煤工尘肺患者血清CuZn-SOD和铜蓝蛋白活性研究

[目的]探讨煤工尘肺发生发展过程中血清含Cu抗氧化酶CuZn-SOD和铜蓝蛋白(CP)的活性及Cu含量的变化。[方法]分别采用亚硝酸盐形成法、对苯二胺盐酸盐法及原子吸收分光光度法,测定70例不同期别煤工尘肺患者(Ⅰ、Ⅱ、Ⅲ期)及30例健康对照者的血清CuZn-SOD活性、铜蓝蛋白(CP)活性及Cu的含量。[结果]对照组、Ⅰ期尘肺组、Ⅱ期尘肺组及Ⅲ期尘肺组的血清CuZn-SOD活性分别为(15.96±2.26)、(17.24±2.28)、(19.81±3.01)、(21.63±3.52) NU/ml;血清CP活性分别为(2.26±0.52)、(2.68±0.67)、(2.97±0.79)、(3.36±0.88)U/ml;血清Cu含量分别为(12.68 ±3.87)、(14.96±4.42)、(17.84±5.12)、(19.38±5.89)μmol/L。与对照组相比,各期别尘肺患者血清与CuZn-SOD和CP 活性及其Cu的含量均显著升高。[结论]煤工尘肺的发生发展涉及含Cu抗氧化酶活性的上调,且其活性的改变与Cu含量变化有平行关系。     

The secretion of acute phase proteins and inflammatory cytokines during Trypanosoma congolense infection is not affected by the absence of the TNF-alpha gene

Tumor necrosis factor-alpha (TNF-alpha) plays a role in the host's defence against infections with African trypanosomes. It helps to control the blood stream form of the parasite and in Trypanosoma congolense infections, it also prolongs survival. The mechanisms by which this cytokine can influence parasitemia and survival are unknown. Therefore, the levels of acute phase proteins and other inflammatory cytokines were monitored in trypano-tolerant wild-type and TNF-alpha-deficient mice during a T. congolense infection. The titres of ceruloplasmin (CP), alpha1-acid glycoprotein (AGP) and serum amyloid P (SAP) increased and reached their peaks at 11 days post-infection, when the first peak of parasitemia was observed. No significant differences were observed in the acute phase protein profiles between the two mouse strains. Also the profiles of serum titres of IFN-gamma, IL-1alpha, IL-6 and IL-10 were not significantly different. Our present results indicate that acute phase protein and cytokine responses can be induced in the absence of TNF-alpha during a T. congolense infection in mice, and that the susceptibility of the TNF-alpha-deficient mice is not due to modulation of expression of these molecules.     

Subclinical Trace Element Deficiency in Children with Undue Susceptibility to Infections

ABSTRACT. Serum concentrations of iron, copper, zinc and magnesium and also serum transferrin and ceruloplasmin were investigated in 28 children aged 10 months to 10 years with undue susceptibility to infections. None of the children had any classical immune defect. Seven of them had had frequent upper respiratory tract infections, 16 had suffered from frequent infections of the middle ear and five from mainly lower respiratory tract infections. Thirteen healthy children aged 9 to 18 years residing in the same area served as controls. The children with undue susceptibility to infections had significantly lower mean serum iron ( p < 0.05) and zinc ( p < 0.001) levels than the healthy controls. The mean serum concentrations of copper and magnesium and of transferrin and ceruloplasmin did not differ between the patients and controls. Children with frequent middle ear infections seemed to account for most of the differences in the serum levels of iron and zinc. An inverse correlation was observed between duration of breast feeding and serum concentration of zinc, and between weight as well as height and serum magnesium. The reasons for these changes and the possible role of trace element deficiency as a factor predisposing to or perpetuating undue susceptibility to infections in children are discussed.     

血清铜蓝蛋白水平正常肝豆状核变性患者的临床特征分析

目的：总结分析血清铜蓝蛋白（CP）正常值的肝豆状核变性（WD）患者的临床特征。方法：以CP≥200mg/L为正常值,选取2018年1月至2022年10月入院的正常CP水平WD患者为CP正常组,选取同一时间入院的CP＜200mg/L的WD患者为对照组,比较两组之间一般资料、并发症、实验室指标、King评分等指标,比较治疗前后两组铜生化指标变化情况。结果：CP正常组82例,对照组82例,CP正常组年龄较对照组大（P＜0.05）,肝硬化、腹水发生率较对照组高（P＜0.05）,TBA、ALT、AST、γ-GGT、血氨、D-二聚体、肝纤维化指标、King评分均较对照组高,ALB较对照组低,差异均有统计学意义（P＜0.05）;治疗后,CP正常组血清CP、血清铜、铜氧化酶均较治疗前下降,44.83%的患者治疗后血清CP仍≥200mg/L,对照组中仅血清铜较治疗前下降。结论：血清CP正常的WD患者以肝型为主,年龄偏大,部分患者肝损害偏重,治疗后血清CP可轻度下降。     

The physiopathological significance of ceruloplasmin. A possible therapeutic approach

This article reviews and comments on the physiological roles of ceruloplasmin (Cp). We show that, in addition to its ascertained involvement in iron homeostasis, the protein, by virtue of its unique structure among multicopper oxidases, is likely involved in other processes of both an enzymatic and a nonenzymatic nature. In particular, based on the analysis of the kinetic parameters, on the one hand, and of the side-products of the oxidation, on the other, we propose that the long-recognized ability of Cp to interact with and oxidize non-iron substrates may be of physiological relevance. The striking example of 6-hydroxydopamine oxidation is presented, where we show that the catalytic action is carried out readily under physiological conditions, without release of potentially toxic oxygen intermediates.     

Clinical relevance of heterozygosis for aceruloplasminemia

Aceruloplasminemia is a rare form of brain iron overload of autosomal recessive inheritance that results from mutations in the CP gene, encoding the iron oxidase ceruloplasmin. Homozygous aceruloplasminemia causes progressive neurodegenerative disease, anemia, and diabetes, and is usually diagnosed late in life upon investigation of anemia, high ferritin, or movement disorders, but its heterozygous state is less characterized and believed to be silent. Here we report two heterozygotes for new mutations causing aceruloplasminemia from whom peripheral blood samples were collected for complete blood counts, iron studies, and genotyping by automated sequencing. We then performed a systematic review of preview reports of heterozygotes with data on genotype and clinical findings. Heterozygosity for aceruloplasminemia invariably causes reduced ceruloplasmin levels, and similarly to previews reports in the literature, our cases did not present with anemia. Mild hyperferritinemia was found only in two reports. Nevertheless, 5 out of 11 variants have been associated with significant neurological symptoms despite the presence of one wild‐type alelle. This review contributes to better genetic counseling of heterozygotes for CP gene variants and supports that measuring ceruloplasmin levels may be useful when investigating patients with movement disorders or rare cases of unexplained high ferritin.     

Single-nucleotide polymorphisms and haplotypes of non-coding area in the CP gene are correlated with Parkinson’s disease

Our previous studies have demonstrated that ceruloplasmin (CP) dysmetabolism is correlated with Parkinson’s disease (PD). However, the causes of decreased serum CP levels in PD patients remain to be clarified. This study aimed to explore the potential association between genetic variants of the CP gene and PD. Clinical features, serum CP levels, and the CP gene (both promoter and coding regions) were analyzed in 60 PD patients and 50 controls. A luciferase reporter system was used to investigate the function of promoter single-nucleotide polymorphisms (SNPs). High-density comparative genomic hybridization microarrays were also used to detect large-scale copy-number variations in CP and an additional 47 genes involved in PD and/or copper/iron metabolism. The frequencies of eight SNPs (one intronic SNP and seven promoter SNPs of the CP gene) and their haplotypes were significantly different between PD patients, especially those with lowered serum CP levels, and controls. However, the luciferase reporter system revealed no significant effect of the risk haplotype on promoter activity of the CP gene. Neither these SNPs nor their haplotypes were correlated with the Hoehn and Yahr staging of PD. The results of this study suggest that common genetic variants of CP are associated with PD and further investigation is needed to explore their functions in PD.

Electronic Supplementary Material

Supplementary material is available for this article at 10.1007/s12264-014-1512-6 and is accessible for authorized users.     

Copper incorporation into ceruloplasmin is regulated by Niemann–Pick C1 protein

Aim: Wilson disease is a genetic disorder of copper metabolism characterized by impaired biliary copper excretion. Wilson disease gene product (ATP7B) functions in copper incorporation to ceruloplasmin (Cp) and biliary copper excretion. Our previous study showed the late endosome localization of ATP7B and described the copper transport pathway from the late endosome to trans‐Golgi network (TGN). However, the cellular localization of ATP7B and copper metabolism in hepatocytes remains controversial. The present study was performed to evaluate the role of Niemann–Pick type C (NPC) gene product NPC1 on intracellular copper transport in hepatocytes. Methods: We induced the NPC phenotype using U18666A to modulate the vesicle traffic from the late endosome to TGN. Then, we examined the effect of NPC1 overexpression on the localization of ATP7B and secretion of holo‐Cp, a copper‐binding mature form of Cp. Results: Overexpression of NPC1 increased holo‐Cp secretion to culture medium of U18666A‐treated cells, but did not affect the secretion of albumin. Manipulation of NPC1 function affected the localization of ATP7B and late endosome markers, but did not change the localization of a TGN marker. ATP7B co‐localized with the late endosome markers, but not with the TGN marker. Conclusion: These findings suggest that ATP7B localizes in the late endosomes and that copper in the late endosomes is transported to the secretory compartment via an NPC1‐dependent pathway and incorporated into Cp.     

肝豆状核变性患者肝脏剪切波速度与实验室指标间的相关性研究

目的:通过声触诊组织量化技术(virtual touch tissue quantification,VTQ)测量肝豆状核变性(hepatolenticular degeneration,HLD)患者肝脏组织的剪切波速度(shear wave velocity,SWV)来评估肝脏的质地,并探讨HLD患者肝脏SWV与铜生化指标、血清肝纤维化指标之间是否存在相关性。方法:采用西门子ACUSON-S2000型彩色多普勒超声诊断仪,系统配有声脉冲辐射力成像技术。对HLD患者的肝脏右后叶进行VTQ检测,记录SWV值,并测量HLD患者铜生化指标中的血清铜离子(copperion,Cu2+)、铜蓝蛋白(ceruloplasmin,CP)、铜氧化酶(copper oxidase,SCO)三项指标以及肝纤维化中的Ⅲ型前胶原(procollagen type Ⅲ,PC-Ⅲ)、Ⅳ型胶原(collagen type Ⅳ,Ⅳ-C)、层黏蛋白(laminin,LN)以及透明质酸(hyaluronic acid,HA)四项指标,应用SPSS18.0软件分析SWV值与Cu2+、CP、SCO以及PC-Ⅲ、Ⅳ-C、LN、HA之间是否存在相关性。结果:肝脏SWV值与Cu2+、CP均无相关关系(P>0.05),与SCO值呈负相关(P<0.05);SWV值与肝脏纤维化四项指标(PC-Ⅲ、Ⅳ-C、LN、HA)均呈正相关关系(P<0.05~P<0.01)。结论:超声VTQ技术,可在一定程度上反映HLD患者铜的转运活力及肝脏的纤维化程度,在HLD的诊断和病情判断中有着较高的临床应用价值。