Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavio...Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice.Mice were randomly divided into four groups:sham,controlled cortical impact only,adeno-associated virus(AAV)-green fluorescent protein,and AAV-shEndorepellin-green fluorescent protein groups.In the controlled cortical impact model,the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+proliferating endothelial cells and the functional microvessel density in mouse brain.These changes resulted in improved neurological function compared with controlled cortical impact mice.Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein.Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization,which may further improve neurobehavioral outcomes.Furthermore,an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control.Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor-and angiopoietin-1-related signaling pathways.展开更多
Central nervous system(CNS)injuries,including stroke,traumatic brain injury,and spinal cord injury,are essential causes of death and long-term disability and are difficult to cure,mainly due to the limited neuron rege...Central nervous system(CNS)injuries,including stroke,traumatic brain injury,and spinal cord injury,are essential causes of death and long-term disability and are difficult to cure,mainly due to the limited neuron regeneration and the glial scar formation.Herein,we apply extracellular vesicles(EVs)secreted by M2 microglia to improve the differentiation of neural stem cells(NSCs)at the injured site,and simultaneously modify them with the injured vascular targeting peptide(DA7R)and the stem cell recruiting factor(SDF-1)on their surface via copper-free click chemistry to recruit NSCs,inducing their neuronal differentiation,and serving as the nanocarriers at the injured site(Dual-EV).Results prove that the Dual-EV could target human umbilical vascular endothelial cells(HUVECs),recruit NSCs,and promote the neuronal differentiation of NSCs in vitro.Furthermore,10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis,and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs,miR30b-3p,miR-222-3p,miR-129-5p,and miR-155-5p may exert effect of inducing NSC to differentiate into neurons.In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice,potentiate NSCs recruitment,and increase neurogenesis.This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells,and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.展开更多
Dear Editor,Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer,infection,inflammation,etc.1 However,the application of nanotechnology is greatly restricted in the treat...Dear Editor,Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer,infection,inflammation,etc.1 However,the application of nanotechnology is greatly restricted in the treatment of central nervous system(CNS)disorders due to physiological CNS barriers.For example,the blood-brain barrier(BBB)can be the“Maginot line”for pharmacologically active molecules,blocking them out of the CNS.展开更多
Ischaemic stroke is a leading cause of long-term disability in the world,with limited effective treatments.Increasing evidence demonstrates that exosomes are involved in ischaemic pathology and exhibit restorative the...Ischaemic stroke is a leading cause of long-term disability in the world,with limited effective treatments.Increasing evidence demonstrates that exosomes are involved in ischaemic pathology and exhibit restorative therapeutic effects by mediating cell–cell communication.The potential of exosome therapy for ischaemic stroke has been actively investigated in the past decade.In this review,we mainly discuss the current knowledge of therapeutic applications of exosomes from different cell types,different exosomal administration routes,and current advances of exosome tracking and targeting in ischaemic stroke.We also briefly summarised the pathology of ischaemic stroke,exosome biogenesis,exosome profile changes after stroke as well as registered clinical trials of exosome-based therapy.展开更多
Background Healthy plasma therapy reverses cognitive deficits and promotes neuroplasticity in ageing brain disease.However,whether healthy plasma therapy improve blood-brain barrier integrity after stroke remains unkn...Background Healthy plasma therapy reverses cognitive deficits and promotes neuroplasticity in ageing brain disease.However,whether healthy plasma therapy improve blood-brain barrier integrity after stroke remains unknown.Methods Here,we intravenously injected healthy female mouse plasma into adult female ischaemic stroke C57BL/6 mouse induced by 90 min transient middle cerebral artery occlusion for eight consecutive days.Infarct volume,brain atrophy and neurobehavioural tests were examined to assess the outcomes of plasma treatment.Cell apoptosis,blood-brain barrier integrity and fibroblast growth factor 21 knockout mice were used to explore the underlying mechanism.Results Plasma injection improved neurobehavioural recovery and decreased infarct volume,brain oedema and atrophy after stroke.Immunostaining showed that the number of transferase dUTP nick end labelling+/NeuN+cells decreased in the plasma-injected group.Meanwhile,plasma injection reduced ZO-1,occluding and claudin-5 tight junction gap formation and IgG extravasation at 3 days after ischaemic stroke.Western blot results showed that the FGF21 expression increased in the plasma-injected mice.However,using FGF21 knockout mouse plasma injecting to the ischaemic wild-type mice diminished the neuroprotective effects.Conclusions Our study demonstrated that healthy adult plasma treatment protected the structural and functional integrity of blood-brain barrier,reduced neuronal apoptosis and improved functional recovery via FGF21,opening a new avenue for ischaemic stroke therapy.展开更多
Objective:Priapism refers to a condition with persistent abnormal erection of the penis,which is usually caused by disease or injury in the brain or spinal cord,or obstruction to the outflow of blood through the dorsa...Objective:Priapism refers to a condition with persistent abnormal erection of the penis,which is usually caused by disease or injury in the brain or spinal cord,or obstruction to the outflow of blood through the dorsal vein at the root of the penis,without sexual desires.The effect of cerebral ischaemia on sexual function is unknown.The aim of this study is to explore whether priapism occurs in adult mice.Furthermore,we examined the relationship between priapism and the region of infarct in the brain.Design:Adult male CD-1 mice who underwent permanent middle cerebral artery occlusion(pMCAO)were closely examined from 2 hours to 14 days postoperation.Results:We found that priapism occurs in∼80%of the mice with pMCAO,which could persist up to 14 days.Further study has demonstrated that the occurrence of priapism is related to the infarct region:priapism is found only in mice with ischaemic injury extending to the hypothalamus and the hippocampus regions.Conclusion:Our result suggested priapism may be used as a deep brain injury marker for evaluating brain injury in mice after pMCAO.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81801236(to ZX),81974189(to HT)a grant from Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,No.ynlc201719(to QZ).
文摘Endorepellin plays a key role in the regulation of angiogenesis,but its effects on angiogenesis after traumatic brain injury are unclear.This study explored the effects of endorepellin on angiogenesis and neurobehavioral outcomes after traumatic brain injury in mice.Mice were randomly divided into four groups:sham,controlled cortical impact only,adeno-associated virus(AAV)-green fluorescent protein,and AAV-shEndorepellin-green fluorescent protein groups.In the controlled cortical impact model,the transduction of AAV-shEndorepellin-green fluorescent protein downregulated endorepellin while increasing the number of CD31+/Ki-67+proliferating endothelial cells and the functional microvessel density in mouse brain.These changes resulted in improved neurological function compared with controlled cortical impact mice.Western blotting revealed increased expression of vascular endothelial growth factor and angiopoietin-1 in mice treated with AAV-shEndorepellin-green fluorescent protein.Synchrotron radiation angiography showed that endorepellin downregulation promoted angiogenesis and increased cortical neovascularization,which may further improve neurobehavioral outcomes.Furthermore,an in vitro study showed that downregulation of endorepellin increased tube formation by human umbilical vein endothelial cells compared with a control.Mechanistic analysis found that endorepellin downregulation may mediate angiogenesis by activating vascular endothelial growth factor-and angiopoietin-1-related signaling pathways.
基金support from Harvard/MITsupport by grants from the National Key R&D Program of China(2019YFA0112000)+5 种基金National Natural Science Foundation of China(Nos.81930051,82003658,81801170)the Interdisciplinary Program of Shanghai Jiao Tong University(ZH2018ZDA04,China)Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20171906,China)China Postdoctoral Science Foundation(2019M661546)National Postdoctoral Program for Innovative Talents(BX20200212,China)Zhejiang Provincial Natural Science Foundation of China(No.LQ21H300009,China)。
文摘Central nervous system(CNS)injuries,including stroke,traumatic brain injury,and spinal cord injury,are essential causes of death and long-term disability and are difficult to cure,mainly due to the limited neuron regeneration and the glial scar formation.Herein,we apply extracellular vesicles(EVs)secreted by M2 microglia to improve the differentiation of neural stem cells(NSCs)at the injured site,and simultaneously modify them with the injured vascular targeting peptide(DA7R)and the stem cell recruiting factor(SDF-1)on their surface via copper-free click chemistry to recruit NSCs,inducing their neuronal differentiation,and serving as the nanocarriers at the injured site(Dual-EV).Results prove that the Dual-EV could target human umbilical vascular endothelial cells(HUVECs),recruit NSCs,and promote the neuronal differentiation of NSCs in vitro.Furthermore,10 miRNAs are found to be upregulated in Dual-M2-EVs compared to Dual-M0-EVs via bioinformatic analysis,and further NSC differentiation experiment by flow cytometry reveals that among these miRNAs,miR30b-3p,miR-222-3p,miR-129-5p,and miR-155-5p may exert effect of inducing NSC to differentiate into neurons.In vivo experiments show that Dual-EV nanocarriers achieve improved accumulation in the ischemic area of stroke model mice,potentiate NSCs recruitment,and increase neurogenesis.This work provides new insights for the treatment of neuronal regeneration after CNS injuries as well as endogenous stem cells,and the click chemistry EV/peptide/chemokine and related nanocarriers for improving human health.
基金supported by grants from the National Key R&D Program of China(2019YFA0112000)Zhejiang Provincial Natural Science Foundation of China(No.LQ21H300009)+1 种基金National Natural Science Foundation of China(81930051,82003658,82202785)GuangCi Professorship Program of Ruijin Hospital Shanghai Jiao Tong University School of Medicine.
文摘Dear Editor,Nanotechnology-based therapeutic strategies have been proven effective in diseases including cancer,infection,inflammation,etc.1 However,the application of nanotechnology is greatly restricted in the treatment of central nervous system(CNS)disorders due to physiological CNS barriers.For example,the blood-brain barrier(BBB)can be the“Maginot line”for pharmacologically active molecules,blocking them out of the CNS.
基金funded by 2019YFA0112000,NSFC 81801170,ZH2018QNA16,ZH2018ZDA04.
文摘Ischaemic stroke is a leading cause of long-term disability in the world,with limited effective treatments.Increasing evidence demonstrates that exosomes are involved in ischaemic pathology and exhibit restorative therapeutic effects by mediating cell–cell communication.The potential of exosome therapy for ischaemic stroke has been actively investigated in the past decade.In this review,we mainly discuss the current knowledge of therapeutic applications of exosomes from different cell types,different exosomal administration routes,and current advances of exosome tracking and targeting in ischaemic stroke.We also briefly summarised the pathology of ischaemic stroke,exosome biogenesis,exosome profile changes after stroke as well as registered clinical trials of exosome-based therapy.
基金This study was supported by grants from the Scientific Research and Innovation Program of Shanghai Education Commission 2019-01-07-00-02-E00064(G-YY)National Key R&D,Program of China#2016YFC1300602(G-YY),#2019YFA0112000(YT)+1 种基金the National Natural Science Foundation of China(NSFC)projects 81771251(G-YY),81801170(YT),82071284(YT),81771244(ZZ),81974179(ZZ),81870921(YW)K.C.Wong Education Foundation(G-YY,no award/grant number).
文摘Background Healthy plasma therapy reverses cognitive deficits and promotes neuroplasticity in ageing brain disease.However,whether healthy plasma therapy improve blood-brain barrier integrity after stroke remains unknown.Methods Here,we intravenously injected healthy female mouse plasma into adult female ischaemic stroke C57BL/6 mouse induced by 90 min transient middle cerebral artery occlusion for eight consecutive days.Infarct volume,brain atrophy and neurobehavioural tests were examined to assess the outcomes of plasma treatment.Cell apoptosis,blood-brain barrier integrity and fibroblast growth factor 21 knockout mice were used to explore the underlying mechanism.Results Plasma injection improved neurobehavioural recovery and decreased infarct volume,brain oedema and atrophy after stroke.Immunostaining showed that the number of transferase dUTP nick end labelling+/NeuN+cells decreased in the plasma-injected group.Meanwhile,plasma injection reduced ZO-1,occluding and claudin-5 tight junction gap formation and IgG extravasation at 3 days after ischaemic stroke.Western blot results showed that the FGF21 expression increased in the plasma-injected mice.However,using FGF21 knockout mouse plasma injecting to the ischaemic wild-type mice diminished the neuroprotective effects.Conclusions Our study demonstrated that healthy adult plasma treatment protected the structural and functional integrity of blood-brain barrier,reduced neuronal apoptosis and improved functional recovery via FGF21,opening a new avenue for ischaemic stroke therapy.
基金The study is supported by the National Natural Science Foundation of China,81471178(GYY),U1232205(GYY)and 81371305(YW).
文摘Objective:Priapism refers to a condition with persistent abnormal erection of the penis,which is usually caused by disease or injury in the brain or spinal cord,or obstruction to the outflow of blood through the dorsal vein at the root of the penis,without sexual desires.The effect of cerebral ischaemia on sexual function is unknown.The aim of this study is to explore whether priapism occurs in adult mice.Furthermore,we examined the relationship between priapism and the region of infarct in the brain.Design:Adult male CD-1 mice who underwent permanent middle cerebral artery occlusion(pMCAO)were closely examined from 2 hours to 14 days postoperation.Results:We found that priapism occurs in∼80%of the mice with pMCAO,which could persist up to 14 days.Further study has demonstrated that the occurrence of priapism is related to the infarct region:priapism is found only in mice with ischaemic injury extending to the hypothalamus and the hippocampus regions.Conclusion:Our result suggested priapism may be used as a deep brain injury marker for evaluating brain injury in mice after pMCAO.
