AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in vario...AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.展开更多
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
The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system(CNS)injury.Maintaining brain immune homeostasis is crucial for restoring neuro...The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system(CNS)injury.Maintaining brain immune homeostasis is crucial for restoring neurovascular function.In this study,an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit,thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery.This immunomodulatory crosstalk microsphere(MP/RIL4)was composed of microglia-targeted RAP12 peptide-modified interleukin-4(IL-4)nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques.We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β,iNOS,and CD86,while upregulating levels of anti-inflammatory factors such as IL-10,Arg-1,and CD206 in microglia.In addition,injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke,promoted neurobehavioral recovery,and enhanced the crosstalk between immune cells and the neurovascular unit,thus increasing angiogenesis and neurogenesis of stroke mice.In summary,the immunomodulatory microspheres,capable of orchestrating the interaction between immune cells and neurovascular unit,hold considerable therapeutic potential for ischemic stroke and other CNS diseases.展开更多
Due to the limited effects of current treatments on brain repair and regeneration,stroke continues to be the predominant cause of death and long-term disability on a global scale.In recent years,hydrogel-based biomate...Due to the limited effects of current treatments on brain repair and regeneration,stroke continues to be the predominant cause of death and long-term disability on a global scale.In recent years,hydrogel-based biomaterials combined with stem cells and extracellular vesicles have emerged as promising new treatments to improve brain regeneration after stroke.However,the clinical translation of hydrogel-based biomaterials for the treatment of brain injury is still far from satisfactory.In this review,we first summarise the present status of stroke-related clinical treatments and the advantages provided by hydrogel-based materials in combination with stem cells and extracellular vesicles in preclinical studies.We then focus on the possible causes of the gap between preclinical studies and clinical translation of hydrogel-based biomaterials from the perspective of biocompatibility and safety,the choices of preclinical models,the lack of clinical noninvasive imaging methods,standardisation and quality control,manufacturing scalability,and regulatory compliance.With the progress in the abovementioned areas,we believe that the clinical translation of hydrogel-based biomaterials will greatly improve brain regeneration after stroke and that this improvement will be realised by the general public in the near future.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
Background Low-intensity focused ultrasound stimulation(LIFUS)has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents.However,the cellular and molec...Background Low-intensity focused ultrasound stimulation(LIFUS)has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents.However,the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear.Methods Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion.Angiogenesis was measured by laser speckle imaging and histological analyses.Electromyography and fibre photometry records were used for synaptogenesis.Brain atrophy volume and neurobehaviour were assessed 0–14 days after ischaemia.iTRAQ proteomic analysis was performed to explore the differentially expressed protein.scRNA-seq was used for subcluster analysis of astrocytes.Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1.Results Optimal ultrasound stimulation increased cerebral blood flow,and improved neurobehavioural outcomes in ischaemic mice(p<0.05).iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment(p<0.05).scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain.LIFUS upregulated HMGB1 expression,accompanied by VEGFA elevation compared with the control group(p<0.05).Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow(p<0.05).LIFUS reduced CAMK2N1 expression level,accompanied by increased extracellular calcium ions and glutamatergic synapses(p<0.05).CAMK2N1 overexpression in astrocytes decreased dendritic spines,and aggravated neurobehavioural outcomes(p<0.05).Conclusion Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes,suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.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
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
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.81870921(to YW),81974179(to ZZ),82271320(to ZZ),82071284(to YT)National Key R&D Program of China,No.2022YFA1603600(to ZZ),2019YFA0112000(to YT)+1 种基金Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY).
文摘AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.
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supported by National Natural Science Foundation of China 81930051(WC)“Chenguang Program”(22CGA16)supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission,the National Key R&D Program of China#2019YFA0112000(YT)+4 种基金National Natural Science Foundation of China 82071284(YT),82371307(YT),82372120(HR)Shanghai Rising-Star Program(21QA1405200,YT)Young Leading Scientists Cultivation Plan supported by Shanghai Municipal Education Commission(ZXWH1082101,YT)“Two Hundred Talent”Program supported by Shanghai Jiao Tong University School of Medicine(20240701,HR)the Fundamental Research Funds for the Central Universities(YG2023ZD02,YT).
文摘The crosstalk between immune cells and the neurovascular unit plays a pivotal role in neural regeneration following central nervous system(CNS)injury.Maintaining brain immune homeostasis is crucial for restoring neurovascular function.In this study,an interactive bridge was developed via an immunomodulatory hydrogel microsphere to link the interaction network between microglia and the neurovascular unit,thereby precisely regulating immune-neurovascular crosstalk and achieving neural function recovery.This immunomodulatory crosstalk microsphere(MP/RIL4)was composed of microglia-targeted RAP12 peptide-modified interleukin-4(IL-4)nanoparticles and boronic ester-functionalized hydrogel using biotin-avidin reaction and air-microfluidic techniques.We confirmed that the immunomodulatory microspheres reduced the expression of pro-inflammatory factors including IL-1β,iNOS,and CD86,while upregulating levels of anti-inflammatory factors such as IL-10,Arg-1,and CD206 in microglia.In addition,injection of the MP/RIL4 significantly mitigated brain atrophy volume in a mouse model of ischemic stroke,promoted neurobehavioral recovery,and enhanced the crosstalk between immune cells and the neurovascular unit,thus increasing angiogenesis and neurogenesis of stroke mice.In summary,the immunomodulatory microspheres,capable of orchestrating the interaction between immune cells and neurovascular unit,hold considerable therapeutic potential for ischemic stroke and other CNS diseases.
基金the National Key R&D Program of China,No.2019YFA0112000(to YT)the National Natural Science Foundation of China(NSFC),Nos.82071284(to YT),82371307(to YT),82172529(to JW),32060184(to HM)+4 种基金Natural Science Foundation of Shanghai,No.21ZR1451700(to HL)Young Leading Scientists Cultivation Plan supported by Shanghai Municipal Education Commission,No.ZXWH1082101(to YT)Interdisciplinary Program of Shanghai Jiao Tong University,No.ZH2018QNA16(to YT)Key Projects of the National Center for Translational Medicine SUITM-202306(to YT)and Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University,No.202101AY070001-044(to HM).
文摘Due to the limited effects of current treatments on brain repair and regeneration,stroke continues to be the predominant cause of death and long-term disability on a global scale.In recent years,hydrogel-based biomaterials combined with stem cells and extracellular vesicles have emerged as promising new treatments to improve brain regeneration after stroke.However,the clinical translation of hydrogel-based biomaterials for the treatment of brain injury is still far from satisfactory.In this review,we first summarise the present status of stroke-related clinical treatments and the advantages provided by hydrogel-based materials in combination with stem cells and extracellular vesicles in preclinical studies.We then focus on the possible causes of the gap between preclinical studies and clinical translation of hydrogel-based biomaterials from the perspective of biocompatibility and safety,the choices of preclinical models,the lack of clinical noninvasive imaging methods,standardisation and quality control,manufacturing scalability,and regulatory compliance.With the progress in the abovementioned areas,we believe that the clinical translation of hydrogel-based biomaterials will greatly improve brain regeneration after stroke and that this improvement will be realised by the general public in the near future.
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Scientific Research and Innovation Program of Shanghai Education Commission 2019-01-07-00-02-E00064(G-YY)National Natural Science Foundation of China 82271320(ZZ),82172529(WJ),81974179(ZZ),82071284(YT)+2 种基金Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,20JC1411900(G-YY)National Key R&D Program of China 2022YFA1603604(ZZ),2019YFA0112000(YT),2018YFA0701400(WQ)and 2021ZD0200401(WQ)Shenzhen Foundation Grant JCYJ20200109114237902(WQ),SGDX2020110309400200(WQ).
文摘Background Low-intensity focused ultrasound stimulation(LIFUS)has been developed to enhance neurological repair and remodelling during the late acute stage of ischaemic stroke in rodents.However,the cellular and molecular mechanisms of neurological repair and remodelling after LIFUS in ischaemic stroke are unclear.Methods Ultrasound stimulation was treated in adult male mice 7 days after transient middle cerebral artery occlusion.Angiogenesis was measured by laser speckle imaging and histological analyses.Electromyography and fibre photometry records were used for synaptogenesis.Brain atrophy volume and neurobehaviour were assessed 0–14 days after ischaemia.iTRAQ proteomic analysis was performed to explore the differentially expressed protein.scRNA-seq was used for subcluster analysis of astrocytes.Fluorescence in situ hybridisation and Western blot detected the expression of HMGB1 and CAMK2N1.Results Optimal ultrasound stimulation increased cerebral blood flow,and improved neurobehavioural outcomes in ischaemic mice(p<0.05).iTRAQ proteomic analysis revealed that the expression of HMGB1 increased and CAMK2N1 decreased in the ipsilateral hemisphere of the brain at 14 days after focal cerebral ischaemia with ultrasound treatment(p<0.05).scRNA-seq revealed that this expression pattern belonged to a subcluster of astrocytes after LIFUS in the ischaemic brain.LIFUS upregulated HMGB1 expression,accompanied by VEGFA elevation compared with the control group(p<0.05).Inhibition of HMGB1 expression in astrocytes decreased microvessels counts and cerebral blood flow(p<0.05).LIFUS reduced CAMK2N1 expression level,accompanied by increased extracellular calcium ions and glutamatergic synapses(p<0.05).CAMK2N1 overexpression in astrocytes decreased dendritic spines,and aggravated neurobehavioural outcomes(p<0.05).Conclusion Our results demonstrated that LIFUS promoted angiogenesis and synaptogenesis after focal cerebral ischaemia by upregulating HMGB1 and downregulating CAMK2N1 in a subcluster of astrocytes,suggesting that LIFUS activated specific astrocyte subcluster could be a key target for ischaemic brain therapy.
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.
