DOI•
Bis-choline tetrathiomolybdate prevents copper-induced blood-brain barrier damage.
01 Mar 2022-Vol. 5, Iss: 3
TL;DR: In this paper, the authors showed that copper loosely bound to albumin may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells.
Abstract: In Wilson disease, excessive copper accumulates in patients' livers and may, upon serum leakage, severely affect the brain according to current viewpoints. Present remedies aim at avoiding copper toxicity by chelation, for example, by D-penicillamine (DPA) or bis-choline tetrathiomolybdate (ALXN1840), the latter with a very high copper affinity. Hence, ALXN1840 may potentially avoid neurological deterioration that frequently occurs upon DPA treatment. As the etiology of such worsening is unclear, we reasoned that copper loosely bound to albumin, that is, mimicking a potential liver copper leakage into blood, may damage cells that constitute the blood-brain barrier, which was found to be the case in an in vitro model using primary porcine brain capillary endothelial cells. Such blood-brain barrier damage was avoided by ALXN1840, plausibly due to firm protein embedding of the chelator bound copper, but not by DPA. Mitochondrial protection was observed, a prerequisite for blood-brain barrier integrity. Thus, high-affinity copper chelators may minimize such deterioration in the treatment of neurologic Wilson disease.
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TL;DR: A review of side effects associated with metal antagonists can be found in this article , where the authors discuss metal poisoning from nontraditional sources and its treatment, such as iron overload through intentional poisoning and exposure to heavy metals through microplastics.
Abstract: Metal antagonists are drugs associated with significant side effects; with limited options, medical practitioners must be vigilant in strategically adjusting dosage, desensitizing patients, and at times halting treatment altogether. Gastrointestinal chelating agents, the polystyrene sulphonates, are associated with gastrointestinal perforations from the esophagus to the colon that may lead to, bleeding, sepsis, and necrosis. The orally bioavailable chelating agents deferiprone and deferasirox are also associated with gastrointestinal symptoms, as is the inducer of fetal hemoglobin production hydroxyurea. d-Penicillamine, used to alleviate elevated copper associated with Wilson's disease, is associated with allergic responses. Sodium zirconium silicate is associated with potassium depletion. Development of side effects can happen months or years after initiation of treatment, and careful consideration of the risks of metal overload vs the risks of side effects is warranted. Also discussed in the review is metal poisoning from nontraditional sources and its treatment, such as iron overload through intentional poisoning and exposure to heavy metals through microplastics.
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TL;DR: In this paper , the role of Cu imbalance in the development of various neurological challenges was highlighted, including Alzheimer's disease, Parkinson disease, Huntington disease, Autism, Creutzfeldt-Jacob's disease and distal motor neuropathy.
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TL;DR: In this paper , the authors investigated the relationship between adequate selenite supplementation and the respective consequences for Cu transfer into the brain applying an in vitro model of the blood-brain barrier (BBB).
TL;DR: In this paper , the authors discuss the epidemiology and pathogenesis of the neurological form of Wilson disease, its clinical and behavioral implications, diagnostic features, and treatment modalities (current and emerging therapies), further aiding healthcare professionals in early diagnosis and management strategies.
Abstract: Wilson disease (WD) is a complex metabolic disorder caused by disruptions to copper regulation within the body, leading to an unregulated accumulation of copper within various tissues. A less understood organ affected by the collection of copper is the brain, which further leads to the generation of oxygen-free radicals and resultant demyelination. Healthcare providers must keep the neurological form of WD in their list of differentials when patients present with diverse neurological manifestations. The initial step to diagnosis will be to distinguish the characteristic disease presentation with a thorough history and physical and neurological examination. A high clinical disease suspicion of WD should warrant further investigation by laboratory workup and imaging modalities to support the clinical findings and confirm the diagnosis of WD. Once a WD diagnosis is established, the healthcare provider should treat the underlying biological process of WD symptomatically. This review article discusses the epidemiology and pathogenesis of the neurological form of WD, its clinical and behavioral implications, diagnostic features, and treatment modalities (current and emerging therapies), further aiding healthcare professionals in early diagnosis and management strategies.
TL;DR: Wilson's disease (WD), also called hepatolenticular degeneration, is an autosomal recessive copper dysfunction disorder that is among the few treatable neurogenetic disorders as mentioned in this paper .
References
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TL;DR: The various physical factors affecting measured diffraction intensities are discussed, as are the scaling models which may be used to put the data on a consistent scale and algorithms used by the CCP4 scaling program SCALA.
Abstract: The various physical factors affecting measured diffraction intensities are discussed, as are the scaling models which may be used to put the data on a consistent scale. After scaling, the intensities can be analysed to set the real resolution of the data set, to detect bad regions (e.g. bad images), to analyse radiation damage and to assess the overall quality of the data set. The significance of any anomalous signal may be assessed by probability and correlation analysis. The algorithms used by the CCP4 scaling program SCALA are described. A requirement for the scaling and merging of intensities is knowledge of the Laue group and point-group symmetries: the possible symmetry of the diffraction pattern may be determined from scores such as correlation coefficients between observations which might be symmetry-related. These scoring functions are implemented in a new program POINTLESS.
4,211 citations
TL;DR: The dye exclusion test as discussed by the authors is used to determine the number of viable cells present in a cell suspension, based on the principle that live cells possess intact cell membranes that exclude certain dyes, such as trypan blue, Eosin, or propidium, whereas dead cells do not.
Abstract: The dye exclusion test is used to determine the number of viable cells present in a cell suspension. It is based on the principle that live cells possess intact cell membranes that exclude certain dyes, such as trypan blue, Eosin, or propidium, whereas dead cells do not. In this test, a cell suspension is simply mixed with dye and then visually examined to determine whether cells take up or exclude dye. In the protocol presented here, a viable cell will have a clear cytoplasm whereas a nonviable cell will have a blue cytoplasm.
1,885 citations