■大量证据表明卵巢氧化应激可导致严重的卵巢功能障碍。
■本文的目的是研究SIRT6通过抑制氧化应激缓解卵巢早衰(POF)的潜力。
■要模仿POF,小鼠每天皮下注射d-半乳糖。E2,FSH,LH,AMH,测定血清中的孕酮,随着卵泡和SIRT6水平的变化。小鼠用SIRT6激动剂MDL-800,SIRT6水平,卵泡,和上述激素被重新评估。随后鉴定了MDL-800对氧化应激和细胞凋亡的影响。原代颗粒细胞从小鼠中分离,以及H2O2和MDL-800对细胞活力的影响,氧化应激,SIRT6级,和细胞凋亡进行评估。此外,SIRT6对H3K9AC/p66SHC的调节通过检测蛋白质水平的变化来验证,启动子活性,和p66SHC过表达的逆转效应。
■MDL-800缓解了激素波动,减少卵巢组织中的卵泡消耗,并减轻小鼠的氧化应激和凋亡。体外实验表明,MDL-800增强了原代颗粒细胞对H2O2的抵抗力,这可以通过增加细胞活力,减少氧化应激和凋亡来证明。此外,SIRT6被发现降低H3K9AC和p66SHC水平,以及减弱p66SHC启动子的活性。p66SHC过表达后,MDL-800对细胞的保护作用被逆转。
■总之,这项研究强调了SIRT6的激活可以通过降解H3K9AC和抑制颗粒细胞中的p66Shc水平来减轻POF和减少氧化应激。
UNASSIGNED: Substantial evidence suggests that ovarian oxidative stress can result in severe ovarian dysfunction.
UNASSIGNED: The purpose of this article is to investigate the potential of SIRT6 in alleviating premature ovarian failure (POF) by inhibiting oxidative stress.
UNASSIGNED: To mimic POF, mice were administered daily subcutaneous injections of d-galactose. The levels of E2, FSH, LH, AMH, and progesterone in serum were measured, along with changes in follicles and SIRT6 levels. Mice were treated with the SIRT6 agonist MDL-800, SIRT6 levels, follicles, and aforementioned hormones were reassessed. The effects of MDL-800 on oxidative stress and apoptosis were subsequently identified. Primary granulosa cells were isolated from mice, and the effects of H2O2 and MDL-800 on cell viability, oxidative stress, SIRT6 level, and apoptosis were evaluated. In addition, the regulation of SIRT6 on H3K9AC/
p66SHC was verified by examining changes in protein levels, promoter activity, and the reversal effects of
p66SHC overexpression.
UNASSIGNED: MDL-800 mitigated hormone fluctuations, reduced follicle depletion in ovarian tissue, and attenuated oxidative stress and apoptosis in mice. In vitro experiments demonstrated that MDL-800 enhanced the resilience of primary granulosa cells against H2O2, as evidenced by increased cell viability and reduced oxidative stress and apoptosis. Furthermore, SIRT6 was found to decrease H3K9AC and
p66SHC levels, as well as attenuate
p66SHC promoter activity. The protective effects of MDL-800 on cells were reversed upon
p66SHC overexpression.
UNASSIGNED: In summary, this study highlights that activation of SIRT6 can alleviate POF and reduce oxidative stress by degrading H3K9AC and suppressing
p66Shc levels in granulosa cells.