Potential application of natural compounds in ischaemic stroke: Focusing on the mechanisms underlying “lysosomocentric” dysfunction of the autophagy-lysosomal pathway
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引用次数: 0
Abstract
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。
期刊介绍:
Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.