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Opportunities and challenges in the therapeutic exploitation of histamine and histamine receptor pharmacology in inflammation-driven disorders 利用组胺和组胺受体药理学治疗炎症引起的疾病的机遇与挑战。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-19 DOI: 10.1016/j.pharmthera.2024.108722
Ekaterini Tiligada , Charikleia Stefanaki , Madeleine Ennis , Detlef Neumann
Inflammation-driven diseases encompass a wide array of pathological conditions characterised by immune system dysregulation leading to tissue damage and dysfunction. Among the myriad of mediators involved in the regulation of inflammation, histamine has emerged as a key modulatory player. Histamine elicits its actions through four rhodopsin-like G-protein-coupled receptors (GPCRs), named chronologically in order of discovery as histamine H1, H2, H3 and H4 receptors (H14R). The relatively low affinity H1R and H2R play pivotal roles in mediating allergic inflammation and gastric acid secretion, respectively, whereas the high affinity H3R and H4R are primarily linked to neurotransmission and immunomodulation, respectively. Importantly, however, besides the H4R, both H1R and H2R are also crucial in driving immune responses, the H2R tending to promote yet ill-defined and unexploited suppressive, protective and/or resolving processes. The modulatory action of histamine via its receptors on inflammatory cells is described in detail. The potential therapeutic value of the most recently discovered H4R in inflammatory disorders is illustrated via a selection of preclinical models. The clinical trials with antagonists of this receptor are discussed and possible reasons for their lack of success described.
炎症驱动的疾病包括一系列病理状况,其特点是免疫系统失调导致组织损伤和功能障碍。在众多参与炎症调节的介质中,组胺已成为一个关键的调节因子。组胺通过四种类似于视黄醛的 G 蛋白偶联受体(GPCR)发挥作用,这四种受体按发现的时间顺序被命名为组胺 H1、H2、H3 和 H4 受体(H1-4R)。亲和力相对较低的 H1R 和 H2R 分别在介导过敏性炎症和胃酸分泌方面发挥关键作用,而亲和力较高的 H3R 和 H4R 则分别主要与神经传递和免疫调节有关。然而,重要的是,除了 H4R 外,H1R 和 H2R 也是驱动免疫反应的关键因素,其中 H2R 倾向于促进尚未明确和开发的抑制、保护和/或解决过程。本文详细介绍了组胺通过其受体对炎症细胞的调节作用。通过一些临床前模型,说明了最近发现的 H4R 在炎症性疾病中的潜在治疗价值。此外,还讨论了使用该受体拮抗剂进行的临床试验,并阐述了试验不成功的可能原因。
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引用次数: 0
The influence of glutamate receptors on insulin release and diabetic neuropathy 谷氨酸受体对胰岛素释放和糖尿病神经病变的影响
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-18 DOI: 10.1016/j.pharmthera.2024.108724
Enza Palazzo, Ida Marabese, Federica Ricciardi, Francesca Guida, Livio Luongo, Sabatino Maione

Diabetes causes macrovascular and microvascular complications such as peripheral neuropathy. Glutamate regulates insulin secretion in pancreatic β-cells, and its increased activity in the central nervous system is associated with peripheral neuropathy in animal models of diabetes. One strategy to modulate glutamatergic activity consists in the pharmacological manipulation of metabotropic glutamate receptors (mGluRs), which, compared to the ionotropic receptors, allow for a fine-tuning of neurotransmission that is compatible with therapeutic interventions. mGluRs are a family of eight G-protein coupled receptors classified into three groups (I-III) based on sequence homology, transduction mechanisms, and pharmacology. Activation of group II and III or inhibition of group I represents a strategy to counteract the glutamatergic hyperactivity associated with diabetic neuropathy. In this review article, we will discuss the role of glutamate receptors in the release of insulin and the development/treatment of diabetic neuropathy, with particular emphasis on their manipulation to prevent the glutamatergic hyperactivity associated with diabetic neuropathy.

糖尿病会引起大血管和微血管并发症,如周围神经病变。谷氨酸可调节胰岛β细胞的胰岛素分泌,其在中枢神经系统中的活性增加与糖尿病动物模型中的周围神经病变有关。调节谷氨酸能活动的一种策略是对代谢型谷氨酸受体(mGluRs)进行药理学操作,与离子型受体相比,mGluRs 可对神经传递进行微调,从而与治疗干预措施相兼容。激活 II 组和 III 组或抑制 I 组是对抗与糖尿病神经病变相关的谷氨酸能亢进的一种策略。在这篇综述文章中,我们将讨论谷氨酸受体在胰岛素释放和糖尿病神经病变的发生/治疗中的作用,特别强调操纵谷氨酸受体以防止与糖尿病神经病变相关的谷氨酸能亢进。
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引用次数: 0
Gene editing in common cardiovascular diseases 常见心血管疾病的基因编辑
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-14 DOI: 10.1016/j.pharmthera.2024.108720
Anna-Maria Lauerer , Xurde M. Caravia , Lars S. Maier , Francesco Chemello , Simon Lebek

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide, highlighting the high socioeconomic impact. Current treatment strategies like compound-based drugs or surgeries are often limited. On the one hand, systemic administration of substances is frequently associated with adverse side effects; on the other hand, they typically provide only short-time effects requiring daily intake. Thus, new therapeutic approaches and concepts are urgently needed. The advent of CRISPR-Cas9 genome editing offers great promise for the correction of disease-causing hereditary mutations. As such mutations are often very rare, gene editing strategies to correct them are not broadly applicable to many patients. Notably, there is recent evidence that gene editing technology can also be deployed to disrupt common pathogenic signaling cascades in a targeted, specific, and efficient manner, which offers a more generalizable approach. However, several challenges remain to be addressed ranging from the optimization of the editing strategy itself to a suitable delivery strategy up to potential immune responses to the editing components. This review article discusses important CRISPR-Cas9-based gene editing approaches with their advantages and drawbacks and outlines opportunities in their application for treatment of cardiovascular diseases.

心血管疾病是全球发病率和死亡率的主要原因,对社会经济影响巨大。目前的治疗策略,如复方药物或手术,往往存在局限性。一方面,全身用药经常会产生不良副作用;另一方面,这些药物通常只能在短期内见效,需要每天服用。因此,迫切需要新的治疗方法和理念。CRISPR-Cas9 基因组编辑技术的出现为纠正致病遗传突变带来了巨大希望。由于这类基因突变通常非常罕见,因此纠正这些突变的基因编辑策略并不能广泛适用于许多患者。值得注意的是,最近有证据表明,基因编辑技术也可用于以靶向、特异和高效的方式破坏常见的致病信号级联,这提供了一种更具普遍性的方法。然而,从编辑策略本身的优化到合适的传递策略,再到对编辑成分的潜在免疫反应,仍有一些挑战有待解决。这篇综述文章讨论了基于CRISPR-Cas9的重要基因编辑方法及其优缺点,并概述了这些方法在心血管疾病治疗中的应用机会。
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引用次数: 0
Organic anion transporters in remote sensing and organ crosstalk 遥感和器官串联中的有机阴离子转运体
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-14 DOI: 10.1016/j.pharmthera.2024.108723
Jeffry C. Granados , Sanjay K. Nigam

The organic anion transporters, OAT1 and OAT3, regulate the movement of drugs, toxins, and endogenous metabolites. In 2007, we proposed that OATs and other SLC22 transporters are involved in “remote sensing” and organ crosstalk. This is now known as the Remote Sensing and Signaling Theory (RSST). In the proximal tubule of the kidney, OATs regulate signaling molecules such as fatty acids, bile acids, indoxyl sulfate, kynurenine, alpha-ketoglutarate, urate, flavonoids, and antioxidants. OAT1 and OAT3 function as key hubs in a large homeostatic network involving multi-, oligo- and monospecific transporters, enzymes, and nuclear receptors. The Remote Sensing and Signaling Theory emphasizes the functioning of OATs and other “drug” transporters in the network at multiple biological scales (inter-organismal, organism, organ, cell, organelle). This network plays an essential role in the homeostasis of urate, bile acids, prostaglandins, sex steroids, odorants, thyroxine, gut microbiome metabolites, and uremic toxins. The transported metabolites have targets in the kidney and other organs, including nuclear receptors (e.g., HNF4a, AHR), G protein-coupled receptors (GPCRs), and protein kinases. Feed-forward and feedback loops allow OAT1 and OAT3 to mediate organ crosstalk as well as modulate energy metabolism, redox state, and remote sensing. Furthermore, there is intimate inter-organismal communication between renal OATs and the gut microbiome. Extracellular vesicles containing microRNAs and proteins (exosomes) play a key role in the Remote Sensing and Signaling System as does the interplay with the neuroendocrine, hormonal, and immune systems. Perturbation of function with OAT-interacting drugs (e.g., probenecid, diuretics, antivirals, antibiotics, NSAIDs) can lead to drug-metabolite interactions. The RSST has general applicability to other multi-specific SLC and ABC “drug” transporters (e.g., OCT1, OCT2, SLCO1B1, SLCO1B3, ABCG2, P-gp, ABCC2, ABCC3, ABCC4). Recent high-resolution structures of SLC22 and other transporters, together with chemoinformatic and artificial intelligence methods, will aid drug development and also lead to a deeper mechanistic understanding of polymorphisms.

有机阴离子转运体 OAT1 和 OAT3 可调节药物、毒素和内源性代谢物的移动。2007 年,我们提出 OAT 和其他 SLC22 转运体参与 "遥感 "和器官串联。这一理论现在被称为 "遥感和信号理论"(RSST)。在肾脏近端小管中,OATs 可调节脂肪酸、胆汁酸、硫酸吲哚啉、犬尿氨酸、α-酮戊二酸、尿酸盐、类黄酮和抗氧化剂等信号分子。OAT1 和 OAT3 是一个庞大的平衡网络中的关键枢纽,该网络涉及多特异性、寡特异性和单特异性转运体、酶和核受体。遥感和信号理论强调 OAT 和其他 "药物 "转运体在多个生物尺度(生物体间、生物体、器官、细胞、细胞器)的网络中发挥作用。该网络在尿酸盐、胆汁酸、前列腺素、性类固醇、臭味剂、甲状腺素、肠道微生物组代谢物和尿毒症毒素的平衡中发挥着重要作用。转运的代谢物在肾脏和其他器官中具有靶标,包括核受体(如 HNF4a、AHR)、G 蛋白偶联受体(GPCR)和蛋白激酶。前馈和反馈回路使 OAT1 和 OAT3 能够介导器官串联,并调节能量代谢、氧化还原状态和遥感。此外,肾脏 OAT 与肠道微生物组之间也存在着密切的器官间交流。含有微核糖核酸(microRNA)和蛋白质的胞外囊泡(外泌体)在遥感和信号系统中发挥着关键作用,与神经内分泌、荷尔蒙和免疫系统的相互作用也是如此。与 OAT 有相互作用的药物(如丙磺舒、利尿剂、抗病毒药、抗生素、非甾体抗炎药)对功能的干扰会导致药物代谢物之间的相互作用。RSST 还普遍适用于其他多特异性 SLC 和 ABC "药物 "转运体(如 OCT1、OCT2、SLCO1B1、SLCO1B3、ABCG2、P-gp、ABCC2、ABCC3、ABCC4)。SLC22 和其他转运体的最新高分辨率结构以及化学信息学和人工智能方法将有助于药物开发,并加深对多态性机理的理解。
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引用次数: 0
Potential application of natural compounds in ischaemic stroke: Focusing on the mechanisms underlying “lysosomocentric” dysfunction of the autophagy-lysosomal pathway 天然化合物在缺血性中风中的潜在应用:聚焦自噬-溶酶体通路 "以溶酶体为中心 "的功能障碍机制
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-14 DOI: 10.1016/j.pharmthera.2024.108721
Yueyang Liu , Qingbo Liu , Hanxiao Shang , Jichong Li , He Chai , Kaixuan Wang , Zhenkun Guo , Tianyu Luo , Shiqi Liu , Yan Liu , Xuemei Wang , Hangyi Zhang , Chunfu Wu , Shao-Jiang Song , Jingyu Yang

Ischaemic stroke (IS) is the second leading cause of death and a major cause of disability worldwide. Currently, the clinical management of IS still depends on restoring blood flow via pharmacological thrombolysis or mechanical thrombectomy, with accompanying disadvantages of narrow therapeutic time window and risk of haemorrhagic transformation. Thus, novel pathophysiological mechanisms and targeted therapeutic candidates are urgently needed. The autophagy-lysosomal pathway (ALP), as a dynamic cellular lysosome-based degradative process, has been comprehensively studied in recent decades, including its upstream regulatory mechanisms and its role in mediating neuronal fate after IS. Importantly, increasing evidence has shown that IS can lead to lysosomal dysfunction, such as lysosomal membrane permeabilization, impaired lysosomal acidity, lysosomal storage disorder, and dysfunctional lysosomal ion homeostasis, which are involved in the IS-mediated defects in ALP function. There is tightly regulated crosstalk between transcription factor EB (TFEB), mammalian target of rapamycin (mTOR) and lysosomal function, but their relationship remains to be systematically summarized. Notably, a growing body of evidence emphasizes the benefits of naturally derived compounds in the treatment of IS via modulation of ALP function. However, little is known about the roles of natural compounds as modulators of lysosomes in the treatment of IS. Therefore, in this context, we provide an overview of the current understanding of the mechanisms underlying IS-mediated ALP dysfunction, from a lysosomal perspective. We also provide an update on the effect of natural compounds on IS, according to their chemical structural types, in different experimental stroke models, cerebral regions and cell types, with a primary focus on lysosomes and autophagy initiation. This review aims to highlight the therapeutic potential of natural compounds that target lysosomal and ALP function for IS treatment.

缺血性中风(IS)是全球第二大死亡原因,也是导致残疾的主要原因。目前,缺血性中风的临床治疗仍然依赖于通过药物溶栓或机械取栓来恢复血流,但同时也存在治疗时间窗狭窄和出血转化风险等缺点。因此,迫切需要新的病理生理机制和靶向治疗候选药物。自噬-溶酶体途径(ALP)作为一种基于细胞溶酶体的动态降解过程,近几十年来已得到全面研究,包括其上游调控机制及其在IS后介导神经元命运的作用。重要的是,越来越多的证据表明,IS 可导致溶酶体功能障碍,如溶酶体膜通透性、溶酶体酸度受损、溶酶体贮存障碍和溶酶体离子平衡失调,而这些都与 IS 介导的 ALP 功能缺陷有关。转录因子 EB(TFEB)、哺乳动物雷帕霉素靶标(mTOR)和溶酶体功能之间存在紧密的相互调控关系,但它们之间的关系仍有待系统总结。值得注意的是,越来越多的证据强调了天然提取的化合物通过调节 ALP 功能治疗 IS 的益处。然而,人们对天然化合物作为溶酶体调节剂在治疗 IS 中的作用知之甚少。因此,在此背景下,我们从溶酶体的角度概述了目前对 IS 介导的 ALP 功能障碍机制的理解。我们还根据天然化合物的化学结构类型,介绍了天然化合物在不同的实验性中风模型、脑区和细胞类型中对 IS 的最新影响,主要侧重于溶酶体和自噬的启动。本综述旨在强调针对溶酶体和 ALP 功能的天然化合物在治疗 IS 方面的治疗潜力。
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引用次数: 0
Artificial intelligence with mass spectrometry-based multimodal molecular profiling methods for advancing therapeutic discovery of infectious diseases 人工智能与基于质谱的多模态分子剖析方法,促进传染病的治疗发现。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-09-04 DOI: 10.1016/j.pharmthera.2024.108712
Jingjing Liu , Chaohui Bao , Jiaxin Zhang , Zeguang Han , Hai Fang , Haitao Lu

Infectious diseases, driven by a diverse array of pathogens, can swiftly undermine public health systems. Accurate diagnosis and treatment of infectious diseases—centered around the identification of biomarkers and the elucidation of disease mechanisms—are in dire need of more versatile and practical analytical approaches. Mass spectrometry (MS)-based molecular profiling methods can deliver a wealth of information on a range of functional molecules, including nucleic acids, proteins, and metabolites. While MS-driven omics analyses can yield vast datasets, the sheer complexity and multi-dimensionality of MS data can significantly hinder the identification and characterization of functional molecules within specific biological processes and events. Artificial intelligence (AI) emerges as a potent complementary tool that can substantially enhance the processing and interpretation of MS data. AI applications in this context lead to the reduction of spurious signals, the improvement of precision, the creation of standardized analytical frameworks, and the increase of data integration efficiency. This critical review emphasizes the pivotal roles of MS based omics strategies in the discovery of biomarkers and the clarification of infectious diseases. Additionally, the review underscores the transformative ability of AI techniques to enhance the utility of MS-based molecular profiling in the field of infectious diseases by refining the quality and practicality of data produced from omics analyses. In conclusion, we advocate for a forward-looking strategy that integrates AI with MS-based molecular profiling. This integration aims to transform the analytical landscape and the performance of biological molecule characterization, potentially down to the single-cell level. Such advancements are anticipated to propel the development of AI-driven predictive models, thus improving the monitoring of diagnostics and therapeutic discovery for the ongoing challenge related to infectious diseases.

由各种病原体引起的传染病会迅速破坏公共卫生系统。传染病的准确诊断和治疗以生物标志物的鉴定和疾病机理的阐明为中心,亟需更多用途和实用的分析方法。以质谱(MS)为基础的分子剖析方法可以提供包括核酸、蛋白质和代谢物在内的一系列功能分子的大量信息。虽然 MS 驱动的全息分析可以产生庞大的数据集,但 MS 数据的复杂性和多维性会严重阻碍对特定生物过程和事件中功能分子的识别和表征。人工智能(AI)作为一种有效的补充工具,可以大大提高 MS 数据的处理和解释能力。人工智能在这方面的应用可减少虚假信号、提高精确度、创建标准化分析框架并提高数据整合效率。这篇重要综述强调了基于 MS 的全局策略在发现生物标记物和阐明传染病方面的关键作用。此外,本综述还强调了人工智能技术的变革能力,即通过改进全局分析产生的数据的质量和实用性,提高基于 MS 的分子剖析在传染病领域的实用性。总之,我们主张采取前瞻性战略,将人工智能与基于 MS 的分子图谱分析相结合。这种整合的目的是改变生物分子表征的分析格局和性能,有可能达到单细胞水平。预计这种进步将推动人工智能驱动的预测模型的发展,从而改善诊断监测和治疗发现,应对与传染病有关的持续挑战。
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引用次数: 0
CircRNAs as upstream regulators of miRNA//HMGA2 axis in human cancer CircRNA 是人类癌症中 miRNA//HMGA2 轴的上游调节因子。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-31 DOI: 10.1016/j.pharmthera.2024.108711
Qiqi Sun , Xiaoyong Lei , Xiaoyan Yang
High mobility group protein A2 (HMGA2) is widely recognized as a chromatin-binding protein, whose overexpression is observed in nearly all human cancers. It exerts its oncogenic effects by influencing various cellular processes such as the epithelial-mesenchymal transition, cell differentiation, and DNA damage repair. MicroRNA (miRNA) serves as a pivotal gene expression regulator, concurrently modulating multiple genes implicated in cancer progression, including HMGA2. It also serves as a significant biomarker for cancer. Circular RNA (circRNA) plays a crucial role in gene regulation primarily by sequestering miRNAs and impeding their ability to enhance the expression of other genes, including HMGA2. Increasingly, studies have underscored the vital role of miRNA/HMGA2 interactions in cancer. Given the significance of circRNA as an upstream regulatory mediator and the complexity of regulatory mechanisms, we hereby present a comprehensive overview of the pivotal role of circRNAs as upstream regulators of the miRNA//HMGA2 axis in human cancers. This insight may herald a novel direction for future cancer research.
高迁移率基团蛋白 A2(HMGA2)被广泛认为是一种染色质结合蛋白,几乎所有人类癌症中都能观察到它的过表达。它通过影响上皮-间质转化、细胞分化和 DNA 损伤修复等各种细胞过程来发挥致癌作用。微小核糖核酸(miRNA)是一种关键的基因表达调节因子,可同时调节与癌症进展有关的多个基因,包括 HMGA2。它还是癌症的重要生物标志物。环状 RNA(circRNA)在基因调控中起着至关重要的作用,主要是通过封闭 miRNA,阻碍其增强包括 HMGA2 在内的其他基因的表达。越来越多的研究强调了 miRNA/HMGA2 相互作用在癌症中的重要作用。鉴于 circRNA 作为上游调控介质的重要性和调控机制的复杂性,我们在此全面概述了 circRNA 作为 miRNA//HMGA2 轴上游调控因子在人类癌症中的关键作用。这一见解可能预示着未来癌症研究的新方向。
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引用次数: 0
microRNAs in kidney diseases: Regulation, therapeutics, and biomarker potential 肾脏疾病中的 microRNAs:调节、治疗和生物标记潜力。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-22 DOI: 10.1016/j.pharmthera.2024.108709
Zhiwen Liu , Ying Fu , Mingjuan Yan , Subing Zhang , Juan Cai , Guochun Chen , Zheng Dong

MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions.

微小 RNA(miRNA)是一种非编码 RNA 小分子,通过抑制其特定目标信使 RNA 的翻译,在调节基因表达方面发挥着至关重要的作用。迄今为止,已有大量研究表明,在人类患者和实验模型中,在急性肾损伤(AKI)和慢性肾病(CKD)的整个进展过程中,肾脏中 miRNA 的表达都会发生变化。特定 microRNA 在肾脏疾病发病机制中的作用也已得到证实。进一步的研究阐明了这些 microRNA 在患病肾脏中的调控作用。此外,在肾脏疾病患者的血浆和/或尿液中检测到某些 miRNA,它们是潜在的诊断生物标志物。在这篇综述中,我们概述了在了解 miRNA 如何导致肾脏疾病方面的最新进展。我们还探讨了 miRNAs 作为这些疾病的生物标志物和治疗靶点的潜力,并强调了未来的研究方向。
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引用次数: 0
Targeting organ-specific mitochondrial dysfunction to improve biological aging 针对器官特异性线粒体功能障碍改善生物衰老。
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-22 DOI: 10.1016/j.pharmthera.2024.108710
Corina T. Madreiter-Sokolowski , Ursula Hiden , Jelena Krstic , Katrin Panzitt , Martin Wagner , Christian Enzinger , Michael Khalil , Mahmoud Abdellatif , Ernst Malle , Tobias Madl , Elena Osto , Markus Schosserer , Christoph J. Binder , Andrea Olschewski

In an aging society, unveiling new anti-aging strategies to prevent and combat aging-related diseases is of utmost importance. Mitochondria are the primary ATP production sites and key regulators of programmed cell death. Consequently, these highly dynamic organelles play a central role in maintaining tissue function, and mitochondrial dysfunction is a pivotal factor in the progressive age-related decline in cellular homeostasis and organ function.

The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics.

We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues.

In conclusion, this review highlights the therapeutic potential of addressing mitochondrial dysfunction to mitigate organ-specific aging, focusing on the skin, liver, lung, brain, skeletal muscle, and lung, as well as on the reproductive, immune, and cardiovascular systems. Based on a comprehensive understanding of the multifaceted roles of mitochondria, innovative therapeutic strategies may be developed and optimized to combat biological aging and promote healthy aging across diverse organ systems.

在老龄化社会中,揭示新的抗衰老战略以预防和抗击与衰老有关的疾病至关重要。线粒体是产生 ATP 的主要场所,也是细胞程序性死亡的关键调节器。因此,这些高度动态的细胞器在维持组织功能方面发挥着核心作用,而线粒体功能障碍是与年龄相关的细胞稳态和器官功能逐渐衰退的关键因素。本综述探讨了了解线粒体功能障碍与器官特异性衰老之间相互作用的最新进展。通过探讨线粒体 DNA 的作用、活性氧平衡、代谢活动、损伤相关分子模式、生物生成、周转和动力学,我们剖析了线粒体损伤与器官功能衰退相关的分子机制。我们还重点介绍了临床前和临床试验中有望恢复线粒体功能的新兴治疗策略,如抗氧化剂、线粒体生物生成刺激剂以及线粒体更替和动态调节剂。此外,我们还讨论了与使用这些干预措施相关的潜在益处和挑战,并强调鉴于不同组织线粒体的独特性,有必要采用针对特定器官的方法。总之,本综述强调了解决线粒体功能障碍以缓解器官特异性衰老的治疗潜力,重点关注皮肤、肝脏、肺、大脑、骨骼肌和肺,以及生殖、免疫和心血管系统。在全面了解线粒体多方面作用的基础上,可以开发和优化创新的治疗策略,以对抗生物衰老,促进不同器官系统的健康衰老。
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引用次数: 0
C-type natriuretic peptide (CNP): The cardiovascular system and beyond C 型钠尿肽(CNP):心血管系统及其他
IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-21 DOI: 10.1016/j.pharmthera.2024.108708
Yasmin A. Dickinson, Amie J. Moyes, Adrian J. Hobbs

C-type natriuretic peptide (CNP) represents the ‘local’ member of the natriuretic peptide family, functioning in an autocrine or paracrine capacity to modulate a hugely diverse portfolio of physiological processes. Whilst the best-characterised of these regulatory roles are in the cardiovascular system, akin to its predominantly endocrine siblings atrial (ANP) and brain (BNP) natriuretic peptides, CNP governs many additional, unrelated mechanisms including bone growth, gamete maturation, auditory processing, and neuronal integrity. Furthermore, there is currently great interest in mimicking the biological activity of CNP for therapeutic gain in many of these disparate organ systems. Herein, we provide an overview of the physiology, pathophysiology and pharmacology of CNP in both cardiovascular and non-cardiovascular settings.

C 型利钠肽 (CNP) 是利钠肽家族中的 "本地 "成员,以自分泌或旁分泌的方式调节着多种多样的生理过程。CNP 在心血管系统中的调控作用最为突出,这与其主要作用于内分泌的同胞兄弟心房钠尿肽(ANP)和脑钠尿肽(BNP)类似,CNP 还能调控许多其他不相关的机制,包括骨骼生长、配子成熟、听觉处理和神经元完整性。此外,目前人们对模仿 CNP 的生物活性以在这些不同器官系统中获得治疗效果非常感兴趣。在此,我们将概述 CNP 在心血管和非心血管环境中的生理学、病理生理学和药理学。
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Pharmacology & Therapeutics
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