Search Results (40)

Background/Objectives: The lifelong treatment of Wilson’s disease (WD) currently relies on copper chelators with relatively poor metal specificity, which frequently exhibit serious adverse effects. There is a real medical need for a specific copper chelator to regulate the copper excess efficiently, at lower doses than those used for penicillamine (DPA) or trientine (TETA), and with lower toxicity in long-term treatments. Methods: The efficiency of the specific Cu(II) chelator named TDMQ20 was evaluated by oral treatment of TX mice, used as a WD model, and compared with those of DPA, TETA, and also tetrathiomolybdate (bcTTM). We documented TDMQ20′s ability to (i) decrease the hepatic copper load, (ii) increase the amount and ferroxidase activity of ceruloplasmin (CP), and (iii) regulate liver proteins that are impaired in WD mice. Results: Compared to the other copper chelators, TDMQ20 was the only one that efficiently mediated excretion of Cu and restoration of active ceruloplasmin levels at doses 8 times lower than DPA. Such efficacy is related to the design of this chelator, which specifically coordinates Cu(II) as a discrete and soluble complex. Conversely, DPA, TETA, and bcTTM give rise to various complexes with copper ions, often with oligomeric or cluster structures that can be retained in blood circulation or sequestered by proteins. Conclusions: Taking into consideration all the advantages of TDMQ20 compared to other ligands, including its lack of toxicity during long-term administration in mice, the drug candidate TDMQ20 appears to be a first-class challenger to the currently used treatments, i.e., DPA, TETA, and bcTTM. Full article

Background and Clinical Significance: Cystinuria is the most common genetic cause of pediatric nephrolithiasis, characterized by impaired renal cystine reabsorption and resulting in increased urinary cystine excretion. Due to the poor solubility of cystine at normal urine pH, increased urinary cystine excretion leads to urine supersaturation and precipitation of cystine, resulting in nephrolithiasis. Case Presentation: Here, we report two cases of female patients diagnosed with cystinuria caused by SLC7A9 mutations. Both patients were initially managed with conservative treatments to minimize stone recurrence including increased oral fluid intake, a low-salt/low-protein diet, and potassium citrate supplementation with the goal of reducing urinary cystine levels and minimizing stone recurrences. Due to persistent stone formation, the patients were started on two distinct cystine-binding thiol medications. One patient was initiated on tiopronin, and the other on D-penicillamine. Tiopronin and D-penicillamine are both used in the treatment of pediatric cystinuria, although tiopronin is often preferred due to its more favorable side effect profile. However, due to insurance constraints, D-penicillamine was initiated for one patient in place of tiopronin. Since the initiation of these two distinct cystine-binding thiol medications, both patients have demonstrated reduced urinary cystine excretion and minimal to no recurrence of kidney stones. Conclusions: Cystine-binding thiols, including tiopronin and D-penicillamine, can both be used in the management of cystinuria in pediatric patients. Full article

Copper accumulation in neurons induces oxidative stress, disrupts mitochondrial activity, and accelerates neuronal death, which is central to the pathophysiology of neurodegenerative diseases like Wilson disease. Standard treatments for copper toxicity, such as D-penicillamine, trientine, and chloroquine, are frequently associated with severe side effects, creating a need for safer therapeutic alternatives. To address this, we developed a curcumin-loaded nanoemulsion (CUR-NE) using the spontaneous emulsification technique, aimed at enhancing the bioavailability and therapeutic efficacy of curcumin. The optimized nanoemulsion displayed a particle size of 76.42 nm, a zeta potential of −20.4 mV, and a high encapsulation efficiency of 93.69%, with a stable and uniform structure. The in vitro tests on SH-SY5Y neuroblastoma cells demonstrated that CUR-NE effectively protected against copper-induced toxicity, promoting significant cellular uptake. Pharmacokinetic studies revealed that CUR-NE exhibited a longer half-life and extended circulation time compared to free curcumin. Additionally, pharmacodynamic evaluations, including biochemical assays and histopathological analysis, confirmed that CUR-NE provided superior neuroprotection in copper overload conditions. These results emphasize the ability of CUR-NE to augment the therapeutic effects of curcumin, presenting a novel approach for managing copper-induced neurodegeneration. The study highlights the effectiveness of nanoemulsion-based delivery platforms in improving chelation treatments for neurological diseases. Full article

Wilson’s disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD. Full article

Chirality plays a significant part in many vital processes, and to further our level of understanding, there is a steadily growing interest in enhancing the yield of enantioselective processes. Here, a multilayer with etched grooves is activated in a Kretschmann geometry and consists of alternating platinum Pt, silica SiO₂, and silicon Si, as well as a silver Ag layer. Due to the production process, the groove surface exhibits a micrometric roughness, characterized by a typical vibrational mode at ω = 96 MHz. The mode is attributed to a localized acoustic vibration and has been detected as a transmitted signal. The outcomes of the inquiry include plasmonic amplification of the transmitted signal and its wavevector-less nature; in addition, it is shown that the signal is depolarized in reference to the incident beam because of the rough surface. When the Kretschmann scheme is combined with the depolarization brought on by the roughness, a built-in asymmetry results in a higher optical flux of spectrum photons in the depolarized plane than the co-polarized plane, resulting in distinct, enantioselective, and solely polarization-dependent spectral contrast. In conclusion, enantioselectivity is demonstrated for the D,L-penicillamine. Full article

Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu²⁺ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber–Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well-treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge. Full article

D-penicillamine (D-PA) is a sulfur-containing drug that has been used for various health conditions. However, like any medication, overdosing on D-PA can have adverse effects and may require additional treatment. Therefore, developing simple and sensitive methods for sensing D-PA can play a crucial role in improving its efficacy and reducing its side effects. Sensing technologies, such as electrochemical sensors, can enable accurate and real-time measurement of D-PA concentrations. In this work, we developed a novel electrochemical sensor for detecting D-PA by modifying a carbon paste electrode (CPE) with a multi-walled carbon nanotube-Co₃O₄ nanocomposite, benzoyl-ferrocene (BF), and ionic liquid (IL) (MWCNT-Co₃O₄/BF/ILCPE). Cyclic voltammetry (CV), differential pulse voltammetry (DPV), and chronoamperometry (CHA) were employed to explore the electrochemical response of D-PA on the developed sensor, the results of which verified a commendable electrochemical performance towards D-PA. Under optimized conditions, the developed sensor demonstrated a rapid response to D-PA with a linear dynamic range of 0.05 μM–100.0 μM, a low detection limit of 0.015 μM, and a considerable sensitivity of 0.179 μA μM⁻¹. Also, the repeatability, stability, and reproducibility of the MWCNT-Co₃O₄/BF/ILCPE sensor were studied and showed good characteristics. In addition, the detection of D-PA in pharmaceutical and biological matrices yielded satisfactory recoveries and relative standard deviation (RSD) values. Full article

(1) Background: In patients with Wilson’s disease, the deficiency of the copper carrier ATP7B causes the accumulation of copper in the liver, brain and various other organs. Lifelong treatment is therefore mandatory, using copper chelators to increase the excretion of copper and to avoid life-threatening damage. The clinically used reference drug, D-penicillamine, exhibit numerous adverse effects, especially a frequent severe and irreversible neurological worsening, mainly due to its lack of metal selectivity; (2) Methods: A new tetradentate ligand based on an 8-aminoquinoline entity, named TDMQ20, which is highly selective for copper compared with other metal ions, is evaluated in “toxic milk” TX mice as an oral treatment of this Wilson’s disease murine model; (3) Results: The concentration of copper in the liver of “toxic milk” TX mice decreased and the fecal excretion of copper increased upon oral treatment with TDMQ20. Both effects are dose-dependent, and more pronounced than those of D-penicillamine; (4) Conclusions: The TDMQ20 copper chelator is more efficient than the reference drug D-penicillamine for the treatment of a Wilson’s disease murine model. Pharmacological data obtained with TDMQ20 on the TX mouse model strongly support the selection of this ligand as a drug candidate for this genetic disease. Full article

Wilson’s disease (WD) is a genetic disorder with copper accumulation in various tissues leading to related clinical symptoms (mainly hepatic and neuropsychiatric) which can be in 85% of patients successfully treated with anti-copper agents. However, during WD treatment neurological deterioration may occur in several patients. D-penicillamine (DPA) is one of the most frequently used drugs in WD treatment. Despite its efficacy, DPA can produce many adverse drug reactions, which should be recognized early. We present the case of a 51-year-old man diagnosed with the hepatic form of WD and initially treated with DPA in whom after 15 months of treatment, diplopia and evening ptosis occurred. WD treatment non-compliance as well as overtreatment were excluded. Supported by neurological symptoms, a positive edrophonium test, and high serum levels of antibodies against acetylcholine receptors (AChR-Abs), as well as low concentrations of antibodies against muscle-specific kinase (MuSK-Abs), the diagnosis of myasthenia gravis (MG), induced by DPA, was established. DPA was stopped; zinc sulfate for WD and pyridostigmine for MG symptoms were introduced. Diplopia and ptosis subsided after a few days, which supported our diagnosis. During a follow-up visit after 6 months, the patient did not present any MG symptoms. AChR-Abs level gradually decreased and MuSK-Abs were no longer detected. Pyridostigmine was stopped, and within 9 months of follow-up, the neurological symptoms of MG did not reoccur. The authors discussed the patient’s neurological deterioration, performed a systematic review of DPA-induced MG in WD and concluded that MG is a rare and usually reversible complication of DPA treatment. DPA-induced MG generally occurs 2–12 months after treatment initiation and ocular symptoms predominate. Response to pyridostigmine treatment is good and MG symptoms usually reverse within one year after DPA treatment cessation. However, symptoms may persist in some cases where DPA treatment is only a trigger factor for MG occurrence. Full article

Background: The aim of this study was to demonstrate that both neurological and hepatic symptoms respond to copper chelation therapy in Wilson disease (WD). However, the time course of their recovery is different. Methods: Eighteen patients with neurological WD from a single specialized center who had been listed for liver transplantation during the last ten years and two newly diagnosed homozygous twins were recruited for this retrospective study. The mean duration of conventional treatment was 7.3 years (range: 0.25 to 36.2 years). A custom Wilson disease score with seven motor items, three non-motor items, and 33 biochemical parameters of the blood and urine, as well as the MELD score, was determined at various checkup visits during treatment. These data were extracted from the charts of the patients. Results: Treatment was initiated with severity-dependent doses (≥900 mg) of D-penicillamine (DPA) or triethylene-tetramin-dihydrochloride (TRIEN). The motor score improved in 10 and remained constant in 8 patients. Worsening of neurological symptoms was observed only in two patients who developed comorbidities (myasthenia gravis or hemispheric stroke). The neurological symptoms continuously improved over the years until the majority of patients became only mildly affected. In contrast to this slow recovery of the neurological symptoms, the MELD score and liver enzymes had already started to improve after 1 month and rapidly improved over the next 6 months in 19 patients. The cholinesterase levels continued to increase significantly (p < 0.0074) even further. One patient whose MELD score indicated further progression of liver disease received an orthotopic liver transplantation 3 months after the diagnosis of WD and the onset of DPA treatment. Conclusions: Neurological and hepatic symptoms both respond to copper chelation therapy. For patients with acute liver failure, the first 4 months are critical. This is the time span in which patients have to wait either for a donor organ or until significant improvement has occurred under conventional therapy. For patients with severe neurological symptoms, it is important that they are treated with fairly high doses over several years. Full article

Background: One of the most prevalent illnesses in neonates that needs care and treatment is neonatal jaundice. Several drugs are used as pharmacological modalities for treating hyperbilirubinemia, like intravenous immunoglobulin, D-penicillamine, metalloporphyrin, phenobarbital, zinc sulfate and clofibrate. Previous studies suggest the usefulness of fenofibrate in the treatment of hyperbilirubinemia. Objectives: The study aims at assessing the effectiveness of oral fenofibrate in the treatment of indirect neonatal hyperbilirubinemia in full-term neonates. Method: This is a quasi-experimental study that was conducted at Heevi Pediatrics Teaching Hospital in Duhok, which is located in the Kurdistan Region of Iraq. It involved term infants who had jaundice. The neonates who were eligible for the study were randomly assigned to one of two groups: the intervention group or the control group. Both groups were treated with conventional phototherapy. Fenofibrate was administered in a single oral dose of 10 mg/kg to the participants in the intervention group. Throughout the entirety of the treatment, levels of total serum bilirubin were compared and contrasted between the two groups. Results: After 12 h of treatment, a statistically significant difference (p-value = 0.001) was seen in the serum bilirubin levels between the two groups. The difference in serum bilirubin levels became significantly progressively pronounced after 24, 48, and 72 h. The average time of discharge was 63.6 h for the intervention group and 90.9 h for the control group, and this difference was statistically significant (p-value < 0.001). Conclusions: The time it takes to lower high bilirubin levels in neonates may be shortened by combining conventional phototherapy with a single oral dosage of 10 mg/kg fenofibrate. Consequently, these neonates will experience a shorter hospitalization and an accelerated discharge from the hospital. Full article

Inorganic chiral nanoparticles are attracting more and more attention due to their peculiar optical properties and potential biological applications, such as bioimaging, therapeutics, and diagnostics. Among inorganic chiral nanoparticles, gold chiral nanostructures were demonstrated to be very interesting in this context, with good physical chemical stability and also the possibility to decorate the surface, improving biomedical application as the interaction with the bio-systems. Gold (Au) nanostructures were synthesized according to a seed-mediated procedure which envisages the use of cetyltrimethylammonium bromide (CTAB) as the capping agent and L- and D-cysteine to promote chirality. Au nanostructures have been demonstrated to have opposite circular dichroism signals depending on the amino acid enantiomer used during the synthesis. Then, a procedure to decorate the Au surface with penicillamine, a drug used for the treatment of Wilson’s disease, was developed. The composite material of gold nanoparticles/penicillamine was characterized using electron microscopy, and the penicillamine functionalization was monitored by means of UV-Visible, Raman, and infrared spectroscopy, highlighting the formation of the Au–S bond. Furthermore, electron circular dichroism was used to monitor the chirality of the synthesized nanostructures and it was demonstrated that both penicillamine enantiomers can be successfully bonded with both the enantiomers of the gold nanostructures without affecting gold nanoparticles’ chirality. The effective modification of nanostructures’ surfaces via penicillamine introduction allowed us to address the important issue of controlling chirality and surface properties in the chiral nano-system. Full article

A highly sensitive and accurate dual-signal strategy is developed for trace Cu²⁺ detection based on the inner filter effect (IFE) between Tween 20-gold nanoparticles (AuNPs) and CdSe/ZnS quantum dots (QDs). Tween 20-AuNPs are utilized as colorimetric probes and excellent fluorescent absorbers. The fluorescence of CdSe/ZnS QDs can be quenched efficiently by Tween 20-AuNPs via IFE. In the presence of D-penicillamine, D-penicillamine induces the aggregation of Tween 20-AuNPs and the fluorescent recovery of CdSe/ZnS QDs at high ionic strength. Upon addition of Cu²⁺, D-penicillamine tends to selectively chelate with Cu²⁺ and then forms the mixed-valence complexes, which consequently inhibits the aggregation of Tween 20-AuNPs and the fluorescent recovery. The dual-signal method is used to quantitatively detect trace Cu²⁺, with low detection limits of 0.57 μg/L and 0.36 μg/L for colorimetry and fluorescence, respectively. In addition, the proposed method using a portable spectrometer is applied to the detection of Cu²⁺ in water. This sensitive, accurate and miniature sensing system has potential in environmental evaluations. Full article

Arsenic in inorganic form is a known human carcinogen; even low levels of arsenic can interfere with the endocrine system. In mammalian development, arsenic exposure can cause a malformation of fetuses and be lethal. This study examined the effects of sodium arsenite (SA) as the inorganic form of arsenic in embryonic bodies (EBs) with three germ layers in the developmental stage. This condition is closer to the physiological condition than a 2D cell culture. The SA treatment inhibited EBs from differentiating into cardiomyocytes. A treatment with 1 μM SA delayed the initiation of beating, presenting successful cardiomyocyte differentiation. In particular, mitochondria function analysis showed that SA downregulated the transcription level of the Complex IV gene. SA increased the fission form of mitochondrion identified by the mitochondria number and length. In addition, a treatment with D-penicillamine, an arsenic chelator, restored the beat of EBs against SA, but not mitochondrial dysfunction. These findings suggest that SA is a toxicant that induces mitochondrial damage and interferes with myocardial differentiation and embryogenesis. This study suggests that more awareness of SA exposure during pregnancy is required because even minuscule amounts have irreversible adverse effects on embryogenesis through mitochondria dysfunction. Full article

D-penicillamine (PA) is a sulfur group-containing drug prescribed for various health issues, but overdoses have adverse effects. Therefore, regular, selective, and sensitive sensing is essential to reduce the need for further treatment. In this study, diphenylamine (DPA) was electropolymerized in an aqueous acidic medium. The PA detection sensitivity, selectivity, and limit of detection were enhanced by electropolymerizing DPA on an electrochemically reduced graphene oxide (ERGO)/glassy carbon (GC) surface. The formation of p-DPA and ERGO was investigated using various techniques. The as-prepared p-DPA@ERGO/GC revealed the excellent redox-active (N–C to N=C) sites of p-DPA. The p-DPA@ERGO/GC electrode exhibited excellent electrochemical sensing ability towards PA determination because of the presence of the –NH–functional moiety and effective interactions with the –SH group of PA. The p-DPA@ERGO/GC exhibited a high surface coverage of 9.23 × 10⁻¹² mol cm⁻². The polymer-modified p-DPA@ERGO/GC electrode revealed the amperometric determination of PA concentration from the 1.4 to 541 μM wide range and the detection limit of 0.10 μM. The real-time feasibility of the developed p-DPA@ERGO/GC electrode was tested with a realistic PA finding in human blood serum samples and yielded a good recovery of 97.5–101.0%, confirming the potential suitability in bio-clinical applications. Full article