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Eph receptor A4 regulates motor neuron ferroptosis in spinal cord ischemia/reperfusion injury in rats

Neural Regeneration Research 2023年第10期18卷 2219-2228页

作者： Yan Dong Chunyu Ai Ying Chen Zaili Zhang Dong Zhang Sidan Liu Xiangyi Tong Hong Ma Department of Anesthesiology the First Hospital of China Medical UniversityShenyangLiaoning ProvinceChina

Previous studies have shown that the receptor tyrosine kinase Eph receptor A4(EphA4) is abundantly expressed in the nervous system. The EphA4 signaling pathway plays an important role in regulating motor neuron ferroptosis in motor neuron disease. To investigate whether EphA4 signaling is involved in ferroptosis in spinal cord ischemia/reperfusion injury, in this study we established a rat model of spinal cord ischemia/reperfusion injury by clamping the left carotid artery and the left subclavian artery. We found that spinal cord ischemia/reperfusion injury increased EphA4 expression in the neurons of anterior horn, markedly worsened ferroptosis-related indicators, substantially increased the number of mitochondria exhibiting features consistent with ferroptosis, promoted deterioration of motor nerve function, increased the permeability of the blood-spinal cord barrier, and increased the rate of motor neuron death. Inhibition of EphA4 largely rescued these effects. However, intrathecal administration of the ferroptosis inducer Erastin counteracted the beneficial effects conferred by treatment with the EphA4 inhibitor. Mass spectrometry and a PubMed search were performed to identify proteins that interact with EphA4, with the most notable being Beclin1 and Erk1/2. Our results showed that inhibition of EphA4 expression reduced binding to Beclin1, markedly reduced p-Beclin1, and reduced Beclin1-XCT complex formation. Inhibition of EphA4 also reduced binding to p-Erk1/2 and markedly decreased the expression of c-Myc, transferrin receptor 1, and p-Erk1/2. Additionally, we observed co-localization of EphA4 and p-Beclin1 and of EphA4 and p-ERK1/2 in neurons in the anterior horn. In conclusion, EphA4 participates in regulating ferroptosis of spinal motor neurons in the anterior horn in spinal cord ischemia/reperfusion injury by promoting formation of the Beclin1-XCT complex and activating the Erk1/2/c-Myc/transferrin receptor 1 axis.

关键词： Beclin1 c-Myc EphA4 Erk1/2 ferroptosis motor neuron p-Erk1/2 rat spinal cord ischemia/reperfusion injury transferrin receptor 1

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Upregulation of CDGSH iron sulfur domain 2 attenuates cerebral ischemia/reperfusion injury

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Neural Regeneration Research 2023年第7期18卷 1512-1520页

作者： Miao Hu Jie Huang Lei Chen Xiao-Rong Sun Zi-Meng Yao Xu-Hui Tong Wen-Jing Jin Yu-Xin Zhang Shu-Ying Dong Department of Pharmacology School of PharmacyBengbu Medical CollegeBengbuAnhui ProvinceChina Key Laboratory of Cardiovascular and Cerebrovascular Diseases Bengbu Medical CollegeBengbuAnhui ProvinceChina Anhui Engineering Technology Research Center of Biochemical Pharmaceutical BengbuAnhui ProvinceChina

CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

关键词： cerebral ischemia/reperfusion injury CDGSH iron sulfur domain 2 ferroptosis glutathione peroxidase 4 heme oxygenase 1 HT22 nuclear-factor E2-related factor 2 oxygen-glucose deprivation/reoxygenation injury stroke transferrin receptor 1

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TfR1 Extensively Regulates the Expression of Genes Associated with Ion Transport and Immunity

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Current Medical Science 2020年第3期40卷 493-501页

作者： Nan HUANG Lei-Lei ZHAN Yi CHENG Xiao-long WANG Ya-xun WEI Qi WANG Wen-jing LI Department of Allergy Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Center for Genome Analysis ABLife Inc.Wuhan430075China Department of Oncology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

transferrin receptor 1(TfR1),encoded by the TFRC gene,is the gatekeeper of cellular iron uptake for cells.A variety of molecular mechanisms are at work to tightly regulate TfR1 expression,and abnormal TfR1 expression has been associated with various diseases.In the current study,to determine the regulation pattern of TfR1,we cloned and overexpressed the human TFRC gene in HeLa cells.RNA-sequencing(RNA-seq)was used to analyze the global transcript levels in overexpressed(OE)and normal control(NC)samples.A total of 1669 differentially expressed genes(DEGs)were identified between OE and NC.Gene ontology(GO)analysis was carried out to explore the functions of the DEGs.It was found that multiple DEGs were associated with ion transport and immunity.Moreover,the regulatory network was constructed on basis of DEGs associated with ion transport and immunity,highlighting that TFRC was the node gene of the network.These results together suggested that precisely controlled TfR1 expression might be not only essential for iron homeostasis,but also globally important for cell physiology,including ion transport and immunity.

关键词： transferrin receptor 1 overexpression RNA-seq differentially expressed genes ion transport cellular immunity

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