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Nitric Oxide Signaling and Regulation in the Cardiovascular System: Recent Advances. 一氧化氮在心血管系统中的信号传递和调节:最新进展。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001060
Mattias Carlström, Eddie Weitzberg, Jon O Lundberg

Nitric oxide (NO) from endothelial NO synthase importantly contributes to vascular homeostasis. Reduced NO production or increased scavenging during disease conditions with oxidative stress contribute to endothelial dysfunction and NO deficiency. In addition to the classical enzymatic NO synthases (NOS) system, NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches aimed at increasing NO bioactivity, especially in the cardiovascular system, have been the focus of much research since the discovery of this small gaseous signaling molecule. Despite wide appreciation of the biological role of NOS/NO signaling, questions still remain about the chemical nature of NOS-derived bioactivity. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase, and directly activate the soluble guanylyl cyclase-cGMP-protein kinase G pathway without intermediacy of free NO. Moreover, interaction between red blood cells and the endothelium in the regulation of vascular NO homeostasis have gained much attention, especially in conditions with cardiometabolic disease. In this review we discuss both classical and nonclassical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. SIGNIFICANCE STATEMENT: After four decades of intensive research, questions persist about the transduction and control of nitric oxide (NO) synthase bioactivity. Here we discuss NO signaling in cardiovascular health and disease, highlighting new findings, such as the important role of red blood cells in cardiovascular NO homeostasis. Nonclassical signaling modes, like the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system are discussed. Existing and potential pharmacological treatments/strategies, as well as dietary components influencing NO generation and signaling are covered.

内皮一氧化氮合酶(eNOS)产生的一氧化氮(NO)对血管稳态起着重要作用。在疾病和氧化应激条件下,一氧化氮生成减少或清除增加会导致内皮功能障碍和一氧化氮缺乏。除了经典的酶促 NOS 系统外,NO 还可通过硝酸盐-亚硝酸盐-NO 途径产生。自发现这种小型气体信号分子以来,旨在提高 NO 生物活性(尤其是在心血管系统中)的饮食和药物方法一直是许多研究的重点。尽管人们广泛认识到 NOS/NO 信号传导的生物学作用,但对 NOS 衍生生物活性的化学本质仍然存在疑问。最近的研究表明,类似于 NO 的生物活性可以通过可移动的 NO-铁血黄素物种有效地传递,这种物种可以在蛋白质之间转移,分化成疏水相,并直接激活 sGC-cGMP-PKG 通路,而不需要游离 NO 作为中介。此外,红细胞和血管内皮在调节血管 NO 平衡过程中的相互作用也备受关注,尤其是在心血管代谢疾病的情况下。在这篇综述中,我们将讨论心血管系统中 NO 生成的经典和非经典途径,以及如何调节这些途径以达到治疗目的。意义声明 经过四十年的深入研究,有关 NO 合成酶生物活性的传导和控制的问题依然存在。在此,我们讨论了心血管健康和疾病中的 NO 信号传导,重点介绍了一些新发现,如红细胞在心血管 NO 平衡中的重要作用。我们还讨论了硝酸盐-亚硝酸盐-NO 通路等非典型信号模式,以及与 NO 系统有关的治疗机会。内容还包括现有和潜在的药物治疗/策略,以及影响 NO 生成和信号转导的饮食成分。
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引用次数: 0
Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. 代谢性疾病、炎症性疾病和药物开发中的胆汁酸信号转导。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.000978
Tiangang Li, John Y L Chiang

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

胆汁酸是胆固醇分解代谢的最终产物。肝脏合成的胆汁酸占人体每日胆固醇周转量的大部分。胆汁分泌胆汁酸可产生胆汁流,促进胆汁分泌脂质、内源性代谢物和异种生物。在肠道中,胆汁酸可促进食物中脂类和脂溶性维生素的消化和吸收。胆汁酸通过激活核受体和 G 蛋白偶联受体以及与肠道微生物群的相互作用,对宿主的新陈代谢以及先天性和适应性免疫进行重要调节,并参与胆汁淤积症、代谢功能障碍相关性脂肪肝(MASLD)、酒精相关性肝病(ALD)、2 型糖尿病和炎症性肠病(IBD)的发病机制。胆汁酸及其衍生物已被开发为治疗慢性代谢性和炎症性肝病以及胃肠道疾病的潜在治疗药物。意义声明 胆汁酸可促进胆汁中胆固醇的溶解和饮食中脂质的吸收,调节宿主代谢和免疫,并调节肠道微生物组。以胆汁酸代谢和信号传导为靶点,有望治疗代谢性和炎症性疾病。
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引用次数: 0
Somatostatin: Linking Cognition and Alzheimer Disease to Therapeutic Targeting. 生长抑素:将认知和阿尔茨海默病与治疗目标联系起来。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001117
Karin E Sandoval, Ken A Witt

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications. SIGNIFICANCE STATEMENT: Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin-mediated processes has significant therapeutic potential for the treatment of Alzheimer disease.

四十多年的研究证明,阿尔茨海默病(AD)与体促素(体促素释放抑制因子,SRIF)之间存在联系。SRIF 和 SRIF 表达神经元在大脑功能中发挥着至关重要的作用,可调节海马活动和记忆形成。大脑中 SRIF 和 SRIF 表达神经元的丧失是淀粉样β肽(Aβ)驱动的一系列相互依存的病理事件的中心,最终导致认知能力下降和痴呆症。SRIF 与痴呆症之间的联系进一步延伸到神经精神症状、癫痫发作活动和炎症。而临床前注意力缺失症研究表明,服用 SRIF 或 SRIF 受体激动剂能够增强认知能力。尤其是 SRIF 受体亚型-4 激活具有独特的属性,有可能缓解学习和记忆衰退,减轻合并症状,并增强大脑中 Aβ 的酶降解。在此,我们回顾了SRIF与AD之间的联系以及治疗意义。意义声明 大脑中的体生长抑素和表达体生长抑素的神经元广泛参与认知过程。在阿尔茨海默病中,体生长抑素和体生长抑素表达神经元的丧失是导致认知能力下降和痴呆的一系列相互依存的病理事件的中心。以体生长抑素介导的过程为靶点,在治疗阿尔茨海默病方面具有巨大的治疗潜力。
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引用次数: 0
International Union of Basic and Clinical Pharmacology CXV: The Class F of G Protein-Coupled Receptors. 国际基础与临床药理学联合会。CXV:G 蛋白偶联受体 F 类。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001062
Gunnar Schulte

The class F of G protein-coupled receptors (GPCRs) consists of 10 Frizzleds (FZD1-10) and Smoothened (SMO). FZDs bind and are activated by secreted lipoglycoproteins of the Wingless/Int-1 (WNT) family, and SMO is indirectly activated by the Hedgehog (Hh) family of morphogens acting on the transmembrane protein Patched. The advance of our understanding of FZDs and SMO as dynamic transmembrane receptors and molecular machines, which emerged during the past 14 years since the first-class F GPCR IUPHAR nomenclature report, justifies an update. This article focuses on the advances in molecular pharmacology and structural biology providing new mechanistic insight into ligand recognition, receptor activation mechanisms, signal initiation, and signal specification. Furthermore, class F GPCRs continue to develop as drug targets, and novel technologies and tools such as genetically encoded biosensors and CRISP/Cas9 edited cell systems have contributed to refined functional analysis of these receptors. Also, advances in crystal structure analysis and cryogenic electron microscopy contribute to the rapid development of our knowledge about structure-function relationships, providing a great starting point for drug development. Despite the progress, questions and challenges remain to fully understand the complexity of the WNT/FZD and Hh/SMO signaling systems. SIGNIFICANCE STATEMENT: The recent years of research have brought about substantial functional and structural insight into mechanisms of activation of Frizzleds and Smoothened. While the advance furthers our mechanistic understanding of ligand recognition, receptor activation, signal specification, and initiation, broader opportunities emerge that allow targeting class F GPCRs for therapy and regenerative medicine employing both biologics and small molecule compounds.

F 类 G 蛋白偶联受体(GPCR)由十个 Frizzleds(FZD1-10)和 Smoothened(SMO)组成。FZDs与Wingless/Int-1(WNT)家族分泌的脂糖蛋白结合并被激活,SMO则被作用于跨膜蛋白Patched(PTCH)的形态发生因子Hedgehog(Hh)家族间接激活。自第一份 F 类 GPCR IUPHAR 命名报告发布以来的 14 年间,我们对 FZDs 和 SMO 作为动态跨膜受体和分子机器的认识不断进步,因此有必要对其进行更新。本文重点介绍分子药理学和结构生物学方面的进展,这些进展为配体识别、受体激活机制、信号启动和信号规范提供了新的机制认识。此外,F 类 GPCR 继续发展成为药物靶点,基因编码生物传感器和 CRISP/Cas9 编辑细胞系统等新技术和工具也有助于对这些受体进行精细的功能分析。此外,晶体结构分析和低温电子显微镜技术的进步也促进了我们对结构-功能关系知识的快速发展,为药物开发提供了一个很好的起点。尽管取得了这些进展,但要全面了解 WNT/FZD 和 Hh/SMO 信号系统的复杂性,仍然存在问题和挑战。意义声明 近年来的研究从功能和结构上深入了解了 Frizzleds 和 Smoothened 的激活机制。这些进展进一步加深了我们对配体识别、受体激活、信号规范和启动的机理认识,同时也带来了更广泛的机遇,使我们能够利用生物制剂和小分子化合物,针对 F 类 GPCRs 进行治疗和再生医学研究。
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引用次数: 0
Posttranslational Modifications of α-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases. α-突触核蛋白的翻译后修饰、其治疗潜力以及在健康和神经退行性疾病中的相互影响。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.123.001111
Kambiz Hassanzadeh, Jun Liu, Santhosh Maddila, M Maral Mouradian

α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. SIGNIFICANCE STATEMENT: α-Synuclein is a key pathogenic protein in Parkinson's disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in α-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.

路易体和路易神经元中的α-突触核蛋白(α-Syn)聚集已成为帕金森病(PD)、路易体痴呆症和多系统萎缩症的主要致病特征。包括翻译后修饰(PTM)在内的各种因素都会影响α-Syn的错误折叠和聚集倾向。PTM 是蛋白质在翻译过程中或翻译后发生的生化修饰,通常由酶介导。PTMs 可调节蛋白质的多个特性,包括结构、活性、定位和稳定性。α-Syn 会发生各种翻译后修饰,包括磷酸化、泛素化、SUMOylation、乙酰化、糖化、O-GlcNAcylation、硝化、氧化、多胺化、精氨酸化和截短。蛋白质的不同 PTM 可相互发生物理作用,或共同影响特定的生理或病理特征,这一过程被称为 PTMs 串扰。近年来,PTMs 共现检测技术的发展揭示了以前未被认识到的 PTMs 串扰机制。这导致出现了支持α-Syn PTMs串扰与突触核蛋白病之间关联的证据。在这篇综述中,我们全面评估了α-Syn PTMs、它们对错误折叠和致病性的影响、靶向它们的药理学手段以及它们作为疾病生物标志物的潜力。我们还强调了这些 PTMs 在 α-Syn 功能和聚集中相互影响的重要性。深入了解这些PTMS及其串扰的复杂性,可以提高我们对突触核蛋白病发病机制的认识,并确定具有治疗潜力的新靶点。意义声明 α-突触核蛋白是帕金森病和其他突触核蛋白病的主要致病蛋白,使其成为改变疾病的主要治疗靶点。在α-突触核蛋白的不同位点会发生多种翻译后修饰,并改变其生物物理和病理特性,其中一些相互影响,增加了该蛋白致病性的复杂性。本综述将详细介绍这些修饰、它们对疾病的影响以及潜在的治疗机会。
{"title":"Posttranslational Modifications of <b>α</b>-Synuclein, Their Therapeutic Potential, and Crosstalk in Health and Neurodegenerative Diseases.","authors":"Kambiz Hassanzadeh, Jun Liu, Santhosh Maddila, M Maral Mouradian","doi":"10.1124/pharmrev.123.001111","DOIUrl":"10.1124/pharmrev.123.001111","url":null,"abstract":"<p><p><i>α</i>-Synuclein (<i>α</i>-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Various factors, including posttranslational modifications (PTMs), can influence the propensity of <i>α</i>-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. <i>α</i>-Syn undergoes various posttranslational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the cooccurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between <i>α</i>-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of <i>α</i>-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in <i>α</i>-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. SIGNIFICANCE STATEMENT: <i>α</i>-Synuclein is a key pathogenic protein in Parkinson's disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple posttranslational modifications occur at various sites in <i>α</i>-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease, and potential therapeutic opportunities.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pharmacological Approaches to Hearing Loss. 听力损失的药物治疗方法。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.001195
Christopher R Cederroth, Jonas Dyhrfjeld-Johnsen, Barbara Canlon

Hearing disorders pose significant challenges to individuals experiencing them and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Current treatment options often focus on amplification devices, cochlear implants, or other rehabilitative therapies, leaving a substantial gap regarding effective pharmacological interventions. Advancements in our understanding of the molecular and cellular mechanisms involved in hearing disorders induced by noise, aging, and ototoxicity have opened new avenues for drug development, some of which have led to numerous clinical trials, with promising results. The development of optimal drug delivery solutions in animals and humans can also enhance the targeted delivery of medications to the ear. Moreover, large genome studies contributing to a genetic understanding of hearing loss in humans combined with advanced molecular technologies in animal studies have shown a great potential to increase our understanding of the etiologies of hearing loss. The auditory system exhibits circadian rhythms and temporal variations in its physiology, its vulnerability to auditory insults, and its responsiveness to drug treatments. The cochlear clock rhythms are under the control of the glucocorticoid system, and preclinical evidence suggests that the risk/benefit profile of hearing disorder treatments using chronopharmacological approaches would be beneficial. If translatable to the bedside, such approaches may improve the outcome of clinical trials. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug formulation and delivery as well as optimized timing of drug administration, holds great promise of more effective treatments. SIGNIFICANCE STATEMENT: Hearing disorders pose significant challenges to individuals and their overall quality of life, emphasizing the critical need for advanced pharmacological approaches to address these conditions. Ongoing research into the molecular and genetic basis of auditory disorders, coupled with advancements in drug delivery procedures and optimized timing of drug administration, holds the promise of more effective treatments.

听力障碍给患者及其整体生活质量带来了巨大挑战,因此迫切需要先进的药物治疗方法来解决这些问题。目前的治疗方案通常侧重于扩音设备、人工耳蜗或其他康复疗法,在有效的药物干预方面还存在很大差距。我们对噪音、老化和耳毒性引起的听力障碍所涉及的分子和细胞机制的了解不断加深,这为药物开发开辟了新的途径,其中一些已促成了一些临床试验,并取得了可喜的成果。在动物和人体中开发最佳给药方案也有助于加强耳部药物的定向给药。此外,有助于从遗传学角度了解人类听力损失的大型基因组研究与动物研究中的先进分子技术相结合,显示出极大的潜力,可提高我们对听力损失病因的了解。听觉系统在其生理、对听觉损伤的易感性以及对药物治疗的反应性方面都表现出昼夜节律和时间变化。耳蜗的时钟节律受糖皮质激素系统的控制,临床前的证据表明,使用时相药理学方法治疗听力障碍的风险/效益分析。如果这种方法可以应用于临床,则可能会改善临床试验的结果。对听觉障碍的分子和遗传基础的持续研究,加上药物制剂和给药方面的进步,以及给药时机的优化,都为更有效的治疗带来了巨大希望。意义声明 听力障碍对个人及其整体生活质量构成重大挑战,因此亟需先进的药物治疗方法来解决这些问题。对听觉障碍的分子和遗传基础的持续研究、给药程序的进步以及给药时机的优化,都为更有效的治疗带来了希望。
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引用次数: 0
Drug-Drug Interactions and Synergy: From Pharmacological Models to Clinical Application. 药物之间的相互作用和协同作用:从药理学模型到临床应用。
IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-16 DOI: 10.1124/pharmrev.124.000951
Luigino Calzetta, Clive Page, Maria Gabriella Matera, Mario Cazzola, Paola Rogliani

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts, such as concentration-response curves, additive effects, and predictive models, are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. Although various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors, such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. SIGNIFICANCE STATEMENT: Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug-drug interactions research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.

这篇综述探讨了药理学中的协同作用概念,强调了通过联合使用具有不同作用机制的药物来优化治疗效果的重要性。根据特定的预测模型,协同作用被定义为大于单个药物所产生的预期相加效应,它为提高疗效同时最大限度地减少不良反应提供了一种前景广阔的方法。从古代文明到现代药理学,协同作用研究的历史演变突显了人们对了解和利用协同作用的不断探索。书中详细讨论了浓度反应曲线、相加效应和预测模型等关键概念,强调了在整个转化药物开发过程中对精确评估方法的需求。虽然存在各种用于协同作用分析的数学模型,但选择合适的模型和软件工具仍然是一项挑战,需要仔细考虑实验设计和数据解释。此外,本综述还讨论了协同作用评估中的实际考虑因素,包括临床前和临床方法、作用机制和统计分析。优化协同作用需要注意浓度/剂量比、靶点定位和给药时机,以确保在临床实践中能够转化在工作台上发现的联合疗法的益处。总之,综述提倡采用系统的方法进行协同作用评估,其中包括稳健的统计分析、有效和简化的预测模型,以及学术机构、制药公司和监管机构等关键部门的通力合作。通过克服关键挑战并最大限度地发挥治疗潜力,在药物开发过程中进行有效的协同作用评估有望促进患者护理。意义声明 将具有不同作用机制的药物组合在一起进行协同作用,可优化治疗效果和安全性。准确解释协同作用需要确定预期的相加效应。尽管有创新的模型来预测相加效应,但在药物相互作用研究方面仍缺乏共识,这阻碍了联合疗法的临床开发。科学界、工业界和监管部门之间的合作对于推进联合疗法的开发至关重要,可确保在临床环境中严格应用预测模型。
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引用次数: 0
Biochemistry, pharmacology and in vivo function of arginases. 精氨酸酶的生物化学、药理学和体内功能。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1124/pharmrev.124.001271
Sophia K Heuser,Junjie Li,Silke Pudewell,Anthea LoBue,Zhixin Li,Miriam M Cortese-Krott
Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.
精氨酸酶催化 L-精氨酸水解为 L-鸟氨酸和尿素。现有的两种同工酶 Arg1 和 Arg2 显示出不同的细胞定位和代谢功能。精氨酸酶的活性对于尿素循环中的氮解毒、多胺的合成以及控制 L-精氨酸的生物利用率和一氧化氮的产生至关重要。尽管在了解精氨酸酶的生物化学和功能方面取得了重大进展,但仍存在一些未决问题。最近的研究发现,Arg1 和 Arg2 的调控和功能具有细胞类型特异性和物种特异性,而且在小鼠和人类中存在很大差异。主要差异体现在 Arg1 和 Arg2 在免疫细胞和红细胞中的分布和功能上。与之前的想法相反,在血管壁的平衡状态下,Arg1 的活性似乎只与血管氮氧化物信号传导有部分关系,但在疾病状态下,其表达会增加,并可能成为精氨酸酶抑制剂治疗的目标。Arg2 似乎主要是一种参与合成 L-鸟氨酸、多胺和脯氨酸的分解代谢酶,但至少在小鼠体内可能在血压控制方面发挥着潜在作用。精氨酸酶介导的精氨酸耗竭的免疫抑制作用是一个很有希望的癌症治疗目标。这篇综述对精氨酸酶的生物化学、药理学和体内功能进行了批判性修订和讨论,重点是分析细胞特异性 Arg1 和 Arg2 基因敲除小鼠以及使用精氨酸酶抑制剂或聚乙二醇化重组精氨酸酶的人体研究中获得的见解。意义声明 这篇综述强调,考虑到 Arg1 和 Arg 2 的定位、物种特异性以及多种生化和生理作用,我们有必要开展进一步研究,以加深对 Arg1 和 Arg 2 在不同细胞类型中调控作用的理解。这将为针对肝脏、心血管、血液、免疫/感染疾病和癌症的精氨酸酶活性制定更好的药理策略。
{"title":"Biochemistry, pharmacology and in vivo function of arginases.","authors":"Sophia K Heuser,Junjie Li,Silke Pudewell,Anthea LoBue,Zhixin Li,Miriam M Cortese-Krott","doi":"10.1124/pharmrev.124.001271","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001271","url":null,"abstract":"Arginase catalyzes the hydrolysis of L-arginine into L-ornithine and urea. The two existing isoforms Arg1 and Arg2 show different cellular localizations and metabolic functions. Arginase activity is crucial for nitrogen detoxification in the urea cycle, synthesis of polyamines, and control of l-arginine bioavailability and nitric oxide production. Despite significant progress in the understanding of the biochemistry and function of arginases, several open questions remain. Recent studies have revealed that the regulation and function of Arg1 and Arg2 are cell-type-specific, species-specific, and profoundly different in mice and humans. The main differences were found in the distribution and function of Arg1 and Arg2 in immune and erythroid cells. Contrary to what was previously thought, Arg1 activity appears to be only partially related to vascular NO signaling under homeostatic conditions in the vascular wall, but its expression is increased under disease conditions and may be targeted by treatment with arginase inhibitors. Arg2 appears to be mainly a catabolic enzyme involved in the synthesis of L-ornithine, polyamine, and proline but may play a putative role in blood pressure control, at least in mice. The immunosuppressive role of arginase-mediated arginine depletion is a promising target for cancer treatment. This review critically revises and discusses the biochemistry, pharmacology, and in vivo function of arginase, focusing on the insights gained from the analysis of cell-specific Arg1 and Arg2 knockout mice and human studies using arginase inhibitors or pegylated recombinant arginase. Significance Statement The review emphasizes the need for further research to deepen our understanding of the regulation of Arg1 and Arg 2 in different cell types under consideration of their localization, species-specificity, and multiple biochemical and physiological roles. This could lead to better pharmacological strategies to target arginase activity in liver, cardiovascular, hematological, immune/infection diseases and cancer.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Promising tools for future drug discovery and development in antiarrhythmic therapy. 未来抗心律失常治疗药物发现和开发的有望工具。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1124/pharmrev.124.001297
Gema Mondejar-Parreño,Patricia Sanchez-Perez,Francisco Miguel Cruz,Jose Jalife
Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks. The number of novel antiarrhythmic drug in the development pipeline has decreased substantially during the last decade and underscores uncertainties regarding future developments in this field. Consequently, arrhythmia treatment poses significant challenges, prompting the need for alternative approaches. Remarkably, innovative drug discovery and development technologies show promise in helping advance antiarrhythmic therapies. Here, we review unique characteristics and the transformative potential of emerging technologies that offer unprecedented opportunities for transitioning from traditional antiarrhythmics to next-generation therapies. We assess stem cell technology, emphasizing the utility of innovative cell profiling using multi-omics, high-throughput screening, and advanced computational modeling in developing treatments tailored precisely to individual genetic and physiological profiles. We offer insights into gene therapy, peptide and peptibody approaches for drug delivery. We finally discuss potential strengths and weaknesses of such techniques in reducing adverse effects and enhancing overall treatment outcomes, leading to more effective, specific, and safer therapies. Altogether, this comprehensive overview introduces innovative avenues for personalized rhythm therapy, with particular emphasis on drug discovery, aiming to advance the arrhythmia treatment landscape and the prevention of SCD. Significance Statement Arrhythmias and sudden cardiac death account for 15-20% of deaths worldwide. However, current antiarrhythmic therapies are ineffective and with dangerous side effects. Here, we review the field of arrhythmia treatment underscoring the slow progress in advancing the cardiac rhythm therapy pipeline and the uncertainties regarding evolution of this field. We provide information on how emerging technological and experimental tools can help accelerate progress and address the limitations of antiarrhythmic drug discovery.
心律失常是指心率和心律不齐,症状从轻微的心悸到危及生命的心律失常和心脏性猝死(SCD)。心律失常的分子性质复杂,使得选择适当的治疗方法变得复杂。目前的治疗方法包括使用抗心律失常药物(I-IV 类),但疗效有限,副作用危险;植入式心脏起搏器和心律转复除颤器,但存在与硬件相关的并发症和不适当的电击。在过去十年中,研发管道中新型抗心律失常药物的数量大幅减少,凸显了该领域未来发展的不确定性。因此,心律失常的治疗面临着巨大的挑战,促使人们需要寻找替代方法。值得注意的是,创新药物发现和开发技术有望帮助推动抗心律失常疗法的发展。在此,我们回顾了新兴技术的独特性和变革潜力,这些技术为从传统抗心律失常疗法过渡到下一代疗法提供了前所未有的机遇。我们对干细胞技术进行了评估,强调了利用多组学、高通量筛选和先进的计算建模进行创新细胞剖析在开发精确针对个体遗传和生理特征的治疗方法方面的效用。我们深入探讨了基因疗法、多肽和多肽抗体给药方法。最后,我们将讨论这些技术在减少不良反应和提高整体治疗效果方面的潜在优势和不足,从而开发出更有效、更特异、更安全的疗法。总之,本综述介绍了个性化心律治疗的创新途径,特别强调了药物发现,旨在推动心律失常治疗的发展和 SCD 的预防。意义声明 心律失常和心脏性猝死占全球死亡人数的 15-20%。然而,目前的抗心律失常疗法疗效不佳且具有危险的副作用。在此,我们回顾了心律失常治疗领域,强调了心律治疗管道的缓慢进展以及该领域发展的不确定性。我们将介绍新兴技术和实验工具如何帮助加快进度并解决抗心律失常药物研发的局限性。
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引用次数: 0
Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes. 综合考虑种系基因组和肿瘤基因组,创新癌症药物疗法。
IF 21.1 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1124/pharmrev.124.001049
Roman Tremmel,Daniel Hübschmann,Elke Schaeffeler,Sebastian Pirmann,Stefan Fröhling,Matthias Schwab
Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.
癌症精准医疗已广泛确立,许多针对不同肿瘤实体的分子靶向药物已获批准或正在开发中。迄今为止,肿瘤学中的个性化药物治疗主要基于肿瘤特征,如体细胞突变。然而,对药物治疗的反应还取决于药理学过程,即 ADME(吸收、分布、代谢和排泄)。五十多年来,ADME 基因的变异一直是深入研究的主题,考虑的是个体患者的基因构成,即药物基因组学(PGx)。人们对患者肿瘤基因组和种系基因组的综合影响仅有部分了解,在癌症治疗中往往没有充分考虑。部分原因可能是缺乏对这两个数据层进行综合分析的方法。因此,优化的个性化癌症疗法应以整合肿瘤和种系的分子信息为目标,同时考虑到现有的药物治疗 PGx 指南。此外,这种策略还应该提供机会,考虑以前未知功能意义的基因变异。需要开发生物信息学分析方法和相应的数据解读算法,以便在跨学科分子肿瘤委员会中考虑 PGx 数据,在该委员会中讨论癌症患者,根据个体肿瘤特征为临床管理提供循证建议。意义声明 个性化肿瘤学时代出现了针对与癌症生物学相关的基因变异而定制的药物。然而,由于主要关注获得性肿瘤特异性改变,靶向治疗的潜力仍未得到充分挖掘。优化癌症治疗必须在药物基因组学原则的指导下整合肿瘤和患者基因组。实现癌症患者真正个性化药物治疗的一个重要前提是开发生物信息学工具,以全面分析现代精准肿瘤学项目中生成的所有数据层。
{"title":"Innovation in cancer pharmacotherapy through integrative consideration of germline and tumor genomes.","authors":"Roman Tremmel,Daniel Hübschmann,Elke Schaeffeler,Sebastian Pirmann,Stefan Fröhling,Matthias Schwab","doi":"10.1124/pharmrev.124.001049","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001049","url":null,"abstract":"Precision cancer medicine is widely established, and numerous molecularly targeted drugs for various tumor entities are approved or in development. Personalized pharmacotherapy in oncology has so far been based primarily on tumor characteristics, e.g., somatic mutations. However, the response to drug treatment also depends on pharmacological processes summarized under the term ADME (absorption, distribution, metabolism, and excretion). Variations in ADME genes have been the subject of intensive research for more than five decades, considering individual patients' genetic makeup, referred to as pharmacogenomics (PGx). The combined impact of a patient's tumor and germline genome is only partially understood and often not adequately considered in cancer therapy. This may be attributed, in part, to the lack of methods for combined analysis of both data layers. Optimized personalized cancer therapies should, therefore, aim to integrate molecular information about the tumor and the germline, taking into account existing PGx guidelines for drug therapy. Moreover, such strategies should provide the opportunity to consider genetic variants of previously unknown functional significance. Bioinformatic analysis methods and corresponding algorithms for data interpretation need to be developed to consider PGx data in interdisciplinary molecular tumor boards, where cancer patients are discussed to provide evidence-based recommendations for clinical management based on individual tumor profiles. Significance Statement The era of personalized oncology has seen the emergence of drugs tailored to genetic variants associated with cancer biology. However, full potential of targeted therapy remains untapped due to the predominant focus on acquired tumor-specific alterations. Optimized cancer care must integrate tumor and patient genomes, guided by pharmacogenomic principles. An essential prerequisite for realizing truly personalized drug treatment of cancer patients is the development of bioinformatic tools for comprehensive analysis of all data layers generated in modern precision oncology programs.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Pharmacological Reviews
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