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Ting Dong Ming-cai Wu Lu-lu Tang Hai-lin Jiang Ping Zhou Chun-jun Kuang Li-wei Tian Wen-ming Yang 《Bioscience reports》2021,41(1)
Wilson’s disease (WD) is an autosomal recessive disease caused by mutation of the ATPase copper transporting β (ATP7B) gene, resulting in abnormal copper metabolism. We aimed to investigate the protective effect of GanDouLing (GDL) on neural stem cell (NSC) function in a mouse model of WD. NSCs were treated with different concentrations of GDL alone or in combination with penicillamine, following which we evaluated cellular growth, apoptosis, and differentiation. Nuclear factor E2-related factor 2 (Nrf2) pathway and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation were analyzed via Western blotting. Treatment with GDL alone or in combination with penicillamine significantly increased proliferation and inhibited apoptosis of NSCs in a dose-dependent manner. In addition, GDL treatment remarkably promoted differentiation of NSCs. Consistently, levels of class III β-tubulin (Tuj1) and microtubule-associated protein 2 (MAP2) were significantly elevated, whereas glial fibrillary acidic protein (GFAP) levels were obviously suppressed in the presence of GDL or penicillamine. In vivo assays confirmed that GDL increased the ratio of Ki67+, Tuj1+, and MAP2+ cells and suppressed apoptosis in the hippocampal region in WD mice. Behavioral assays revealed that both GDL and penicillamine improved memory ability in WD models. Mechanistically, GDL treatment led to activation of Nrf2 signaling and suppression of the NLRP3 inflammasome in WD mice. Notably, inhibition of Nrf2 signaling reversed the protective effects of GDL on hippocampal NSCs. Collectively, these findings demonstrate that GDL exerts a protective effect on NSCs and promotes neurogenesis by targeting Nrf2 signaling and the NLRP3 inflammasome in WD. 相似文献
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Impaired cellular homeostasis of metals, particularly of Cu, Fe and Mn may trigger neurodegeneration through various mechanisms, notably induction of oxidative stress, promotion of α-synuclein aggregation and fibril formation, activation of microglial cells leading to inflammation and impaired production of metalloproteins. In this article we review available studies concerning Fe, Cu and Mn in Parkinson's disease and Wilson's disease. In Parkinson's disease local dysregulation of iron metabolism in the substantia nigra (SN) seems to be related to neurodegeneration with an increase in SN iron concentration, accompanied by decreased SN Cu and ceruloplasmin concentrations and increased free Cu concentrations and decreased ferroxidase activity in the cerebrospinal fluid. Available data in Wilson's disease suggest that substantial increases in CNS Cu concentrations persist for a long time during chelating treatment and that local accumulation of Fe in certain brain nuclei may occur during the course of the disease. Consequences for chelating treatment strategies are discussed. 相似文献
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Lili Liu Christopher O'Grady Sean A. Dalrymple Lata Prasad Oleg Y. Dmitriev Louis T. J. Delbaere 《Acta Crystallographica. Section F, Structural Biology Communications》2009,65(6):621-624
Wilson disease associated protein (ATP7B) is essential for copper transport in human cells. Mutations that affect ATP7B function result in Wilson's disease, a chronic copper toxicosis. Disease‐causing mutations within the N‐domain of ATP7B (WND) are known to disrupt ATP binding, but a high‐resolution X‐ray structure of the ATP‐binding site has not been reported. The N‐domain was modified to delete the disordered loop comprising residues His1115–Asp1138 (WNDΔ1115–1138). Unlike the wild‐type N‐domain, WNDΔ1115–1138 formed good‐quality crystals. Synchrotron diffraction data have been collected from WNDΔ1115–1138 at the Canadian Light Source. A native WNDΔ1115–1138 crystal diffracted to 1.7 Å resolution and belonged to space group P42212, with unit‐cell parameters a = 39.2, b = 39.2, c = 168.9 Å. MAD data were collected to 2.7 Å resolution from a SeMet‐derivative crystal with unit‐cell parameters a = 38.4, b = 38.4, c = 166.7 Å. The WNDΔ1115–1138 structure is likely to be solved by phasing from multiwavelength anomalous diffraction (MAD) experiments. 相似文献
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《Journal of trace elements in medicine and biology》2014,28(1):8-12
Wilson's disease (WND) is an inherited disorder of copper metabolism. Divalent metal transporter1 (DMT1) and ATP7A play important roles in metal transport in humans. The frequency of two single nucleotide polymorphisms of the DMT1 gene: DMT1 IVS4 C>A, DMT1 11245 T>C and two of the ATP7A gene: rs1062472 T>C, ATP7A rs 2227291 G>C have been evaluated in a population of 108 Wilson's disease patients and 108 sex- and age-matched healthy volunteers. The DMT1 IVS4 C(+) allele occurred more frequently in WND than in the healthy controls. The allele frequencies of other studied polymorphisms in WND group were in line with frequencies obtained for healthy volunteers. Neither of the polymorphisms had an impact on the age at onset or clinical phenotype of WND. 相似文献
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Wilson's disease (WD) is a rare disorder of copper metabolism resulting in accumulation of copper in liver and other organs. We present a liver failure patient, who was misdiagnosed for two years, with normal ceruloplasmin and low serum alkaline phosphatase. Molecular testing revealed a novel p.Ala982Thr mutation within ATP7B gene. The pathology of liver sample showed a large amount of copper deposition in the hepatocytes and confirmed the diagnosis of WD. Our data highlighted the importance of molecular testing in the early diagnosis of atypical WD. 相似文献
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《Journal of trace elements in medicine and biology》2014,28(4):441-447
We have developed an easy and specific enzyme-linked immunoassay (ELISA) for the simultaneous determination of serum metallothinein-1 (MT-1) and 2 (MT-2) in both humans and experimental animals. A competitive ELISA was established using a specific polyclonal antibody against rat MT-2. The antibody used for this ELISA had exhibited the same cross-reactivity with MT in humans and experimental animals. The NH2 terminal peptide of MT containing acetylated methionine was shown to be the epitope of this antibody. The reactivity of this ELISA system with the liver, kidney and brain in MT1/2 knock-out mice was significantly low, but was normal in an MT-3 knock-out mouse. The lowest detection limit of this ELISA was 0.6 ng/ml and the spiked MT-1was fully recovered from the plasma.We investigated the normal range of MT1/2 (25–75%tile) in 200 healthy human serum and found it to be 27–48 ng/ml, and this was compared with the serum levels in various liver diseases. The serum MT1/2 levels in chronic hepatitis C (HCV) patients were significantly lower than healthy controls and also other liver diseases. In the chronic hepatitis cases, the MT1/I2 levels increased gradually, followed by the progression of the disease to liver cirrhosis and hepatocellular carcinoma. In particular, we found significantly elevated MT1/2 plasma levels in Wilson's disease patients, levels which were very similar to those in the Long–Evans Cinnamon (LEC) rat (model animal of Wilson's disease). Furthermore, a significantly elevated MT1/2 level was found in patients with Menkes disease, an inborn error of copper metabolism such as Wilson's disease. 相似文献
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摘要 目的：探讨肝豆汤联合驱铜治疗方案对湿热内蕴型肝豆状核变性（WD）患者肝脏代谢和认知功能的影响。方法：按照随机数字表法将2018年1月至2021年12月期间我院收治的80例WD患者分为观察组（n=40,接受肝豆汤联合驱铜治疗）、对照组（n=40,接受驱铜治疗）。观察两组中医证候积分、24 h尿铜、肝功能指标、肝纤维化指标和认知功能变化情况。结果：治疗4个疗程后,两组手足震颤、言语含糊、行动困难、步履艰难、肢僵挛缩、口涎不止、口苦或臭、头目昏眩、纳谷不香、腹胀痞满、尿赤便结、鼻衄齿衄、黄疸水臌评分均降低,且观察组均低于对照组（P<0.05）。治疗4个疗程后,两组24 h尿铜升高,且观察组高于对照组（P<0.05）。治疗4个疗程后,两组丙氨酸氨基转移酶（ALT）、天门冬氨酸转氨酶（AST）、总胆红素（TBIL）均下降,且观察组均低于对照组（P<0.05）。治疗4个疗程后,两组透明质酸（HA）、Ⅲ型前胶原肽（PⅢP）、层黏连蛋白（LN）、Ⅳ型胶原（CⅣ）均下降,且观察组均低于对照组（P<0.05）。治疗4个疗程后,两组视空间与执行功能、命名、注意力、语言、抽象能力、延迟回忆、定向力评分均升高,且观察组均高于对照组（P<0.05）。结论：肝豆汤联合驱铜治疗方案治疗湿热内蕴型WD患者,可有效缓解临床症状,调节肝脏代谢,改善认知功能。 相似文献
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Sorina Georgiana Boaru Uta Merle Ricarda Uerlings Astrid Zimmermann Christa Flechtenmacher Claudia Willheim Elisabeth Eder Peter Ferenci Wolfgang Stremmel Ralf Weiskirchen 《Journal of cellular and molecular medicine》2015,19(4):806-814
Wilson's disease is an autosomal recessive disorder in which the liver does not properly release copper into bile, resulting in prominent copper accumulation in various tissues. Affected patients suffer from hepatic disorders and severe neurological defects. Experimental studies in mutant mice in which the copper‐transporting ATPase gene (Atp7b) is disrupted revealed a drastic, time‐dependent accumulation of hepatic copper that is accompanied by formation of regenerative nodes resembling cirrhosis. Therefore, these mice represent an excellent exploratory model for Wilson's disease. However, the precise time course in hepatic copper accumulation and its impact on other trace metals within the liver is yet poorly understood. We have recently established novel laser ablation inductively coupled plasma mass spectrometry protocols allowing quantitative metal imaging in human and murine liver tissue with high sensitivity, spatial resolution, specificity and quantification ability. By use of these techniques, we here aimed to comparatively analyse hepatic metal content in wild‐type and Atp7b deficient mice during ageing. We demonstrate that the age‐dependent accumulation of hepatic copper is strictly associated with a simultaneous increase in iron and zinc, while the intrahepatic concentration and distribution of other metals or metalloids is not affected. The same findings were obtained in well‐defined human liver samples that were obtained from patients suffering from Wilson's disease. We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content. 相似文献
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Lydia K. Nyasae Michael J. Schell Ann L. Hubbard 《Traffic (Copenhagen, Denmark)》2014,15(12):1344-1365
Physiologic Cu levels regulate the intracellular location of the Cu ATPase ATP7B. Here, we determined the routes of Cu‐directed trafficking of endogenous ATP7B in the polarized hepatic cell line WIF‐B and in the liver in vivo. Copper (10 µm ) caused ATP7B to exit the trans‐Golgi network (TGN) in vesicles, which trafficked via large basolateral endosomes to the apical domain within 1 h. Although perturbants of luminal acidification had little effect on the TGN localization of ATP7B in low Cu, they blocked delivery to the apical membrane in elevated Cu. If the vesicular proton‐pump inhibitor bafilomycin‐A1 (Baf) was present with Cu, ATP7B still exited the TGN, but accumulated in large endosomes located near the coverslip, in the basolateral region. Baf washout restored ATP7B trafficking to the apical domain. If ATP7B was staged apically in high Cu, Baf addition promoted the accumulation of ATP7B in subapical endosomes, indicating a blockade of apical recycling, with concomitant loss of ATP7B at the apical membrane. The retrograde pathway to the TGN, induced by Cu removal, was far less affected by Baf than the anterograde (Cu‐stimulated) case. Overall, loss of acidification‐impaired Cu‐regulated trafficking of ATP7B at two main sites: (i) sorting and exit from large basolateral endosomes and (ii) recycling via endosomes near the apical membrane. 相似文献
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Franz Hefti 《Developmental neurobiology》1994,25(11):1418-1435
The ability of neurotrophic factors to regulate developmental neuronal survival and adult nervous system planticity suggests the use of these molecuales to treat neurodegeneration associated with human diseases. Solid rationales exist for the use of NGF and neurotrophin-3 in the treatment of neuropathies of the peripheral sensory system, insulin-like growth factor and ciliary neurotrophic factor in motor neuron atrophy, and NGF in Alzheimer's disease. Growth factors have been identified for neurons affected in Parkinson's disease, Huntington's disease, and acute brain and spinal cord injury. Various strategies are actively pursued to deliver neurotrophic factors to the brain, and develop therapeutically useful molecules that mimic neurotrophic factor actions or stimulate their production or receptor mechanisms. 1994 John Wiley & Sons, Inc. 相似文献
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Ceruloplasmin (CP) is a 132kd cuproprotein which, together with transferrin, provides the majority of anti-oxidant capacity in serum. Increased iron deposition and lipid peroxidation in the basal ganglia of subjects with hereditary CP deficiency suggest that CP may serve as an anti-oxidant in the brain as well. The present study compared CP immunoreactivity in brain specimens from normal controls and subjects with neurodegenerative disorders (Alzheimer's disease [AD], Parkinson's disease [PD], progressive supranuclear palsy [PSP], and Huntington's disease [HD]) (n = 5 per group). The relative intensity of neuronal CP staining and the numbers of CP-stained neurons per 25x microscope field were determined in hippocampus (CA1, subiculum, and parahippocampal gyrus), parietal cortex, frontal cortex, substantia nigra, and caudate. CP was detected in both neurons and astrocytes in all specimens, and in senile plaques and occasional neurofibrillary tangles in AD brain. Neuronal CP staining intensity tended to increase in most AD brain regions, but was statistically significant vs controls only in the CA1 region of hippocampus (p = .016). Neuronal CP staining in brain specimens from other neurodegenerative disorders showed a slight but nonsignificant increase vs controls. The numbers of CP-stained neurons per field did not differ between the various neurodegenerative disorders and controls. These results suggest that a modest increase in neuronal CP content is present in the AD brain, and lesser elevations in neuronal CP occur in the other neurodegenerative disorders in this study. Though CP functions as both an acute phase protein and an anti-oxidant in peripheral tissues, whether it does so in the brain remains to be determined. 相似文献
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