Chemokine receptors like CXCR4, which are often overexpressed and heavily glycosylated in AML, serve as targets for therapeutic intervention. By externally inducing or inhibiting specific PTMs, it may be possible to further refine therapeutic strategies, unlocking new possibilities for developing more effective and less toxic treatments. This review highlights the importance of understanding the dynamic relationship between glycosylation and biased signaling in AML, which is essential for the development of more effective treatments and overcoming drug resistance, ultimately leading to better patient outcomes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"270 ","pages":"Article 108848"},"PeriodicalIF":12.0,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802099","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":"Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets","authors":"Yi Chu,&nbsp;Su Yang,&nbsp;Xiaodong Chen","doi":"10.1016/j.pharmthera.2025.108844","DOIUrl":"10.1016/j.pharmthera.2025.108844","url":null,"abstract":"<div><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a significant hepatic manifestation of metabolic syndrome, with its prevalence increasing globally alongside the epidemics of obesity and diabetes. MAFLD represents a continuum of liver damage, spanning from uncomplicated steatosis to metabolic dysfunction-associated steatohepatitis (MASH). This condition can advance to more severe outcomes, including fibrosis and cirrhosis. Fibroblast growth factor receptors (FGFRs) are a family of four receptor tyrosine kinases (FGFR1–4) that interact with both paracrine and endocrine fibroblast growth factors (FGFs). This interaction activates the phosphorylation of tyrosine kinase residues, thereby triggering downstream signaling pathways, including RAS-MAPK, JAK-STAT, PI3K-AKT, and PLCγ. In the context of MAFLD, paracrine FGF-FGFR signaling is predominantly biased toward the development of liver fibrosis and carcinogenesis. In contrast, endocrine FGF-FGFR signaling is primarily biased toward regulating the metabolism of bile acids, carbohydrates, lipids, and phosphate, as well as maintaining the overall balance of energy metabolism in the body. The interplay between these biased signaling pathways significantly influences the progression of MAFLD. This review explores the critical functions of FGFR signaling in MAFLD from three perspectives: first, it examines the primary roles of FGFRs relative to their structure; second, it summarizes FGFR signaling in hepatic lipid metabolism, elucidating mechanisms underlying the occurrence and progression of MAFLD; finally, it highlights recent advancements in drug development aimed at targeting FGFR signaling for the treatment of MAFLD and its associated diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108844"},"PeriodicalIF":12.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143668685","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":"Plant-derived nanovesicles and therapeutic application","authors":"Dokyung Jung ,&nbsp;Na-Eun Kim ,&nbsp;Sua Kim ,&nbsp;Ju-Hyun Bae ,&nbsp;Il-Young Jung ,&nbsp;Kyung-Won Doh ,&nbsp;Byungheon Lee ,&nbsp;Do-Kyun Kim ,&nbsp;Young-Eun Cho ,&nbsp;Moon-Chang Baek","doi":"10.1016/j.pharmthera.2025.108832","DOIUrl":"10.1016/j.pharmthera.2025.108832","url":null,"abstract":"<div><div>Plant-derived nanovesicles (PDNVs) are becoming more popular as promising therapeutic tools owing to their diversity, cost-effectiveness, and biocompatibility with very low toxicity. Therefore, this review aims to discuss the methods for isolating and characterizing PDNVs and emphasize their versatile roles in direct therapeutic applications and drug delivery systems. Their ability to effectively encapsulate and deliver large nucleic acids, proteins, and small-molecule drugs was highlighted. Moreover, advanced engineering strategies, such as surface modification and fusion with other vesicles, have been developed to enhance the therapeutic effects of PDNVs. Additionally, we describe key challenges related to this field, encouraging further research to optimize PDNVs for various clinical applications for prevention and therapeutic purposes. The distinctive properties and diverse applications of PDNVs could play a crucial role in the future of personalized medicine, fostering the development of innovative therapeutic strategies.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108832"},"PeriodicalIF":12.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536358","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}