Pharmacology & Therapeutics最新文献

{"title":"Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets.","authors":"Yi Chu, Su Yang, Xiaodong Chen","doi":"10.1016/j.pharmthera.2025.108844","DOIUrl":"https://doi.org/10.1016/j.pharmthera.2025.108844","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":" ","pages":"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}

{"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":"2025-02-27","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}

{"title":"Receptor dimers and biased ligands: Novel strategies for targeting G protein-coupled receptors","authors":"Wenkai Liu ,&nbsp;Dexiu Wang ,&nbsp;Luoqi Wang ,&nbsp;Shujuan Hu ,&nbsp;Yunlu Jiang ,&nbsp;Yixiang Wang ,&nbsp;Xin Cai ,&nbsp;Jing Chen","doi":"10.1016/j.pharmthera.2025.108829","DOIUrl":"10.1016/j.pharmthera.2025.108829","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are the largest superfamily of membrane receptors. They regulate physiological and pathological processes such as metabolic homeostasis, cell proliferation and differentiation, and the immune response, and are one of the most important classes of drug targets, being targeted by 30–40 % of marketed drugs. A growing number of studies continue to reveal the complexity of GPCRs, especially their ability to interact with each other to form higher-order structures such as homodimers and heterodimers, which have different functions than monomers, and are involved in disease development and progression. The existence of GPCR homodimers and heterodimers is opening up new directions in drug discovery and development to harness their therapeutic potential. Particularly striking is the ability of GPCR dimers to trigger unique biased signalling pathways, which exquisitely balance the relationship between therapeutic effects and side effects. By suppressing adverse reactions and enhancing beneficial drug effects, GPCR dimers provide an unprecedented opportunity to minimise side effects, maximise therapeutic efficacy and enhance safety. This review aims to highlight the latest research advances in GPCR dimerization and GPCR-biased signalling, focusing on the development of dimer-targeting and biased ligands as innovative drugs that will likely provide new strategies for treating GPCR-related diseases as well as a better understanding of drug design for compounds that target GPCRs. GPCRs will play an increasingly important role in precision medicine and personalised therapy, leading us towards a safer, more efficient and smarter pharmaceutical future.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108829"},"PeriodicalIF":12.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536362","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":"Inflammatory bowel disease and neuropsychiatric disorders: Mechanisms and emerging therapeutics targeting the microbiota-gut-brain axis","authors":"Giulia Petracco ,&nbsp;Isabella Faimann ,&nbsp;Florian Reichmann","doi":"10.1016/j.pharmthera.2025.108831","DOIUrl":"10.1016/j.pharmthera.2025.108831","url":null,"abstract":"<div><div>Crohn's disease (CD) and ulcerative colitis (UC) are the two major entities of inflammatory bowel disease (IBD). These disorders are known for their relapsing disease course and severe gastrointestinal symptoms including pain, diarrhoea and bloody stool. Accumulating evidence suggests that IBD is not only restricted to the gastrointestinal tract and that disease processes are able to reach distant organs including the brain. In fact, up to 35 % of IBD patients also suffer from neuropsychiatric disorders such as generalized anxiety disorder and major depressive disorder. Emerging research in this area indicates that in many cases these neuropsychiatric disorders are a secondary condition as a consequence of the disturbed communication between the gut and the brain via the microbiota-gut-brain axis. In this review, we summarise the current knowledge on IBD-associated neuropsychiatric disorders. We examine the role of different pathways of the microbiota-gut-brain axis in the development of CNS disorders highlighting altered neural, immunological, humoral and microbial communication. Finally, we discuss emerging therapies targeting the microbiota-gut-brain axis to alleviate IBD and neuropsychiatric symptoms including faecal microbiota transplantation, psychobiotics, microbial metabolites and vagus nerve stimulation.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108831"},"PeriodicalIF":12.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536356","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":"Improvement of chronic metabolic inflammation and regulation of gut homeostasis: Tea as a potential therapy","authors":"Shiyi Yu ,&nbsp;Xuan Zhu ,&nbsp;Xiayu Zhao ,&nbsp;Yan Li ,&nbsp;Xinghe Niu ,&nbsp;Yinghua Chen ,&nbsp;Jian Ying","doi":"10.1016/j.pharmthera.2025.108828","DOIUrl":"10.1016/j.pharmthera.2025.108828","url":null,"abstract":"&lt;div&gt;&lt;div&gt;Chronic metabolic inflammation is a common mechanism linked to the development of metabolic disorders such as obesity, diabetes, and cardiovascular disease (CVD). Chronic metabolic inflammation often related to alterations in gut homeostasis, and pathological processes involve the activation of endotoxin receptors, metabolic reprogramming, mitochondrial dysfunction, and disruption of intestinal nuclear receptor activity. Recent investigations into homeostasis and chronic metabolic inflammation have revealed a novel mechanism which is characterized by a timing interaction involving multiple components and targets. This article explores the positive impact of tea consumption on metabolic health of populations, with a special focus on the improvement of inflammatory indicators and the regulation of gut microbiota. Studies showed that tea consumption is related to the enrichment of gut microbiota. The relative proportion of Firmicutes/Bacteroidetes (F/B) is altered, while the abundance of &lt;em&gt;Lactobacillus&lt;/em&gt;, &lt;em&gt;Bifidobacterium&lt;/em&gt;, and &lt;em&gt;A. muciniphila&lt;/em&gt; increased significantly in most of the studies. Thus, tea consumption could provide potential protection from the development of chronic diseases by improving gut homeostasis and reducing chronic metabolic inflammation. The direct impact of tea on intestinal homeostasis primarily targets lipopolysaccharide (LPS)-related pathways. This includes reducing the synthesis of intestinal LPS, inhibiting LPS translocation, and preventing the binding of LPS to TLR4 receptors to block downstream inflammatory pathways. The TLR4/MyD88/NF-κB p65 pathway is crucial for anti-metaflammatory responses. The antioxidant properties of tea are linked to enhancing mitochondrial function and mitigating mitochondria-related inflammation by eliminating free radicals, inhibiting NLRP3 inflammasomes, and modulating Nrf2/ARE activity. Tea also contributes to safeguarding the intestinal barrier through various mechanisms, such as promoting the synthesis of short-chain fatty acids in the intestine, activating intestinal aryl hydrocarbon receptor (AhR) and farnesoid X receptor (FXR), and improving enteritis. Functional components that improve chronic metabolic inflammation include tea polyphenols, tea pigments, TPS, etc. Tea metabolites such as 4-Hydroxyphenylacetic acid and 3,4-Dihydroxyflavan derivatives, etc., also contribute to anti-chronic metabolic inflammation effects of tea consumption. The raw materials and processing technologies affect the functional component compositions of tea; therefore, consuming different types of tea may result in varying action characteristics and mechanisms. However, there is currently limited elaboration on this aspect. Future research should conduct in-depth studies on the mechanism of tea and its functional components in improving chronic metabolic inflammation. Researchers should pay attention to whether there are interactions between tea and other foods or drugs, explor","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108828"},"PeriodicalIF":12.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530825","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":"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":"2025-02-25","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":"2025-02-25","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":"The anti-inflammatory effects of saponins from natural herbs","authors":"Qinpin Zheng ,&nbsp;Tian Wang ,&nbsp;Sensen Wang ,&nbsp;Zhuoxi Chen ,&nbsp;Xue Jia ,&nbsp;Hui Yang ,&nbsp;Huijin Chen ,&nbsp;Xin Sun ,&nbsp;Kejun Wang ,&nbsp;Leiming Zhang ,&nbsp;Fenghua Fu","doi":"10.1016/j.pharmthera.2025.108827","DOIUrl":"10.1016/j.pharmthera.2025.108827","url":null,"abstract":"<div><div>Inflammation is a protective mechanism that also starts the healing process. However, inflammatory reaction may cause severe tissue damage. The increased influx of phagocytic leukocytes may produce excessive amount of reactive oxygen species, which leads to additional cell injury. Inflammatory response activates the leukocytes and thus induces tissue damage and prolongs inflammation. The inflammation-induced activation of the complement system may also contribute to cell injury. Non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids are chief agents for treating inflammation associated with the diseases. However, the unwanted side effects of NSAIDs (<em>e.g.</em>, gastrointestinal disturbances, skin reactions, adverse renal effects, cardiovascular side effects) and glucocorticoids (<em>e.g.</em>, suppression of immune system, Cushing's syndrome, osteoporosis, hyperglycemia) limit their use in patients. Natural herbs are important sources of anti-inflammatory drugs. The ingredients extracted from natural herbs display anti-inflammatory effects to work through multiple pathways with lower risk of adverse reaction. At present, the main anti-inflammatory natural agents include saponins, flavonoids, alkaloids, polysaccharides, and so on. The present article will review the anti-inflammatory effects of saponins including escin, ginsenosides, glycyrrhizin, astragaloside, Panax notoginseng saponins, saikosaponin, platycodin, timosaponin, ophiopogonin D, dioscin, senegenin.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108827"},"PeriodicalIF":12.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522254","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 role of macrophages in asthma-related fibrosis and remodelling","authors":"Xin Yuan Yang ,&nbsp;Fuguang Li ,&nbsp;Guojun Zhang ,&nbsp;Paul S. Foster ,&nbsp;Ming Yang","doi":"10.1016/j.pharmthera.2025.108820","DOIUrl":"10.1016/j.pharmthera.2025.108820","url":null,"abstract":"<div><div>Airway remodelling significantly contributes to the progressive loss of lung function and heightened symptom severity in chronic asthma. Additionally, it often persists and demonstrates reduced responsiveness to the mainstay treatments. The excessive deposition of collagen and extracellular matrix proteins leads to subepithelial fibrosis and airway remodelling, resulting in increased stiffness and decreased elasticity in the airway. Studies have emphasized the crucial role of subepithelial fibrosis in the pathogenesis of asthma. Fibrotic processes eventually cause airway narrowing, reduced lung function, and exacerbation of asthma symptoms. Macrophages play a crucial role in this process by producing pro-fibrotic cytokines, growth factors, and enzymes such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Additionally, identification of novel genetic markers has provided evidence for a strong genetic component in fibrosis within macrophage regulated fibrosis. Although macrophages contribute to the progression of airway remodelling and subepithelial fibrosis, interventions targeting macrophage-driven fibrotic changes have not yet been developed. This review synthesizes research on the intricate pathways through which macrophages contribute to subepithelial fibrosis in chronic asthma and its' pathological features. Understanding the interplay between macrophages, fibrosis, and asthma pathogenesis is essential for developing effective therapeutic strategies to manage severe asthma and improve patient outcomes.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"269 ","pages":"Article 108820"},"PeriodicalIF":12.0,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143472117","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}