The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, No. 818 East Tianyuan Rd., Nanjing 211166, China.
Department of Nutrition, The Affiliated Suzhou Hospital of Nanjing Medical University, No. 16 West Baita Rd., Suzhou 215000, China.
Oxid Med Cell Longev. 2021 Jun 21;2021:6673343. doi: 10.1155/2021/6673343. eCollection 2021.
The oxysterol 27-hydroxycholesterol (27HC) is the first identified endogenous selective estrogen receptor modulator (SERM), which like endogenous estrogen 17-estradiol (E) induces the proliferation of estrogen receptor- (ER-) positive breast cancer cells . However, 27HC differs from E in that it shows adverse effects in the nervous system. Our previous study confirmed that 27HC could induce neural senescence by activating phosphorylated signal transducer and activator of transcription, which E could not. The purpose of the present study is to investigate whether STAT3 acetylation was involved in 27HC-induced neural senescence. Microglia (BV2 cells) and rat pheochromocytoma cells (PC12 cells) were used to explore the effect of resveratrol (REV) on 27HC-induced neural senescence. Senescence-associated -galactosidase (SA--Gal) staining was performed using an SA--Gal Staining Kit in cells and zebrafish larvae. Zebrafish were used to assess the effect of 27HC on locomotor behavior and aging. We found that 27HC could induce senescence in neural cells, and REV, which has been employed as a Sirtuin-1 (SIRT1) agonist, could attenuate 27HC-induced senescence by inhibiting STAT3 signaling via SIRT1. Moreover, in the zebrafish model, REV attenuated 27HC-induced locomotor behavior disorder and aging in the spinal cord of zebrafish larvae, which was also associated with the activation of SIRT1-mediated STAT3 signaling. Our findings unveiled a novel mechanism by which REV alleviates 27HC-induced senescence in neural cells and affects zebrafish locomotor behavior by activating SIRT1-mediated STAT3 signaling.
胆甾烷 27-羟胆固醇（27HC）是第一个被鉴定的内源性选择性雌激素受体调节剂（SERM），它与内源性雌激素 17-β-雌二醇（E）一样，诱导雌激素受体阳性（ER+）乳腺癌细胞增殖。然而，27HC 与 E 不同，它在神经系统中表现出不良反应。我们之前的研究证实，27HC 通过激活磷酸化信号转导和转录激活物（STAT3）诱导神经衰老，而 E 则不能。本研究旨在探讨 STAT3 乙酰化是否参与 27HC 诱导的神经衰老。使用小胶质细胞（BV2 细胞）和大鼠嗜铬细胞瘤细胞（PC12 细胞）来研究白藜芦醇（REV）对 27HC 诱导的神经衰老的影响。使用衰老相关-β-半乳糖苷酶（SA-β-Gal）染色试剂盒在细胞和斑马鱼幼虫中进行 SA-β-Gal 染色。使用斑马鱼评估 27HC 对运动行为和衰老的影响。我们发现 27HC 可诱导神经细胞衰老，而白藜芦醇（REV）作为 Sirtuin-1（SIRT1）激动剂，可通过 SIRT1 抑制 STAT3 信号通路来减轻 27HC 诱导的衰老。此外，在斑马鱼模型中，REV 减轻了 27HC 诱导的斑马鱼幼虫脊髓运动行为障碍和衰老，这也与 SIRT1 介导的 STAT3 信号通路的激活有关。我们的研究结果揭示了一种新的机制，即 REV 通过激活 SIRT1 介导的 STAT3 信号通路来减轻 27HC 诱导的神经细胞衰老，并影响斑马鱼的运动行为。
