Parkinson’s disease(PD)is a neurodegenerative disorder characterized by the loss of dopaminergic neurons,and its prevalence is increasing,alongside global population aging.Neuroinflammation has been widely recognized...Parkinson’s disease(PD)is a neurodegenerative disorder characterized by the loss of dopaminergic neurons,and its prevalence is increasing,alongside global population aging.Neuroinflammation has been widely recognized as a pivotal contributor to PD pathogenesis,particularly owing to the dual role of microglia in this process.This review systematically identifies the multiple factors regulating microglial function and phenotype,thereby driving PD initiation and progression.Furthermore,aging,a major risk factor for PD,and its profound effects on microglial state and functional dynamics are discussed.Notably,microglial hyperactivation is shown to establish a self-perpetuating cycle of“inflammation–damage–reinflammation”through the excessive release of pro-inflammatory cytokines and chemokines,which exacerbates neuronal degeneration.Lastly,the potential therapeutic strategies targeting microglial dysfunction,including interventions against the senescence-associated secretory phenotype and the modulation of microglial activity,are summarized.By elucidating how multifactorial alterations in microglial states influence PD pathology,this review provides novel insights and directions for advancing therapeutic research in PD.展开更多
目的探讨不同剂量重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)在宫内缺血缺氧时透过胎盘屏障及胎鼠血脑屏障的通透性。方法孕19d(孕晚期)SD大鼠,分为3组:rhEPO治疗组(Treat组)、假手术对照组(Sham组)和生理盐水缺血...目的探讨不同剂量重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)在宫内缺血缺氧时透过胎盘屏障及胎鼠血脑屏障的通透性。方法孕19d(孕晚期)SD大鼠,分为3组:rhEPO治疗组(Treat组)、假手术对照组(Sham组)和生理盐水缺血对照组(I/R组)。Treat组和I/R组制备宫内缺血缺氧模型,Sham组只进行开关腹手术。Treat组和Sham组根据注射rhEPO的剂量不同各自再分为3组,分别在宫内缺血缺氧处理或开关腹手术前30min经孕鼠尾静脉注射125I标记的rhEPO 2500U/kg、5000U/kg、7500U/kg,I/R组在宫内缺血缺氧处理前30min经尾静脉注入生理盐水。均于缺血缺氧处理或开关腹手术后24h取胎盘、羊水及胎鼠脑、肝、心、肺和肾,检测并比较各组织中125I-rhEPO的放射比活性。结果 Treat组和Sham组胎盘、羊水及胎鼠各组织中均能检测到125I-rhEPO的分布。125I-rhEPO在胎盘、羊水及胎鼠各组织中的分布均随rhEPO注射剂量的增加而增加。在各剂量组中,Treat组胎鼠各组织中的125I-rhEPO含量均高于Sham组(P<0.05)。结论在宫内缺血缺氧环境下,胎盘屏障及胎鼠血脑屏障对外源性rhEPO的通透性增加。展开更多
Objective Alzheimer's disease(AD)is a progressive neurodegenerative disease associated with metabolic dysregulation.This study aimed to investigate the role of homogentisic acid(HGA),a tyrosine metabolite,in AD pa...Objective Alzheimer's disease(AD)is a progressive neurodegenerative disease associated with metabolic dysregulation.This study aimed to investigate the role of homogentisic acid(HGA),a tyrosine metabolite,in AD pathogenesis and explore its potential as a noninvasive diagnostic biomarker.Methods Human saliva samples from AD patients and controls were analyzed.In vivo experiments were conducted using APP/PS1(Aβ-driven)and P301S(tauopathy-focused)mouse models,which received exogenous HGA via gavage.Key techniques included behavioral tests(Morris water maze,novel object recognition,fear conditioning),Western blot,immu-nofluorescence,real-time PCR,and mass spectrometry to assess cognitive function,blood-brain barrier(BBB)integrity,Aβaggregation,synaptic protein expression,and HGA metabolism.In vitro experiments were performed on HT22,SY5Y cells,and primary brain microvascular endothelial cells(BMECs)to verify HGA's direct effects.Results Salivary HGA levels were higher in AD patients than in controls,correlating with BBB impairment.Exogenous HGA significantly exacerbated cognitive deficits,BBB leakage,Aβdeposition,and loss of synaptic proteins(PSD93,synaptophy-sin)in mice,with effects more pronounced in the APP/PS1 than in the P301S model.In vitro,HGA exerted dose-dependent neurotoxicity,promoted Aβaggregation,and downregulated tight junction proteins(claudin-5,occludin,ZO-1)in BMECs.Mechanistically,AD patients showed reduced expression of HGA-metabolizing enzymes(homogentisate 1,2-dioxygenase,maleylacetoacetate isomerase)and downstream metabolites,indicating impaired HGA catabolism.These findings confirm HGA promotes AD progression via two mutually reinforcing pathways:(1)accelerating Aβaggregation and synaptic dys-function;(2)disrupting BBB integrity through downregulating tight junction proteins.Conclusion This study identifies salivary HGA as a potential noninvasive biomarker and highlights targeting HGA metabo-lism or BBB protection as promising strategies for early AD intervention.展开更多
Traumatic brain injury(TBI)is a leading cause of death and disability worldwide,with∼50 million people experiencing TBI each year.Ferroptosis,a form of regulated cell death triggered by iron ioncatalyzed and reactive...Traumatic brain injury(TBI)is a leading cause of death and disability worldwide,with∼50 million people experiencing TBI each year.Ferroptosis,a form of regulated cell death triggered by iron ioncatalyzed and reactive oxygen species-induced lipid peroxidation,has been identified as a potential contributor to traumatic central nervous system conditions,suggesting its involvement in the pathogenesis of TBI.Alterations in iron metabolism play a crucial role in secondary injury following TBI.This study aimed to explore the role of ferroptosis in TBI,focusing on iron metabolism disorders,lipid metabolism disorders and the regulatory axis of system Xc−/glutathione/glutathione peroxidase 4 in TBI.Additionally,we examined the involvement of ferroptosis in the chronic TBI stage.Based on these findings,we discuss potential therapeutic interventions targeting ferroptosis after TBI.In conclusion,this review provides novel insights into the pathology of TBI and proposes potential therapeutic targets.展开更多
基金supported by the National Natural Science Foundation of China(32161143021,81271410)the Henan Natural Science Foundation(182300410313).
文摘Parkinson’s disease(PD)is a neurodegenerative disorder characterized by the loss of dopaminergic neurons,and its prevalence is increasing,alongside global population aging.Neuroinflammation has been widely recognized as a pivotal contributor to PD pathogenesis,particularly owing to the dual role of microglia in this process.This review systematically identifies the multiple factors regulating microglial function and phenotype,thereby driving PD initiation and progression.Furthermore,aging,a major risk factor for PD,and its profound effects on microglial state and functional dynamics are discussed.Notably,microglial hyperactivation is shown to establish a self-perpetuating cycle of“inflammation–damage–reinflammation”through the excessive release of pro-inflammatory cytokines and chemokines,which exacerbates neuronal degeneration.Lastly,the potential therapeutic strategies targeting microglial dysfunction,including interventions against the senescence-associated secretory phenotype and the modulation of microglial activity,are summarized.By elucidating how multifactorial alterations in microglial states influence PD pathology,this review provides novel insights and directions for advancing therapeutic research in PD.
文摘目的探讨不同剂量重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)在宫内缺血缺氧时透过胎盘屏障及胎鼠血脑屏障的通透性。方法孕19d(孕晚期)SD大鼠,分为3组:rhEPO治疗组(Treat组)、假手术对照组(Sham组)和生理盐水缺血对照组(I/R组)。Treat组和I/R组制备宫内缺血缺氧模型,Sham组只进行开关腹手术。Treat组和Sham组根据注射rhEPO的剂量不同各自再分为3组,分别在宫内缺血缺氧处理或开关腹手术前30min经孕鼠尾静脉注射125I标记的rhEPO 2500U/kg、5000U/kg、7500U/kg,I/R组在宫内缺血缺氧处理前30min经尾静脉注入生理盐水。均于缺血缺氧处理或开关腹手术后24h取胎盘、羊水及胎鼠脑、肝、心、肺和肾,检测并比较各组织中125I-rhEPO的放射比活性。结果 Treat组和Sham组胎盘、羊水及胎鼠各组织中均能检测到125I-rhEPO的分布。125I-rhEPO在胎盘、羊水及胎鼠各组织中的分布均随rhEPO注射剂量的增加而增加。在各剂量组中,Treat组胎鼠各组织中的125I-rhEPO含量均高于Sham组(P<0.05)。结论在宫内缺血缺氧环境下,胎盘屏障及胎鼠血脑屏障对外源性rhEPO的通透性增加。
基金supported by the Hubei Provincial Natural Science Foundation of China for Distinguished Young Scholars(No.2022CFA104 to Yi-yuan Xia)the Key Research and Development Program of Wuhan(No.2024020802030159 to Yi-yuan Xia)+1 种基金the National Natural Science Foundation of China(No.82371195 to Xi-ji Shu)the Research Fund of Jianghan University(No.2022XKZX26 to Shi-chao Deng).
文摘Objective Alzheimer's disease(AD)is a progressive neurodegenerative disease associated with metabolic dysregulation.This study aimed to investigate the role of homogentisic acid(HGA),a tyrosine metabolite,in AD pathogenesis and explore its potential as a noninvasive diagnostic biomarker.Methods Human saliva samples from AD patients and controls were analyzed.In vivo experiments were conducted using APP/PS1(Aβ-driven)and P301S(tauopathy-focused)mouse models,which received exogenous HGA via gavage.Key techniques included behavioral tests(Morris water maze,novel object recognition,fear conditioning),Western blot,immu-nofluorescence,real-time PCR,and mass spectrometry to assess cognitive function,blood-brain barrier(BBB)integrity,Aβaggregation,synaptic protein expression,and HGA metabolism.In vitro experiments were performed on HT22,SY5Y cells,and primary brain microvascular endothelial cells(BMECs)to verify HGA's direct effects.Results Salivary HGA levels were higher in AD patients than in controls,correlating with BBB impairment.Exogenous HGA significantly exacerbated cognitive deficits,BBB leakage,Aβdeposition,and loss of synaptic proteins(PSD93,synaptophy-sin)in mice,with effects more pronounced in the APP/PS1 than in the P301S model.In vitro,HGA exerted dose-dependent neurotoxicity,promoted Aβaggregation,and downregulated tight junction proteins(claudin-5,occludin,ZO-1)in BMECs.Mechanistically,AD patients showed reduced expression of HGA-metabolizing enzymes(homogentisate 1,2-dioxygenase,maleylacetoacetate isomerase)and downstream metabolites,indicating impaired HGA catabolism.These findings confirm HGA promotes AD progression via two mutually reinforcing pathways:(1)accelerating Aβaggregation and synaptic dys-function;(2)disrupting BBB integrity through downregulating tight junction proteins.Conclusion This study identifies salivary HGA as a potential noninvasive biomarker and highlights targeting HGA metabo-lism or BBB protection as promising strategies for early AD intervention.
基金supported by the National Natural Science Foundation of China(No.82204389,No.82301342,and No.82201455)the Henan Medical Science and Technique Foundation(No.LHGJ20210351).
文摘Traumatic brain injury(TBI)is a leading cause of death and disability worldwide,with∼50 million people experiencing TBI each year.Ferroptosis,a form of regulated cell death triggered by iron ioncatalyzed and reactive oxygen species-induced lipid peroxidation,has been identified as a potential contributor to traumatic central nervous system conditions,suggesting its involvement in the pathogenesis of TBI.Alterations in iron metabolism play a crucial role in secondary injury following TBI.This study aimed to explore the role of ferroptosis in TBI,focusing on iron metabolism disorders,lipid metabolism disorders and the regulatory axis of system Xc−/glutathione/glutathione peroxidase 4 in TBI.Additionally,we examined the involvement of ferroptosis in the chronic TBI stage.Based on these findings,we discuss potential therapeutic interventions targeting ferroptosis after TBI.In conclusion,this review provides novel insights into the pathology of TBI and proposes potential therapeutic targets.
