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Neurological Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
This is a rare autosomal recessive disorder of copper metabolism due to mutations in the gene encoding ATP7B, a copper transporting-P-type ATPase. Patients may present with liver disease in childhood or with the neurological syndrome in adolescence. Neurological symptoms include impaired concentration, declining intellect, behavioural problems, involuntary movements and generalized dystonia, ataxia or an akinetic–rigid syndrome. Patients have a typical smiling facial appearance with drooling and often have slurred speech. There may be copper deposition in Descemet's membrane of the cornea, giving a greenish brown pigmentary (Kayser–Fleischer) ring, which may only be visible at slit-lamp examination.
Mouse Knockout Models of Biliary Epithelial Cell Formation and Disease
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
ATP8B1 encodes a P/type ATPase that is mutated in benign intrahepatic cholestasis (BRIC) as well as familial intrahepatic cholestasis (FIC1) The mice have a milder hepatic phenotype due to abnormalities in trans location of aminophospholipids between membrane leaflets resulting in aberrant intestinal bile salt absorption. Also known as BSEP (bile salt export protein), and SPGP (sister for P/glycoprotein), ABCBl 1 is an ATP/dependent membrane transporter expressed in the canalicular membrane of hepatocytes that functions in transporting bile acids out of hepatocyte into the canaliculus. Mouse mutants (or ABCB1 1 show mild cholestasis, reduced hepatic bile acid output and high amounts of tetra hydroxylated bile acids suggesting an alternative protective mechanism for bile acid export. 50–52
Non-viral liver disease
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
John ML Christie, Roger WG Chapman
Wilson’s disease, or hepatolenticular degeneration, is a rare autosomal disorder of copper accumulation.73 The Wilson’s gene is located on chromosome 13 and encodes a copper-transporting P-type ATPase protein.74, 75 Deficiency of the gene product is likely to be responsible for the lack of copper incorporation into caerulo-plasmin and the defective biliary excretion of copper seen in Wilson’s disease. This results in excess copper accumulation in the liver, brain and other organs including the kidney and cornea, resulting in Kayser-Fleischer rings (a golden-brown or greenish discoloration in the limbic area seen best during slit-lamp examination). The copper accumulation eventually leads to tissue damage.
Molecular Targets of Curcumin and Its Therapeutic Potential for Ovarian Cancer
Published in Nutrition and Cancer, 2022
Malihe Mohamadian, Afsane Bahrami, Maryam Moradi Binabaj, Fereshteh Asgharzadeh, Gordon A. Ferns
Curcumin has also been shown to induce apoptosis in human SKOV3 cells in a dose-dependent manner by activating the Rho A/Rho-kinase signal pathway (50). RhoA is a member of the Rho GTPases family and its downstream effectors are involved in the regulation of actin dynamics and different actin-associated cellular functions. Curcumin-induced apoptosis was reported in another investigation through an increase in cytosolic Ca2+ concentration. Curcumin inhibits sarcoendoplasmic reticulum calcium transport ATPase (SERCA) activity (Ca2+ P-type ATPase) but has no effect on SERCA2 protein levels. Curcumin-induced cytosolic Ca2+ levels were reduced by the overexpression of SERCA2b. Curcumin-induced cleavage of poly (ADP-ribose) polymerase (PARP) (51) was also inhibited by overexpression of SERCA2b (28). PRAP is a family of proteins involved in several cellular processes such as DNA repair, genomic stability, and programmed cell death.
Investigation of Thiol/Disulfide Homeostasis and Ischemia-Modified Albumin Levels in Children with Wilson Disease
Published in Fetal and Pediatric Pathology, 2022
Ferit Durankuş, Yakup Albayrak, Yavuz Tokgöz, Ömer Faruk Beşer, Ramazan Durankuş, Sebahat Çam, Eda Sünnetçi, Ömer Akarsu, Cemil Nural, Özcan Erel
Wilson disease (WD) results from the recessive inheritance of copper metabolism disorder related to mutations of the ATP7B gene. Copper accumulates and causes toxicities that commonly affect the tissues of the liver and brain. The childhood form of WD typically presents with a predominantly hepatic phenotype [1]. The clinical prevalence of WD is estimated at about 1:7026, and heterozygosity in the UK has been predicted as 2.5% of the general population [2, 3]. The etiopathogenesis is characterized by the defective functioning of the copper-transporting P-type ATPase due to mutations of the ATP7B gene. The defective ATPase causes a decreased production of ceruloplasmin, thereby preventing the export of copper from cells and promoting the increased accumulation of copper in the cells and the resultant toxicity [4].
Metal-metal interaction and metal toxicity: a comparison between mammalian and D. melanogaster
Published in Xenobiotica, 2021
Xiaoyu Yu, Xianhan Tian, Yiwen Wang, Chunfeng Zhu
Although DMT1 can absorb Cu2+, copper transporter 1 (Ctr1) is the main absorption mechanism in mammals. Three high-affinity homologs, Ctr1A, Ctr1B, and Ctr1C have been identified in the fruit fly (Zhou et al.2003, Petris 2004). Ceruloplasmin in blood transports Cu2+ to the reductase on the surface of the cell membrane and reduces it to Cu+, which is then transferred by Ctr1 on the membrane (Espinoza et al.2012). Cu entering cells can bind to Cu-specific chaperones such as COX17, CCS, and ATOX1, which can be further transported to cytochrome c oxidase in mitochondria (Banci et al.2008)(copper chaperones for superoxide dismutase) SOD1 (Schmidt et al.2000) and ATP7A. ATP7A also transports Pb out of cells. However, at present, there is only one Cu P-type ATPase transporter called ATP7 in D. melanogaster, which is expressed widely (Norgate et al.2006). Its function is similar to ATP7A and can transfer Cu to the secretory pathway or to the circulatory system through intestinal cells (Burke et al.2008).