Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in...Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.展开更多
Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study ...Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 （DMT1） in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls＇ iron. Results showed massive loss of tyrosine hydroxylase （TH）-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.展开更多
Objective To investigate the potential involvement of DMT1（IRE） protein in the brain vascular system in vivo during Pb exposure. Methods Three groups of male Sprague-Dawley rats were exposed to Pb in drinking water,...Objective To investigate the potential involvement of DMT1（IRE） protein in the brain vascular system in vivo during Pb exposure. Methods Three groups of male Sprague-Dawley rats were exposed to Pb in drinking water, among which two groups were concurrently administered by oral gavage once every other day as the low and high Fe treatment group, respectively, for 6 weeks. At the same time, the group only supplied with high Fe was also set as a reference. The animals were decapitated, then brain capillary-rich fraction was isolate from cerebral cortex. Western blot method was used to identify protein expression, and RT-PCR to detect the change of the m RNA. Results Pb exposure significantly increased Pb concentrations in cerebral cortex. Low Fe dose significantly reduced the cortex Pb levels, However, high Fe dose increased the cortex Pb levels. Interestingly, changes of DMT1（IRE） protein in brain capillary-rich fraction were highly related to the Pb level, but those of DMT1（IRE） m RNA were not significantly different. Moreover, the consistent changes in the levels of p-ERK1/2 or IRP1 with the changes in the levels of DMT1（IRE）. Conclusion These results suggest that Pb is transported into the brain through DMT1（IRE）, and the ERK MAPK pathway is involved in DMT1（IRE）-mediated transport regulation in brain vascular system in vivo.展开更多
目的:研究运动性低血色素大鼠小肠铁吸收蛋白二价金属离子转运体1(divalent metal transporter1,DMT1)和膜铁转运蛋白1(ferroportin1,FPN1)表达的变化,探讨运动性低血色素的发生机制。方法:12只雄性Wistar大鼠随机分为对照组(CG)和实验...目的:研究运动性低血色素大鼠小肠铁吸收蛋白二价金属离子转运体1(divalent metal transporter1,DMT1)和膜铁转运蛋白1(ferroportin1,FPN1)表达的变化,探讨运动性低血色素的发生机制。方法:12只雄性Wistar大鼠随机分为对照组(CG)和实验组(EG)。实验组进行5周跑台训练,建立运动性低血色素模型。5周递增负荷跑台运动后,检测两组大鼠血常规和血清铁,采用Western Blot检测小肠上皮细胞DMT1和FPN1表达。结果:(1)实验组Hb显著低于对照组(P<0.01),运动性低血色素造模成功。(2)实验组大鼠小肠上皮细胞DMT1表达比对照组显著降低(P<0.05),FPN1表达比对照组显著下降(P<0.01)。(3)实验组血清铁和转铁蛋白饱合度显著低于对照组(P<0.05,P<0.01)。结论:长时间大强度运动会减少机体肠铁吸收,降低机体运铁能力,是引发运动性低血色素的原因之一。展开更多
目的:研究运动性低血色素形成中大鼠十二指肠铁转运蛋白血红素转运蛋白1(heme carrier protein 1,HCP1)、二价金属离子转运体1(divalent metal transporter1,DMT1)及膜铁转运蛋白1(ferroportin1,FPN1)表达的动态变化,探讨运动性低血色...目的:研究运动性低血色素形成中大鼠十二指肠铁转运蛋白血红素转运蛋白1(heme carrier protein 1,HCP1)、二价金属离子转运体1(divalent metal transporter1,DMT1)及膜铁转运蛋白1(ferroportin1,FPN1)表达的动态变化,探讨运动性低血色素的发生机制。方法:36只雄性Wistar大鼠随机分为对照组和运动组。运动组大鼠进行为期5周、6 d/周、坡度为0、速度30 m/min的递增负荷跑台训练。前2周每天训练1次,时间从1 min开始,每次递增2 min。从第3周开始,每天训练2次。分别于运动第3、4、5周末取材,采用血细胞自动分析仪测定血红蛋白(Hb)含量;Western Blot检测十二指肠上皮细胞HCP1、DMT1及FPN1表达。结果:(1)长时间大强度运动后大鼠Hb含量逐渐降低。运动组3周末Hb与其对照组相比有下降趋势,4周和5周末显著低于其对照组(P<0.05,P<0.01)。(2)运动组大鼠3周末小肠上皮细胞HCP1、DMT1及FPN1表达均显著高于其对照组(P<0.01),4周末与其对照组相比均无显著差异(P>0.05),5周末均显著低于对照组(P<0.01)。结论:大强度运动开始阶段,机体通过增加肠铁吸收维持运动机体对铁的需求,随运动时间延长,机体肠铁吸收能力降低,这是引发运动性低血色素的重要原因之一。展开更多
目的研究二价金属离子转运体1(divalent metal transporter 1,DMT1)在APP/PS1转基因小鼠大脑皮层内的定位分布,探讨DMT1异常表达影响脑铁代谢平衡从而参与AD发病的可能机制。方法应用免疫组织化学方法观察DMT1在9月龄APPsw/PS1小鼠大脑...目的研究二价金属离子转运体1(divalent metal transporter 1,DMT1)在APP/PS1转基因小鼠大脑皮层内的定位分布,探讨DMT1异常表达影响脑铁代谢平衡从而参与AD发病的可能机制。方法应用免疫组织化学方法观察DMT1在9月龄APPsw/PS1小鼠大脑皮层的阳性分布;应用免疫荧光双标技术和共聚焦激光扫描显微镜观察DMT1蛋白和β淀粉样蛋白(β-amyloid peptide,Aβ)在APP/PS1转基因小鼠大脑皮层老年斑内的一致性分布和位置关系。结果APP/PS1转基因小鼠大脑皮层老年斑内均有DMT1阳性表达;DMT1和Aβ免疫双标发现DMT1免疫阳性产物与Aβ共存于老年斑,二者分布具有一致性。结论DMT1在APP/PS1转基因小鼠大脑皮层老年斑内大量表达,其分布与Aβ具有一致性,提示DMT1可能参与AD脑内Aβ沉积和老年斑形成。展开更多
The transport properties were studied for rare earth manganese oxide La_(0.67)Ca_(0.33)Mn_(1-x)Fe_xO_3 (x=0～0.3) systems. It is found that with increasing Fe^(3+)-doping content x, the resistance increases and the in...The transport properties were studied for rare earth manganese oxide La_(0.67)Ca_(0.33)Mn_(1-x)Fe_xO_3 (x=0～0.3) systems. It is found that with increasing Fe^(3+)-doping content x, the resistance increases and the insulator-metal transition temperature (T_(IM)) shifts to lower temperature. If the doping content is small, the transport properties manifest metallic characteristics in the temperature range of T<T_(IM), while they will obey a thermal activation model in the temperature range of T>T_(IM). Such a behavior may be attributed to the Fe^(3+)-doping and possible Mn ions scattering to electrons. The Fe^(3+) doping may lead to the formation of Fe^(3+)-O^(2-)-Mn^(4+) channels, which could terminate the double exchange Mn^(3+)-O^(2-)-Mn^(4+) channels. The antiferromagnetic clusters of Fe ions may induce the Mn ions to scetter to the electrons.展开更多
The amyloid beta precursor protein (APP) and its pathogenic byproduct β-amyloid peptide (Aβ) play central roles in the pathogenesis of Alzheimer’s disease (AD). Reduction in
基金We thank Dr Wei-dong Le for providing the MES23.5 cell line. This work was supported by grants from the National Program of Basic Research sponsored by the Ministry of Science and Tech- nology of China （2006CB500704）, the National Natural Science Foundation of China （30930036, 30770757, 30870858） and the Natural Science Fund of Shandong Province for Distinguished Young Scholars （JQ200807）.
文摘Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.
基金the Scientific Research Common Program of Beijing Municipal Commission of Education,No.KM200610025008
文摘Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 （DMT1） in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls＇ iron. Results showed massive loss of tyrosine hydroxylase （TH）-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.
基金Supported by"2009 Clinical and Basic Clinical Research Contest"of the Bureau for Clinical Research Support from the University of Chile Clinical Hospital
文摘AIM: To describe the variation that divalent metal transporter 1 (DMT1) shows in patients after Roux-en-Y gastric bypass (RYGB) surgery.
基金supported by National Natural Science Foundation of China(No.81472478)Medical Science Youth Breeding Project of PLA(13QNP161)
文摘Objective To investigate the potential involvement of DMT1（IRE） protein in the brain vascular system in vivo during Pb exposure. Methods Three groups of male Sprague-Dawley rats were exposed to Pb in drinking water, among which two groups were concurrently administered by oral gavage once every other day as the low and high Fe treatment group, respectively, for 6 weeks. At the same time, the group only supplied with high Fe was also set as a reference. The animals were decapitated, then brain capillary-rich fraction was isolate from cerebral cortex. Western blot method was used to identify protein expression, and RT-PCR to detect the change of the m RNA. Results Pb exposure significantly increased Pb concentrations in cerebral cortex. Low Fe dose significantly reduced the cortex Pb levels, However, high Fe dose increased the cortex Pb levels. Interestingly, changes of DMT1（IRE） protein in brain capillary-rich fraction were highly related to the Pb level, but those of DMT1（IRE） m RNA were not significantly different. Moreover, the consistent changes in the levels of p-ERK1/2 or IRP1 with the changes in the levels of DMT1（IRE）. Conclusion These results suggest that Pb is transported into the brain through DMT1（IRE）, and the ERK MAPK pathway is involved in DMT1（IRE）-mediated transport regulation in brain vascular system in vivo.
基金This work was supported by the National Natural Science Foundation of China (No. 30271441) Key Project of Shandong Educational Committee (J01 K03) and Qingdao Municipal Science & Technology Commission (02-1-KJ-YJ-49).
文摘目的:研究运动性低血色素大鼠小肠铁吸收蛋白二价金属离子转运体1(divalent metal transporter1,DMT1)和膜铁转运蛋白1(ferroportin1,FPN1)表达的变化,探讨运动性低血色素的发生机制。方法:12只雄性Wistar大鼠随机分为对照组(CG)和实验组(EG)。实验组进行5周跑台训练,建立运动性低血色素模型。5周递增负荷跑台运动后,检测两组大鼠血常规和血清铁,采用Western Blot检测小肠上皮细胞DMT1和FPN1表达。结果:(1)实验组Hb显著低于对照组(P<0.01),运动性低血色素造模成功。(2)实验组大鼠小肠上皮细胞DMT1表达比对照组显著降低(P<0.05),FPN1表达比对照组显著下降(P<0.01)。(3)实验组血清铁和转铁蛋白饱合度显著低于对照组(P<0.05,P<0.01)。结论:长时间大强度运动会减少机体肠铁吸收,降低机体运铁能力,是引发运动性低血色素的原因之一。
文摘目的研究二价金属离子转运体1(divalent metal transporter 1,DMT1)在APP/PS1转基因小鼠大脑皮层内的定位分布,探讨DMT1异常表达影响脑铁代谢平衡从而参与AD发病的可能机制。方法应用免疫组织化学方法观察DMT1在9月龄APPsw/PS1小鼠大脑皮层的阳性分布;应用免疫荧光双标技术和共聚焦激光扫描显微镜观察DMT1蛋白和β淀粉样蛋白(β-amyloid peptide,Aβ)在APP/PS1转基因小鼠大脑皮层老年斑内的一致性分布和位置关系。结果APP/PS1转基因小鼠大脑皮层老年斑内均有DMT1阳性表达;DMT1和Aβ免疫双标发现DMT1免疫阳性产物与Aβ共存于老年斑,二者分布具有一致性。结论DMT1在APP/PS1转基因小鼠大脑皮层老年斑内大量表达,其分布与Aβ具有一致性,提示DMT1可能参与AD脑内Aβ沉积和老年斑形成。
文摘The transport properties were studied for rare earth manganese oxide La_(0.67)Ca_(0.33)Mn_(1-x)Fe_xO_3 (x=0～0.3) systems. It is found that with increasing Fe^(3+)-doping content x, the resistance increases and the insulator-metal transition temperature (T_(IM)) shifts to lower temperature. If the doping content is small, the transport properties manifest metallic characteristics in the temperature range of T<T_(IM), while they will obey a thermal activation model in the temperature range of T>T_(IM). Such a behavior may be attributed to the Fe^(3+)-doping and possible Mn ions scattering to electrons. The Fe^(3+) doping may lead to the formation of Fe^(3+)-O^(2-)-Mn^(4+) channels, which could terminate the double exchange Mn^(3+)-O^(2-)-Mn^(4+) channels. The antiferromagnetic clusters of Fe ions may induce the Mn ions to scetter to the electrons.
文摘目的进一步确定二价金属离子转运体1(DMT1)在人胎盘绒毛膜癌细胞(Be Wo)中的表达定位,以及缺铁状态下m RNA的表达变化。方法采用免疫细胞化学技术观察DMT1在Be Wo细胞中的表达定位,采用实时荧光定量聚合酶链反应检测DMT1在Be Wo细胞缺铁状态下m RNA的表达变化。结果 DMT1在Be Wo细胞中呈阳性表达,其弥漫性表达定位于细胞质和细胞膜上;DMT1+IRE m RNA和DMT1-IRE m RNA的相对表达量随缺铁干预浓度和时间的增加而上调。DMT1+IRE m RNA的相对表达量高于DMT1-IRE m RNA。结论DMT1大量表达在Be Wo细胞质和细胞膜上,且表达受机体不同铁水平的调节,说明其在胎盘铁转运过程中发挥重要作用,为进一步探讨胎盘铁转运分子机制提供实验基础。
文摘The amyloid beta precursor protein (APP) and its pathogenic byproduct β-amyloid peptide (Aβ) play central roles in the pathogenesis of Alzheimer’s disease (AD). Reduction in
