Nelson Vinod Kumar, Begum M Yasmin, Dera Ayed A, Ali Syed Parween, Suryadevara Punna Rao
Department of Pharmaceutical Chemistry, Mahathi College of Pharmacy, Madanapalle, Andhra Pradesh, India.
Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.
Eur J Pharmacol. 2025 Aug 5;1005:178034. doi: 10.1016/j.ejphar.2025.178034.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disease that affects millions of people every year globally. In addition to a drastic rise in AD cases, there is a significant increase in the death rate as well. According to the latest statistics, the death rate increased to 1.62 million in 2019 and is expected to rise further. The primary pathological hallmark of the disease is the accumulation of misfolded aggregates, such as amyloid beta (Aβ) plaques and tau neurofibrillary tangles, which induce toxic effects and initiate neuronal dysfunction, ultimately leading to disease symptoms, including cognitive impairment. Hence, targeting and eliminating these protein aggregates could significantly inhibit the disease pathogenesis. Previous studies have also suggested that the activation of heat shock factor 1 (HSF1) and the up-regulation of its encoded heat shock proteins (HSPs) can clear toxic aggregates by triggering proteostasis mechanisms, such as autophagy and the ubiquitin-proteasome system (UPS). However, in neurodegenerative diseases (NDs) like AD, the proteotoxic stress response (PSR) is defective and can't effectively remove harmful aggregates. In such conditions, the forced activation of HSF1 and its targeted molecular chaperone proteins, such as HSPs, by using various plant-derived compounds, such as celastrol, curcumin, and resveratrol, has shown promising neuroprotective effects by eliminating protein aggregates across multiple AD models. Hence, this review focused on various plant-derived compounds and their mode of activating HSF1 and its encoded HSPs. This review also described other compounds from multiple natural sources that affect HSF1 and HSPs in different disease models. In this way, the current review will be a complete reference for natural compounds that activate HSF1 and help researchers identify potential drug candidates for NDs like Alzheimer's disease.
阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病，每年在全球影响数百万人。除了AD病例急剧增加外，死亡率也显著上升。根据最新统计数据，2019年死亡率增至162万，且预计还会进一步上升。该疾病的主要病理标志是错误折叠聚集体的积累，如β-淀粉样蛋白（Aβ）斑块和tau神经原纤维缠结，这些聚集体会诱导毒性作用并引发神经元功能障碍，最终导致包括认知障碍在内的疾病症状。因此，靶向并消除这些蛋白质聚集体可显著抑制疾病发病机制。先前的研究还表明，热休克因子1（HSF1）的激活及其编码的热休克蛋白（HSPs）的上调可通过触发蛋白质稳态机制（如自噬和泛素-蛋白酶体系统（UPS））来清除毒性聚集体。然而，在像AD这样的神经退行性疾病（NDs）中，蛋白质毒性应激反应（PSR）存在缺陷，无法有效清除有害聚集体。在这种情况下，通过使用各种植物来源的化合物（如雷公藤红素、姜黄素和白藜芦醇）来强制激活HSF1及其靶向分子伴侣蛋白（如HSPs），已在多个AD模型中通过消除蛋白质聚集体显示出有前景的神经保护作用。因此，本综述聚焦于各种植物来源的化合物及其激活HSF1及其编码的HSPs的方式。本综述还描述了来自多种天然来源的其他化合物，它们在不同疾病模型中影响HSF1和HSPs。通过这种方式，当前综述将成为激活HSF1的天然化合物的完整参考资料，并帮助研究人员识别针对阿尔茨海默病等神经退行性疾病的潜在候选药物。
