Pharmacology & Therapeutics最新文献_第6页

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 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub 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

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.

遗传性心肌病是所有年龄组心力衰竭的主要原因，通常在青春期或成年早期发病。大约100个基因中的1000多个变异与心肌病有关。有趣的是，许多遗传性心肌病在患者中表现出重叠的表型缺陷，尽管初始致病变异的多样性。了解遗传性心肌病的潜在病理生理学如何导致这些表型，将提高对患者病程的了解，并为构思治疗策略创造机会。此外，基于共同表型的治疗策略可用于治疗多种心肌病。人诱导多能干细胞来源的心肌细胞（hiPSC-CMs）为研究遗传性心肌病的分子和细胞特征提供了可靠的、高通量的模型。hiPSC-CMs的产生相对容易，要么直接从患者身上产生，要么在健康品系中引入患者特异性遗传变异。本文综述了90项关于24个心肌病相关基因的研究，并系统总结了在hiPSC-CMs中观察到的形态学和功能表型。此外，对应用于心肌病hiPSC-CMs的治疗策略进行了编制和有效性评分。在具有不同变异的心肌细胞中发现了多个重叠的表型缺陷，而某些特征仅与特定的遗传变异相关。基于这些发现，讨论了常见的机制、治疗前景和未来研究的考虑，旨在改善从hiPSC-CMs到患者的临床转化。

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引用次数: 0

Cardiovascular therapeutic targets of sodium-glucose co-transporter 2 (SGLT2) inhibitors beyond heart failure 钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂在心力衰竭之外的心血管治疗靶点

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-15 DOI: 10.1016/j.pharmthera.2025.108861

Matteo Armillotta , Francesco Angeli , Pasquale Paolisso , Marta Belmonte , Emanuel Raschi , Guido Di Dalmazi , Sara Amicone , Lisa Canton , Damiano Fedele , Nicole Suma , Alberto Foà , Luca Bergamaschi , Carmine Pizzi

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.

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.

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.

钠-葡萄糖共转运蛋白2 （SGLT2）抑制剂是一种口服降糖药，在心力衰竭（HF）患者中显示出心血管和肾脏结局的显著改善，无论糖尿病状态如何，使其成为基础治疗。除了血糖控制和渗透利尿作用外，抑制SGLT2还能改善内皮功能和血管舒张，优化心肌能量代谢，保持心脏收缩力。此外，SGLT2抑制剂可能具有抗炎特性，减轻急性心肌缺血/再灌注损伤，从而减小心肌梗死面积，增强左心室功能，减轻心律失常。这些多效性作用已被证明对各种心血管疾病有效，从急性到慢性冠状动脉综合征，并扩展到心律失常、瓣膜性心脏病、心肌病、心脏肿瘤和脑血管疾病。本文综述了目前关于SGLT2抑制剂治疗心衰以外多种心血管疾病的潜在机制的文献。

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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 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-11 DOI: 10.1016/j.pharmthera.2025.108851

Robert Ramer, Burkhard Hinz

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.

近几十年来，大麻素在癌症研究中引起了越来越多的关注。目前临床前和临床研究的一个主要焦点是与化疗药物、靶向治疗和其他抗癌策略联合使用时的相互作用和潜在风险。鉴于大量的临床前数据表明，化疗药物和大麻素在共同施用时具有添加剂、协同作用和某些情况下的拮抗肿瘤细胞杀伤作用，对这些数据进行批判性分析似乎是必要的。现有数据主要涉及胶质母细胞瘤、血液恶性肿瘤和乳腺癌的联合治疗，但也涉及其他类型的癌症。这样的分析也是必要的，因为大麻素被用作治疗化疗引起的恶心和呕吐以及肿瘤相关疼痛的一种选择，癌症患者有时在没有医疗处方的情况下服用大麻素。此外，最近的许多临床前研究也表明大麻素介导的其他化疗相关副作用的缓解，如周围神经病变、肾毒性、心脏毒性、膀胱炎、膀胱并发症和粘膜炎。总而言之，迄今为止的数据表明大麻素可能会增加化疗药物的疗效，同时减少其副作用。然而，抗癌相互作用的临床前研究大多局限于细胞毒性分析。对这些组合对免疫系统和血管生成、侵袭和转移的致瘤水平的影响的同样彻底的研究仍有待完成。在此基础上，可以对大麻素靶向治疗各种癌症的评价有一个全面的了解。

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引用次数: 0

Resetting the aging clock through epigenetic reprogramming: Insights from natural products 通过表观遗传重编程重置衰老时钟：来自天然产品的见解

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-10 DOI: 10.1016/j.pharmthera.2025.108850

Xin Liu , Jing Feng , Madi Guo , Chen Chen , Tong Zhao , Xiuxiu Sun , Yong Zhang

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.

表观遗传修饰在各种生理和病理条件下调控基因表达起着至关重要的作用。表观遗传修饰重编程是公认的衰老标志，也是用于区分实足年龄和生物年龄的衰老时钟的关键组成部分。潜在的前瞻性诊断和调控能力定位表观遗传修饰作为一个新兴的药物靶点，延长寿命和减轻与年龄相关的器官功能障碍。在过去的几十年里，大量的临床前研究已经证明了天然产物在包括衰老在内的各种人类疾病中的治疗潜力，其中一些已经进入临床试验和临床应用阶段。这篇综述强调了衰老时钟的发现和最新进展，以及天然产物通过纠正无序的表观遗传重编程作为抗衰老疗法的潜在用途。具体来说，重点是组蛋白修饰的不平衡，DNA甲基化模式的改变，atp依赖性染色质重塑的中断，以及RNA修饰的变化。通过对这些领域的探索，可以为衰老预测和抗衰老干预提供新的见解。

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引用次数: 0

The multifaceted role of agents counteracting metabolic syndrome: A new hope for gastrointestinal cancer therapy 抗代谢综合征药物的多方面作用：胃肠道肿瘤治疗的新希望

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-10 DOI: 10.1016/j.pharmthera.2025.108847

Elena Crecca , Gianfranco Di Giuseppe , Claudia Camplone , Virginia Vigiano Benedetti , Ombretta Melaiu , Teresa Mezza , Chiara Cencioni , Francesco Spallotta

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.

代谢综合征（MetS）被定义为至少存在5个临床参数中的3个，包括腹部肥胖、胰岛素抵抗、甘油三酯升高、高密度脂蛋白（HDL）降低和高血压。描述MetS的主要特征已被公认为癌症发病的危险因素，对胃肠道（GI）肿瘤具有惊人的影响。有趣的是，治疗性用药以改善血糖控制和血脂异常（包括二甲双胍，他汀类药物）已被证明对几种癌症的发展和预后改善具有预防作用。总的来说，这些观察结果强调了代谢改变在癌症风险发展中的关键作用，并揭示了抗mets药物在其常规药理作用之外的再利用潜力。本文综述了目前关于抗糖尿病和抗血脂药物在胃肠道肿瘤发生和发展中的抗肿瘤活性的研究进展。在这里，他们的治疗潜力的临床前证据和他们在新的引人注目的治疗策略整合将被讨论。这些专门针对胃肠道肿瘤患者的新型联合治疗方案的可能临床结果将受到关注。在未来，这些新的治疗方案应该被考虑，以改善常规化疗的反应和这组患者的预后。

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引用次数: 0

Where are we now? Biased signalling of Class B G protein-coupled receptor-targeted therapeutics 我们现在在哪里？B类G蛋白偶联受体靶向治疗的偏导信号

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-09 DOI: 10.1016/j.pharmthera.2025.108846

Zoe Tasma , Michael L. Garelja , Aqfan Jamaluddin , Tyla I. Alexander , Tayla A. Rees

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.

B 类 G 蛋白偶联受体（GPCR）是由 15 种肽类激素受体组成的亚家族，在生理功能和疾病发病机制中发挥着不同的作用。在过去十年中，针对这些受体的几种新型疗法已被批准用于治疗偏头痛、糖尿病和肥胖症等疾病，其中许多疗法都是突破性的首创疗法。这些疗法大多是激动剂类似物，其内源性肽序列经过修饰，可增强受体的激活或稳定性。一些小分子和单克隆抗体拮抗剂也已获得批准或处于后期开发阶段。这些治疗配体在序列和结构上的差异导致了不同的信号特征，包括对特定途径的偏向行为或抑制。了解这种偏倚药理学为提高疗效和减少不良反应提供了独特的开发机会。本综述总结了目前有关已批准的 B 类 GPCR 药物配体偏倚的知识，重点介绍了完善和利用其药理特征的策略，并讨论了开发新疗法时与受体结构、定位和调控有关的主要考虑因素。

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引用次数: 0

G-protein coupled receptors in metabolic reprogramming and cancer 代谢重编程和癌症中的g蛋白偶联受体

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-07 DOI: 10.1016/j.pharmthera.2025.108849

Songyeon Ahn , Benny Abraham Kaipparettu

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 in vitro and in vivo 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 in vivo 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.

g蛋白偶联受体（GPCR）是目前研究较多的药物靶点之一。gpcr参与了许多导致各种疾病的人类病理生理学，如癌症、糖尿病和肥胖。GPCR受体根据配体和组织类型激活多种信号通路。然而，本文将仅限于gpcr介导的代谢调节和相关信号通路的激活在癌症治疗中的应用。癌细胞通常具有重编程的细胞代谢，以支持肿瘤生长和转移可塑性。许多侵袭性癌细胞维持混合代谢状态，利用糖酵解和线粒体代谢来获得更好的代谢可塑性。除了葡萄糖和谷氨酰胺途径外，脂肪酸是一些癌症亚型的关键线粒体能量来源。近年来，针对脂肪酸β -氧化（FAO）等替代能量途径引起了人们对癌症治疗的极大兴趣。在不同癌症模型中进行的几项体外和体内实验报告了对FAO抑制剂的令人鼓舞的反应。然而，由于临床试验中FAO抑制剂的潜在肝毒性，间接靶向代谢重编程的新方法对于体内靶向癌细胞是必要的。本文特别关注游离脂肪酸受体（FFAR）和β-肾上腺素能受体（β-AR），因为它们在线粒体代谢和癌症中具有重要意义。进一步了解gpcr的药理学及其在癌症代谢中的作用将有助于重新定位gpcr靶向药物用于癌症治疗，并开发新的药物发现策略，将其与标准癌症治疗相结合，以增加抗癌潜力并克服耐药性。

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引用次数: 0

Investigation into biased signaling, glycosylation, and drug vulnerability of acute myeloid leukemia 急性髓性白血病的偏倚信号、糖基化和药物易感性的研究。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-04-05 DOI: 10.1016/j.pharmthera.2025.108848

Tomasz Pienkowski , Aleksandra Golonko , Lukasz Bolkun , Katarzyna Wawrzak-Pienkowska , Lukasz Szczerbinski , Adam Kretowski , Michal Ciborowski , Wlodzimierz Lewandowski , Waldemar Priebe , Renata Swislocka

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.

理解和利用偏倚信号为开发新的治疗策略或加强现有治疗提供了巨大的潜力。通过管理偏倚信号，可以最大限度地减少包括毒性在内的不良反应，并通过选择性地靶向有益途径来优化治疗结果。急性髓系白血病（AML）是一种高度侵袭性的血癌，其特征是骨髓和血液中异常髓系细胞的快速增殖，这些信号通路的失调，特别是涉及G蛋白偶联受体（gpcr）和受体酪氨酸激酶（RTKs）的信号通路的失调，显著促进了疾病进展和治疗耐药性。AML的传统治疗方法经常与耐药性和毒性作斗争，导致患者预后不佳。然而，通过利用偏倚信号的概念，研究人员可能能够设计出选择性激活抑制癌细胞生长的途径的药物，同时避免那些有助于抵抗或毒性的途径。糖基化是一种关键的翻译后修饰（PTM），通过改变受体构象和配体结合亲和力，在偏倚信号传导中起着至关重要的作用，从而影响偏倚信号传导的结果。趋化因子受体如CXCR4，在AML中经常过度表达和严重糖基化，可作为治疗干预的靶点。通过外部诱导或抑制特异性ptm，有可能进一步完善治疗策略，为开发更有效、毒性更低的治疗方法提供新的可能性。这篇综述强调了理解AML中糖基化和偏倚信号之间的动态关系的重要性，这对于开发更有效的治疗方法和克服耐药性至关重要，最终导致更好的患者预后。

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引用次数: 0

Fibroblast growth factor receptor signaling in metabolic dysfunction-associated fatty liver disease: Pathogenesis and therapeutic targets 代谢功能障碍相关脂肪肝的成纤维细胞生长因子受体信号：发病机制和治疗靶点

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-03-18 DOI: 10.1016/j.pharmthera.2025.108844

Yi Chu, Su Yang, Xiaodong Chen

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.

代谢功能障碍相关脂肪性肝病（MAFLD）已成为代谢综合征的一种重要肝脏表现，随着肥胖和糖尿病的流行，其患病率在全球范围内不断上升。MAFLD代表了一个连续的肝损伤，从简单的脂肪变性到代谢功能障碍相关的脂肪性肝炎（MASH）。这种情况可以发展为更严重的结果，包括纤维化和肝硬化。成纤维细胞生长因子受体（FGFRs）是一个由四个受体酪氨酸激酶（FGFR1-4）组成的家族，可与旁分泌和内分泌成纤维细胞生长因子（FGFs）相互作用。这种相互作用激活酪氨酸激酶残基的磷酸化，从而触发下游信号通路，包括RAS-MAPK、JAK-STAT、PI3K-AKT和PLCγ。在MAFLD的背景下，旁分泌FGF-FGFR信号主要倾向于肝纤维化和癌变的发展。相比之下，内分泌FGF-FGFR信号主要倾向于调节胆汁酸、碳水化合物、脂质和磷酸盐的代谢，以及维持体内能量代谢的整体平衡。这些偏倚信号通路之间的相互作用显著地影响了MAFLD的进展。本文从三个方面探讨了FGFR信号在MAFLD中的关键功能：首先，它检查了FGFR相对于其结构的主要作用；其次，综述了FGFR信号在肝脏脂质代谢中的作用，阐明了MAFLD发生发展的机制；最后，它强调了靶向FGFR信号治疗MAFLD及其相关疾病的药物开发的最新进展。

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引用次数: 0

Plant-derived nanovesicles and therapeutic application 植物源性纳米囊泡及其治疗应用。

IF 12 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-02-27 DOI: 10.1016/j.pharmthera.2025.108832

Dokyung Jung , Na-Eun Kim , Sua Kim , Ju-Hyun Bae , Il-Young Jung , Kyung-Won Doh , Byungheon Lee , Do-Kyun Kim , Young-Eun Cho , Moon-Chang Baek

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.

植物衍生纳米微粒（PDNVs）因其多样性、成本效益高、生物相容性好且毒性极低，正逐渐成为一种前景广阔的治疗工具。因此，本综述旨在讨论分离和表征 PDNVs 的方法，并强调它们在直接治疗应用和药物输送系统中的多功能作用。重点介绍了它们有效封装和递送大分子核酸、蛋白质和小分子药物的能力。此外，人们还开发了先进的工程策略，如表面修饰和与其他囊泡融合，以增强 PDNV 的治疗效果。此外，我们还介绍了与这一领域相关的主要挑战，鼓励进一步研究如何优化 PDNV，使其能用于各种预防和治疗目的的临床应用。PDNVs 的独特性质和多样化应用可在未来的个性化医疗中发挥关键作用，促进创新治疗策略的发展。

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引用次数: 0