Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe n...Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.展开更多
Background Sex differences affect the occurrence,progression and regression of subarachnoid haemorrhage(SAH).Oestrogen plays a protective role in alleviating the vasospasm and neuronal apoptosis induced by SAH.However...Background Sex differences affect the occurrence,progression and regression of subarachnoid haemorrhage(SAH).Oestrogen plays a protective role in alleviating the vasospasm and neuronal apoptosis induced by SAH.However,whether oestrogen affects blood‒brain barrier(BBB)integrity has not been fully studied.Oestrogen has been found to regulate the sonic hedgehog(SHH)signalling pathway through the oestrogen receptor in gastric cancer and adrenal glands,and the SHH signalling pathway has an important role in maintaining the BBB by upregulating the expression of tight junction proteins.In this study,we investigated the relationship between oestrogen and the SHH signalling pathway using clinical data and established an experimental SAH model to explore whether oestrogen could ameliorate BBB damage after SAH through the SHH pathway.Methods Correlations between oestrogen and the SHH pathway were analysed by patients’cerebrospinal fluid(CSF)samples and the Genotype-Tissue Expression database(GTEx).Then,an experimental rat SAH model was established using the endovascular perforation method and treated with oestrogen,oestrogen inhibitors and SHH signalling pathway inhibitors.Then,the effects of oestrogen on BBB damage were analysed by western blot,immunofluorescence and neurobehavioural experiments.Results ESLIA detection and correlation analysis showed that oestrogen levels in patients’CSF were positively correlated with the SHH pathway,which was further verified by GTEx gene-correlation analysis.SHH was found to be mainly expressed in neurons and astrocytes in rats under physiological conditions and was upregulated by oestrogen pretreatment.In the SAH model,oestrogen pretreatment was found to reverse SAH-induced decreases in the SHH pathway,which were counteracted by oestrogen receptor inhibitors.Furthermore,oestrogen pretreatment reduced SAH-induced BBB damage,brain oedema and neurological dysfunction,which were eliminated by SHH pathway inhibitors.Conclusion In conclusion,we demonstrate here that oestrogen pretreatment ameliorates brain injury after SAH,at least in part through SHH pathway-mediated BBB protection.展开更多
Background Subarachnoid haemorrhage(SAH)can result in a highly unfavourable prognosis.In recent years,the study of SAH has focused on early brain injury(EBI),which is a crucial progress that contributes to adverse pro...Background Subarachnoid haemorrhage(SAH)can result in a highly unfavourable prognosis.In recent years,the study of SAH has focused on early brain injury(EBI),which is a crucial progress that contributes to adverse prognosis.SAH can lead to various complications,including mitochondrial dysfunction and DNA damage.Apurinic/apyrimidinic endonuclease 1(APE1)is an essential protein with multifaceted functionality integral to DNA repair and redox signalling.However,the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear.Methods Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention.Then,the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot,immunofluorescence,quantitative real-time PCR,mitochondrial bioenergetics measurement and neurobehavioural experiments.Results We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH.Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH.In vitro,after primary neurons exposed to oxyhaemoglobin,APE1 expression significantly decreased along with increased mitochondrial DNA damage,a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction.Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis.Conclusion In conclusion,APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain.APE1 may potentially play a vital role in the EBI stage after SAH,making it a critical target for treatment.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82071307(to HL),82271362(to HL),82171294(to JW),82371303(to JW),and 82301460(to PX)the Natural Science Foundation of Jiangsu Province,No.BK20211552(to HL)+1 种基金Suzhou Medical Technology Innovation Project-Clinical Frontier,No.SKY2022002(to ZY)the Science and Education Foundation for Health of Suzhou for Youth,No.KJXW2023001(to XL)。
文摘Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.
基金This work was supported by the National Natural Science Foundation of China(81830036,82220108012,82071307 and 82271362)Natural Science Foundation of Jiangsu Province(BK20211552)Gusu Health Personnel Training Project(GSWS2020022 and GSWS2019030).
文摘Background Sex differences affect the occurrence,progression and regression of subarachnoid haemorrhage(SAH).Oestrogen plays a protective role in alleviating the vasospasm and neuronal apoptosis induced by SAH.However,whether oestrogen affects blood‒brain barrier(BBB)integrity has not been fully studied.Oestrogen has been found to regulate the sonic hedgehog(SHH)signalling pathway through the oestrogen receptor in gastric cancer and adrenal glands,and the SHH signalling pathway has an important role in maintaining the BBB by upregulating the expression of tight junction proteins.In this study,we investigated the relationship between oestrogen and the SHH signalling pathway using clinical data and established an experimental SAH model to explore whether oestrogen could ameliorate BBB damage after SAH through the SHH pathway.Methods Correlations between oestrogen and the SHH pathway were analysed by patients’cerebrospinal fluid(CSF)samples and the Genotype-Tissue Expression database(GTEx).Then,an experimental rat SAH model was established using the endovascular perforation method and treated with oestrogen,oestrogen inhibitors and SHH signalling pathway inhibitors.Then,the effects of oestrogen on BBB damage were analysed by western blot,immunofluorescence and neurobehavioural experiments.Results ESLIA detection and correlation analysis showed that oestrogen levels in patients’CSF were positively correlated with the SHH pathway,which was further verified by GTEx gene-correlation analysis.SHH was found to be mainly expressed in neurons and astrocytes in rats under physiological conditions and was upregulated by oestrogen pretreatment.In the SAH model,oestrogen pretreatment was found to reverse SAH-induced decreases in the SHH pathway,which were counteracted by oestrogen receptor inhibitors.Furthermore,oestrogen pretreatment reduced SAH-induced BBB damage,brain oedema and neurological dysfunction,which were eliminated by SHH pathway inhibitors.Conclusion In conclusion,we demonstrate here that oestrogen pretreatment ameliorates brain injury after SAH,at least in part through SHH pathway-mediated BBB protection.
基金supported by the National Natural Science Foundation of China(NSFC)grant(82002643).
文摘Background Subarachnoid haemorrhage(SAH)can result in a highly unfavourable prognosis.In recent years,the study of SAH has focused on early brain injury(EBI),which is a crucial progress that contributes to adverse prognosis.SAH can lead to various complications,including mitochondrial dysfunction and DNA damage.Apurinic/apyrimidinic endonuclease 1(APE1)is an essential protein with multifaceted functionality integral to DNA repair and redox signalling.However,the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear.Methods Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention.Then,the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot,immunofluorescence,quantitative real-time PCR,mitochondrial bioenergetics measurement and neurobehavioural experiments.Results We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH.Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH.In vitro,after primary neurons exposed to oxyhaemoglobin,APE1 expression significantly decreased along with increased mitochondrial DNA damage,a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction.Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis.Conclusion In conclusion,APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain.APE1 may potentially play a vital role in the EBI stage after SAH,making it a critical target for treatment.
