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 ...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.展开更多
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 ferrop...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.展开更多
Transferrin receptor 1(TfR1),a widely expressed type Ⅱ transmembrane glycoprotein located on the plasma membrane,is well known for its established role in cellular iron uptake.Nevertheless,emerging evidence implies t...Transferrin receptor 1(TfR1),a widely expressed type Ⅱ transmembrane glycoprotein located on the plasma membrane,is well known for its established role in cellular iron uptake.Nevertheless,emerging evidence implies that TfR1 exhibits previously unrecognized noncanonical functions.Herein,we demonstrated the nuclear translocation of TfR1 and revealed the interaction between TfR1 and p53 within the nucleus.Through comprehensive analyses at the proteomic,genomic,and transcriptomic levels,we demonstrated that this interaction significantly influences the transcriptional activity of p53 on its downstream target genes,which are highly enriched in DNA damage repair functions.Specifically,our investigation revealed the indispensable role of nuclear TfR1 in the regulation of the nucleotide excision repair(NER)pathway,exemplified by the transcriptional regulation of XPC.展开更多
目的探讨小剂量泼尼松联合他克莫司治疗老年IgA肾病的疗效。方法选择2020年3月至2021年1月在濮阳市安阳地区医院就诊的94例老年IgA肾病患者为研究对象。采用随机数字表法将患者分为对照组和观察组,每组47例。2组患者均给予基础支持治疗...目的探讨小剂量泼尼松联合他克莫司治疗老年IgA肾病的疗效。方法选择2020年3月至2021年1月在濮阳市安阳地区医院就诊的94例老年IgA肾病患者为研究对象。采用随机数字表法将患者分为对照组和观察组,每组47例。2组患者均给予基础支持治疗。对照组患者口服泼尼松60 mg,每日1次,连续服用8周后改为0.2 mg·kg^(-1)·d^(-1)维持剂量,继续服用6个月。观察组患者口服他克莫司和小剂量泼尼松进行治疗,他克莫司初始剂量4~5 mg·kg^(-1)·d^(-1),分2次口服,服用8周后缓慢减量至2~3 mg·kg^(-1)·d^(-1);小剂量泼尼松最大剂量45 mg,每日1次,连续服用8周后减为0.1 mg·kg^(-1)·d^(-1)维持剂量,服用6个月。分别于治疗前和治疗8个月后采集2组患者外周静脉血5 mL,使用全自动生物化学分析仪测定血肌酐(Scr)、血尿素氮(BUN)水平,并计算估算的肾小球滤过率(eGFR);采用酶联免疫法测定血清中转化生长因子-β_(1)(TGF-β_(1))、可溶性转铁蛋白受体(sTfR)水平。分别于治疗前和治疗8个月后收集2组患者24 h尿液,采用比色法测定24 h尿蛋白定量(24 h UTP)。比较2组患者治疗8个月后临床疗效。结果观察组和对照组患者的治疗总有效率分别为91.49%(43/47)、74.47%(35/47),观察组患者的治疗总有效率显著高于对照组(χ^(2)=24.821,P<0.05)。治疗前2组患者的Scr、BUN水平及24 h UTP、eGFR比较差异均无统计学意义(P>0.05)。2组患者治疗后的Scr、BUN水平及24 h UTP显著低于治疗前,eGFR显著高于治疗前(P<0.05)。治疗后,观察组患者的Scr、BUN水平及24 h UTP显著低于对照组,eGFR显著高于对照组(P<0.05)。治疗前2组患者血清中TGF-β_(1)、sTfR水平比较差异无统计学意义(P>0.05)。2组患者治疗后血清中TGF-β_(1)、sTfR水平显著低于治疗前(P<0.05)。治疗后,观察组患者血清中TGF-β_(1)、sTfR水平显著低于对照组(P<0.05)。结论小剂量泼尼松联合他克莫司可有效降低老年IgA肾病患者尿蛋白水平,改善患者肾功能,提高临床疗效。展开更多
基金The work was supported by the General Fund of Health Commission of Hubei Province(No.WJ2019M147).
文摘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.
基金supported by the National Natural Science Foundation of China,No.81771342 (to HM)。
文摘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.
基金financially supported by the National Key Research and Development Program of China(2021YFA1201102)the National Natural Science Foundation of China(No.32301163,82072054)+1 种基金the Youth Innovation Promotion Association of the Chinese Academy of Sciences(Y2023024)the Beijing Nova Program(Z211100002121023,20220484207).
文摘Transferrin receptor 1(TfR1),a widely expressed type Ⅱ transmembrane glycoprotein located on the plasma membrane,is well known for its established role in cellular iron uptake.Nevertheless,emerging evidence implies that TfR1 exhibits previously unrecognized noncanonical functions.Herein,we demonstrated the nuclear translocation of TfR1 and revealed the interaction between TfR1 and p53 within the nucleus.Through comprehensive analyses at the proteomic,genomic,and transcriptomic levels,we demonstrated that this interaction significantly influences the transcriptional activity of p53 on its downstream target genes,which are highly enriched in DNA damage repair functions.Specifically,our investigation revealed the indispensable role of nuclear TfR1 in the regulation of the nucleotide excision repair(NER)pathway,exemplified by the transcriptional regulation of XPC.
文摘目的探讨小剂量泼尼松联合他克莫司治疗老年IgA肾病的疗效。方法选择2020年3月至2021年1月在濮阳市安阳地区医院就诊的94例老年IgA肾病患者为研究对象。采用随机数字表法将患者分为对照组和观察组,每组47例。2组患者均给予基础支持治疗。对照组患者口服泼尼松60 mg,每日1次,连续服用8周后改为0.2 mg·kg^(-1)·d^(-1)维持剂量,继续服用6个月。观察组患者口服他克莫司和小剂量泼尼松进行治疗,他克莫司初始剂量4~5 mg·kg^(-1)·d^(-1),分2次口服,服用8周后缓慢减量至2~3 mg·kg^(-1)·d^(-1);小剂量泼尼松最大剂量45 mg,每日1次,连续服用8周后减为0.1 mg·kg^(-1)·d^(-1)维持剂量,服用6个月。分别于治疗前和治疗8个月后采集2组患者外周静脉血5 mL,使用全自动生物化学分析仪测定血肌酐(Scr)、血尿素氮(BUN)水平,并计算估算的肾小球滤过率(eGFR);采用酶联免疫法测定血清中转化生长因子-β_(1)(TGF-β_(1))、可溶性转铁蛋白受体(sTfR)水平。分别于治疗前和治疗8个月后收集2组患者24 h尿液,采用比色法测定24 h尿蛋白定量(24 h UTP)。比较2组患者治疗8个月后临床疗效。结果观察组和对照组患者的治疗总有效率分别为91.49%(43/47)、74.47%(35/47),观察组患者的治疗总有效率显著高于对照组(χ^(2)=24.821,P<0.05)。治疗前2组患者的Scr、BUN水平及24 h UTP、eGFR比较差异均无统计学意义(P>0.05)。2组患者治疗后的Scr、BUN水平及24 h UTP显著低于治疗前,eGFR显著高于治疗前(P<0.05)。治疗后,观察组患者的Scr、BUN水平及24 h UTP显著低于对照组,eGFR显著高于对照组(P<0.05)。治疗前2组患者血清中TGF-β_(1)、sTfR水平比较差异无统计学意义(P>0.05)。2组患者治疗后血清中TGF-β_(1)、sTfR水平显著低于治疗前(P<0.05)。治疗后,观察组患者血清中TGF-β_(1)、sTfR水平显著低于对照组(P<0.05)。结论小剂量泼尼松联合他克莫司可有效降低老年IgA肾病患者尿蛋白水平,改善患者肾功能,提高临床疗效。
