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Exosomes derived from microglia overexpressing miR-124-3p alleviate neuronal endoplasmic reticulum stress damage after repetitive mild traumatic brain injury

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Neural Regeneration Research 2024年第9期19卷 2010-2018页

作者： Yan Wang Dai Li Lan Zhang Zhenyu Yin Zhaoli Han Xintong Ge Meimei Li Jing Zhao Shishuang Zhang Yan Zuo Xiangyang Xiong Han Gao Qiang Liu Fanglian chen Ping Lei Department of Geriatrics Tianjin Medical University General HospitalTianjinChina Tianjin Geriatrics Institute Tianjin Medical University General HospitalTianjinChina Tianjin Neurological Institute Tianjin Medical University General HospitalTianjinChina

We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.

关键词： apoptosis c/ebp homologous protein endoplasmic reticulum stress exosome inositol-requiring enzyme 1α microglia miR-124-3p neuron repetitive mild traumatic brain injury X-box binding protein 1

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Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury:PERK as a potential target for intervention

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Neural Regeneration Research 2025年第5期20卷 1455-1466页

作者： Ju Zheng Yixin Li Ting Zhang Yanlin Fu Peiyan Long Xiao Gao Zhengwei Wang Zhizhong Guan Xiaolan Qi Wei Hong Yan Xiao Key Laboratory of Endemic and Ethnic Diseases Ministry of Education&Key Laboratory of Medical Molecular Biology of Guizhou ProvinceGuizhou Medical UniversityGuiyangGuizhou ProvinceChina Guizhou center for Disease control and Prevention GuiyangGuizhou ProvinceChina Department of Histology and Embryology Guizhou Medical UniversityGuiyangGuizhou ProvinceChina collaborative Innovation center for Prevention and control of Endemic and Ethnic Regional Diseases co-constructed by the Province and Ministry GuiyangGuizhou ProvinceChina

Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in Pc12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-c/ebp homologous protein(cHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.

关键词： apoptosis ATF4 autophagy c/ebp homologous protein cerebral ischemia/reperfusion injury eIF2α endoplasmic reticulum stress PERK

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Valproate reduces retinal ganglion cell apoptosis in rats after optic nerve crush

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Neural Regeneration Research 2023年第7期18卷 1607-1612页

作者： Feng Pan Dan Hu Li-Juan Sun Qian Bai Yu-Sheng Wang Xu Hou Eye Institute of chinese PLA and Department of Ophthalmology Xijing HospitalFourth Military Medical UniversityXi’anShaanxi ProvinceChina

The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor c/ebp homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-c/ebp homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.

关键词： apoptosis c/ebp homologous protein caspase-12 endoplasmic reticulum glucose-regulated protein 78 optic nerve crush phosphorylated eukaryotic translation initiation factor 2α retinal ganglion cells unfolded protein response valproate

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Polyphyllin I promotes cell death via suppressing UPR-mediated cHOP ubiquitination and degradation in non-small cell lung cancer

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chinese Journal of Natural Medicines 2021年第4期19卷 255-266页

作者： LIU Ming-Ming ZHU Miao-Lin DONG Rui-Fang ZHANG chao ZHANG Hao YANG Lei KONG Ling-Yi XIA Yuan-Zheng Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Jiangsu cancer Hospital Nanjing 210009China

Polyphyllin I(PPI)purified from Polyphylla rhizomes displays puissant cytotoxicity in many kinds of cancers.Several researches investigated its anti-cancer activity.But novel mechanisms are still worth investigation.This study aimed to explore PPI-induced endoplasmic reticulum(ER)stress as well as the underlying mechanism in non-small cell lung cancer(NScLc).cell viability or colony-forming was detected by MTT or crystal violet respectively.cell cycle,apoptosis,reactive oxygen species(ROS)and mitochondrial membrane potential were assessed by flow cytometry.Gene and protein levels were evaluated by q RT-PcR and immunoblotting respectively.protein interaction was determined by immunoprecipitation or immunofluorescence assay.Gene overexpression or silencing was carried out by transient transfection with plasmids or small interfering RNAs.The cancer Genome Atlas(TcGA)database was used for Gene Set Enrichment Analysis(GSEA),survival analysis,gene expression statistics or pathway enrichment assay.PPI inhibited the propagation of NScLc cells,increased non-viable apoptotic cells,arrested cell cycle at G2/M phase,induced ROS levels but failed to decrease mitochondrial membrane potential.High levels of GRP78 indicates poor prognosis in NScLc patients.PPI selectively suppressed unfolded protein response(UPR)-induced GRP78 expression,subsequently protected cHOP from GRP78-mediated ubiquitination and degradation.We demonstrated that the natural product PPI,obtained from traditional herbal medicine,deserves for further study as a valuable candidate for lead compound in the chemotherapy of NScLc.

关键词： Non-small cell lung cancer Polyphyllin I Endoplasmic reticulum stress c/ebp homologous protein Ubiquitination

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Modulation of valosin-containing protein by Kyoto University Substances(KUS) as a novel therapeutic strategy for ischemic neuronal diseases

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Neural Regeneration Research 2017年第8期12卷 1252-1255页

作者： Masayuki Hata Hanako Ohashi Ikeda Department of Ophthalmology and Visual Sciences Kyoto University Graduate School of Medicine Neuroprotective Treatment Project for Ocular Diseases Institute for Advancement of Clinical and Translational Science Kyoto University Hospital

Retinal ischemia causes several vision-threatening diseases, including diabetic retinopathy, retinal artery occlusion, and retinal vein occlusion. Intracellular adenosine triphosphate（ATP） depletion and subsequent induced endoplasmic reticulum（ER） stress are proposed to be the underlying mechanisms of ischemic retinal cell death. Recently, we found that a naphthalene derivative can inhibit ATPase activity of valosin-containing protein, universally expressed within various types of cells, including retinal neural cells, with strong cytoprotective activity. Based on the chemical structure, we developed novel valosin-containing protein modulators, Kyoto University Substances（KUSs）, that not only inhibit intracellular ATP depletion, but also ameliorate ER stress. Suppressing ER stress by KUSs is associated with neural cell survival in animal models of several neurodegenerative diseases, such as glaucoma and retinal degeneration. Given that a major pathology of ischemic retinal diseases, other than intracellular ATP depletion, is ER stress-induced cell death, KUSs may provide a novel strategy for cell protection in ischemic conditions. Hence, we investigated the efficacy of KUS121 in a rat model of retinal ischemic injury. Intravitreal injections of KUS121, which is clinically preferable route of drug administration in retinal diseases, significantly suppressed inner retinal thinning and retinal cell death, and maintained visual functions. Valosin-containing protein modulation by KUS is a promising novel therapeutic strategy for ischemic retinal diseases.

关键词： adenosine triphosphatase c/ebp homologous protein central retinal artery occlusion endoplasmicreticulum stress neuroprotective therapy retinal ganglion cell

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