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Immunopharmacology and Immunotoxicology Feb 2024To study the reeducation effect of copper thiol complexes on macrophage morphology and cytokine expression.
OBJECTIVE
To study the reeducation effect of copper thiol complexes on macrophage morphology and cytokine expression.
METHODS
The effect of copper thiol complexes was assessed on murine macrophages by the cell morphology observed through optical microscopy, while the expression of cytokines by protein abundance after stimulation. A viability experiment was performed on PMBC to confirm that copper complexes do not affect other cells.
RESULTS
The M1 shape was reported after treatment with copper thiol complexes at 1-200 µM, while M2 behavior was documented between 50 and 800 µM. Surprisingly, a thin elongate morphology was observed between 400-800 µM like the M2 shape. The expression of M1 cytokines was noted ranging from 1 to 100 µM, with the highest yield at 1 µM (2243 pg/µL) for the copper-penicillamine complex. M2 production behavior was observed at 1-800 µM, with the highest abundance close to 1150 pg/µL (200-400 µM) was quantified from the copper-cysteine complex. Finally, LCCu complexes did not induce a cytotoxic response on PBMC while exhibiting a high IL-4 and IL-10 production, similar to their gold analogs.
CONCLUSIONS
The capacity of copper thiol complexes to reeducate M1 to M2 morphoexpression can be promising for cell protection by using copper thiol penicillamine or immuno-regeneration of tissues when using copper thiol cysteine.
Topics: Mice; Animals; Cytokines; Copper; Sulfhydryl Compounds; Cysteine; Leukocytes, Mononuclear; Macrophages; Penicillamine
PubMed: 37584252
DOI: 10.1080/08923973.2023.2245559 -
Bioorganic Chemistry Oct 2023The amount of copper ions in the environment has an immediate effect on ecology and food safety, Menkes syndrome and Wilson's disease cause accumulation and deficiency...
A reversible and ratiometric fluorescent probe based on rhodol derivative with an ESIPT unit for monitoring copper ion content and in situ evaluation of related drugs in cells.
The amount of copper ions in the environment has an immediate effect on ecology and food safety, Menkes syndrome and Wilson's disease cause accumulation and deficiency of copper ions in the body, respectively, and neurodegenerative diseases are also closely related to copper ion levels. However, the current copper ion detection technology has a high cost, complex operation, and other disadvantages. In this study, a ratiometric fluorescent probe (RB-DH) was rationally constructed to detect copper ions by coupling benzothiazole to rhodol derivatives. It can be used to determine copper ion concentrations in water samples, agricultural products, cells, and zebrafish. Importantly, due to the reversible response of RB-DH to copper ions, the fluctuation of intracellular copper ion content during the release of copper ion-related drugs (Copper gluconate and D-penicillamine) was successfully monitored with RB-DH for the first time. This study demonstrates RB-DH's potential application in the evaluation of related drug release effects and serves as a guide for the establishment of portable detection techniques for other important substances.
Topics: Animals; Fluorescent Dyes; Copper; Zebrafish; Ions; Spectrometry, Fluorescence
PubMed: 37517156
DOI: 10.1016/j.bioorg.2023.106733 -
Journal of Clinical Medicine Jul 2023The 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...
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 ( < 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.
PubMed: 37510976
DOI: 10.3390/jcm12144861 -
Children (Basel, Switzerland) Jul 2023One of the most prevalent illnesses in neonates that needs care and treatment is neonatal jaundice. Several drugs are used as pharmacological modalities for treating...
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 (-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 (-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.
PubMed: 37508689
DOI: 10.3390/children10071192 -
Frontiers in Pediatrics 2023Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success...
PURPOSE
Retinopathy of prematurity (ROP) is the leading cause of preventable childhood blindness worldwide. Although interventions such as anti-VEGF and laser have high success rates in treating severe ROP, current treatment and preventative strategies still have their limitations. Thus, we aim to identify drugs and chemicals for ROP with comprehensive safety profiles and tolerability using a computational bioinformatics approach.
METHODS
We generated a list of genes associated with ROP to date by querying PubMed Gene which draws from animal models, human studies, and genomic studies in the NCBI database. Gene enrichment analysis was performed on the ROP gene list with the ToppGene program which draws from multiple drug-gene interaction databases to predict compounds with significant associations to the ROP gene list. Compounds with significant toxicities or without known clinical indications were filtered out from the final drug list.
RESULTS
The NCBI query identified 47 ROP genes with pharmacologic annotations present in ToppGene. Enrichment analysis revealed multiple drugs and chemical compounds related to the ROP gene list. The top ten most significant compounds associated with ROP include ascorbic acid, simvastatin, acetylcysteine, niacin, castor oil, penicillamine, curcumin, losartan, capsaicin, and metformin. Antioxidants, NSAIDs, antihypertensives, and anti-diabetics are the most common top drug classes derived from this analysis, and many of these compounds have potential to be readily repurposed for ROP as new prevention and treatment strategies.
CONCLUSION
This bioinformatics analysis creates an unbiased approach for drug discovery by identifying compounds associated to the known genes and pathways of ROP. While predictions from bioinformatic studies require preclinical/clinical studies to validate their results, this technique could certainly guide future investigations for pathologies like ROP.
PubMed: 37492605
DOI: 10.3389/fped.2023.1151239 -
Journal of the American Chemical Society Aug 2023With the growing popularity of serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) in chemical protein synthesis, facile and general approaches for...
With the growing popularity of serine/threonine ligation (STL) and cysteine/penicillamine ligation (CPL) in chemical protein synthesis, facile and general approaches for the preparation of peptide salicylaldehyde (SAL) esters are urgently needed, especially those viable for obtaining expressed protein SAL esters. Herein, we report the access of SAL ester surrogates from peptide hydrazides (obtained either synthetically or recombinantly) via nitrite oxidation and phenolysis by 3-(1,3-dithian-2-yl)-4-hydroxybenzoic acid (SAL(-COOH)). The resulting peptide SAL(-COOH) esters can be activated to afford the reactive peptide SAL(-COOH) esters for subsequent STL/CPL. While being operationally simple for both synthetic peptides and expressed proteins, the current strategy facilitates convergent protein synthesis and combined application of STL with NCL. The generality of the strategy is showcased by the N-terminal ubiquitination of the growth arrest and DNA damage-inducible protein (Gadd45a), the efficient synthesis of ubiquitin-like protein 5 (UBL-5) via a combined N-to-C NCL-STL strategy, and the C-to-N semisynthesis of a myoglobin (Mb) variant.
Topics: Protein C; Peptides; Proteins; Cysteine; Serine; Threonine; Esters
PubMed: 37470345
DOI: 10.1021/jacs.3c05190 -
Analytical Chemistry Jul 2023Organophosphate pesticides are used in agriculture due to their high effectiveness and low persistence in eradicating insects and pests. However, conventional detection...
d-Penicillamine@Ag/Cu Nanocluster-Based Fluorescent Nanoneuron for Logic Screening Phosphonate-Type Organophosphate Pesticides and Steganographically Encrypting Information.
Organophosphate pesticides are used in agriculture due to their high effectiveness and low persistence in eradicating insects and pests. However, conventional detection methods encounter the limitation of undesired detection specificity. Thus, screening phosphonate-type organophosphate pesticides (OOPs) from their analogues, phosphorothioate organophosphate pesticides (SOPs), remains a challenge. Here, we reported a d-penicillamine@Ag/Cu nanocluster (DPA@Ag/Cu NCs)-based fluorescence assay to screen OOPs from 21 kinds of organophosphate pesticides, which can be used for logic sensing and information encryption. Acetylthiocholine chloride was enzymatically split by acetylcholinesterase (AChE) to produce thiocholine, which reduced the fluorescence of DPA@Ag/Cu NCs due to the transmission of electrons from DPA@Ag/Cu NCs donor to the thiol group acceptor. Impressively, OOPs acted as an AChE inhibitor and retained the high fluorescence of DPA@Ag/Cu NCs due to the stronger positive electricity of the phosphorus atom. Conversely, SOPs possessed weak toxicity to AChE, which led to low fluorescence intensity. By setting 21 kinds of organophosphate pesticides as the inputs and the fluorescence of the resulting products as the outputs, DPA@Ag/Cu NCs could serve as a fluorescent nanoneuron to construct Boolean logic tree and complex logic circuit for molecular computing. As a proof of concept, by converting the selective response patterns of DPA@Ag/Cu NCs into binary strings, molecular crypto-steganography for encoding, storing, and concealing information was successfully achieved. This study is expected to advance the progress and practical application of nanoclusters in the area of logic detection and information security while also enhancing the relationship between molecular sensors and the world of information.
Topics: Penicillamine; Organophosphonates; Acetylcholinesterase; Organophosphorus Compounds; Insecticides; Coloring Agents; Blood Group Antigens; Organophosphates; Logic; Copper; Metal Nanoparticles; Pesticides
PubMed: 37428145
DOI: 10.1021/acs.analchem.3c02030 -
CEN Case Reports Apr 2024A 11-year-old girl was referred to the pediatric nephrology services of our hospital for evaluation of vitamin-D-refractory rickets. She was born to second-degree...
A 11-year-old girl was referred to the pediatric nephrology services of our hospital for evaluation of vitamin-D-refractory rickets. She was born to second-degree consanguineous parents. On examination, she had wrist widening and bilateral genu varum. She had normal anion gap metabolic acidosis, hypokalemia, and hyperchloremia. The fractional excretion of bicarbonate was 3% and the urine anion gap was positive. She also had hypercalciuria, but no phosphaturia, glucosuria or aminoaciduria. In view of a family history of an elder sister having rigidity with cognitive and speech impairment, an ophthalmic evaluation by slit lamp examination was performed in the index case that revealed bilateral Kayser-Fleischer rings. Serum ceruloplasmin was low and 24-h urine copper was elevated in the index case. Whole exome sequencing unveiled a novel pathogenic variant in exon 2 of the ATP7B gene (chr13: c.470del; Depth: 142x) (homozygous) that resulted in a frameshift and premature truncation of the protein, 15 amino acids downstream to codon 157 (p. Cys157LeufsTer15; NM_000053.4) confirming Wilson disease. There were no mutations in the ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, WDR72 genes or other genes that are known to cause distal RTA. Therapy with D-penicillamine and zinc supplements was initiated. A low dose of 2.5 mEq/kg/day of potassium citrate supplementation normalized the serum bicarbonate levels. This case was notable for the absence of hepatic or neurological involvement at admission. Wilson disease is well known to cause proximal renal tubular acidosis and Fanconi syndrome, with relatively lesser involvement of the distal renal tubules in the literature. However, isolated distal renal tubular involvement as presenting manifestation of Wilson disease (without hepatic or neurological involvement) is rare and can lead to diagnostic confusion.
Topics: Aged; Child; Female; Humans; Acidosis, Renal Tubular; Bicarbonates; Forkhead Transcription Factors; Hepatolenticular Degeneration; Mutation; Potassium Citrate; Vacuolar Proton-Translocating ATPases
PubMed: 37415038
DOI: 10.1007/s13730-023-00806-6 -
Clinical Neurology and Neurosurgery Aug 2023A variety of dietary adjuncts are known to affect the pathophysiology of glioma, making them a potential therapeutic adjunct to standard of care. We systematically... (Review)
Review
BACKGROUND
A variety of dietary adjuncts are known to affect the pathophysiology of glioma, making them a potential therapeutic adjunct to standard of care. We systematically reviewed clinical outcomes in glioma patients treated with one or more nutritional adjunct and/or an antimetabolite drug.
METHODOLOGY
A systematic review of the literature following PRISMA guidelines was performed using Pubmed from inception till February 2023. In total, 22 manuscripts on nutrition representing 828 patients were included in the review. Statistical analyses were performed to compare the outcomes of various adjuncts.
RESULTS
The median overall survival (OS) increased for newly diagnosed (21 months) and recurrent cases (10 months) when compared to historical data. For newly diagnosed cases, a ketogenic diet had the highest median OS of all the adjuncts (42.6 months) while in recurrent cases, a low copper diet coupled with 1 g penicillamine had the highest median OS (18.5 months). However, no statistically significant difference was observed in OS or progression-free survival (PFS) of newly diagnosed or recurrent gliomas.
CONCLUSION
While nutritional adjuncts may offer a therapeutic benefit in the treatment of glioma, more human subject research is needed to derive meaningful conclusions.
Topics: Humans; Neoplasm Recurrence, Local; Glioma; Progression-Free Survival; Brain Neoplasms
PubMed: 37390567
DOI: 10.1016/j.clineuro.2023.107853