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Journal of Colloid and Interface Science Jun 2024Bacteria-associated infections and thrombus formation are the two major complications plaguing the application of blood-contacting medical devices. Therefore,...
Bacteria-associated infections and thrombus formation are the two major complications plaguing the application of blood-contacting medical devices. Therefore, functionalized surfaces and drug delivery for passive and active antifouling strategies have been employed. Herein, we report the novel integration of bio-inspired superhydrophobicity with nitric oxide release to obtain a functional polymeric material with anti-thrombogenic and antimicrobial characteristics. The nitric oxide release acts as an antimicrobial agent and platelet inhibitor, while the superhydrophobic components prevent non-specific biofouling. Widely used medical-grade silicone rubber (SR) substrates that are known to be susceptible to biofilm and thrombus formation were dip-coated with fluorinated silicon dioxide (SiO) and silver (Ag) nanoparticles (NPs) using an adhesive polymer as a binder. Thereafter, the resulting superhydrophobic (SH) SR substrates were impregnated with S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) to obtain a superhydrophobic, Ag-bound, NO-releasing (SH-SiAgNO) surface. The SH-SiAgNO surfaces had the lowest amount of viable adhered E. coli (> 99.9 % reduction), S. aureus (> 99.8 % reduction), and platelets (> 96.1 % reduction) as compared to controls while demonstrating no cytotoxic effects on fibroblast cells. Thus, this innovative approach is the first to combine SNAP with an antifouling SH polymer surface that possesses the immense potential to minimize medical device-associated complications without using conventional systemic anticoagulation and antibiotic treatments.
Topics: Humans; Nitric Oxide; Silver; S-Nitroso-N-Acetylpenicillamine; Staphylococcus aureus; Escherichia coli; Silicon Dioxide; Anti-Bacterial Agents; Anti-Infective Agents; Hydrophobic and Hydrophilic Interactions; Thrombosis; Polymers
PubMed: 38503078
DOI: 10.1016/j.jcis.2024.03.082 -
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 -
Gastroenterologia Y Hepatologia Oct 2023There is uncertainty regarding Wilson's disease (WD) management.
UNLABELLED
There is uncertainty regarding Wilson's disease (WD) management.
OBJECTIVES
To assess, in a multicenter Spanish retrospective cohort study, whether the approach to WD is homogeneous among centers.
METHODS
Data on WD patients followed at 32 Spanish hospitals were collected.
RESULTS
153 cases, 58% men, 20.6 years at diagnosis, 69.1% hepatic presentation, were followed for 15.5 years. Discordant results in non-invasive laboratory parameters were present in 39.8%. Intrahepatic copper concentration was pathologic in 82.4%. Genetic testing was only done in 56.6% with positive results in 83.9%. A definite WD diagnosis (Leipzig score ≥4) was retrospectively confirmed in 92.5% of cases. Chelating agents were standard initial therapy (75.2%) with frequent modifications (57%), particularly to maintenance zinc. Enzyme normalization was not achieved by one third, most commonly in the setting of poor compliance, lack of genetic mutations and/or presence of cardiometabolic risk factors. Although not statistically significant, there were trends for sex differences in number of diagnosed cases, age at diagnosis and biochemical response.
CONCLUSIONS
Significant heterogeneity in diagnosis and management of WD patients emerges from this multicenter study that includes both small and large reference centers. The incorporation of genetic testing will likely improve diagnosis. Sex differences need to be further explored.
Topics: Humans; Female; Male; Hepatolenticular Degeneration; Retrospective Studies; Chelating Agents; Zinc; Copper; Penicillamine
PubMed: 36372257
DOI: 10.1016/j.gastrohep.2022.10.018 -
Bulletin of Experimental Biology and... Jan 2024A comparative analysis of the infarct-limiting activity of δ- and κ-opioid receptors (OR) agonists was carried out on a model of coronary occlusion (45 min) and...
A comparative analysis of the infarct-limiting activity of δ- and κ-opioid receptors (OR) agonists was carried out on a model of coronary occlusion (45 min) and reperfusion (120 min) in male Wistar rats. We used selective δ-OR agonist deltorphin II (0.12 mg/kg), δ-OR agonists BW373U86 and p-Cl-Phe DPDPE (0.1 and 1 mg/kg), selective agonists of δ-OR DPDPE (0.1 and 0.969 mg/kg), κ-OR U-50,488 (0.1 and 1 mg/kg), κ-OR GR-89696 (0.1 mg/kg), and κ-OR ICI-199,441 (0.1 mg/kg). All drugs were administered intravenously 5 min before reperfusion. Deltorphin II, BW373U86 (1 mg/kg), p-Cl-Phe DPDPE (1 mg/kg), U-50,488 (1 mg/kg), and ICI-199,441 had a cardioprotective effect. The most promising compounds for drug development are ICI-199,441 and deltorphin II.
Topics: Rats; Animals; Male; Rats, Wistar; Receptors, Opioid, delta; Enkephalin, D-Penicillamine (2,5)-; Myocardial Reperfusion; Infarction; Benzamides; Piperazines
PubMed: 38340196
DOI: 10.1007/s10517-024-06020-3 -
Journal of Pediatric Gastroenterology... May 2024Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This... (Observational Study)
Observational Study
OBJECTIVES
Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD.
METHODS
Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier.
RESULTS
Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity.
CONCLUSION
Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.
Topics: Humans; Hepatolenticular Degeneration; Penicillamine; Female; Male; Recurrence; Prospective Studies; Adolescent; Child; Drug Therapy, Combination; Chelating Agents; Alanine Transaminase; Aspartate Aminotransferases; Zinc; Liver Function Tests; Copper; Withholding Treatment
PubMed: 38695602
DOI: 10.1002/jpn3.12128 -
Chemico-biological Interactions Jun 2024Copper is a toxic heavy metal that causes various damage when it accumulates in the body beyond the physiological threshold. Wilson disease (WD) is an inherited disorder...
Copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to testicular damage and impaired spermatogenesis in Wilson disease.
Copper is a toxic heavy metal that causes various damage when it accumulates in the body beyond the physiological threshold. Wilson disease (WD) is an inherited disorder characterized by impaired copper metabolism. Reproductive damage in male patients with WD is gradually attracting attention. However, the underlying mechanisms of copper toxicity are unclear. In this study, we investigated the role of inflammation and PANoptosis in testicular damage and impaired spermatogenesis caused by copper deposition using the WD model toxic milk (TX) mice. Copper chelator-penicillamine and toll-like receptor 4 (TLR4) inhibitor-eritoran were used to intervene in TX mice in our animal experiment methods. Testis samples were collected from mice for further analysis. The results showed that the morphology and ultrastructure of the testis and epididymis in TX mice were damaged, and the sperm counts decreased significantly. The TLR4/nuclear factor kappa-B (NF-κB) signaling pathway was activated by copper deposition, which led to the upregulation of serum and testicular inflammatory factors in TX mice. Meanwhile, pyroptosis, apoptosis, and necroptosis were significant in the testis of TX mice. Both chelated copper or inhibited TLR4 expression markedly suppressed the TLR4/NF-κB signaling pathway, thereby reducing the expression of inflammatory factors. PANoptosis in the testis of TX mice was also reversed. Our study indicated that pathological copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to toxic testicular damage and impaired spermatogenesis in WD.
Topics: Animals; Male; Toll-Like Receptor 4; Copper; Spermatogenesis; Testis; NF-kappa B; Signal Transduction; Mice; Hepatolenticular Degeneration; Inflammation; Apoptosis; Penicillamine
PubMed: 38761876
DOI: 10.1016/j.cbi.2024.111060 -
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 -
Analytical Chemistry May 2024To date, achieving enantioselective electroanalysis for electrochemically silent chiral molecules is still highly desired. Here, an ionic covalent organic framework...
π-π Interaction Promoting the Absorption of Electroactive Chiral Selectors into the Cavity of Conductive Covalent Organic Framework for Enantioselective Sensing of Electrochemically Silent Molecules.
To date, achieving enantioselective electroanalysis for electrochemically silent chiral molecules is still highly desired. Here, an ionic covalent organic framework (COF) consisting of the pyridinium cation was derived from the tripyridinium Zincke salt and 1,4-phenylenediamine in a one-pot reaction. The electrochemical measurements revealed that the ionic backbone contributed to the electron transfer with a low charge transfer resistance. Besides, the π-π interaction between the pyridinium cation and ferrocenyl unit can promote the absorption of electroactive chiral ferrocenyl reagents into the hole of COF, so as to afford the electrochemical signals by themselves, replacing the testing enantiomers. As a result, the electroactive complex used as an electrochemical platform was highly effective at enantiomerically recognizing amino alcohols (prolinol, valinol, leucinol, and alaninol) and amino acids (methionine, serine, and penicillamine), giving the ratios of current intensity between l- and d-enantiomers in the range of 1.46-1.72. Moreover, the density functional theory calculations determined the possible intermolecular interactions between the testing enantiomers and chiral selector: namely, hydrogen bonds and electrostatic attractions. Overall, the present work offers an effective strategy to enlarge the electrochemical scope for chiral recognition based on electroactive chiral COFs.
PubMed: 38688014
DOI: 10.1021/acs.analchem.4c00526 -
Journal of the American Chemical Society Jun 2024Persulfides (RSSH) are biologically important reactive sulfur species that are endogenously produced, protect key cysteine residues from irreversible oxidation, and are...
Persulfides (RSSH) are biologically important reactive sulfur species that are endogenously produced, protect key cysteine residues from irreversible oxidation, and are important intermediates during different enzymatic processes. Although persulfides are stronger nucleophiles than their thiol counterparts, persulfides can also act as electrophiles in their neutral, protonated form in specific environments. Moreover, persulfides are electrophilic at both sulfur atoms, and the reaction with a thiolate can lead to either HS release with disulfide formation or alternatively result in transpersulfidation. Despite the broad acceptance of these reaction pathways, the specific properties that control whether persulfides react through the HS-releasing or transpersulfidation pathway remain elusive. Herein, we use a combined computational and experimental approach to directly investigate the reactivity between persulfides and thiols to answer these questions. Using density functional theory (DFT) calculations, we demonstrate that increasing steric bulk or electron withdrawal near the persulfide can shunt persulfide reactivity through the transpersulfidation pathway. Building from these insights, we use a synthetic persulfide donor and an -iodoacetyl l-tyrosine methyl ester (TME-IAM) trapping agent to experimentally monitor and measure transpersulfidation from a bulky penicillamine-based persulfide to a cysteine-based thiol, which, to the best of our knowledge, is the first direct observation of transpersulfidation between low-molecular-weight species. Taken together, these combined approaches highlight how the properties of persulfides are directly impacted by local environments, which has significant impacts in understanding the complex chemical biology of these reactive species.
PubMed: 38935871
DOI: 10.1021/jacs.4c05874 -
Chembiochem : a European Journal of... May 2024In this work, a highly sensitive and selective method for detecting folic acid (FA) was developed using D-penicillamine (DPA) stabilized Ag/Cu alloy nanoclusters...
In this work, a highly sensitive and selective method for detecting folic acid (FA) was developed using D-penicillamine (DPA) stabilized Ag/Cu alloy nanoclusters (DPA@Ag/Cu NCs). The yellow emission of DPA@Ag/Cu NCs was found to be quenched upon the addition of FA to the system. The fluorescence intensity quenching value demonstrated a linear relationship with FA concentrations ranging from 0.01 to 1200 μM, with a limit of detection (LOD) of 5.3 nM. Furthermore, the detection mechanism was investigated through various characterization analyses, including high resolution transmission electron microscopy, fluorescence spectra, ultraviolet-visible absorption spectra, and fluorescence lifetime. The results indicated that the fluorescence quenching induced by FA was a result of electron transfer from FA to the ligands of DPA@Ag/Cu NCs. The selectivity of the FA sensor was also evaluated, showing that common amino acids and inorganic ions had minimal impact on the detection of FA. Moreover, the standard addition method was successfully applied to detect FA in human serum, chewable tablets and FA tablets with promising results. The use of DPA@Ag/Cu NCs demonstrates significant potential for detecting FA in complex biological samples.
PubMed: 38757240
DOI: 10.1002/cbic.202400254