Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent reports indicate that autophagy serves as a stress response and may participate in pathophysiology of cerebral ischemia. Nicotinamide phosphoribosyltransferase (Nampt, also known as visfatin), the rate-limiting enzyme in mammalian NAD (+) biosynthesis, protects against ischemic stroke through inhibiting neuronal apoptosis and necrosis. This study was taken to determine the involvement of autophagy in neuroprotection of Nampt in cerebral ischemia. Middle cerebral artery occlusion (MCAO) in rats and oxygen-glucose deprivation (OGD) in cultured cortical neurons were performed. Nampt was overexpressed or knocked-down using lentivirus-mediated gene transfer in vivo and in vitro. Immunochemistry (LC3-II), electron microscope and immunoblotting assays (LC3-II, beclin-1, mammalian target of rapamycin [mTOR], S6K1 and tuberous sclerosis complex-2 [TSC2]) were performed to assess autophagy. We found that overexpression of Nampt increased autophagy (LC3 puncta immunochemistry staining, LC3-II/beclin-1 expression and autophagosomes number) both in vivo and in vitro at 2 hours after MCAO. At the early stage of OGD, autophagy inducer rapamycin protected against neuronal injury induced by Nampt knockdown, whereas autophagy inhibitor 3-methyladenine abolished the neuroprotective effect of Nampt partly. Overexpression or knockdown of Nampt regulated the phosphorylation of mTOR and S6K1 signaling pathway upon OGD stress through enhancing phosphorylation of TSC2 at Ser1387 but not Thr1462 site. Furthermore, in cultured SIRT1-knockout neurons, the regulation of Nampt on autophagic proteins LC3-II and beclin-1 was abolished. Our results demonstrate that Nampt promotes neuronal survival through inducing autophagy via regulating TSC2-mTOR-S6K1 signaling pathway in a SIRT1-dependent manner during cerebral ischemia.
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PMID:Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. 3201 95

Catalpol and puerarin are two monomers of Rehmannia glutinosa and Lobed Kudzuvine Root, which are two herbs commonly used together in ancient prescriptions of traditional Chinese medicine for cerebral ischemia. Our previous study shows that the lyophilized powder of the two monomers improved the outcome of cerebral ischemia excellently in rodents. However, if it protects vessels from ischemia is unknown. The present research studied the protection of lyophilized powder of catalpol and puerarin (CP) on endothelial cells and the relative mechanism in vivo and in vitro. Middle cerebral artery occlusion (MCAO) rats were used to study the improvement of CP on neurological deficiency, regional cerebral blood flow (rCBF), and infarct volume. The morphology of vessels and the apoptosis of brain vascular endothelial cells (BVECs) were observed and detected by immunohistochemistry approaches. To study how CP protected primary BVECs (pBVECs) from ischemic penumbra, oxygen glucose deprivation (OGD)-damaged pBVECs were cultured in the condition of insufficient nutrition and low oxygen which recapitulate the low perfusion of ischemic penumbra. Using the cell model, the mechanism by which CP protected pBVECs was studied by shRNA and pathway inhibitors. CP at the dose of 65.4 mg/kg increased regional cerebral blood flow (rCBF), reduced infarct volume, protected vessel integrity and inhibited endothelial cell apoptosis in vivo. But it only improved rCBF, vessel integrity and BVECs apoptosis at the dose of 32.7 mg/kg. In vitro, the protection of CP on pBVECs was proved to be ERK/HIF-1a- and PI3K/AKT/mTOR/HIF-1a-dependent. This study indicates a possibility of CP being a new drug for cerebral ischemia. Besides, this research provides an alternative cell model for penumbra ECs study.
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PMID:Lyophilized Powder of Catalpol and Puerarin Protected Cerebral Vessels from Ischemia by Its Anti-apoptosis on Endothelial Cells. 2836 97

Background: Ischemic cerebral infarction is a severe clinical condition that can cause serious mortality. Artesunate, an anti-malarial drug that is widely used in cancer treatment, is known to facilitate accelerated cell apoptosis. The aim of this study is to explore the possible neuroprotective effects of artesunate on hypoxic-ischemic cells in rats. Methods: Middle cerebral artery occlusion (MCAO) rats were treated with artesunate in different doses to observe their survival rate. Primary hippocampal neurons were deprived of oxygen-glucose to induce ischemia symptoms. Western blot was performed to determine the protein expressions of p-mTOR, Beclin-1, and Mcl-1. A five-point scale was used to detect neurological deficit. Cell apoptosis was measured using a TUNEL assay. Results: Artesunate supplementation protected MCAO rats from death and ameliorated brain injury among them. Artesunate administration decreased the expression of p-mTOR, increased the expressions of Beclin-1 and Mcl-1, and decreased the activity of caspase-3 in both the rats' ischemia cerebral cortices and their primary ischemia hippocampal neurons when compared with artesunate-absent ischemic brains and cells. The neuroprotective effects of artesunate were abolished by either leucine (LEU) or 3-MA, while the effects of rapamycin were reversed by 3-MA. In vivo experiments verified the protective effects of artesunate on brain-infarct rats. Conclusion: The results indicate the protectiveness of artesunate against ischemic cerebral infarction, whereas the protectiveness might increase autophagy through regulating the activity of mTOR.
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PMID:Protectiveness of Artesunate Given Prior Ischemic Cerebral Infarction Is Mediated by Increased Autophagy. 3017 40