Background
SC 79 is an activator of osmotic Akt phosphorylation in the brain and an inhibitor of AKT-PH domain translocation[1].
SC 79 enhances phosphorylation of all three Akt isotypes and enhances Akt activation in a variety of cell types[1]. Treatment of BRAT1 knockdown cells with Akt activator SC 79 can improve their proliferation and reduces mitochondrial ROS concentration[4]. In both SH-SY5Y cells and primary murine dopaminergic neurons, pre-treatment with SC 79 largely inhibited hydrogen peroxide (H2O2)-induced cell viability reduction, apoptosis and necrosis. SC 79 activated Akt in the neuronal cells, which was required for its neuroprotection against H2O2[5]. In primary murine osteoblasts and osteoblastic MC3T3-E1 cells, pretreatment with SC 79 significantly attenuated Dex-induced cell death. Further, Dex-induced mitochondrial permeability transition pore (mPTP) opening, cytochrome C release and apoptosis activation were dramatically alleviated with SC 79 pretreatment in above cells[6]. The protective role of SC 79 against H/R of hepatocytes or hepatic I/R injury is related to activation of phosphorylation of Akt, resulting in the decrease of pro-apoptotic protein of Bim, Bax, and Bad, and increase of the anti-apoptotic protein Bcl-2 and Bcl-xL induced by cell H/R and hepatic I/R injury[7].
SC 79 enhances Akt activity during neuronal cell death in an in vivo mouse model of ischemia, SC 79 attenuates stroke-induced neuron death[1]. SC 79 protects hepatocytes from apoptosis induced by agonistic anti-Fas antibody CH11 (for humans) or Jo2 (for mice) and significantly prolongs the survival of mice given a lethal dose of Jo2[2]. Akt activator SC 79 protects hepatocytes from TNF-α-induced apoptosis and protects mice from d-galactosamine (d-Gal)/lipopolysaccharide (LPS)-induced TNF-α-mediated liver injury and damage. SC 79 not only enhances the nuclear factor-κB (NF-κB) prosurvival signaling in response to TNF-α stimulation, but also increases the expression of cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein L and S (FLIPL/S), which consequently inhibits the activation of procaspase-8[2].
参考文献:
[1]: Jo H, Mondal S, et,al. Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10581-6. doi: 10.1073/pnas.1202810109. Epub 2012 Jun 11. PMID: 22689977; PMCID: PMC3387065.
[2]: Liu W, Jing ZT, et,al. A Novel AKT Activator, SC79, Prevents Acute Hepatic Failure Induced by Fas-Mediated Apoptosis of Hepatocytes. Am J Pathol. 2018 May;188(5):1171-1182. doi: 10.1016/j.ajpath.2018.01.013. PMID: 29673487.
[3]: Jing ZT, Liu W, et,al. AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury. Am J Physiol Gastrointest Liver Physiol. 2019 Mar 1;316(3):G387-G396. doi: 10.1152/ajpgi.00350.2018. Epub 2019 Jan 10. PMID: 30629471.
[4]: So EY, Ouchi T. BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction. BMC Cancer. 2014 Jul 29;14:548. doi: 10.1186/1471-2407-14-548. PMID: 25070371; PMCID: PMC4129107.
[5]: Xu Y, Gao YW, et,al. SC79 protects dopaminergic neurons from oxidative stress. Oncotarget. 2017 Dec 20;9(16):12639-12648. doi: 10.18632/oncotarget.23538. PMID: 29560097; PMCID: PMC5849161.
[6]: Li ST, Chen NN, et,al. SC79 rescues osteoblasts from dexamethasone though activating Akt-Nrf2 signaling. Biochem Biophys Res Commun. 2016 Oct 7;479(1):54-60. doi: 10.1016/j.bbrc.2016.09.027. Epub 2016 Sep 7. PMID: 27614310.
[7]: Zhou H, Yu Y,et,al. Protective Effects the Akt Activator SC79 in Hepatic Ischemia-Reperfusion Injury. Med Sci Monit. 2018 Jun 24;24:4346-4354. doi: 10.12659/MSM.911178. PMID: 29936516; PMCID: PMC6049012.
SC 79 是大脑中渗透性 Akt 磷酸化的激活剂和 AKT-PH 结构域易位的抑制剂[1]。
SC 79 增强所有三种 Akt 的磷酸化同种型并增强多种细胞类型中的 Akt 活化[1]。用 Akt 激活剂 SC 79 处理 BRAT1 敲低细胞可以改善它们的增殖并降低线粒体 ROS 浓度 [4]。在 SH-SY5Y 细胞和原代小鼠多巴胺能神经元中，用 SC 79 预处理在很大程度上抑制了过氧化氢 (H2O2) 诱导的细胞活力降低、细胞凋亡和坏死。 SC 79 激活神经元细胞中的 Akt，这是其针对 H2O2 的神经保护作用所必需的 [5]。在原代小鼠成骨细胞和成骨细胞 MC3T3-E1 细胞中，用 SC 79 预处理显着减弱了 Dex 诱导的细胞死亡。此外，SC 79 预处理上述细胞后，Dex 诱导的线粒体通透性转换孔 (mPTP) 打开、细胞色素 C 释放和细胞凋亡激活得到显着缓解 [6]。 SC 79 对肝细胞 H/R 或肝 I/R 损伤的保护作用与激活 Akt 磷酸化有关，导致 Bim、Bax 和 Bad 促凋亡蛋白减少，抗细胞 H/R 和肝 I/R 损伤诱导的凋亡蛋白 Bcl-2 和 Bcl-xL[7]。
SC 79 在体内小鼠缺血模型中增强神经元细胞死亡期间的 Akt 活性， SC 79 可减轻中风引起的神经元死亡[1]。 SC 79 可保护肝细胞免受激动性抗 Fas 抗体 CH11（用于人类）或 Jo2（用于小鼠）诱导的细胞凋亡，并在给予致死剂量的 Jo2[2] 后显着延长小鼠的存活期。 Akt 激活剂 SC 79 保护肝细胞免受 TNF-α 诱导的细胞凋亡，并保护小鼠免受 d-半乳糖胺 (d-Gal)/脂多糖 (LPS) 诱导的 TNF-α 介导的肝损伤和损伤。 SC 79 不仅增强核因子-κ；B (NF-κ；B) 响应 TNF-α 的促存活信号；刺激，但也会增加细胞 FLICE（FADD 样 IL-1β；-转化酶）-抑制蛋白 L 和 S (FLIPL/S) 的表达，从而抑制 procaspase-8 的激活[2].
Protocol
| Kinase experiment [1]: |
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Preparation Method
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Hela cells were serum-starved for 1 h, treated with IGF or SC 79 (4 μg/mL) for 30 min, lysed in lysis buffer, supplemented with protease inhibitors, and analyzed for phospho-Akt by Western blotting
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Reaction Conditions
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SC 79 (4 μg/mL) for 30 min
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Applications
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SC 79, which inhibits PH AkT-GFP plasma membrane translocation but enhances Akt phosphorylation and activation in the cytosols
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| Cell experiment [2]: |
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Cell lines
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HsSultan and NB4 cells
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Preparation Method
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SC 79(8 ug/mL) was added to HsSultan or NB4 cell medium and incubated overnight (16-20 h).
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Reaction Conditions
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8 ug/mL SC 79 for 16-20 h
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Applications
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SC 79 enhances phosphorylation of all three Akt isotypes and enhances Akt activation in a variety of cell types.
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| Animal experiment [3]: |
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Animal models
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MCAO mice
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Preparation Method
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SC 79 was administered by intraperitoneal injection at a concentration of 0.04mg/g body weight.
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Dosage form
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0.04mg/g SC 79
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Applications
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SC 79 enhances Akt activity during neuronal cell death in an in vivo mouse model of ischemia, SC 79 attenuates stroke-induced neuron death.
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参考文献:
[1]. Jo H, Mondal S, et,al. Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10581-6. doi: 10.1073/pnas.1202810109. Epub 2012 Jun 11. PMID: 22689977; PMCID: PMC3387065.
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