Aminothiols exchange in coronavirus disease 2019

Objective:Clinical manifestation of the inflammatory process in its relation to biochemical markers(total cysteine[Cys],cysteine-glycine[CysGly],glutathione[GSH],glutamate-cysteine[Glu-Cys],homocysteine[Hcy],the ratio of reduced to oxidized glutathione[GSH/GSSG],the ratio of reduced to oxidized cysteine[CySH/CySS],malondialdehyde-oxidized low-density lipoproteins[MDA-oxLDL])has been studied in patients with coronavirus disease 2019(COVID-19).Material and methods:48 patients with mild to severe COVID-19 and 20 healthy volunteers were included in our research.The participants were divided into 4 experimental groups according to inflammation intensity estimated based on the serum levels of interleukin 6(IL-6).Results:All 4 groups showed the prevalence of male patients and elevated serum levels of IL-6(by 54.6%).There was no comorbidity in patients with mild COVID-19(nasopharyngitis symptoms)and in healthy control subjects.50%of patients with lung damage had accompanying diseases.Alterations of aminoethyl metabolism were detected in COVID-19 patients:as reflected by the decreased levels of Cys,CysGly,and Glu-Cys and the increased levels of GSH as compared to the control group.Conclusion:Elevation of IL-6 over 7.5 pg/mL was associated with decreased GSH/GSSG and CySH/CySS ratios indicating enhanced oxidative stress and was followed by protein oxidation,specifically MDA-oxLDL.

Blood concentration of aminothiols in children with relapse of nephrotic syndrome

Background:The role of idiopathic nephrotic syndrome(INS)in the pathogenesis of atherosclerosis in childhood has not been clearly elucidated.However,antioxidative defense in INS is thought to be imbalanced.This study aimed to assess the changes of plasma concentration of selected aminothiols in the blood of children with INS at various stages of the disease.Methods:This cross-sectional study was conducted in 125 children aged 2-18 years.The children were divided into 4 groups:group A,early relapse(n=37);group B,early remission for 4-6 weeks from the onset(n=37);group C,late steroid-free remission(n=31);and group D,long-term remission for 2-5 years(n=20).Control group(E)consisted of 30 age-and gender-matched healthy children.The study protocol comprised an analysis of plasma concentrations of glutathione,homocysteine,cysteine and cysteinylglycine by high-performance liquid chromatography.Fractions of protein-bound and free aminothiols were measured.Endothelial injury was assessed by thrombomodulin,PAI-1 concentration,and von Willebrand factor activity.Results:The children with INS had unbalanced aminothiol metabolism only in relapse and early remission,that shifted towards increased oxidative processes.Administration of cyclosporine A caused a significant increase in homocysteine and cysteine concentration.Changes in aminothiol metabolism were significantly related to endothelial injury.Conclusion:The fi ndings of this study may be helpful in elucidating the pathogenesis of premature atherosclerosis in patients with INS refractory to the treatment or in the case of frequent relapse.

Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation

AIM To overcome the hazardous effects on liver caused by long-term use of antitubercular agent isoniazid(INH) by developing a novel hepatoprotective prodrug strategy by conjugating INH with aminothiols as antioxidant promoities for probable synergistic effect.METHODS INH was conjugated with N-acetyl cysteine(NAC) and N-(2)-mercaptopropionyl glycine using the SchottenBaumann reaction and with L-methionine using Boc-anhydride through a biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis, and in vitro and in vivo release studies were carried out using HPLC. Their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, measuring markers of oxidative stress and carrying out histopathology studies.RESULTS Prodrugs were found to be stable in acidic(pH 1.2) and basic(pH 7.4) buffers and in rat stomach homogenates, whereas they were hydrolysed significantly(59.43%-94.93%) in intestinal homogenates over a period of 6 h. Upon oral administration of prodrug NI to rats, 52.4%-61.3% INH and 47.4%-56.8% of NAC were recovered in blood in 8-10 h. Urine and faeces samples pooled over a period of 24 h exhibited 1.3%-2.5% and 0.94%-0.9% of NAC, respectively, without any presence of intact NI or INH. Prodrugs were biologically evaluated for hepatoprotective activity. All the prodrugs were effective in abating oxidative stress and re-establishing the normal hepatic physiology. The effect of prodrug of INH with NAC in restoring the levels of the enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy especially. CONCLUSION The findings of this investigation demonstrated that the reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.