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Exosomes from young healthy human plasma promote functional recovery from intracerebral hemorrhage via counteracting ferroptotic injury

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Bioactive Materials 2023年第9期27卷 1-14页

作者： Wenqin Yang Ning Ding Ran Luo Qian Zhang Zhenhua Li Fengchun Zhao Shuixian Zhang Xuyang Zhang Tengyuan Zhou Haomiao Wang Long Wang Shengli Hu Guixue Wang Hua Feng Rong Hu Department of Neurosurgery Key Laboratory of NeurotraumaSouthwest HospitalThird Military Medical University(Army Medical University)400038ChongqingChina Bioengineering College of Chongqing University Chongqing400030China Medical Research Center Southwest HospitalThird Military Medical University(Army Medical University)400038ChongqingChina Affiliated Dongguan Hospital Southern Medical UniversityDongguan523059China Key Laboratory of Biorheological and Technology of Ministry of Education State and Local Joint Engineering Laboratory for Vascular ImplantsBioengineering College of Chongqing UniversityChongqing400030China JinFeng Laboratory Chongqing401329China

intracerebral hemorrhage (ICH), as a type of life-threatening and highly disabled disease, has limited therapeutic approaches. Here, we show that exosomes derived from young healthy human plasma exhibiting typical exosomes features could facilitate functional recovery of ICH mice. When these exosomes are intraventricularly delivered into the brain after ICH, they mainly distribute around the hematoma and could be internalized by neuronal cells. Strikingly, exosomes administration markedly enhanced the behavioral recovery of ICH mice through reducing brain injury and cell ferroptosis. MiRNA sequencing revealed that microRNA-25-3p (miR-25- 3p) was differentially expressed miRNA in the exosomes from young healthy human plasma, compared with exosomes from the old control. Importantly, miR-25-3p mimicked the treatment effect of exosomes on behavioral improvement, and mediated the neuroprotective effect of exosomes against ferroptosis in ICH. Furthermore, luciferase assay and western blotting data illustrated that P53 as assumed the role of a downstream effector of miR-25-3p, thereby regulating SLC7A11/GPX4 pathway to counteract ferroptosis. Taken together, these findings firstly reveal that exosomes from young healthy human plasma improve functional recovery through counteracting ferroptotic injury by regulating P53/SLC7A11/GPX4 axis after ICH. Given the easy availability of plasma exosomes, our study provides a potent therapeutic strategy for ICH patients with quick clinical translation in the near future.

关键词： intracerebral hemorrhage Exosomes Young human plasma Ferroptosis Functional recovery

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Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice

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Neural Regeneration Research 2022年第1期17卷 210-216页

作者： Yuan Zhu Yi Huang Jin Yang Rong Tu Xin Zhang Wei-Wei He Chang-Yue Hou Xiao-Ming Wang Ju-Ming Yu Guo-Hui Jiang Department of Neurology Affiliated Hospital of North Sichuan Medical CollegeNanchongSichuan ProvinceChina Institute of Neurological Diseases North Sichuan Medical CollegeNanchongSichuan ProvinceChina Department of Intensive Care Unit Affiliated Hospital of North Sichuan Medical CollegeNanchongSichuan ProvinceChina

In Alzheimer’s disease and ischemic stroke,intranasal insulin can act as a neuroprotective ***,whether intranasal insulin has a neuroprotective effect in intracerebral hemorrhage and its potential mechanisms remain poorly *** this study,a mouse model of autologous blood-induced intracerebral hemorrhage was treated with 0.5,1,or 2 IU insulin via intranasal delivery,twice per day,until 24 or 72 hours after *** with saline treatment,1 IU intranasal insulin treatment significantly reduced hematoma volume and brain edema after cerebral hemorrhage,decreased blood-brain barrier permeability and neuronal degeneration damage,reduced neurobehavioral deficits,and improved the survival rate of *** levels of p-AKT and p-GSK3βwere significantly increased in the perihematoma tissues after intranasal insulin *** findings suggest that intranasal insulin therapy can protect the neurological function of mice after intracerebral hemorrhage through the AKT/GSK3βsignaling *** study was approved by the Ethics Committee of the North Sichuan Medical College of China(approval ***(A)2019(01))on January 7,2019.

关键词： AKT blood-brain barrier brain edema glycogen synthase kinase-3 hematoma insulin intracerebral hemorrhage intranasal insulin neurological impairment neuronal degeneration neuroprotection

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Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage

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Journal of Pharmaceutical Analysis 2023年第8期13卷 862-879页

作者： Jingwei Zheng Haijian Wu Xiaoyu Wang Guoqiang Zhang Jia'nan Lu Weilin Xu Shenbin Xu Yuanjian Fang Anke Zhang Anwen Shao Sheng Chen Zhen Zhao Jianmin Zhang Jun Yu Department of Neurosurgery Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou310000China Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases Hangzhou310000China Stroke Research Center for Diagnostic and Therapeutic Technologies of Zhejiang Province Hangzhou310000China Center for Neurodegeneration and Regeneration Zilkha Neurogenetic Institute and Department of Physiology and BiophysicsKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA90089USA

The role of glial scar after intracerebral hemorrhage(ICH)remains *** study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial *** used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar *** transcriptomics(ST)analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different *** the early stage,sustained microglial depletion induced disorganized astrocytic scar,enhanced neutrophil infiltration,and impaired tissue *** analysis indicated that microglia-derived insulin like growth factor 1(IGF1)modulated astrocytic scar formation via mechanistic target of rapamycin(mTOR)signaling ***,repopulating microglia(RM)more strongly activated mTOR signaling,facilitating a more protective scar *** combination of IGF1 and osteopontin(OPN)was necessary and sufficient for RM function,rather than IGF1 or OPN *** the chronic stage of ICH,the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse *** vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ***,early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic *** prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes,and develop elaborate treatment strategies at precise time points after ICH.

关键词： Microglia Astrocytes Glial scar intracerebral hemorrhage

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MicroRNA-181c provides neuroprotection in an intracerebral hemorrhage model

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Neural Regeneration Research 2020年第7期15卷 1274-1282页

作者： Xi Lu Hui-Yuan Zhang Zhi-Yi He First Affiliated Hospital of China Medical University

Apoptosis is an important factor during the early stage of intracerebral ***-181 c plays a key regulatory role in ***,whether miR-181 c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains ***,in vitro and in vivo experiments were conducted to test this *** vivo experiments:collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage ***-181 c mimic or inhibitor was injected in situ 4 hours after intracerebral *** functional defects(neurological severity scores)were assessed 1,7,and 14 days after model *** deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model *** vitro experiments:PC12 cells were cultured under oxygen-glucose deprivation,and hemins were added to simulate intracerebral hemorrhage in ***-181 c mimic or inhibitor was added to regulate miR-181 c expression.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay,luciferase reporter system,and western blot assay were *** results revealed differences in miR-181 c expression in brain tissues of both patients and rats with cerebral *** addition,in vitro experiments found that miR-181 c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis,while inhibition of miR-181 c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of *** of apoptosis occurred through the phosphoinositide 3 kinase(PI3 K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten(PTEN).Higher miR-181 c overexpression correlated with lower neurological severity scores,indicating better recovery of neurological *** conclusion,miR-181 c affects the prognosis of intracerebral hemorrhage by regulating apoptosis,and these effects might

关键词： apoptosis Bcl-2/Bax intracerebral hemorrhage miR-181c nerve cells neurological function neuroprotection PTEN regulation

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Effect of Zhutan Tongluo Tang on fibrinolytic activity following intracerebral hemorrhage in rats

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Neural Regeneration Research 2011年第21期6卷 1640-1645页

作者： Yongxi Jin Xu Li Gaowen Li Lei Guo Fang Li Guoying Liu Songfang Chen Shijue Liu Department of Rehabilitation Wenzhou Municipal Hospital of Traditional Chinese Medicine Wenzhou 325005 Zhejiang Province China Department of Physiology Wenzhou Medical College Wenzhou 325035 Zhejiang Province China Department of Pharmacology Ningbo Tian Yi Vocational and Technical College Ningbo 315100 Zhejiang Province China Department of Urology Central Hospital of Xinyang Xinyang 464000 Henan Province China The Second Affiliated Hospital of Wenzhou Medical College Wenzhou 325027 Zhejiang Province China

The neuroprotective effect of Zhutan Tongluo Tang is associated with the activities of the fibrinolytic system. Thus the present study was designed to investigate therapeutic effects of Zhutan Tongluo Tang on intracerebral hemorrhage in rats, induced by injecting collagenase into one side of the caudate nucleus. Fibrinolytic indices including tissue plasminogen activator, plasminogen activator inhibitor-1 and D-Dimer were determined. The results obtained demonstrated that Zhutan Tongluo Tang treatment could alleviate the neural and behavioral impairments of intracerebral hemorrhaging rats. Increased frequencies of placing their forelimb correctly and decreased frequencies of turning left were observed. Enzyme linked immunosorbent assay showed that Zhutan Tongluo Tang could significantly elevate the concentration of plasma tissue plasminogen activator and D-Dimer, while depress plasminogen activator inhibitor-1. Immunohistochemistry demonstrated increased levels of catalase and glutathione in whole brain rat tissue following intracerebral hemorrhage. In addition, elevated expression of Bcl-2 in various hippocampal regions was seen. These findings describe the ability of Zhutan Tongluo Tang to activate the fibrinolytic system, and suggests that antioxidant and apoptosis inhibitory mechanisms may be playing a crucial role in protecting against collagenase-induced intracerebral hemorrhage.

关键词： Zhutan Tongluo Tang intracerebral hemorrhage tissue plasminogen activator plasminogen activator inhibitor-1 D-Dimer hippocampus apoptosis neural regeneration

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Neurotoxic role of interleukin-17 in neural stem cell differentiation after intracerebral hemorrhage

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Neural Regeneration Research 2020年第7期15卷 1350-1359页

作者： Lu Gao Ping-Ping Li Tian-Yu Shao Xiang Mao Hao Qi Bing-Shan Wu Ming Shan Lei Ye Hong-Wei Cheng Department of Neurosurgery First Affiliated Hospital of Anhui Medical University

Interleukin 17(IL-17)and its main producer,T cell receptorγδcells,have neurotoxic effects in the pathogenesis of intracerebral hemorrhage(ICH),aggravating brain *** investigate the correlation between IL-17 and ICH,we dynamically screened serum IL-17 concentrations using enzyme-linked immunosorbent assay and explored the clinical values of IL-17 in ICH *** was a significant negative correlation between serum IL-17 level and neurological recovery status in ICH patients(r=–0.498,P<0.01).To study the neurotoxic role of IL-17,C57 BL/6 mice were used to establish an ICH model by injecting autologous blood into the caudate ***,the mice were treated with mouse neural stem cells(NSCs)and/or IL-17 neutralizing antibody for 72 *** cytometry,brain water content detection,Nissl staining,and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling results indicated that NSC transplantation significantly reduced IL-17 expression in peri-hematoma tissue,but there was no difference in T cell receptorγδ*** with the ICH group,there were fewer apoptotic bodies and more Nissl bodies in the ICH+NSC group and the ICH+NSC+IL-17 *** investigate the potential effect of IL-17 on directional differentiation of NSCs,we cultured mouse NSCs(NE-4 C)alone or co-cultured them with T cell receptorγδcells,which were isolated from mouse peripheral blood mononuclear cells,for 7 *** results of western blot assays revealed that IL-17 secreted by T cell receptorγδcells reduced the differentiation of NSCs into astrocytes and neurons,while IL-17 neutralization relieved the inhibition of directional differentiation into astrocytes rather than *** conclusion,serum IL-17 levels were elevated in the early stage of ICH and were negatively correlated with outcome in ICH *** experiments and cytological investigations therefore demonstrated that IL-17 probably has neurotoxic roles in ICH because of its inhibitory effects

关键词： antibody neutralization astrocytes directional differentiation interleukin 17 intracerebral hemorrhage neural stem cells Nissl staining recovery T cell receptorγδcells TUNEL staining

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Small interfering RNAs based therapies for intracerebral hemorrhage: challenges and progress in drug delivery systems

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Neural Regeneration Research 2022年第8期17卷 1717-1725页

作者： Daniyah A.Almarghalani Sai H.S.Boddu Mohammad Ali Akhila Kondaka Devin Ta Rayyan A.Shah Zahoor A.Shah Department of Pharmacology and Experimental Therapeutics College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledoOHUSA Department of Medicinal and Biological Chemistry College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoToledoOHUSA Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesAjman UniversityAjmanUnited Arab Emirates

intracerebral hemorrhage(ICH)is a subtype of stroke associated with higher rates of ***,no effective drug treatment is available for *** molecular pathways following ICH are complicated and *** acid therapeutics such as gene knockdown by small interfering RNAs(siRNAs)have been developed in recent years to modulate ICH’s destructive pathways and mitigate its ***,siRNAs delivery to the central nervous system is challenging and faces many *** barriers to systemic delivery of siRNA limit the use of naked siRNA;therefore,siRNA-vectors developed to protect and deliver these therapies into the specific-target areas of the brain,or cell types seem quite *** delivery of siRNA via nanoparticles emerged as a viable and effective alternative therapeutic tool for central nervous system-related *** review discusses the obstacles to siRNA delivery,including the advantages and disadvantages of viral and nonviral ***,we provide a comprehensive overview of recent progress in nanotherapeutics areas,primarily focusing on the delivery system of siRNA for ICH treatment.

关键词： intracerebral hemorrhage lipid-based nanoparticle nanoparticles nanotechnology nonviral vectors peptide-mediated nanoparticle polymer-based nanoparticle siRNA therapeutics siRNA-barriers viral vectors

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A novel aged mouse model of recurrent intracerebral hemorrhage in the bilateral striatum

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Neural Regeneration Research 2023年第2期18卷 344-349页

作者： Li-Min Wang Zhi-Hua Liu Hong-Lei Ren Xue-Mei Chen Jun-Min Wang Hui-Min Cai Li-Ping Wei Hui-Hong Tian Jian Wang Li-Juan Wang The Second School of Clinical Medicine Southern Medical UniversityGuangzhouGuangdong ProvinceChina Department of Neurology Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangdong Neuroscience InstituteGuangzhouGuangdong ProvinceChina School of Medicine South China University of TechnologyGuangzhouGuangdong ProvinceChina Department of Neurology Tianjin Neurological InstituteTianjin Medical University General HospitalTianjinChina Department of Anatomy School of Basic Medical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina

The current animal models of stroke primarily model a single intracerebral hemorrhage(ICH)attack,and there is a lack of a reliable model of recurrent *** this study,we established 16-month-old C57 B L/6 male mouse models of ICH by injecting collagenaseⅦ-S into the left ***-one days later,we injected collagenaseⅦ-S into the right striatum to simulate recurrent *** results showed that mice subjected to bilateral striatal hemorrhage had poorer neurological function at the early stage of hemorrhage,delayed recovery in locomotor function,motor coordination,and movement speed,and more obvious emotional and cognitive dysfunction than mice subjected to unilate ral striatal *** findings indicate that mouse models of bilateral striatal hemorrhage can well simulate clinically common recurrent *** models should be used as a novel tool for investigating the pathogenesis and treatment targets of recurrent ICH.

关键词： animal model cognition impairment depression-like behavior dopaminergic neurons emotion intracerebral hemorrhage motor neurologic function recurrent intracerebral hemorrhage

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Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage

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Neural Regeneration Research 2023年第3期18卷 560-567页

作者： Liu-Ting Hu Bing-Yang Wang Yu-Hua Fan Zhi-Yi He Wen-Xu Zheng Department of Neurology The First Affiliated HospitalSun Yat-Sen UniversityGuangzhouGuangdong ProvinceChina Department of Neurology The First Affiliated Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Geriatric Department of Dalian Friendship Hospital DalianLiaoning ProvinceChina

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage(ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase Ⅶ into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10(PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3(NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.

关键词： bone marrow mesenchymal stem cells exosomal miRNAs intracerebral hemorrhage miR-23b neuroinflammation NLRP3 inflammasome Nrf2 oxidative stress PTEN pyroptosis

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ATAT1 deficiency enhances microglia/macrophage-mediated erythrophagocytosis and hematoma absorption following intracerebral hemorrhage

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Neural Regeneration Research 2024年第5期19卷 1072-1077页

作者： Yihua Zhang Ping Huang Min Cao Yi Chen Xinhu Zhao Xuzhi He Lunshan Xu Department of Neurosurgery Daping HospitalArmy Medical UniversityChongqingChina

MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral *** cytoskeletal changes accompany ***,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain *** this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in *** first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell ***α-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during ***,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 *** with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral ***,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral *** findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral *** results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.

关键词： acetylatedα-tubulin α-tubulin acetyltransferase 1(ATAT1) erythrophagocytosis hematoma absorption intracerebral hemorrhage macrophage microglia

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