Prion protein promotes copper toxicity in Wilson disease.

Copper (Cu) is a vitally important micronutrient, whose balance between essential and toxic levels requires a tightly regulated network of proteins. Dysfunction in key components of this network leads to the disruption of Cu homeostasis, resulting in fatal disorders such as Wilson disease, which is caused by mutations in the hepatic Cu efflux transporter ATP7B. Unfortunately, the molecular targets for normalizing Cu homeostasis in Wilson disease remain poorly understood.

Effect of post-printing curing time on cytotoxicity of direct printed aligners: A pilot study.

Introduction: The aim of this in vitro study was to examine the potential impact of different curing times of 3D-printed orthodontic aligners on their cytotoxicity.

Method: Some 60 samples of aligner material were directly 3D printed using Tera Harz TC-85 DAC resin and randomly allocated to three different curing time groups (14, 24 and 50 min). Zendura FLX samples were used as control.

Full-length ATP7B reconstituted through protein -splicing corrects Wilson disease in mice.

Wilson disease (WD) is a genetic disorder of copper homeostasis, caused by deficiency of the copper transporter ATP7B. Gene therapy with recombinant adeno-associated vectors (AAV) holds promises for WD treatment. However, the full-length human gene exceeds the limited AAV cargo capacity, hampering the applicability of AAV in this disease context.

TFEB Regulates ATP7B Expression to Promote Platinum Chemoresistance in Human Ovarian Cancer Cells.

ATP7B is a hepato-specific Golgi-located ATPase, which plays a key role in the regulation of copper (Cu) homeostasis and signaling. In response to elevated Cu levels, ATP7B traffics from the Golgi to endo-lysosomal structures, where it sequesters excess copper and further promotes its excretion to the bile at the apical surface of hepatocytes. In addition to liver, high ATP7B expression has been reported in tumors with elevated resistance to platinum (Pt)-based chemotherapy.

Infantile -Related End-Stage Liver Disease: An Exceptional Wilson Disease Phenotype From Consecutive Generations.

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism typically presenting after 3 years of age. We describe a girl presenting with neonatal cholestasis rapidly progressing to end-stage liver disease. She presented hepatosplenomegaly, neurological impairment, Coombs-negative hemolytic anemia, central hypothyroidism.

Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B.

Pathogenic mutations in the copper transporter have been hypothesized to affect its protein interaction landscape contributing to loss of function and, thereby, to hepatic copper toxicosis in Wilson disease. Although targeting mutant interactomes was proposed as a therapeutic strategy, druggable interactors for rescue of ATP7B mutants remain elusive. Using proteomics, we found that the frequent H1069Q substitution promotes ATP7B interaction with HSP70, thus accelerating endoplasmic reticulum (ER) degradation of the mutant protein and consequent copper accumulation in hepatic cells.

Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin.

Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B.

Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs.

Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions.

Activation of Autophagy, Observed in Liver Tissues From Patients With Wilson Disease and From ATP7B-Deficient Animals, Protects Hepatocytes From Copper-Induced Apoptosis.

Background & Aims: Wilson disease (WD) is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in the liver and brain. It is caused by mutations in the adenosine triphosphatase copper transporting β gene (ATP7B), which encodes a protein that transports copper from hepatocytes into the bile. We studied ATP7B-deficient cells and animals to identify strategies to decrease copper toxicity in patients with WD.

Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia.

Background: Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission.

Objective: The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase () gene promoter polymorphism in achalasia.

HIF-2α regulates NANOG expression in human embryonic stem cells following hypoxia and reoxygenation through the interaction with an Oct-Sox cis regulatory element.

Low O2 tension is beneficial for human embryonic stem cell (hESC) maintenance but the mechanism of regulation is unknown. HIF-2α was found to bind directly to predicted hypoxic response elements (HREs) in the proximal promoter of OCT4, NANOG and SOX2 only in hESCs cultured under hypoxia (5% O2). This binding induced an array of histone modifications associated with gene transcription while a heterochromatic state existed at atmospheric O2.

Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells.

Energy metabolism is intrinsic to cell viability but surprisingly has been little studied in human embryonic stem cells (hESCs). The current study aims to investigate the effect of environmental O2 tension on carbohydrate utilisation of hESCs. Highly pluripotent hESCs cultured at 5% O2 consumed significantly more glucose, less pyruvate and produced more lactate compared to those maintained at 20% O2.

Role of the cold shock domain protein A in the transcriptional regulation of HBG expression.

Impaired switching from fetal haemoglobin (HbF) to adult globin gene expression leads to hereditary persistence of fetal haemoglobin (HPFH) in adult life. This is of prime interest because elevated HbF levels ameliorate β-thalassaemia and sickle cell anaemia. Fetal haemoglobin levels are regulated by complex mechanisms involving factors linked or not to the β-globin gene (HBB) locus.

Enteric glial-derived S100B protein stimulates nitric oxide production in celiac disease.

Background & Aims: Enteric glia participates to the homeostasis of the gastrointestinal tract. In the central nervous system, increased expression of astroglial-derived S100B protein has been associated with the onset and maintaining of inflammation. The role of enteric glial-derived S100B protein in gastrointestinal inflammation has never been investigated in humans.