OBJECTIVE Ginsenoside Rg1(Rg1),a purified compound from Panax ginseng,has been well documented to be effective against ischemia/reperfusion(I/R) neurotoxicity.However,the underlying mechanism is stil obscure.METHODS T...OBJECTIVE Ginsenoside Rg1(Rg1),a purified compound from Panax ginseng,has been well documented to be effective against ischemia/reperfusion(I/R) neurotoxicity.However,the underlying mechanism is stil obscure.METHODS The anti-I/R effect of Rg1 were investigated in vitro and in vivo,and the dynamics of nuclear accumulation and the transcriptional activity of NF-E2-related factor 2(Nrf2) determined by Western blotting and Dual Luciferase Reporter Assay,respectively.Nrf2 siRNA was employed to investigate Nrf2′s role in the protective effect of Rg1 against I/R.Furthermore,the role of miR-144,which could regulate post-translational Nrf2 levels,was investigated in the anti-I/R effect of Rg1 by injection of AAV-hypoxia-inducible factor miR-144-shRNA in the predicted ischemic penumbra.RESULTS It was found that the anti-I/R effect of Rg1 was related to its anti-oxidative capacity,which is mainly regulated by the Nrf2/antioxidant response element(ARE) pathway.Further study suggested that Rg1 contributes to the enhancement of the Nrf2/ARE pathway,as manifested by increasing the dynamic peak content of Nrf2,which prolonged the maintenance stage,and promoting the expression of ARE-target genes after oxygen glucose deprivation/reperfusion(OGD/R) in PC12 cells.Nrf2-siRNA application significantly reduced these changes.Furthermore,the enhancement of the Nrf2/ARE pathway by Rg1 was independent of disassociation from Keap1;rather it was a result of posttranslational regulations.It was found that Rg1 significantly reduced the expression of miR-144,which down-regulates Nrf2 production by targeting its 3′-untranslated region,after OGD/R.Knockdown of Nrf2 showed no effect on the expression of miR-144,indicating that miR-144 is an upstream regulator of Nrf2.Moreover,direct binding between Nrf2 and miR-144 in the PC12 cells was identified.Application of anti-miR-144 significantly reduced Rg1′s anti-OGD/R capacity.Final y,the role of miR-144 in Rg1′ s anti-I/R effect was tested by inhibiting miR-144 in the predicted ischemic penumbra when hypoxia-inducible-factor was activated.The results showed that loss of miR-144 abolished the anti-I/R effect of Rg1,which included reduced infarct volume,improved neurological scores,attenuated oxidative impairment,as well as activation of the Nrf2/ARE pathway.CONCLUSION Oxidative stress after I/R is alleviated by Rg1 through inhibition of miR-144 activity and subsequent promotion of the Nrf2/ARE pathway at the post-translational level.展开更多
Ginsenosides are the main active components of ginseng,which have been reported to target brain tissues and produce multiple neuroprotective effects.Ginsenosides have been shown to improve learning ability and memory ...Ginsenosides are the main active components of ginseng,which have been reported to target brain tissues and produce multiple neuroprotective effects.Ginsenosides have been shown to improve learning ability and memory in normal aged animals,and in an animal model of memory impairment.However,its underlying pharmacological mechanisms are very complicated,especially with regard to its effects on the activation of protein kinases in neurons.Previous reports have shown that some protein kinases may be affected by ginsenosides,including protein kinase C,calcium/calmodulin-dependent protein kinase Ⅱ,c-Jun-N terminal kinase,and protein tyrosine kinase.In this paper,protein kinases that may underlie the mechanisms of ginsenosides will be discussed.展开更多
基金Funding: National Natural Science Foundation of China (Grant No. 81530099, Grant No.81473375), China Postdoctoral Science Foundation (Grant No. 2013M540066), Research Project Supported by Shanxi Scholarship Council of China (Grant No. 2013-134). Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province, Program for the Innovative Talents of Higher Learning Institutions of Shanxi.
基金The project supported by National Natural Science Foundation of China(81603315 81730096+4 种基金 81373551 81730093U1402221)CAMS Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-004)the Opening Program of Shanxi Key Laboratory of Chinese Medicine Encephalopathy(CME-OP-2017001)
文摘OBJECTIVE Ginsenoside Rg1(Rg1),a purified compound from Panax ginseng,has been well documented to be effective against ischemia/reperfusion(I/R) neurotoxicity.However,the underlying mechanism is stil obscure.METHODS The anti-I/R effect of Rg1 were investigated in vitro and in vivo,and the dynamics of nuclear accumulation and the transcriptional activity of NF-E2-related factor 2(Nrf2) determined by Western blotting and Dual Luciferase Reporter Assay,respectively.Nrf2 siRNA was employed to investigate Nrf2′s role in the protective effect of Rg1 against I/R.Furthermore,the role of miR-144,which could regulate post-translational Nrf2 levels,was investigated in the anti-I/R effect of Rg1 by injection of AAV-hypoxia-inducible factor miR-144-shRNA in the predicted ischemic penumbra.RESULTS It was found that the anti-I/R effect of Rg1 was related to its anti-oxidative capacity,which is mainly regulated by the Nrf2/antioxidant response element(ARE) pathway.Further study suggested that Rg1 contributes to the enhancement of the Nrf2/ARE pathway,as manifested by increasing the dynamic peak content of Nrf2,which prolonged the maintenance stage,and promoting the expression of ARE-target genes after oxygen glucose deprivation/reperfusion(OGD/R) in PC12 cells.Nrf2-siRNA application significantly reduced these changes.Furthermore,the enhancement of the Nrf2/ARE pathway by Rg1 was independent of disassociation from Keap1;rather it was a result of posttranslational regulations.It was found that Rg1 significantly reduced the expression of miR-144,which down-regulates Nrf2 production by targeting its 3′-untranslated region,after OGD/R.Knockdown of Nrf2 showed no effect on the expression of miR-144,indicating that miR-144 is an upstream regulator of Nrf2.Moreover,direct binding between Nrf2 and miR-144 in the PC12 cells was identified.Application of anti-miR-144 significantly reduced Rg1′s anti-OGD/R capacity.Final y,the role of miR-144 in Rg1′ s anti-I/R effect was tested by inhibiting miR-144 in the predicted ischemic penumbra when hypoxia-inducible-factor was activated.The results showed that loss of miR-144 abolished the anti-I/R effect of Rg1,which included reduced infarct volume,improved neurological scores,attenuated oxidative impairment,as well as activation of the Nrf2/ARE pathway.CONCLUSION Oxidative stress after I/R is alleviated by Rg1 through inhibition of miR-144 activity and subsequent promotion of the Nrf2/ARE pathway at the post-translational level.
基金National Natural Science Foundation of China(the Study of Electrochemical Mechanism on the Common Syndrome Factors Concerning Alzheimer's Disease and Parkinson's Disease,No.81273629)Prescription-syndrome Effect of Dihuang Yinzi Treating Alzheimer Disease and Parkinson Disease Based on the Theory of Syndrome Factor,No.81273898+2 种基金Study on the Synergistic Mechanism of Polygala Tenuifolia and Acorus Gramineus Improving Memory Through Modulating Synaptic Plasticity Molecular Network,No.81473375Shanxi Scholarship Council of China(the Study of Electrochemical Mechanism on the Common Syndrome Factors Concerning Brain Degenerative Diseases,No.2013-134)Shanxi Provincial Project of International Science Technology Cooperation(R&D of Screen System for Chinese Medicines of Anti-Neuronal Apoptosis Based on the Modulation Mechanism of Neuroglial Cells,No.2010081065)
文摘Ginsenosides are the main active components of ginseng,which have been reported to target brain tissues and produce multiple neuroprotective effects.Ginsenosides have been shown to improve learning ability and memory in normal aged animals,and in an animal model of memory impairment.However,its underlying pharmacological mechanisms are very complicated,especially with regard to its effects on the activation of protein kinases in neurons.Previous reports have shown that some protein kinases may be affected by ginsenosides,including protein kinase C,calcium/calmodulin-dependent protein kinase Ⅱ,c-Jun-N terminal kinase,and protein tyrosine kinase.In this paper,protein kinases that may underlie the mechanisms of ginsenosides will be discussed.