The mitochondrial permeability transition pore is a nonspecific transmembrane channel.Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling,calcium overloa...The mitochondrial permeability transition pore is a nonspecific transmembrane channel.Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling,calcium overload,and axonal degeneration.Cyclophilin D is an important component of the mitochondrial permeability transition pore.Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear.In this study,we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice,in which pyramidal neurons and axons express yellow fluorescent protein.We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin.We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening.We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage.We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury.In addition,inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage.Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage;inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage.Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.展开更多
To the Editor:Spontaneous intracerebral hemorrhage(sICH)has a high incidence of acute cerebrovascular illness in elderly people in China,with high mortality and long-term functional impairment among survivors.However,...To the Editor:Spontaneous intracerebral hemorrhage(sICH)has a high incidence of acute cerebrovascular illness in elderly people in China,with high mortality and long-term functional impairment among survivors.However,there is still controversy over whether secondary infection during the course of hospitalization after ICH has a negative impact on long-term function.展开更多
Background:Recent advances in surgical and neuroprotective strategies could effectively manage the pathophysiological progression of subarachnoid hemorrhage(SAH).However,pulmonary dysfunction frequently occurs in SAH ...Background:Recent advances in surgical and neuroprotective strategies could effectively manage the pathophysiological progression of subarachnoid hemorrhage(SAH).However,pulmonary dysfunction frequently occurs in SAH patients with an increased risk of unsatisfactory outcomes.Based on the similar microvascular structures in the blood-air barrier and blood-brain barrier and possible brain-lung crosstalks,we believe that pericytes may be involved in both neurological and pulmonary dysfunction after SAH.Methods:In our experiments,platelet-derived growth factor B(PDGF-B)retention motif knockout(PDGF-Bret/ret)mice and adeno-associated virus PDGF-B were employed to show the involvement of pericyte deficiency and PDGF-B expression.Neurological score,SAH grade,hematoxylin-eosin staining,and PaO2/FiO2 ratio analysis were performed to evaluate the neurological deficits and pulmonary functions in endovascular perforation SAH models at 24 h after surgery,as well as western blotting and immunofluorescence staining for underlying molecular expressions.Results:We found that neonatal PDGF-Bret/ret mice exhibited pulmonary atelectasis 12 h after birth.Further investigation showed a decrease in PaO2/FiO2 and lung-specific surfactant proteins in adult PDGF-Bret/ret mice.These dysfunctions were much worse than those in wild-type mice at 24 h after SAH.PDGF-B overexpression alleviated pulmonary dysfunction after SAH.Conclusions:These results suggested pulmonary dysfunction after SAH and the pivotal role of PDGF-B signaling for the pathophysiological process and future therapeutic targets of pulmonary injury treatment after SAH.Further studies are needed for pathophysiological investigations and translational studies on pulmonary injuries after SAH.展开更多
Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole...Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2(LCN2)in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1(EGR1)as the key signals contributing to LCN2-mediated insufficient OPC remyelination.In LCN-knockdown and OPC EGR1 conditional-knockout mice,we discovered enhanced OPC differentiation in developing and injured white matter(WM);consistent with this,the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical,acute WMI due to subarachnoid hemorrhage and typical,chronic WMI due to multiple sclerosis.This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81901267(to YY),82001263(to WXC),81901193(to HLZ)a grant from State Key Laboratory of Trauma,Burn and Combined Injury,No.SKLYQ202002(to YJC)+1 种基金a grant from Wuxi Municipal Health Commission No.2020ZHYB19(to YY)a grant from Wuxi Science and Technology Bureau,No.Y20212045(to LKY)。
文摘The mitochondrial permeability transition pore is a nonspecific transmembrane channel.Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling,calcium overload,and axonal degeneration.Cyclophilin D is an important component of the mitochondrial permeability transition pore.Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear.In this study,we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice,in which pyramidal neurons and axons express yellow fluorescent protein.We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin.We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening.We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage.We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury.In addition,inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage.Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage;inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage.Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.
基金State Key Laboratory of Trauma,Burn and Combined Injury(No.SKLYQ202002)National Natural Science Foundation of China(No.82030036)+1 种基金Chongqing Talent Program(No.4139Z2391)Southwest Hospital(No.SWH2018BJKJ-05)。
文摘To the Editor:Spontaneous intracerebral hemorrhage(sICH)has a high incidence of acute cerebrovascular illness in elderly people in China,with high mortality and long-term functional impairment among survivors.However,there is still controversy over whether secondary infection during the course of hospitalization after ICH has a negative impact on long-term function.
基金This study was supported by the Top-notch Talent Cultivation Plan of Southwest Hospital(SWH2018BJKJ-05)Natural Science Foundation of Liaoning Province(20180550504)the Major Innovation Project of Southwest Hospital(SWH2016ZDCX1011).
文摘Background:Recent advances in surgical and neuroprotective strategies could effectively manage the pathophysiological progression of subarachnoid hemorrhage(SAH).However,pulmonary dysfunction frequently occurs in SAH patients with an increased risk of unsatisfactory outcomes.Based on the similar microvascular structures in the blood-air barrier and blood-brain barrier and possible brain-lung crosstalks,we believe that pericytes may be involved in both neurological and pulmonary dysfunction after SAH.Methods:In our experiments,platelet-derived growth factor B(PDGF-B)retention motif knockout(PDGF-Bret/ret)mice and adeno-associated virus PDGF-B were employed to show the involvement of pericyte deficiency and PDGF-B expression.Neurological score,SAH grade,hematoxylin-eosin staining,and PaO2/FiO2 ratio analysis were performed to evaluate the neurological deficits and pulmonary functions in endovascular perforation SAH models at 24 h after surgery,as well as western blotting and immunofluorescence staining for underlying molecular expressions.Results:We found that neonatal PDGF-Bret/ret mice exhibited pulmonary atelectasis 12 h after birth.Further investigation showed a decrease in PaO2/FiO2 and lung-specific surfactant proteins in adult PDGF-Bret/ret mice.These dysfunctions were much worse than those in wild-type mice at 24 h after SAH.PDGF-B overexpression alleviated pulmonary dysfunction after SAH.Conclusions:These results suggested pulmonary dysfunction after SAH and the pivotal role of PDGF-B signaling for the pathophysiological process and future therapeutic targets of pulmonary injury treatment after SAH.Further studies are needed for pathophysiological investigations and translational studies on pulmonary injuries after SAH.
基金This work was supported by the National Natural Science Foundation of China(81901216 and 82030036)Southwest Hospital(SWH2018BJKJ-05 and SWH2015QN13)the Chongqing Talent Program(4139Z2391).
文摘Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2(LCN2)in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1(EGR1)as the key signals contributing to LCN2-mediated insufficient OPC remyelination.In LCN-knockdown and OPC EGR1 conditional-knockout mice,we discovered enhanced OPC differentiation in developing and injured white matter(WM);consistent with this,the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical,acute WMI due to subarachnoid hemorrhage and typical,chronic WMI due to multiple sclerosis.This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.
