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Bo Gao Xiang-yang Zhang Rong Han Tong-tong Zhang Cheng Chen Zheng-hong Qin Rui Sheng 《Acta pharmacologica Sinica》2013,34(5):657-666
Aim:
To investigate whether endoplasmic reticulum (ER) stress participates in the neuroprotective effects of ischemic preconditioning (IPC)-induced neuroprotection and autophagy activation in rat brains.Methods:
The right middle cerebral artery in SD rats was occluded for 10 min to induce focal cerebral IPC, and was occluded permanently 24 h later to induce permanent focal ischemia (PFI). ER stress inhibitor salubrinal (SAL) was injected via intracerebral ventricle infusion 10 min before the onset of IPC. Infarct volume and motor behavior deficits were examined after the ischemic insult. The protein levels of LC3, p62, HSP70, glucose-regulated protein 78 (GRP 78), p-eIF2α and caspase-12 in the ipsilateral cortex were analyzed using immunoblotting. LC3 expression pattern in the sections of ipsilateral cortex was observed with immunofluorescence.Results:
Pretreatment with SAL (150 pmol) abolished the neuroprotective effects of IPC, as evidenced by the significant increases in mortality, infarct volume and motor deficits after PFI. At the molecular levels, pretreatment with SAL (150 pmol) significantly increased p-eIF2α level, and decreased GRP78 level after PFI, suggesting that SAL effectively inhibited ER stress in the cortex. Furthermore, the pretreatment with SAL blocked the IPC-induced upregulation of LC3-II and downregulation of p62 in the cortex, thus inhibiting the activation of autophagy. Moreover,SAL blocked the upregulation of HSP70, but significantly increased the cleaved caspase-12 level, thus promoting ER stress-dependent apoptotic signaling in the cortex.Conclusion:
ER stress-induced autophagy might contribute to the neuroprotective effect of brain ischemic preconditioning. 相似文献2.
Context: Activation of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis. Quercetin has benefits for liver fibrosis, but the mechanisms are unknown.Objective: We investigated the quercetin effect on HSC survival and the role of endoplasmic reticulum stress (ERS).Materials and methods: Rat HSCs and LO2 hepatocytes were treated with quercetin (0.5–120?μM) for 24?h. Quercetin (10–40?μM) effects on apoptosis for 24?h were analyzed by flow cytometry and TUNEL staining. Quercetin (10–40?μM) effects on the expression of Bcl-2, caspase-9, caspase-3, PARP-1, PERK, IRE1, ATF6, calnexin and CHOP for 24?h were analyzed by Western blot. Quercetin (10–40?μM) effects on mRNA expression of calnexin and CHOP for 24?h were analyzed by Real-time PCR.Results: Quercetin at concentrations greater than 20?μM significantly inhibited HSC proliferation (IC50 27.2?μM), but did not affect hepatocyte growth until 80?μM (IC50 68.5?μM). Quercetin stimulated HSC apoptosis and the apoptotic rate reached 40% at a concentration of 40?μM (EC50 51.6?μM). Quercetin induced downregulation of Bcl-2 and upregulation of Bax, and increased cytochrome C in the cytoplasm in HSCs. The cleaved forms of caspase-9, caspase-3 and PARP-1 were also increased by quercetin. Furthermore, quercetin elevated mRNA and protein expression of calnexin and CHOP in HSCs but not in hepatocytes. Quercetin also increased phosphorylation of PERK and IRE1 and ATF6 cleavage. However, ERS inhibitor salubrinal significantly abrogated quercetin induction of HSC apoptosis.Conclusion: Quercetin activated ERS pathway in HSCs leading to apoptosis. We characterized an ERS-mediated mechanism for quercetin as a promising antifibrotic agent. 相似文献
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Salubrinal is a specific eIF2α phosphatase inhibitor that inhibits ER stress-mediated apoptosis. However, maintaining hyper-phosphorylated eIF2α state with high doses of salubrinal treatment promotes apoptosis in some cancer cells. In this report, we found that salubrinal induced apoptosis of EBV-transformed B cells. Notably, salubrinal induced ROS generation and p38 MPAK activation, which then induced expression of FasL. Moreover, salubrinal subsequently led to activation of caspases, calcium redistribution, Bax translocation, cytochrome c release, and apoptosis. These findings suggest that salubrinal may be a novel therapeutic approach for EBV-associated malignant diseases. 相似文献
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Lovastatin‐induced apoptosis is mediated by activating transcription factor 3 and enhanced in combination with salubrinal 下载免费PDF全文
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