Pharmacological research最新文献_第8页

Type 2 diabetes mellitus and neurodegenerative disorders: The mitochondrial connection 2 型糖尿病与神经退行性疾病：线粒体的联系

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-30 DOI: 10.1016/j.phrs.2024.107439

Isabella R. Baduini , Jose E. Castro Vildosola , Sheida Kavehmoghaddam , Fatmanur Kiliç , S. Aiman Nadeem , Juan J. Nizama , Marietta A. Rowand , Dileep Annapureddy , Chris-Ann Bryan , Lisa H. Do , Samuel Hsiao , Sai A. Jonnalagadda , Akhila Kasturi , Nikhila Mandava , Sachin Muppavaram , Bryan Ramirez , Aleece Siner , Christina N. Suoto , Nasira Tamajal , Ernest R. Scoma , Maria E. Solesio

The incidence of type 2 diabetes mellitus (T2DM) has increased in our society in recent decades as the population ages, and this trend is not expected to revert. This is the same for the incidence of the main neurodegenerative disorders, including the two most common ones, which are, Alzheimer’s and Parkinson’s disease. Currently, no pharmacological therapies have been developed to revert or cure any of these pathologies. Interestingly, in recent years, an increased number of studies have shown a high co-morbidity between T2DM and neurodegeneration, as well as some common molecular pathways that are affected in both types of diseases. For example, while the etiopathology of T2DM and neurodegenerative disorders is highly complex, mitochondrial dysfunction has been broadly described in the early steps of both diseases; accordingly, this dysfunction has emerged as a plausible molecular link between them. In fact, the prominent role played by mitochondria in the mammalian metabolism of glucose places the physiology of the organelle in a central position to regulate many cellular processes that are affected in both T2DM and neurodegenerative disorders. In this collaborative review, we critically describe the relationship between T2DM and neurodegeneration; making a special emphasis on the mitochondrial mechanisms that could link these diseases. A better understanding of the role of mitochondria on the etiopathology of T2DM and neurodegeneration could pave the way for the development of new pharmacological therapies focused on the regulation of the physiology of the organelle. These therapies could, ultimately, contribute to increase healthspan.

近几十年来，随着人口老龄化的加剧，2 型糖尿病（T2DM）的发病率在我们的社会中不断上升，而且预计这一趋势不会逆转。主要神经退行性疾病的发病率也是如此，其中包括两种最常见的疾病，即阿尔茨海默病和帕金森病。目前，还没有研发出任何药物疗法来逆转或治愈这些病症。有趣的是，近年来越来越多的研究表明，T2DM 和神经退行性病变之间存在高度共病性，而且这两种疾病都会影响一些共同的分子通路。例如，虽然 T2DM 和神经退行性疾病的病因病理非常复杂，但线粒体功能障碍在这两种疾病的早期阶段就已被广泛描述；因此，线粒体功能障碍已成为这两种疾病之间的一种可信的分子联系。事实上，线粒体在哺乳动物的葡萄糖代谢过程中扮演着重要角色，这使得线粒体的生理学在调控 T2DM 和神经退行性疾病的许多细胞过程中处于核心地位。在这篇合作性综述中，我们对 T2DM 和神经退行性疾病之间的关系进行了批判性描述，并特别强调了将这些疾病联系在一起的线粒体机制。更好地了解线粒体在 T2DM 和神经退行性病变病因学中的作用，可为开发以调节细胞器生理机能为重点的新药物疗法铺平道路。这些疗法最终将有助于延长健康寿命。

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引用次数: 0

Commentary on “Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke” 关于 "Orosomucoid 2 是神经元线粒体生物生成的内源性调节剂，可促进中风后的功能恢复 "的评论。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-30 DOI: 10.1016/j.phrs.2024.107440

Raja Kannan

引用次数: 0

Deciphering the multifaceted roles and clinical implications of 2-hydroxyglutarate in cancer 解密 2-羟基戊二酸在癌症中的多方面作用和临床意义。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-29 DOI: 10.1016/j.phrs.2024.107437

Jie Hao , Ziyi Huang , Siyue Zhang , Kefan Song , Juncheng Wang , Chao Gao , Zhiqing Fang , Ning Zhang

Increasing evidence indicates that 2-hydroxyglutarate (2HG) is an oncometabolite that drives tumour formation and progression. Due to mutations in isocitrate dehydrogenase (IDH) and the dysregulation of other enzymes, 2HG accumulates significantly in tumour cells. Due to its structural similarity to α-ketoglutarate (αKG), accumulated 2HG leads to the competitive inhibition of αKG-dependent dioxygenases (αKGDs), such as KDMs, TETs, and EGLNs. This inhibition results in epigenetic alterations in both tumour cells and the tumour microenvironment. This review comprehensively discusses the metabolic pathways of 2HG and the subsequent pathways influenced by elevated 2HG levels. We will delve into the molecular mechanisms by which 2HG exerts its oncogenic effects, particularly focusing on epigenetic modifications. This review will also explore the various methods available for the detection of 2HG, emphasising both current techniques and emerging technologies. Furthermore, 2HG shows promise as a biomarker for clinical diagnosis and treatment. By integrating these perspectives, this review aims to provide a comprehensive overview of the current understanding of 2HG in cancer biology, highlight the importance of ongoing research, and discuss future directions for translating these findings into clinical applications.

越来越多的证据表明，2-羟基戊二酸（2HG）是一种促进肿瘤形成和发展的代谢产物。由于异柠檬酸脱氢酶（IDH）的突变和其他酶的失调，2HG在肿瘤细胞中大量积累。由于其结构与α-酮戊二酸（αKG）相似，累积的2HG会导致依赖αKG的二氧酶（αKGDs），如KDMs、TETs和EGLNs受到竞争性抑制。这种抑制会导致肿瘤细胞和肿瘤微环境发生表观遗传学改变。本综述将全面讨论 2HG 的代谢途径以及受 2HG 水平升高影响的后续途径。我们将深入探讨 2HG 发挥致癌作用的分子机制，尤其侧重于表观遗传修饰。本综述还将探讨可用于检测 2HG 的各种方法，重点关注现有技术和新兴技术。此外，2HG有望成为临床诊断和治疗的生物标记物。通过整合这些观点，本综述旨在全面概述目前对癌症生物学中 2HG 的理解，强调正在进行的研究的重要性，并讨论将这些发现转化为临床应用的未来方向。

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引用次数: 0

Tissue Kallikrein supplementation in ischemic phase protects the neurovascular unit and attenuates reperfusion-induced injury in ischemic stroke 缺血期补充组织 Kallikrein 可保护缺血性脑卒中的神经血管单元并减轻再灌注引起的损伤

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-28 DOI: 10.1016/j.phrs.2024.107435

Xiao Ran , Tingting Xu , Hang Ruan , Xiaochuan Wang , Qin Zhang

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

组织钙激酶（TK）已成为缺血性脑卒中（IS）的潜在神经保护剂，但 TK 治疗的最佳时机和机制仍不清楚。在此，我们通过一项回顾性多中心队列研究，确定了较低的基线 TK 水平与中风风险增加之间的因果关系，该研究对 2,115 名最初未中风的受试者进行了长达 5 年的监测。随后，我们观察到缓激肽受体 2（B2R）水平在 IS 模型的缺血阶段显著升高，而 TK 和缓激肽受体 1（B1R）水平保持稳定。耐人寻味的是，再灌注 24 小时后，B1R 和 B2R 都出现了显著升高。临床前模型的进一步研究表明，在缺血阶段，补充 TK 可通过增强 B2R 的表达激活 PI3K/AKT 信号通路，从而导致 Hif-1α 的核转位。这种激活会增强血管内皮生长因子和 eNOS 的表达，从而强化神经血管单元。此外，它还能抑制再灌注损伤诱导的激肽-激肽系统的激活，有效减少炎症、ROS 生成、细胞凋亡和内皮屏障功能障碍。因此，我们的研究结果强调了在缺血阶段补充 TK 对减轻 IS 再灌注诱导损伤的重要意义，为确定 TK 补充治疗的最佳时机提供了机理依据。

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引用次数: 0

Targeting the autoreactive CD8+ T-cell receptor in type 1 diabetes: Insights from scRNA-seq for immunotherapy 靶向 1 型糖尿病患者的自反应 CD8 T 细胞受体：scRNA-seq对免疫疗法的启示。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-27 DOI: 10.1016/j.phrs.2024.107433

Xiaoyang Lai , Junming Luo , Yue Luo , Yijing Zheng , Huan Yang , Fang Zou

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the attack and destruction of Pancreatic islet beta cells by T cells. Understanding the role of T-cell receptor (TCR) in the development of T1D is of paramount importance. This study employs single-cell RNA sequencing (scRNA-seq) to delve into the mechanistic actions and potential therapeutic applications of autoreactive stem cell-like CD8 TCR in T1D. By retrieving T-cell data from non-obese diabetic (NOD) mice via the GEO database, it was revealed that CD8⁺ T cells are the predominant T-cell subset in the pancreatic tissue of T1D mice, along with the identification of T-cell marker genes closely associated with T1D. Moreover, the gene TRAJ23 exhibits a preference for T1D, and its knockout alleviates T1D symptoms and adverse reactions in NOD mice. Additionally, engineered TCR-T cells demonstrate significant cytotoxicity towards β cells in T1D.

1 型糖尿病（T1D）是一种自身免疫性疾病，其特征是 T 细胞攻击和破坏胰岛β细胞。了解T细胞受体（TCR）在T1D发病中的作用至关重要。本研究利用单细胞RNA测序（scRNA-seq）深入研究T1D中自反应干细胞样CD8 TCR的机制作用和潜在治疗应用。通过 GEO 数据库检索非肥胖糖尿病（NOD）小鼠的 T 细胞数据，发现 CD8+ T 细胞是 T1D 小鼠胰腺组织中最主要的 T 细胞亚群，同时还发现了与 T1D 密切相关的 T 细胞标记基因。此外，TRAJ23 基因表现出对 T1D 的偏好，敲除该基因可减轻 NOD 小鼠的 T1D 症状和不良反应。此外，工程化 TCR-T 细胞对 T1D β 细胞具有显著的细胞毒性。

引用次数: 0

The therapeutic potential of bee venom-derived Apamin and Melittin conjugates in cancer treatment: A systematic review 蜂毒衍生的蜂毒素和麦利素共轭物在癌症治疗中的治疗潜力：系统综述

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-26 DOI: 10.1016/j.phrs.2024.107430

Lucas Fornari Laurindo , Enzo Pereira de Lima , Lívia Fornari Laurindo , Victória Dogani Rodrigues , Eduardo Federighi Baisi Chagas , Ricardo de Alvares Goulart , Adriano Cressoni Araújo , Elen Landgraf Guiguer , Karina Torres Pomini , Rose Eli Grassi Rici , Durvanei Augusto Maria , Rosa Direito , Sandra Maria Barbalho

The therapeutic potential of bee venom-derived peptides, particularly apamin and melittin, in cancer treatment has garnered significant attention as a promising avenue for advancing oncology. This systematic review examines preclinical studies highlighting the emerging role of these peptides in enhancing cancer therapies. Melittin and apamin, when conjugated with other therapeutic agents or formulated into novel delivery systems, have demonstrated improved efficacy in targeting tumor cells. Key findings indicate that melittin-based conjugates, such as polyethylene glycol (PEG)ylated versions, show potential in enhancing therapeutic outcomes and minimizing toxicity across various cancer models. Similarly, apamin-conjugated formulations have improved the efficacy of established anti-cancer drugs, contributing to enhanced targeting and reduced systemic toxicity. These developments underscore a growing interest in leveraging bee venom-derived peptides as adjuncts in cancer therapy. The integration of these peptides into treatment regimens offers a promising strategy to address current limitations in cancer treatment, such as drug resistance and off-target effects. However, comprehensive validation through clinical trials is essential to confirm their safety and effectiveness in human patients. This review highlights the global emergence of bee venom-derived peptides in cancer treatment, advocating for continued research and development to fully realize their therapeutic potential.

蜂毒衍生肽（尤其是蜂毒肽和麦利素）在癌症治疗中的治疗潜力已引起人们的极大关注，被认为是推动肿瘤学发展的一条大有可为的途径。这篇系统综述对临床前研究进行了探讨，强调了这些肽在增强癌症疗法中的新作用。麦饭石肽和阿帕明与其他治疗剂共轭或配制成新型给药系统后，在靶向肿瘤细胞方面的疗效有所提高。主要研究结果表明，基于麦利素的共轭物，如聚乙二醇（PEG）酰化版本，在各种癌症模型中显示出提高治疗效果和减少毒性的潜力。同样，阿帕明共轭制剂也提高了既有抗癌药物的疗效，有助于增强靶向性和降低全身毒性。这些发展凸显了人们对利用蜂毒衍生肽作为癌症治疗辅助药物的兴趣与日俱增。将这些肽纳入治疗方案为解决目前癌症治疗中的局限性（如耐药性和脱靶效应）提供了一种前景广阔的策略。然而，要确认其对人类患者的安全性和有效性，必须通过临床试验进行全面验证。本综述强调了蜂毒衍生肽在癌症治疗中的全球性应用，提倡继续研究和开发，以充分发挥其治疗潜力。

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引用次数: 0

The potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health 线粒体在微生物群-肠-脑轴中的潜在作用：对大脑健康的影响

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-25 DOI: 10.1016/j.phrs.2024.107434

Lei Qiao , Ge Yang , Peng Wang , Chunlan Xu

Mitochondria are crucial organelles that regulate cellular energy metabolism, calcium homeostasis, and oxidative stress responses, playing pivotal roles in brain development and neurodegeneration. Concurrently, the gut microbiota has emerged as a key modulator of brain physiology and pathology through the microbiota-gut-brain axis. Recent evidence suggests an intricate crosstalk between the gut microbiota and mitochondrial function, mediated by microbial metabolites that can influence mitochondrial activities in the brain. This review aims to provide a comprehensive overview of the emerging role of mitochondria as critical mediators in the microbiota-gut-brain axis, shaping brain health and neurological disease pathogenesis. We discuss how gut microbial metabolites such as short-chain fatty acids, secondary bile acids, tryptophan metabolites, and trimethylamine N-oxide can traverse the blood-brain barrier and modulate mitochondrial processes including energy production, calcium regulation, mitophagy, and oxidative stress in neurons and glial cells. Additionally, we proposed targeting the mitochondria through diet, prebiotics, probiotics, or microbial metabolites as a promising potential therapeutic approach to maintain brain health by optimizing mitochondrial fitness. Overall, further investigations into how the gut microbiota and its metabolites regulate mitochondrial bioenergetics, dynamics, and stress responses will provide valuable insights into the microbiota-gut-brain axis in both health and disease states.

线粒体是调节细胞能量代谢、钙平衡和氧化应激反应的重要细胞器，在大脑发育和神经退行性变中发挥着关键作用。与此同时，肠道微生物群通过微生物群-肠道-大脑轴成为大脑生理和病理的关键调节器。最近的证据表明，肠道微生物群与线粒体功能之间存在着错综复杂的串联关系，而微生物代谢产物可以影响大脑中线粒体的活动。本综述旨在全面概述线粒体在微生物群-肠道-大脑轴中作为关键介质的新作用，它影响着大脑健康和神经系统疾病的发病机制。我们讨论了短链脂肪酸、次级胆汁酸、色氨酸代谢物和三甲胺 N-氧化物等肠道微生物代谢物如何穿越血脑屏障并调节线粒体过程，包括神经元和神经胶质细胞的能量产生、钙调节、有丝分裂和氧化应激。此外，我们还建议通过饮食、益生元、益生菌或微生物代谢产物来靶向线粒体，这是一种很有前景的潜在治疗方法，可通过优化线粒体健康来维持大脑健康。总之，进一步研究肠道微生物群及其代谢物如何调节线粒体的生物能、动力学和应激反应，将对健康和疾病状态下的微生物群-肠道-大脑轴提供有价值的见解。

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引用次数: 0

Multitarget ligands that comprise opioid/nonopioid pharmacophores for pain management: Current state of the science 由阿片类/非阿片类药物组成的多靶点配体用于疼痛治疗：科学现状。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-21 DOI: 10.1016/j.phrs.2024.107408

Émile Breault , Michael Desgagné , Jolien De Neve , Jérôme Côté , Thomas M.A. Barlow , Steven Ballet , Philippe Sarret

Chronic pain, which affects more than one-third of the world’s population, represents one of the greatest medical challenges of the 21st century, yet its effective management remains sub-optimal. The ‘gold standard’ for the treatment of moderate to severe pain consists of opioid ligands, such as morphine and fentanyl, that target the µ-opioid receptor (MOP). Paradoxically, these opioids also cause serious side effects, including constipation, respiratory depression, tolerance, and addiction. In addition, the development of opioid-use disorders, such as opioid diversion, misuse, and abuse, has led to the current opioid crisis, with dramatic increases in addiction, overdoses, and ultimately deaths. As pain is a complex, multidimensional experience involving a variety of pathways and mediators, dual or multitarget ligands that can bind to more than one receptor and exert complementary analgesic effects, represent a promising avenue for pain relief. Indeed, unlike monomodal therapeutic approaches, the modulation of several endogenous nociceptive systems can often result in an additive or even synergistic effect, thereby improving the analgesic-to-side-effect ratio. Here, we provide a comprehensive overview of research efforts towards the development of dual- or multi-targeting opioid/nonopioid hybrid ligands for effective and safer pain management. We reflect on the underpinning discovery rationale by discussing the design, medicinal chemistry, and in vivo pharmacological effects of multitarget antinociceptive compounds.

慢性疼痛影响着全球三分之一以上的人口，是 21 世纪最大的医学挑战之一，但其有效治疗效果仍未达到最佳。治疗中度至重度疼痛的 "黄金标准 "是以μ-阿片受体（MOP）为靶点的阿片配体，如吗啡和芬太尼。矛盾的是，这些阿片类药物也会导致严重的副作用，包括便秘、呼吸抑制、耐受性和成瘾。此外，阿片类药物使用障碍的发展，如阿片类药物的转移、误用和滥用，导致了当前的阿片类药物危机，成瘾、用药过量和最终死亡人数急剧增加。由于疼痛是一种复杂、多维的体验，涉及多种途径和介质，因此能与一种以上受体结合并产生互补镇痛效果的双靶点或多靶点配体是一种很有前景的镇痛途径。事实上，与单模式治疗方法不同的是，对多个内源性痛觉系统的调节往往能产生叠加甚至协同效应，从而提高镇痛与副作用的比例。在此，我们将全面综述为开发阿片类/非阿片类双靶点或多靶点混合配体以实现更有效、更安全的疼痛治疗而开展的研究工作。通过讨论多靶点抗痛化合物的设计、药物化学和体内药理作用，我们反思了发现的基本原理。

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引用次数: 0

GPR40 agonist ameliorates neurodegeneration and motor impairment by regulating NLRP3 inflammasome in Parkinson’s disease animal models GPR40 激动剂通过调节帕金森病动物模型中的 NLRP3 炎症小体，改善神经退行性变和运动障碍。

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-21 DOI: 10.1016/j.phrs.2024.107432

Tae-Young Ha , Jae-Bong Kim , Yeji Kim , Sang Myun Park , Keun-A Chang

Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and accumulation of intracellular α-synuclein (ɑ-syn) aggregates known as Lewy bodies and Lewy neurites. Levels of polyunsaturated fatty acids (PUFAs) have previously been shown to be reduced in the SN of PD patients. G protein-coupled receptor 40 (GPR40) serves as a receptor for PUFAs, playing a role in neurodevelopment and neurogenesis. Additionally, GPR40 has been implicated in several neuropathological conditions, such as apoptosis and inflammation, suggesting its potential as a therapeutic target in PD.

In this study, we investigated the neuroprotective effects of the GPR40 agonist, TUG469 in PD models. Our results demonstrated that TUG469 reduces the neurotoxicity induced by 6-OHDA in SH-SY5Y cells. In 6-OHDA-induced PD model mice, TUG469 treatment improved motor impairment, preserved dopaminergic fibers and cell bodies in the striatum (ST) or SN, and attenuated 6-OHDA-induced microgliosis and astrogliosis in the brain. Furthermore, in a PD model involving the injection of mouse ɑ-syn fibrils into the brain (mPFFs-PD model), TUG469 treatment reduced the levels of pSer129 ɑ-syn, and decreased microgliosis and astrogliosis. Our investigation also revealed that TUG469 modulates inflammasome activation, apoptosis, and autophagy in the 6-OHDA-PD model, as evidenced by the results of RNA-seq and western blotting analyses.

In summary, our findings highlight the neuroprotective effects of GPR40 agonists on dopaminergic neurons and their potential as therapeutic agents for PD. These results underscore the importance of targeting GPR40 in PD treatment, particularly in mitigating neuroinflammation and preserving neuronal integrity.

帕金森病（PD）的特征是黑质（SN）中的多巴胺能神经元逐渐退化，细胞内α-突触核蛋白（ɑ-syn）聚集体堆积，称为路易体和路易神经元。先前已有研究表明，帕金森病患者SN中的多不饱和脂肪酸（PUFA）水平降低。G 蛋白偶联受体 40（GPR40）是多不饱和脂肪酸的受体，在神经发育和神经发生中发挥作用。此外，GPR40 还与凋亡和炎症等多种神经病理情况有关，这表明它有可能成为帕金森病的治疗靶点。在本研究中，我们研究了 GPR40 激动剂 TUG469 在帕金森病模型中的神经保护作用。结果表明，TUG469 可降低 6-OHDA 在 SH-SY5Y 细胞中诱导的神经毒性。在6-OHDA诱导的帕金森病模型小鼠中，TUG469治疗可改善运动障碍，保留纹状体（ST）或SN中的多巴胺能纤维和细胞体，并减轻6-OHDA诱导的脑内小胶质细胞和星形胶质细胞增生。此外，在向大脑注射小鼠ɑ-syn纤维的帕金森病模型（mPFFs-PD模型）中，TUG469治疗降低了pSer129 ɑ-syn的水平，并减少了小胶质细胞和星形胶质细胞的增生。我们的研究还发现，在6-OHDA-PD模型中，TUG469还能调节炎性体的激活、凋亡和自噬，这一点可以从RNA-seq和Western印迹分析的结果中得到证实。总之，我们的研究结果强调了 GPR40 激动剂对多巴胺能神经元的神经保护作用，以及它们作为治疗药物治疗帕金森病的潜力。这些结果强调了靶向 GPR40 在帕金森病治疗中的重要性，尤其是在减轻神经炎症和保护神经元完整性方面。

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引用次数: 0

Recent developments of topoisomerase inhibitors: Clinical trials, emerging indications, novel molecules and global sales 拓扑异构酶抑制剂的最新进展：临床试验、新兴适应症、新型分子和全球销售额

IF 9.1 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2024-09-20 DOI: 10.1016/j.phrs.2024.107431

Andrey D. Bondarev , Jörgen Jonsson , Vladimir N. Chubarev , Vadim V. Tarasov , Francisco Alejandro Lagunas-Rangel , Helgi B. Schiöth

The nucleic acid topoisomerases (TOP) are an evolutionary conserved mechanism to solve topological problems within DNA and RNA that have been historically well-established as a chemotherapeutic target. During investigation of trends within clinical trials, we have identified a very high number of clinical trials involving TOP inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 233 unique molecules with TOP-inhibiting activity. In this review, we provide an overview of the clinical drug development highlighting advances in current clinical uses and discussing novel drugs and indications under development. A wide range of bacterial infections, along with solid and hematologic neoplasms, represent the bulk of clinically approved indications. Negative ADR profile and drug resistance among the antibacterial TOP inhibitors and anthracycline-mediated cardiotoxicity in the antineoplastic TOP inhibitors are major points of concern, subject to continuous research efforts. Ongoing development continues to focus on bacterial infections and cancer; however, there is a degree of diversification in terms of novel drug classes and previously uncovered indications, such as glioblastoma multiforme or Clostridium difficile infections. Preclinical studies show potential in viral, protozoal, parasitic and fungal infections as well and suggest the emergence of a novel target, TOP IIIβ. We predict further growth and diversification of the field thanks to the large number of experimental TOP inhibitors emerging.

核酸拓扑异构酶（TOP）是一种解决 DNA 和 RNA 拓扑问题的进化保守机制，历来被公认为化疗靶点。在调查临床试验趋势的过程中，我们发现了大量涉及拓扑抑制剂的临床试验，这促使我们进一步评估这类治疗药物的现状。我们总共发现了 233 种具有 TOP 抑制活性的独特分子。在这篇综述中，我们概述了临床药物的开发情况，重点介绍了当前临床应用的进展，并讨论了正在开发的新型药物和适应症。各种细菌感染以及实体肿瘤和血液肿瘤占临床批准适应症的绝大部分。抗菌 TOP 抑制剂的不良 ADR 和耐药性，以及抗肿瘤 TOP 抑制剂中蒽环类药物介导的心脏毒性，都是值得关注的主要问题，需要不断进行研究。正在进行的开发工作仍然以细菌感染和癌症为重点；不过，在新药类别和以前未发现的适应症（如多形性胶质母细胞瘤或艰难梭菌感染）方面也有一定程度的多样化。临床前研究显示，TOP IIIβ 在病毒、原生动物、寄生虫和真菌感染方面也具有潜力，并表明新靶点的出现。我们预测，随着大量实验性 TOP 抑制剂的出现，该领域将进一步发展和多样化。

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引用次数: 0