Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning(DEACMP),including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis...Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning(DEACMP),including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis;however,no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP.Leucine-rich repeat and immunoglobulin-like domain-containing protein-1(LINGO-1)activates the Ras homolog gene family member A(Rho A)/Rho-associated coiled-coil containing protein kinase 2(ROCK2)signaling pathway,which negatively regulates oligodendrocyte myelination,axonal growth,and neuronal survival,causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases.However,whether LINGO-1 is involved in DEACMP remains unclear.A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes,followed by 3000 ppm carbon monoxide gas for an additional 20 minutes.The results showed that compared with control rats,DEACMP rats showed significantly increased water maze latency and increased protein and m RNA expression levels of LINGO-1,Rho A,and ROCK2 in the brain.Compared with normal rats,significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats.From days 1 to 21 after DEACMP,the intraperitoneal injection of retinoic acid(10 mg/kg),which can inhibit LINGO-1 expression,was able to improve the above changes observed in the DEACMP model.Therefore,the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning,activating the Rho A/ROCK2 signaling pathway,which may be an important pathophysiological mechanism underlying DEACMP.This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital(approval No.201612684)on December 26,2016.展开更多
Apelin-13 is a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor,and it may be neuroprotective against cerebral ischemia injury.However,the precise mechanisms of the effects of apelin-1...Apelin-13 is a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor,and it may be neuroprotective against cerebral ischemia injury.However,the precise mechanisms of the effects of apelin-13 remain to be elucidated.To investigate the effects of apelin-13 on apoptosis and autophagy in models of cerebral ischemia/reperfusion injury,a rat model was established by middle cerebral artery occlusion.Apelin-13(50μg/kg)was injected into the right ventricle as a treatment.In addition,an SH-SY5Y cell model was established by oxygen-glucose deprivation/reperfusion,with cells first cultured in sugar-free medium with 95%N2 and 5%CO2 for 4 hours and then cultured in a normal environment with sugar-containing medium for 5 hours.This SH-SY5Y cell model was treated with 10-7 M apelin-13 for 5 hours.Results showed that apelin-13 protected against cerebral ischemia/reperfusion injury.Apelin-13 treatment alleviated neuronal apoptosis by increasing the ratio of Bcl-2/Bax and significantly decreasing cleaved caspase-3 expression.In addition,apelin-13 significantly inhibited excessive autophagy by regulating the expression of LC3B,p62,and Beclin1.Furthermore,the expression of Bcl-2 and the phosphatidylinositol-3-kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR)pathway was markedly increased.Both LY294002(20μM)and rapamycin(500 nM),which are inhibitors of the PI3K/Akt/mTOR pathway,significantly attenuated the inhibition of autophagy and apoptosis caused by apelin-13.In conclusion,the findings of the present study suggest that Bcl-2 upregulation and mTOR signaling pathway activation lead to the inhibition of apoptosis and excessive autophagy.These effects are involved in apelin-13-induced neuroprotection against cerebral ischemia/reperfusion injury,both in vivo and in vitro.The study was approved by the Animal Ethical and Welfare Committee of Jining Medical University,China(approval No.2018-JS-001)in February 2018.展开更多
文摘Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning(DEACMP),including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis;however,no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP.Leucine-rich repeat and immunoglobulin-like domain-containing protein-1(LINGO-1)activates the Ras homolog gene family member A(Rho A)/Rho-associated coiled-coil containing protein kinase 2(ROCK2)signaling pathway,which negatively regulates oligodendrocyte myelination,axonal growth,and neuronal survival,causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases.However,whether LINGO-1 is involved in DEACMP remains unclear.A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes,followed by 3000 ppm carbon monoxide gas for an additional 20 minutes.The results showed that compared with control rats,DEACMP rats showed significantly increased water maze latency and increased protein and m RNA expression levels of LINGO-1,Rho A,and ROCK2 in the brain.Compared with normal rats,significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats.From days 1 to 21 after DEACMP,the intraperitoneal injection of retinoic acid(10 mg/kg),which can inhibit LINGO-1 expression,was able to improve the above changes observed in the DEACMP model.Therefore,the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning,activating the Rho A/ROCK2 signaling pathway,which may be an important pathophysiological mechanism underlying DEACMP.This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital(approval No.201612684)on December 26,2016.
基金supported by the National Natural Science Foundation of China,Nos.81870948(to BB),81671276(to BHC),81501018(to CMW)the Natural Science Foundation of Shandong Province of China,No.ZR2014HL040(to BHC)Program Supporting Foundation for Teachers’Research of Jining Medical University of China,No.JYFC2018KJ003(to SSD).
文摘Apelin-13 is a novel endogenous ligand for an angiotensin-like orphan G-protein coupled receptor,and it may be neuroprotective against cerebral ischemia injury.However,the precise mechanisms of the effects of apelin-13 remain to be elucidated.To investigate the effects of apelin-13 on apoptosis and autophagy in models of cerebral ischemia/reperfusion injury,a rat model was established by middle cerebral artery occlusion.Apelin-13(50μg/kg)was injected into the right ventricle as a treatment.In addition,an SH-SY5Y cell model was established by oxygen-glucose deprivation/reperfusion,with cells first cultured in sugar-free medium with 95%N2 and 5%CO2 for 4 hours and then cultured in a normal environment with sugar-containing medium for 5 hours.This SH-SY5Y cell model was treated with 10-7 M apelin-13 for 5 hours.Results showed that apelin-13 protected against cerebral ischemia/reperfusion injury.Apelin-13 treatment alleviated neuronal apoptosis by increasing the ratio of Bcl-2/Bax and significantly decreasing cleaved caspase-3 expression.In addition,apelin-13 significantly inhibited excessive autophagy by regulating the expression of LC3B,p62,and Beclin1.Furthermore,the expression of Bcl-2 and the phosphatidylinositol-3-kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR)pathway was markedly increased.Both LY294002(20μM)and rapamycin(500 nM),which are inhibitors of the PI3K/Akt/mTOR pathway,significantly attenuated the inhibition of autophagy and apoptosis caused by apelin-13.In conclusion,the findings of the present study suggest that Bcl-2 upregulation and mTOR signaling pathway activation lead to the inhibition of apoptosis and excessive autophagy.These effects are involved in apelin-13-induced neuroprotection against cerebral ischemia/reperfusion injury,both in vivo and in vitro.The study was approved by the Animal Ethical and Welfare Committee of Jining Medical University,China(approval No.2018-JS-001)in February 2018.
