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黎明涛, by Wenya Wang, Chi Ms, Zixa Mao and Mingtao Li
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-1年11月30日
Parkinson's disease is characterized by the pathologicalloss of dopaminergic neurons in the substantia nigra. The current therapy for Parkinson's disease is aimed to replace the lost transmitter. But the ultimate objective in the neurodegenerative therapy is the functional restoration and/or cessation of progression of neuronal loss. Given the critical role that the c-Jun N-terminal kinase (JNK) pathway plays in regulating the cellular processes that are involved in Parkinson's disease, the importance of JNK in this disease's pathogenesis is being increasingly recognized. Much evidence suggests that JNK plays an important role in mediating 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridnium ion (MPP+)-induced neurotoxicity. Therefore, direct blockade of JNK may prevent or effectively slow the progression of Parkinson's disease. Studies including our own showed that the inhibition of JNK with SP-600125, a specific inhibitor of JNK, protects dopaminergic neurous both from MPP+-induced neuronal apoptosis in vitroand in MPTP Parkinson's disease model. These results support JNK inhibition as a potential strategy in treating Parkinson's disease.
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黎明涛, Rongbiao Pi, *, †, , Wenming Li, Nelson T. K. Lee, Hugh H. N. Chan, Yongmei Pu, Ling Nga Chan, ‡, Nikolaus J. Sucher, Donald C. Chang, Mingtao Li§ and Yifan Han*
Journal of Neurochemistry, 2004, 91, 1219~1230,-0001,():
-1年11月30日
Minocycline has been shown to have remarkably neuroprotective qualities, but underlying mechanisms remain elusive. We reported here the robust neuroprotection by minocycline against glutamate-induced apoptosis through regulations of p38 and Akt pathways. Pre-treatment of cerebellar granule neurons (CGNs) with minocycline (10–100 lM) elicited a dose-dependent reduction of glutamate excitotoxicity and blocked glutamate-induced nuclear condensation and DNA fragmentations. Using patch-clamping and fluorescence Ca2+ imaging techniques, it was found that minocycline neither blocked NMDA receptors, nor reduced glutamatecaused rises in intracellular Ca2+. Instead, confirmed by immunoblots, minocycline in vivo and in vitro was shown to directly inhibit the activation of p38 caused by glutamate. A p38-specific inhibitor, SB203580, also attenuated glutamate excitotoxicity. Furthermore, the neuroprotective effects of minocycline were blocked by phosphatidylinositol 3-kinase (PI3-K) inhibitors LY294002 and wortmannin, while pharmacologic inhibition of glycogen synthase kinase 3b (GSK3b) attenuated glutamate-induced apoptosis. In addition, immunoblots revealed that minocycline reversed the suppression of phosphorylated Akt and GSK3b caused by glutamate, as were abolished by PI3-K inhibitors. These results demonstrate that minocycline prevents glutamate-induced apoptosis in CGNs by directly inhibiting p38 activity and maintaining the activation of PI3-K/Akt pathway, which offers a novel modality as to how the drug exerts protective effects.
apoptosis,, glutamate,, minocycline,, NMDA receptors,, p38,, phosphatidylinositol 3-kinase/, Akt.,
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黎明涛, Wenya Wang a, Leyu Shi a, b, Yuanbin Xie b, Chi Mab, Wenming Li c, Xingwen Su a, Shoujian Huang a, Ruzhu Chen a, Zhenyu Zhu b, Zixu Mao d, Yifan Han c, Mingtao Li a, *
Neuroscience Research 48 (2004) 195~202,-0001,():
-1年11月30日
Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study roles of JNK activity in neuronal apoptosis in this model, we blocked JNK activity in vivo using a specific inhibitor of JNK, SP600125. Our data showed that MPTP-induced phospho-c-Jun of substantial nigral neurons, caused apoptosis of dopaminergic neurons, and decreased the dopamine level in striatal area. We found that inhibiting JNK with SP600125 reduced the levels of c-Jun phosphorylation, protected dopaminergic neurons from apoptosis, and partly restored the level of dopamine in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK pathway is the major mediator of the neurotoxic effects of MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to treat PD.
1-Methyl-4-phenyl-1,, 2,, 3,, 6-tetrahydropyridine, SP600125, c-Jun N-terminal kinase, Phospho-c-Jun, Dopaminergic neurons, Parkinson, Mouse
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黎明涛, Jing-Ping Yun, , * Choong-Tsek Liew, Eng Ching Chew, Xiao-Yu Yin, Paul Bo San Lai, Yam Hin Fai, H.K. Richard Li, Mei-Lin Jin, Ming-Xiao Ding, Ming-Tao Li, Han-Liang Lin, and Wan Yee Lau
Journal of Cellular Biochemistry 91: 1269~1279 (2004),-0001,():
-1年11月30日
We explored the feasibility of studying nuclear matrix protein (NMP) expressions of the hepatocytes in normal and cirrhotic rat livers with liver regeneration after partial hepatectomy. Sixteen Wistar healthy rats were studied with experimental liver regeneration and/or liver cirrhosis. Two-dimensional (2-D) gel electrophoresis was used to generate these NMP compositions from these rat liver samples. Several antibodies against cytokeratin, vimentin, actin, B23, HNF4alpha, and heat shock protein 70 were used for identification by Western blot. Totally, 41 strongly stained protein spots were characterized on the 2-D gels. Thirty-four protein spots were detected in all of these rat livers, of which, cytokeratin, vimentin, actin, HNF4alpha, and heat shock protein 70 were identified. B23 was detected in the regenerated livers. Three protein spots (s33, s34, and s35) were detectable only inNMPpreparation extracted from the regenerating rat livers after hepatectomy. Another three protein spots (s36, s37, and s38) were detectable only in NMP preparation extracted from thioacetamide-induced cirrhotic rat livers. Under these conditions including experimental liver regeneration and/or liver cirrhosis, Over thirty higher abundance NMPs of hepatocytes were consistently expressed and considered as common and basic NMPs. Some of the NMPs are specific for liver regeneration and may play a critical role in cell proliferation and cell cycle, and some are specific for liver cirrhosis.
nuclear matrix proteins, liver regeneration, partial hepatectomy, thioacetamide, liver cirrhosis, twodimensional electrophoresis
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黎明涛, Wenming Li‡, Rongbiao Pi‡, Hugh H. N. Chan‡, Hongjun Fu‡, Nelson T. K. Lee‡, Hing Wai Tsang‡, Yongmei Pu§, Donald C. Chang§, Chaoying Li¶‖, Jialie Luo¶, Keming Xiong‖, Zhiwang Li¶, Hong Xue‡, Paul R. Carlier**, Yuanping Pang‡‡, Karl W. K. Tsim§, Mingtao Li§§, and Yifan Han‡¶¶
Vol. 280, No.18, Issue of May 6, pp. 18179~18188, 2005,-0001,():
-1年11月30日
The neuroprotective properties of bis (7)-tacrine, a novel dimeric acetylcholinesterase (AChE) inhibitor, on glutamate-induced excitotoxicity were investigated in primary cultured cerebellar granule neurons (CGNs). Exposure of CGNs to 75
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