SRT2104 (GSK2245840) is a highly selective small-molecule activator of Sirtuin 1 (SIRT1), penetrated the blood-brain barrier, attenuated brain atrophy, improved motor function, and protected against diabetes-induced aortic endothelial dysfunction [1,2].
Treatment with SRT2104 (3μM, 48h) decreased P53 and Ac-P53 protein levels, but not P53 mRNA in HG-treated endothelial cells (ECs) [2]. Treatment with SRT2104 also (3μM, 48h) increased SIRT1 in protein level [2]. SRT2104 (10 μM, 24 h) significantly increased cell counts of KGN (an established cellular model for the majority of granulosa cell tumors (GCTs) and were used to explore the role of SIRT1), and SRT2104 significantly increased SIRT1 deacetylation activity [3].
SRT2104 (fed 0.5% with diet) improved motor function, increased survival, and attenuated brain atrophy in N171-82Q Huntington's disease (HD) mice [1]. SRT2104 (100 mg kg-1) treatment improves whole-body physiology and extends lifespan in mice fed a standard diet [4]. SRT2104-treated mice significantly reduced fasting blood glucose and insulin levels, and insulin resistance index [4]. SRT2104 (100 mg kg-1) treatment increases mitochondrial content and suppresses the inflammatory response [4]. SRT2104 alleviated muscle loss in hindlimb-unloading model in mice, and involutional and disuse-mediated osteoporosis [4]. SRT2104 improved diabetic nephropathy. SRT2104 (100 mg kg-1) protected diabetes mellitus (DM)-induced albuminuria and renal pathological injuries, and the was protective effect abrogated by P53 [5].
参考文献:
[1]. Jiang M, Zheng J, Peng Q, Hou Z, Zhang J, Mori S, Ellis JL, Vlasuk GP, Fries H, Suri V, Duan W. Sirtuin 1 activator SRT 2104 protects Huntington's disease mice. Annals of clinical and translational neurology. 2014 Dec;1(12):1047-52.
[2]. Wu H, Wu J, Zhou S, Huang W, Li Y, Zhang H, Wang J, Jia Y. SRT2104 attenuates diabetes-induced aortic endothelial dysfunction via inhibition of P53. Journal of Endocrinology. 2018 Apr 1;237(1):1-4.
[3]. Schmid N, Dietrich KG, Forne I, Burges A, Szymanska M, Meidan R, Mayr D, Mayerhofer A. Sirtuin 1 and Sirtuin 3 in granulosa cell tumors. International Journal of Molecular Sciences. 2021 Feb 19;22(4):2047.
[4]. Mercken EM, Mitchell SJ, Martin?\Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye?\Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG. SRT 2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging cell. 2014 Oct;13(5):787-96.
[5]. Ma F, Wu J, Jiang Z, Huang W, Jia Y, Sun W, Wu H. P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2019 Aug 1;1866(8):1272-81.
SRT2104 (GSK2245840) 是 Sirtuin 1 (SIRT1) 的高选择性小分子激活剂，可穿透血脑屏障，减轻脑萎缩，改善运动功能，并防止糖尿病引起的主动脉内皮功能障碍 [1,2 ].
用 SRT2104（3µ；M，48 小时）处理可降低 HG 处理的内皮细胞 (EC) 中的 P53 和 Ac-P53 蛋白水平，但不会降低 P53 mRNA [2]。 SRT2104 治疗 (3μM, 48h) 也增加了 SIRT1 的蛋白质水平[2]。 SRT2104 (10 μM, 24 h) 显着增加 KGN 的细胞计数（大多数颗粒细胞瘤 (GCT) 的已建立细胞模型，用于探索 SIRT1 的作用），SRT2104 显着增加 SIRT1 去乙酰化活性[3]。
SRT2104（0.5% 的饮食喂养）改善了 N171-82Q 亨廷顿病 (HD) 小鼠 [1] 的运动功能，增加了存活率，并减轻了脑萎缩。 SRT2104 (100 mg kg-1) 治疗改善了喂食标准饮食的小鼠的全身生理并延长了寿命[4]。 SRT2104 处理的小鼠显着降低了空腹血糖和胰岛素水平，以及胰岛素抵抗指数[4]。 SRT2104 (100 mg kg-1) 处理可增加线粒体含量并抑制炎症反应[4]。 SRT2104 减轻了小鼠后肢卸载模型中的肌肉损失，以及退化和废用介导的骨质疏松症[4]。 SRT2104 改善了糖尿病肾病。 SRT2104 (100 mg kg-1) 保护糖尿病 (DM) 引起的白蛋白尿和肾脏病理损伤，且保护作用被 P53[5] 消除。
| Cell experiment [1]: | |
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Cell lines |
KGN, a human ovarian granulosa-like tumor cell line, derived from a granulosa cell tumors (GCT) patient |
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Preparation Method |
The cells were seeded on cell culture dishes (5 × 105) and treated with EX 527 (50 μM) or SRT2104 (10 μM) for 24 h. Then, the cells were harvested and used for the SIRT Activity Assay Kit. |
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Reaction Conditions |
10 μM, for 24 h |
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Applications |
SRT2104 (GSK2245840) significantly increased SIRT1 deacetylation activity. |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6J mice |
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Preparation Method |
For the longevity study, diets were started at 28 weeks of age after randomization into two groups of 100 mice per group. Mice were fed a standard AIN-93G diet (SD; carbohydrate:protein:fat ratio of 64:19:17 percent of kcal), or a SD supplemented with SRT2104. SRT2104 was added at a dose of 1.33 g drug per kg of chow, formulated to provide daily doses of ~ 100 mg drug kg-1 bodyweight. |
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Dosage form |
100 mg kg-1 |
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Applications |
SRT2104 supplementation resulted in improved survival of SD-fed mice with an increase in mean lifespan of 9.7% and in maximum lifespan (defined as the 10th percentile) of 4.9%. |
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参考文献: [1]: Schmid N, Dietrich KG, Forne I, Burges A, Szymanska M, Meidan R, Mayr D, Mayerhofer A. Sirtuin 1 and Sirtuin 3 in granulosa cell tumors. International Journal of Molecular Sciences. 2021 Feb 19;22(4):2047. | |
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