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81.
Abnormal iron homeostasis is increasingly thought to contribute to the pathogenesis of several neurodegenerative disorders. We have previously reported impaired iron homeostasis in a mouse model of spinal cord injury and in a mouse model of amyotrophic lateral sclerosis. Both these disorders are associated with CNS inflammation. However, what effect inflammation, and in particular, inflammatory cytokines have on iron homeostasis in CNS glia remains largely unknown. Here we report that the proinflammatory cytokine TNF-α, and the anti-inflammatory cytokine TGF-β1 affect iron homeostasis in astrocytes and microglia in distinct ways. Treatment of astrocytes in vitro with TNF-α induced the expression of the iron importer "divalent iron transporter 1" (DMT1) and suppressed the expression of the iron exporter ferroportin (FPN). However, TGF-β1 had no effect on DMT1 expression but increased the expression of FPN in astrocytes. In microglia, on the other hand, both cytokines caused induction of DMT1 and suppression of FPN expression. Iron influx and efflux assays in vitro confirmed that iron homeostasis in astrocytes and microglia is differentially regulated by these cytokines. In particular, TNF-α caused an increase in iron uptake and retention by both astrocytes and microglia, while TGF-β1 promoted iron efflux from astrocytes but caused iron retention in microglia. These data suggest that these two cytokines, which are expressed in CNS inflammation in injury and disease, can have profound and divergent effects on iron homeostasis in astrocytes and microglia. 相似文献
82.
Alfonso Fasano MD Cesare Colosimo MD Hiroaki Miyajima MD Pietro Attilio Tonali MD Thomas J. Re MD MSEE Anna Rita Bentivoglio MD PhD 《Movement disorders》2008,23(5):751-755
Hereditary aceruloplasminemia (HA) is a rare inherited disease characterized by anemia, iron overload, diabetes, and neurodegeneration. HA is caused by the homozygous mutation of the ceruloplasmin (CP) gene. We report two siblings with markedly different phenotypes carrying a novel mutation: a homozygous deletion of two nucleotides (1257–1258 TT del) causing the premature stop of the Cp protein translation (Y401X). An early diagnosis of iron overload was made in the female sibling who was subsequently treated with deferoxamine. At the age of 54, her neurologic symptoms were limited to mild akinetic signs and a history of seizures; moreover, her fasting blood glucose level never exceeded 120 mg/dL. The male sibling, who had not received any specific treatment for HA, developed severe diabetes at the age of 32 and at 48 manifested a progressively disabling neurologic disease. Possible physiopathological bases of these intrafamilial phenotypic variations are discussed. © 2008 Movement Disorder Society 相似文献
83.
Luis F. Gonzalez‐Cuyar George Perry Hiroaki Miyajima Craig S. Atwood Marcela Riveros‐Angel Patrick F. Lyons Sandra L. Siedlak Mark A. Smith Rudy J. Castellani 《Neuropathology》2008,28(5):466-471
Aceruloplasminemia is an autosomal recessive disorder characterized by a ceruloplasmin gene mutation and defective or absent ceruloplasmin function. Because ceruloplasmin functions in iron transport and storage, aceruloplasminemia leads to excessive iron accumulation systemically and within the CNS. The type and form of iron deposited is unclear and while oxidative stress was hypothesized as a potential mechanism of cytotoxicity in this disorder, direct evidence linking oxidative stress to the underlying genetic defect has not been provided. To address these issues, we studied autopsy brain tissue from two subjects with genetically confirmed aceruloplasminemia using an assay developed in our laboratory for redox‐active iron assessment. We found iron deposited in perivascular areas, localizing to terminal astrocytic processes and further showed that this iron was redox active. These data are consistent with the concept that oxidative stress, driven by heavy metal accumulation, represents the primary cellular cytotoxic process, accounting for neuronal damage in affected brain regions. As such, aceruloplasminemia is an excellent model of transition metal‐driven oxidative stress and neurodegeneration. 相似文献
84.
冠脉旁路移植术后血清同型半胱氨酸水平及相关因素变化的临床研究 总被引:1,自引:0,他引:1
目的 探讨冠脉旁路移植术后血清同型半胱氨酸(Hcy)水平升高的原因.方法 选择体外循环和非体外循环患者各20例,测定其术前第1天及术后第1、3、5、7天血清Hcy、铜离子、铜蓝蛋白、铁离子、叶酸、维生素B12、C反应蛋白(CRP)的水平.结果 铜蓝蛋白、铜离子和Hcy分别于术后第3、4、6天明显升高;维生素B12和铁离子均于术后第3天明显下降,此后缓慢上升;CRP于术后第3天显著升高,然后逐渐下降到正常水平;叶酸在手术前后无显著改变.上述指标两组间比较均无显著差异.结论 冠脉旁路移植术后血清Hcy上升可能与体内铜代谢变化有关,而与体外循环无关. 相似文献
85.
Hiroaki Miyajima 《Neuropathology》2015,35(1):83-90
Aceruloplasminemia is characterized by progressive neurodegeneration with brain iron accumulation due to the complete lack of ceruloplasmin ferroxidase activity caused by mutations in the ceruloplasmin gene. Redox‐active iron accumulation was found to be more prominent in the astrocytes than in the neurons. The most characteristic findings were abnormal or deformed astrocytes and globular structures of astrocytes. The lack of ceruloplasmin may primarily damage astrocytes in the aceruloplasminemic brains as a result of lipid peroxidation due to massive iron deposition. In the normal brain, iron may be continuously recycled between astrocytes and neurons, with transferrin acting as a shuttle. The glycosylphosphatidylinositol (GPI)‐linked ceruloplasmin on astrocytes functions as a ferroxidase, mediating the oxidation of ferrous iron transported from the cytosol by ferroportin and its subsequent transfer to transferrin. In cases with aceruloplasminemia, neurons take up the iron from alternative sources of non‐transferrin‐bound iron, because astrocytes without GPI‐linked ceruloplasmin cannot transport iron to transferrin. The excess iron in astrocytes could result in oxidative damage to these cells, and the neuronal cell protection offered by astrocytes would thus be disrupted. Neuronal cell loss may result from iron starvation in the early stage and from iron‐mediated oxidation in the late stage. Ceruloplasmin may therefore play an essential role in neuronal survival in the central nervous system. 相似文献
86.
N. V. Tsymbalenko T. D. Aleinikova L. V. Puchkova V. S. Gaitskhoki 《Bulletin of experimental biology and medicine》1997,123(1):68-70
Molecular heterogeneity of ceruloplasmin mRNA is studied in rat liver polyribosomes. Blot hybridization of RNA with cDNA reveals
three molecular forms of ceruloplasmin mRNA differing in the chain length and structure of the 3′-regions. A correlation between
these mRNAs and three isoforms of ceruloplasmin, which perform different functions in the copper transport, is established.
Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 1, pp. 79–82, January, 1997 相似文献
87.
《Nutrition reviews》1975,33(2):51-53
The ability to store ionic copper in tissues such as the liver and the brain may be one of the main causes of copper accumulation in these organs of patients with Wilson's disease. In rats drinking water high in copper, the organs which can take up ionic copper store it and they are not protected from copper toxicity. On the other hand, those organs which require copper bound in ceruloplasmin for storage, do not show excess copper and thus, are protected from copper toxicity. 相似文献
88.
为探明矽肺病变过程中是否存在肝外铜蓝蛋白(ceruloplasmin,Cp)mRNA表达,我们采用分子杂交手段包括斑点杂交、原位杂交以及NorthernBloting印迹法对染尘21天大鼠肺组织及肺泡巨噬细胞(AM)进行系列分析。结果表明:肺组织有CpmRNA的表达,与生理盐水对照组相比,矽肺组肺组织CpmRNA表达水平增高约2倍。原位杂交结果显示矽肺组织内肺间质细胞和肺泡巨噬细胞均有阳性杂交颗粒,NorthernBloting印迹杂交进一步证实AM中存在CpmRNA表达。矽肺过程中,肺组织是主要的肝外CpmRNA表达器官之一。提示Cp可能在肺组织损伤和修复过程中起重要作用 相似文献
89.
《Nutrition reviews》1977,35(6):136-138
Kayser-Fleischer rings have been described in liver disease states other than Wilson's disease, primarily in patients with primary biliary cirrhosis (PBC). In patients with PBC, hepatic copper, serum copper, urine copper and serum ceruloplasmin concentrations are significantly elevated. In Wilson's disease, excessive copper release from liver cells can cause intravascular hemolysis. 相似文献
90.
The study was designed to investigate the possible correlation between some oxidative stress parameters in Behcet's disease and the clinical manifestations of the disease as well as the possible correlation with the disease severity. Seventy-six patients diagnosed according to the International Study Group criteria for Behcet's disease were included in the study. Sixty patients had mild-to-moderate disease and 16 patients had severe disease. Sixty matched control subjects were also included. After a full history and examination from each subject, 10 mL blood was drawn from each for analysis. Serum malondialdehyde, glutathione, ceruloplasmin, copper and zinc levels were determined. Patients with Behcet's disease showed increased levels of serum malondialdehyde and copper while glutathione and zinc levels were decreased. Comparison between these parameters in patients with mild-to-moderate disease with those with severe disease showed only that serum zinc levels were lower in severe Behcet's disease. Serum malondialdehyde levels were found to be significantly positively correlated with oral ulcer size, duration and frequency. Glutathione levels were found to be inversely correlated with the clinical manifestation index and all oral ulcer parameters. Zinc levels were found to be inversely correlated with the clinical manifestation index and pathergy test positivity grades. Copper levels were found to be positively correlated with oral ulcer number. Although the parameters of oxidative stress did not show correlation with disease severity, they were correlated with the disease manifestations. This points out the importance of oxidative stress in Behcet's disease. 相似文献