A SIRT3 inhibitor
3-TYP inhibit SIRT3 with an IC50 of 16 nM, and is more potent over SIRT1 and SIRT2 with IC50 of 88 nM and 92 nM, respectively.[1]
In vitro, with 50 μM 3-TYP abrogated the barrier protective effect of PD in multiple organs of septic mice. In HUVECs, 3-TYP (50 μM) diminished PD-mediated protection against F-actin redistribution, cadherin–catenin complex dissociation, and endothelial monolayer hyperpermeability.[3] In vitro study it demonstrated that at 100 μM, 3-TYP decreased expression of genes involved in lipolysis and glucose transport GLUT4 compared to HNK. At the meantime, 3-TYP also caused an increase in gene expression of adipocyte-specific cytokines, including IL6, resistin, and TNF-α. In vitro, treatment with 100 μM 3-TYP obviously inhibited glucose uptake in 3T3-L1 adipocytes in contrast to control in the presence of insulin.[5] In A/R-treated H9c2 cells, 4-P-PDOT (10 μM) and 3-TYP (5 μM) treatment resulted in no notable difference in cell viability. In addition, combination wiith 4-P-PDOT and 3-TYP elevated apoptotic signaling by increasing cleaved caspase-3 and Bax expression while decreasing Bcl-2 expression compared with that in the A/R + Mel group.[6]
In vivo experiment it suggested that treatment with 50 mgkg intraperitoneally 3-TYP reversed the induction of mitophagy by decreasing the expression levels of FOXO3α, BINP3, LC3-II/LC3-I, SOD2, PRDX3, and P62.[2] In vivo efficacy test it indicated that C57BL/6 mice were administrated 50 mg/kg 3-TYP abolished TBM's antioxidative effects.[4]
参考文献:
[1].Pi H, et al. SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin. Autophagy. 2015;11(7):1037-51.
[2].Yu W, et al. Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats. Oxid Med Cell Longev. 2020 Nov 20;2020:7385458.
[3].Wu J, et al. Polydatin protects against lipopolysaccharide-induced endothelial barrier disruption via SIRT3 activation. Lab Invest. 2020 Apr;100(4):643-656.
[4].Lv D, et al. Tubeimoside I Ameliorates Myocardial Ischemia-Reperfusion Injury through SIRT3-Dependent Regulation of Oxidative Stress and Apoptosis. Oxid Med Cell Longev. 2021 Nov 9;2021:5577019.
[5]. Lee AY, et al. Sirt3 Pharmacologically Promotes Insulin Sensitivity through PI3/AKT/mTOR and Their Downstream Pathway in Adipocytes. Int J Mol Sci. 2022 Mar 29;23(7):3740.
[6].Wu J, et al. Melatonin Attenuates Anoxia/Reoxygenation Injury by Inhibiting Excessive Mitophagy Through the MT2/SIRT3/FoxO3a Signaling Pathway in H9c2 Cells. Drug Des Devel Ther. 2020 May 25;14:2047-2060.
3-TYP 抑制 SIRT3，IC50 为 16 nM，比 SIRT1 和 SIRT2 更有效，IC50 分别为 88 nM 和 92 nM。[1]
在体外，50 μM 3-TYP 消除了 PD 在脓毒症小鼠多个器官中的屏障保护作用。在 HUVEC 中，3-TYP (50 μM) 降低了 PD 介导的针对肌动蛋白再分布、钙粘蛋白-连环蛋白复合物解离和内皮单层高渗透性的保护作用。[3] 体外研究表明，在 100与 HNK 相比，μM、3-TYP 降低了参与脂肪分解和葡萄糖转运 GLUT4 的基因的表达。同时，3-TYP 还引起脂肪细胞特异性细胞因子的基因表达增加，包括 IL6、抵抗素和 TNF-α。在体外，与胰岛素存在的对照相比，100 μM 3-TYP 处理明显抑制 3T3-L1 脂肪细胞的葡萄糖摄取。[5] 在 A/R 处理的 H9c2 细胞中，4- P-PDOT (10 μM) 和 3-TYP (5 μM) 处理导致细胞活力没有显着差异。此外，与 A/R + Mel 组相比，4-P-PDOT 和 3-TYP 的组合通过增加裂解的 caspase-3 和 Bax 表达同时降低 Bcl-2 表达来提高细胞凋亡信号。[6]
体内实验表明，腹膜内注射 50 mg/kg 3-TYP 通过降低 FOXO3α、BINP3、LC3-II/LC3-I、SOD2、PRDX3 和 P62 的表达水平来逆转线粒体自噬的诱导。 [2] 体内药效试验表明，C57BL/6 小鼠给予 50 mg/kg 3-TYP 可消除 TBM 的抗氧化作用。[4]
| Cell experiment [1]: | |
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Cell lines |
HepG2 cells |
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Preparation Method |
HepG2 cells were pretreated with 3-TYP (50 μM) or the vehicle for 1 h, followed by the treatment with DHM (20 μM) for 2 h and 0.2 mM of PA for 16 h. |
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Reaction Conditions |
50 μM, 16h |
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Applications |
DHM treatment attenuates PA-induced autophagy arrest and oxidative stress in hepatocytes, which was mediated via SIRT3. |
| Animal experiment [2]: | |
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Animal models |
C57BL/6?J male mice |
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Preparation Method |
Both 3-TYP and 2-methoxyestradiol were administered by intraperitoneal injection starting 1 week prior to NE for 7 days 3-TYP was administered at 50 mg/kg/day, and 2-ME was administered at 16 mg/kg/day. |
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Dosage form |
50 mg/kg/day,i.p. |
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Applications |
3-TYP exacerbates noise-induced hair cell damage; 3-TYP increases the acetylation level of SOD2 and aggravates oxidative stress and apoptosis. |
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参考文献: [1]. Huang L, et al. Dihydromyricetin attenuates palmitic acid-induced oxidative stress by promoting autophagy via SIRT3-ATG4B signaling in hepatocytes. Nutr Metab (Lond). 2021 Sep 9;18(1):83. [2].Liang W, et al. Sirtuin-3 Protects Cochlear Hair Cells Against Noise-Induced Damage?via?the Superoxide Dismutase 2/Reactive Oxygen Species Signaling Pathway. Front Cell Dev Biol. 2021 Nov 18;9:766512. |
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