-
BMC Neurology Feb 2023To analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis.
OBJECTIVE
To analyze and explore the risk factors for neurological symptoms in patients with purely hepatic Wilson's disease (WD) at diagnosis.
METHODS
This retrospective study was conducted at the First Affiliated Hospital of the Guangdong Pharmaceutical University on 68 patients with purely hepatic WD aged 20.6 ± 7.2 years. The physical examinations, laboratory tests, color Doppler ultrasound of the liver and spleen, and magnetic resonance imaging (MRI) of the brain were performed.
RESULTS
The elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels and 24-h urinary copper level were higher in the purely hepatic WD who developed neurological symptoms (NH-WD) group than those in the purely hepatic WD (H-WD) group. Adherence to low-copper diet, and daily oral doses of penicillamine (PCA) and zinc gluconate (ZG) were lower in the NH-WD group than those in the H-WD group. Logistic regression analysis showed that insufficient doses of PCA and ZG were associated with the development of neurological symptoms in patients with purely hepatic WD at diagnosis.
CONCLUSION
The development of neurological symptoms in patients with purely hepatic WD was closely associated with insufficient doses of PCA and ZG, and the inferior efficacy of copper-chelating agents. During the course of anti-copper treatment, the patient's medical status and the efficacy of copper excretion should be closely monitored.
Topics: Humans; Brain; Copper; Hepatolenticular Degeneration; Penicillamine; Retrospective Studies; Risk Factors; Zinc
PubMed: 36855079
DOI: 10.1186/s12883-023-03105-w -
Toxics Feb 2023Arsenic 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...
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.
PubMed: 36851018
DOI: 10.3390/toxics11020142 -
Molecules (Basel, Switzerland) Feb 2023New strategies facilitate the design of cyclic peptides which can penetrate the brain. We have designed a bicyclic peptide, OL-CTOP, composed of the sequences of a...
Solid-Phase Synthesis of the Bicyclic Peptide OL-CTOP Containing Two Disulfide Bridges, and an Assessment of Its In Vivo μ-Opioid Receptor Antagonism after Nasal Administration.
New strategies facilitate the design of cyclic peptides which can penetrate the brain. We have designed a bicyclic peptide, OL-CTOP, composed of the sequences of a selective μ-opioid receptor antagonist, CTOP (f-(CYwOTX)T) (X = penicillamine, Pen; O = ornithine) and odorranalectin, OL (YASPK-(CFRYPNGVLAC)T), optimized its solid-phase synthesis and demonstrated its ability for nose-to-brain delivery and in vivo activity. The differences in reactivity of Cys and Pen thiol groups protected with trityl and/or acetamidomethyl protecting groups toward I in different solvents were exploited for selective disulfide bond formation on the solid phase. Both the single step and the sequential strategy applied to macrocyclization reactions generated the desired OL-CTOP, with the sequential strategy yielding a large quantity and better purity of crude OL-CTOP. Importantly, intranasally (i.n.s.) administered OL-CTOP dose-dependently antagonized the analgesic effect of morphine administered to mice through the intracerebroventricular route and prevented morphine-induced respiratory depression. In summary, the results demonstrate the feasibility of our solid-phase synthetic strategy for the preparation of the OL-CTOP bicyclic peptide containing two disulfide bonds and reveal the potential of odorranalectin for further modifications and the targeted delivery to the brain.
Topics: Mice; Animals; Administration, Intranasal; Solid-Phase Synthesis Techniques; Somatostatin; Receptors, Opioid, mu; Peptides; Morphine
PubMed: 36838810
DOI: 10.3390/molecules28041822 -
Medicine Feb 2023Hepatolenticular degeneration, also known as Wilson disease (WD), is an autosomal recessive inherited disease characterized by copper metabolism, which has complex...
RATIONALE
Hepatolenticular degeneration, also known as Wilson disease (WD), is an autosomal recessive inherited disease characterized by copper metabolism, which has complex clinical manifestations, and mainly including liver and nervous system lesions. Pregnancy combined with WD is extremely harmful to mothers and children, with high miscarriage rates, and premature birth rates and perinatal mortality.
PATIENT CONCERNS
Here we introduced the basic information of 4 pregnant women with WD. The first pregnant woman had a 16-year history of WD, stopped taking penicillamine 1 year before pregnancy. The second woman had a 3-year history of WD and was taking penicillamine regularly, unintended pregnancy occurred 1 month after stopping the drug. The third woman had a history of WD for 5 years with penicillamine treatment. The 4th woman was found to have WD due to repeated missed miscarriage with abnormal liver function, after which penicillamine was regularly taken. Fortunately, she was pregnant again a year later.
DIAGNOSES
The pregnant women in case 1 and case 2 were diagnosed with decompensated cirrhosis with coagulation dysfunction during pregnancy. The pregnant woman in case 3 was found to have liver cirrhosis by ultrasound, and the pregnant woman in case 4 did not have liver abnormalities during pregnancy.
INTERVENTIONS
The pregnant woman in case 1 began to take copper-removing drugs and take a low-copper diet after finding the aggravation of the disease in the early stage of pregnancy, and had good compliance during pregnancy. The pregnant woman in case 2 had poor compliance during pregnancy and did not receive any treatment. The pregnant woman in case 3 refused to use copper elimination drugs during pregnancy, but took a low copper diet. The pregnant woman in case 4 had good compliance during pregnancy, and she was treated with drugs and low copper diet during the whole pregnancy.
OUTCOMES
Three of the four pregnant women got a healthy baby but premature, and only the pregnant woman in case 2 had spontaneous abortion at 25 weeks.
LESSONS
After comprehensive monitoring and multidisciplinary management of professional medical staff before and after pregnancy, WD pregnant women still have the opportunity to obtain a better pregnancy outcome and improve quality of life.
Topics: Child; Pregnancy; Female; Humans; Hepatolenticular Degeneration; Copper; Abortion, Spontaneous; Quality of Life; Penicillamine
PubMed: 36800617
DOI: 10.1097/MD.0000000000032968 -
Polymers Jan 2023D-penicillamine (PA) is a sulfur group-containing drug prescribed for various health issues, but overdoses have adverse effects. Therefore, regular, selective, and...
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 mol cm. 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.
PubMed: 36771878
DOI: 10.3390/polym15030577 -
Cureus Dec 2022Hepatitis E virus (HEV) is a single-stranded RNA virus with 20 million cases reported worldwide. Infected individuals may either remain asymptomatic or develop acute or...
Hepatitis E virus (HEV) is a single-stranded RNA virus with 20 million cases reported worldwide. Infected individuals may either remain asymptomatic or develop acute or even fulminant hepatitis. HEV has been implicated in causing Acute-on-Chronic Liver Failure (ACLF) among patients with underlying cirrhosis. Among the causes of cirrhosis, Wilson's disease is an identified cause that results in an increased accumulation of copper in the liver, brain, and other organs. It is noted that Coombs negative hemolytic anaemia is also seen in the clinical spectrum of Wilson's disease, however, Coombs positivity has not been documented. We present a case of a young female who had an undiagnosed chronic liver disease (CLD). The patient developed acute decompensation with HEV infection along with Coombs positive hemolytic anaemia. Her autoimmune hepatitis screen was negative, so the patient was worked up for other causes of CLD, which led to a diagnosis of underlying Wilson's disease. The patient was started on penicillamine and zinc acetate. However, during the disease, the patient developed acute decompensation and unfortunately expired before her transplant could take place. Our case documentation is of importance as Coombs positivity in patients with Wilson's disease has not been reported before. Attending physicians should be suspicious of Wilson's disease in a patient with Coombs positive hemolytic anaemia when other causes cannot be identified. It is also important to promptly identify any other cause of CLD to educate patients regarding factors leading to acute decompensation and progression to ACLF.
PubMed: 36726921
DOI: 10.7759/cureus.33158 -
Frontiers in Microbiology 2022Low-molecular-mass (LMM) thiol compounds are known to be important for many biological processes in various organisms but LMM thiols are understudied in anaerobic...
Low-molecular-mass (LMM) thiol compounds are known to be important for many biological processes in various organisms but LMM thiols are understudied in anaerobic bacteria. In this work, we examined the production and turnover of nanomolar concentrations of LMM thiols with a chemical structure related to cysteine by the model iron-reducing bacterium . Our results show that tightly controls the production, excretion and intracellular concentration of thiols depending on cellular growth state and external conditions. The production and cellular export of endogenous cysteine was coupled to the extracellular supply of Fe(II), suggesting that cysteine excretion may play a role in cellular trafficking to iron proteins. Addition of excess exogenous cysteine resulted in a rapid and extensive conversion of cysteine to penicillamine by the cells. Experiments with added isotopically labeled cysteine confirmed that penicillamine was formed by a dimethylation of the C-3 atom of cysteine and not indirect metabolic responses to cysteine exposure. This is the first report of metabolic synthesis of this compound. Penicillamine formation increased with external exposure to cysteine but the compound did not accumulate intracellularly, which may suggest that it is part of ' metabolic strategy to maintain cysteine homeostasis. Our findings highlight and expand on processes mediating homeostasis of cysteine-like LMM thiols in strict anaerobic bacteria. The formation of penicillamine is particularly noteworthy and this compound warrants more attention in microbial metabolism studies.
PubMed: 36713222
DOI: 10.3389/fmicb.2022.1085214 -
JNMA; Journal of the Nepal Medical... Jul 2022Myasthenia gravis is a neuromuscular junction disorder characterised by fluctuating muscle weakness, improved by using anti-cholinesterase drugs. In addition to the...
UNLABELLED
Myasthenia gravis is a neuromuscular junction disorder characterised by fluctuating muscle weakness, improved by using anti-cholinesterase drugs. In addition to the autoimmune aetiology, various factors such as infections, surgery, and drugs are known to precipitate the condition. We report a case of a 15-year-old boy with D-penicillamine-induced myasthenia gravis who presented with facial diplegia, dysphagia, and drooling of saliva, 6 years after the initiation of treatment for Wilson's disease. Therefore, clinicians should be more vigilant while prescribing patients with chelating drugs like D-penicillamine with regular monitoring of the new symptoms and keeping a very low threshold for the suspicion of myasthenia gravis.
KEYWORDS
d-penicillamine; myasthenia gravis; pyridostigmine; Wilson's disease.
Topics: Male; Humans; Adolescent; Penicillamine; Hepatolenticular Degeneration; Myasthenia Gravis
PubMed: 36705187
DOI: 10.31729/jnma.7607 -
Bioengineering & Translational Medicine Jan 2023Photodynamic therapy (PDT) represents an attractive promising route for melanoma treatment. However, its therapeutic efficacy is compromised by inefficient drug delivery...
Photodynamic therapy (PDT) represents an attractive promising route for melanoma treatment. However, its therapeutic efficacy is compromised by inefficient drug delivery and high glutathione (GSH) levels in cancer cells. To overcome these challenges, microneedles (MNs) system loaded with GSH-scavenging nanocomposites was presented for nitric oxide (NO) enhanced PDT. The nanocomposites consisted of -nitroso--acrylate penicillamine (SNAP; a NO donor) grafted fourth-generation polyamide amine dendrimer (G) and chlorin e6 (Ce6). Upon local insertion of polyvinylpyrrolidone MNs, G-SNAP/Ce6 composites were fast delivered and significantly amplified the therapeutic effects during PDT, via GSH depletion and reactive nitrogen species generation. Even with a single administration and low power light exposure, MNs with G-SNAP/Ce6 effectively halt the tumor progression. The system demonstrated better cancer ablation efficacy than Ce6 alone toward melanoma. The strategy may inspire new ideas for future PDT-related therapy for skin tumors.
PubMed: 36684091
DOI: 10.1002/btm2.10352 -
Proceedings of the National Academy of... Jan 2023In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with...
In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. β-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.
Topics: Humans; Propionates; Histones; Receptors, G-Protein-Coupled; Neuroprotection; Hydrogen Peroxide; Ganglia, Spinal
PubMed: 36669102
DOI: 10.1073/pnas.2216941120