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Toxicology Research Jul 2020D-penicillamine (DPA) is an amino-thiol that has been established as a copper chelating agent for the treatment of Wilson's disease. DPA reacts with metals to form...
D-penicillamine (DPA) is an amino-thiol that has been established as a copper chelating agent for the treatment of Wilson's disease. DPA reacts with metals to form complexes and/or chelates. Here, we investigated the survival rate extension capacity and modulatory role of DPA on Cu-induced toxicity in Adult Wild type (Harwich strain) flies were exposed to Cu (1 mM) and/or DPA (50 μM) in the diet for 7 days. Additionally, flies were exposed to acute Cu (10 mM) for 24 h, followed by DPA (50 μM) treatment for 4 days. Thereafter, the antioxidant status [total thiol (T-SH) and glutathione (GSH) levels and glutathione S-transferase and catalase activities] as well as hydrogen peroxide (HO) level and acetylcholinesterase activity were evaluated. The results showed that DPA treatment prolongs the survival rate of by protecting against Cu-induced lethality. Further, DPA restored Cu-induced depletion of T-SH level compared to the control ( < 0.05). DPA also protected against Cu (1 mM)-induced inhibition of catalase activity. In addition, DPA ameliorated Cu-induced elevation of acetylcholinesterase activity in the flies. The study may therefore have health implications in neurodegenerative diseases involving oxidative stress such as Alzheimer's disease.
PubMed: 32905187
DOI: 10.1093/toxres/tfaa032 -
BMC Neurology May 2022Wilson's disease is a hereditary disorder of copper metabolism resulting mainly in hepatic, neurological, and psychiatric symptoms. Multiple sclerosis (MS) is an... (Review)
Review
BACKGROUND
Wilson's disease is a hereditary disorder of copper metabolism resulting mainly in hepatic, neurological, and psychiatric symptoms. Multiple sclerosis (MS) is an immune-mediated demyelinating disease affecting the central nervous system (CNS). The co-occurrence of these two, although not unheard of in literature, is still considered to be very rare and can give rise to diagnostic difficulties. Also, comorbidity in MS highly influences quality of life and disease progression, which makes the timely diagnosis and treatment of these conditions essential.
CASE PRESENTATION
The aim of this study is to present a patient exhibiting symptoms of both MS and Wilson's disease, as well as to conduct a detailed review of previously reported cases. The patient's neurological symptoms (sensory disorder) as well as MRI and CSF findings were characteristic for MS. The diagnosis of MS preceded that of Wilson's disease and was relatively mild in course. Currently, the patient receives cladribine as an immunomodulatory treatment after escalation from glatiramer acetate therapy. Apart from one episode of acute hepatic decompensation, during which transfusion, albumin supplementation and diuretic treatment was necessary, Wilson's disease manifested as chronic impairment of liver function. The diagnosis of Wilson's disease was established by the analysis of serum coeruloplasmin levels, histological examination and genetic findings. Continuous oral penicillamine therapy led to the slow normalization of hepatic function and significant amelioration of the patient's symptoms. Correlating with cases previously reported, the course of MS was relatively mild, and like in three out of four other known cases, the symptoms of Wilson's disease were mostly restricted to hepatic dysfunction.
CONCLUSION
The case presented in our report is similar to those reported before. The co-occurrence of the two diseases seems to be more a coincidence than a sharing of common factors in their pathogenesis; however, they are considered to influence one another. Regarding rare co-occurrences such as this one, every new case is of high importance, as it enables a better evaluation and understanding of the clinical presentations that are more characteristic of these cases, thus aiding the estimation of disease course as well as possible therapeutic choices.
Topics: Copper; Hepatolenticular Degeneration; Humans; Multiple Sclerosis; Penicillamine; Quality of Life
PubMed: 35578211
DOI: 10.1186/s12883-022-02691-5 -
Global Pediatric Health 2023Wilson disease is a rare autosomal recessive genetic disease, caused by the mutation of the ATP7B gene leading to decreased secretion of serum ceruloplasmin in blood and...
Wilson disease is a rare autosomal recessive genetic disease, caused by the mutation of the ATP7B gene leading to decreased secretion of serum ceruloplasmin in blood and decrease biliary excretion of copper leading to toxic level accumulation in the liver, brain, kidney, and cornea, resulting in development of characteristic liver disease and neuropsychiatric symptoms. Our case presented with mainly clumsiness and gait abnormality without any psychiatric component and any history of liver disease. A 13-year old male, born out of non-consanguineous marriage, presented with clumsy walking and slurring of speech. The child also complained of poor handwriting and slipping of slipper from foot, without any history of abnormal behavior and poor scholastic performance. On examination gait was abnormal with sidewise swaying, increased muscle tone with rigidity and bilateral flexor plantar reflex. Slit lamp examination of eyes revealed bilateral Kayser-Fleischer rings. Serum ceruloplasmin was low (0.03 g/L) and 24-hour urinary copper was high (119.64 μg/day). MRI brain showed B/L putamen hyperintensity and panda sign suggestive of Wilson disease. After the diagnosis of Wilson disease was made, patient was treated with penicillamine and zinc. Child was also followed-up and re-examination showed slight improvement. Though not rare, Wilson disease is an uncommon entity with varied presentations and disabling consequences. Hence high index of suspicion and clinical correlation is required to diagnose it. Early initiation of treatment and good compliance ensure a better outcome.
PubMed: 36992844
DOI: 10.1177/2333794X231163418 -
Euroasian Journal of... 2022Wilson's disease (WD) is a rare autosomal recessive disease, that can involve any organ of the body, the main ones being the liver and the brain. These patients can have...
AIM
Wilson's disease (WD) is a rare autosomal recessive disease, that can involve any organ of the body, the main ones being the liver and the brain. These patients can have varied presentations, ranging from having no symptoms to having neurological manifestations to features of chronic liver disease (CLD). Those patients that end up having CLD are prognosticated the Child-Turcotte-Pugh (CTP) score and the Model for End-stage Liver Disease (MELD) score. However, two specific scores exist for prognostication in patients having WD, namely, the Nazar score and the Dhawan score. However, these are yet to be validated nor has their use been implemented in clinical practice.
MATERIALS AND METHODS
Our study involved 65 patients with WD, comprising both the pediatric and the adult population. We aimed at evaluating the clinical manifestations the lab parameters and the management of these patients. Furthermore, we tried validating the Nazar and the Dhawan score and later compared them with the CTP and the MELD score, which are well-known prognostic tools in CLD.
RESULTS
Our patients were subdivided into the pediatric (more than 50%) and the adult group. The most common presenting complaint noted in both groups was abdominal distension. Values of the urine copper and serum ceruloplasmin did not defer between the pediatric and adult patients. Hepatic involvement is frequently seen in the pediatric age-group. Also, CTP class C was chiefly seen in pediatrics 17/33 (51.5%), while CTP class B was in adults 13/32 (40.6%). The mean Nazar score was 3 ± 3, while the mean Dhawan score was 5 ± 4. The main treatment offered for both groups was zinc along with penicillamine.
CONCLUSION
Our study showed the Dhawan score was comparable to the CTP and the MELD score in terms of predicting the disease severity of WD in our patient population.
HOW TO CITE THIS ARTICLE
Majid Z, Abrar G, Laeeq SM, . Clinical Characteristics and Comparison of Different Prognostic Scores in Wilson's Disease. Euroasian J Hepato-Gastroenterol 2022;12(2):69-72.
PubMed: 36959988
DOI: 10.5005/jp-journals-10018-1379 -
Frontiers in Immunology 2023The pro-inflammatory cytokine interleukin-1β (IL-1β) plays a central role in host defense against infections. High systemic IL-1β levels, however, promote the...
OBJECTIVE
The pro-inflammatory cytokine interleukin-1β (IL-1β) plays a central role in host defense against infections. High systemic IL-1β levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1β release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1β release by human monocytes nicotinic acetylcholine receptor (nAChR) subunits α7, α9 and/or α10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R).
METHODS
Different human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1β was measured in cell culture supernatants. Patch-clamp and intracellular Ca imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain.
RESULTS
The inhibitory effect of nAChR agonists on the BzATP-induced IL-1β release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal eNOS to inhibit the BzATP-induced IL-1β release. Moreover, NO donors (SNAP, S-nitroso-N-acetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1β release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification.
CONCLUSION
We provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1β release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders.
Topics: Humans; Mice; Animals; Interleukin-1beta; Leukocytes, Mononuclear; Receptors, Purinergic P2X7; Monocytes; Adenosine Triphosphate; Nitric Oxide Synthase
PubMed: 36969210
DOI: 10.3389/fimmu.2023.1140592 -
Hepatology (Baltimore, Md.) May 2024Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of...
BACKGROUND AND AIMS
Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption.
APPROACH AND RESULTS
Sixteen healthy volunteers were examined with positron emission tomography (PET)/CT 1 and 15 hours after an oral Copper-64 ( 64 Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64 Cu PET/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64 Cu uptake reflect the effect of drugs on intestinal absorption. 64 Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64 Cu activity 1 hour after 64 Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p <0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p <0.02, indicating strong inhibition of intestinal 64 Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p <0.04.
CONCLUSIONS
In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal copper absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.
Topics: Humans; Penicillamine; Trientine; Copper; Positron Emission Tomography Computed Tomography; Copper Radioisotopes; Hepatolenticular Degeneration; Positron-Emission Tomography
PubMed: 38088886
DOI: 10.1097/HEP.0000000000000708 -
JPGN Reports Aug 2021Wilson disease (WD) is associated with neurological, psychiatric, cognitive, and psychosocial difficulties, but there is little data regarding the nature and prevalence...
UNLABELLED
Wilson disease (WD) is associated with neurological, psychiatric, cognitive, and psychosocial difficulties, but there is little data regarding the nature and prevalence of these problems in children and young people (CYP).
METHODS
A single-center case-note review to establish the incidence and nature of these issues in CYP with WD, managed before and after multidisciplinary team (MDT) clinics, was established.
RESULTS
Out of 69 (43 males) CYP with WD, 37.8% presented with acute liver failure, 48.6% with chronic liver disease and 13.5% after family screening. Medical treatment was with penicillamine (40), trientene (18), zinc and penicillamine/trientene (11), and zinc monotherapy (2). Twenty-one underwent liver transplantation. After a median follow-up of 9.8 (IQR 6.4-16.9) years, 86% are alive. Six died posttransplantation and 7 grafts were lost. Mental health difficulties were recorded in 49.3%, particularly prevalent in the acute liver failure group (70.8%). Nonadherence was common (50.7%) and associated with greater mental health prevalence. Neurological issues were reported in 36.2% and poor cognition/attainment in 14.5%, consistent across modes of presentation. Four patients had diagnoses of autism spectrum conditions, all diagnosed pre WD. CYP seen within an MDT-clinic had more frequent documentation of all issues examined, but lower levels of late graft loss (94% versus 80%, = 0.07).
CONCLUSION
Our data highlight the need to offer management in WD patients especially as these aspects are underrecognized in CYP presenting with liver involvement. We aim to highlight the importance of multidisciplinary input when looking after this population beyond transition through to adult services.
PubMed: 37205947
DOI: 10.1097/PG9.0000000000000094 -
International Journal of Molecular... Aug 2022The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the...
The subventricular zone (SVZ) in lateral ventricles is the largest neurogenic region in adult brain containing high amounts of copper (Cu). This study aims to define the role of Cu in adult neurogenesis by chelating labile Cu ions using a well-established Cu chelator D-Penicillamine (D-Pen). A neurosphere model derived from adult mouse SVZ tissues was established and characterized for its functionality with regards to neural stem/progenitor cells (NSPCs). Applying D-Pen in cultured neurospheres significantly reduced intracellular Cu levels and reversed the Cu-induced suppression of NSPC’s differentiation and migration. An in vivo intracerebroventricular (ICV) infusion model was subsequently established to infuse D-Pen directly into the lateral ventricle. Metal analyses revealed a selective reduction of Cu in SVZ by 13.1% (p = 0.19) and 21.4% (p < 0.05) following D-Pen infusions at low (0.075 μg/h) and high (0.75 μg/h) doses for 28 days, respectively, compared to saline-infused controls. Immunohistochemical studies revealed that the 7-day, low-dose D-Pen infusion significantly increased Ki67(+)/Nestin(+) cell counts in SVZ by 28% (p < 0.05). Quantification of BrdU(+)/doublecortin (DCX)(+) newborn neuroblasts in the rostral migration stream (RMS) and olfactory bulb (OB) further revealed that the short-term, low-dose D-Pen infusion, as compared with saline-infused controls, resulted in more newborn neuroblasts in OB, while the high-dose D-Pen infusion showed fewer newborn neuroblasts in OB but with more arrested in the RMS. Long-term (28-day) infusion revealed similar outcomes. The qPCR data from neurosphere experiments revealed altered expressions of mRNAs encoding key proteins known to regulate SVZ adult neurogenesis, including, but not limited to, Shh, Dlx2, and Slit1, in response to the changed Cu level in neurospheres. Further immunohistochemical data indicated that Cu chelation also altered the expression of high-affinity copper uptake protein 1 (CTR1) and metallothionein-3 (MT3) in the SVZ as well as CTR1 in the choroid plexus, a tissue regulating brain Cu homeostasis. Taken together, this study provides first-hand evidence that a high Cu level in SVZ appears likely to maintain the stability of adult neurogenesis in this neurogenic zone.
Topics: Animals; Brain; Cell Movement; Cell Proliferation; Copper; Lateral Ventricles; Mice; Neurogenesis; Olfactory Bulb
PubMed: 36077284
DOI: 10.3390/ijms23179888 -
Cellular and Molecular Gastroenterology... 2021The pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation resulting from pathogenic variants affecting the ATP7B gene and downstream...
BACKGROUND & AIMS
The pathogenesis of Wilson disease (WD) involves hepatic and brain copper accumulation resulting from pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior methylome investigations in human WD liver and blood and in the Jackson Laboratory (Bar Harbor, ME) C3He-Atp7b/J (tx-j) WD mouse model revealed an epigenetic signature of WD, including changes in histone deacetylase (HDAC) 5. We tested the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD.
METHODS
We investigated class IIa HDAC4 and HDAC5 and H3K9/H3K27 histone acetylation in tx-j mouse livers compared with C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet, D-penicillamine (copper chelator), and choline (methyl group donor). Experiments with copper-loaded hepatoma G2 cells were conducted to validate in vivo studies.
RESULTS
In 9-week tx-j mice, HDAC5 levels increased significantly after 8 days of a 60% kcal fat diet compared with chow. In 24-week tx-j mice, HDAC4/5 levels were reduced 5- to 10-fold compared with C3H, likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were affected by disease progression and accompanied by increased acetylation. D-penicillamine and choline partially restored HDAC4/5 and H3K9ac/H3K27ac to C3H levels. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development, which, in turn, were regulated by histone acetylation in tx-j mice compared with C3H mice, with Pparα and Pparγ among the most relevant targets.
CONCLUSIONS
These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation can regulate gene expression in key metabolic pathways in the pathogenesis of WD.
Topics: Acetylation; Animals; Cell Line; Computational Biology; Copper; Copper-Transporting ATPases; DNA Methylation; Diet, High-Fat; Disease Models, Animal; Disease Susceptibility; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Hepatolenticular Degeneration; Histone Deacetylases; Histones; Humans; Mice; Mice, Knockout; Mutation; Phosphorylation; Signal Transduction
PubMed: 34098115
DOI: 10.1016/j.jcmgh.2021.05.020 -
PloS One 2020Wilson's disease (WD) is a monogenetic liver disease that is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion in...
Wilson's disease (WD) is a monogenetic liver disease that is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion in the liver. The excess Cu accumulates in various organs such as the liver and brain. WD patients show clinical heterogeneity, which can range from acute or chronic liver failure to neurological symptoms. The course of the disease can be improved by a life-long treatment with zinc or chelators such as D-penicillamine in a majority of patients, but serious side effects have been observed in a significant portion of patients, e.g. neurological deterioration and nephrotoxicity, so that a liver transplant would be inevitable. An alternative therapy option would be the genetic correction of the ATP7B gene. The novel gene therapy method CRISPR/Cas9, which has recently been used in the clinic, may represent a suitable therapeutic opportunity. In this study, we first initiated an artificial ATP7B point mutation in a human cell line using CRISPR/Cas9 gene editing, and corrected this mutation by the additional use of single-stranded oligo DNA nucleotides (ssODNs), simulating a gene correction of a WD point mutation in vitro. By the addition of 0.5 mM of Cu three days after lipofection, a high yield of CRISPR/Cas9-mediated ATP7B repaired cell clones was achieved (60%). Moreover, the repair efficiency was enhanced using ssODNs that incorporated three blocking mutations. The repaired cell clones showed a high resistance to Cu after exposure to increasing Cu concentrations. Our findings indicate that CRISPR/Cas9-mediated correction of ATP7B point mutations is feasible and may have the potential to be transferred to the clinic.
Topics: Base Sequence; CRISPR-Cas Systems; Copper-Transporting ATPases; Gene Editing; Gene Knock-In Techniques; Gene Knockout Techniques; HEK293 Cells; Humans; Mutation
PubMed: 32997714
DOI: 10.1371/journal.pone.0239411