Pharmacology & Therapeutics最新文献

{"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":"2025-06-01","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":"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":"2025-06-01","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":"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":"2025-06-01","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":"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":"2025-06-01","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":"2025-06-01","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":"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":"2025-06-01","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":"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":"2025-05-01","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}

{"title":"Recent advances in target identification technology of natural products","authors":"Ting-Ting Liu ,&nbsp;Ke-Wu Zeng","doi":"10.1016/j.pharmthera.2025.108833","DOIUrl":"10.1016/j.pharmthera.2025.108833","url":null,"abstract":"<div><div>Natural products, characterized by their structural diversity, broad spectrum of biological activities, and safe yet effective therapeutic potential, have become pivotal resources in drug research and development. However, the target proteins of many natural products remain unidentified, a significant challenge that impedes their development into viable drug candidates. Therefore, the target identification is crucial for elucidating the pharmacological mechanisms of natural products and facilitating their therapeutic applications. In this review, we present a comprehensive overview of recent advancements in methodologies for target identification of natural products. Additionally, we predict future developments in new technologies for target discovery. Collectively, this review establishes a methodological framework for uncovering the cellular targets and pharmacological mechanisms of natural products, thereby advancing the development of innovative natural product-based drugs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108833"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512720","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":"Neuroimmune modulators derived from natural products: Mechanisms and potential therapies","authors":"Wan-Di Feng,&nbsp;Dong-Ni Liu,&nbsp;Yu-Fu Shang,&nbsp;Wen-Fang Zhang,&nbsp;Shuang Xu,&nbsp;Dan-Hong Feng,&nbsp;Yue-Hua Wang","doi":"10.1016/j.pharmthera.2025.108830","DOIUrl":"10.1016/j.pharmthera.2025.108830","url":null,"abstract":"<div><div>Neuroimmunology is a multidisciplinary field that investigates the interactions between the nervous and immune systems. Neuroimmune interactions persist throughout the entire lifespan, and their dysregulation can lead to the onset and development of multiple diseases. Despite significant progress over the past decades in elucidating the interaction between neuroscience and immunology, the exact mechanism underlying neuroimmune crosstalk has not yet been fully elucidated. In recent years, natural products have emerged as a promising avenue for the therapeutic implications of neuroimmune diseases. Naturally derived anti-neuroimmune disease agents, such as polyphenols, flavonoids, alkaloids, and saponins, have been extensively studied for their potential neuroimmune modulatory effects. This comprehensive review delves into the specific molecular mechanisms of bidirectional neuro-immune interactions, with particular emphasis on the role of neuro-immune units. The review synthesizes a substantial body of evidence from in vitro and in vivo experiments as well as clinical studies, highlighting the therapeutic potential of various natural products in intervening in neuroimmune disorders.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108830"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522234","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":"Understanding the regulatory landscape of protein phosphatase 2A (PP2A): Pharmacological modulators and potential therapeutics","authors":"David A. Neale ,&nbsp;Jonathan C. Morris ,&nbsp;Nicole M. Verrills ,&nbsp;Alaina J. Ammit","doi":"10.1016/j.pharmthera.2025.108834","DOIUrl":"10.1016/j.pharmthera.2025.108834","url":null,"abstract":"<div><div>Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase with a diverse and integral role in cellular signalling pathways. Consequently, its dysfunction is frequently observed in disease states such as cancer, inflammation and Alzheimer’s disease. A growing understanding of both PP2A and its endogenous regulatory proteins has presented numerous targets for therapeutic intervention. This provides important context for the dynamic control and dysregulation of PP2A function in disease states. Understanding the intricate regulation of PP2A signalling in disease has resulted in the development of novel pharmacological agents aimed at restoring cellular homeostasis. Herein we review the structure and function of PP2A together with pharmacological modulators, both endogenous (proteins) and exogenous (small molecules and peptides), with relevance to targeting PP2A as a future pharmacotherapeutic strategy.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108834"},"PeriodicalIF":12.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536363","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}