Oxime reactivators of acetylcholinesterase (AChE) are used as causal antidotes for intended and unintended poisoning by organophosphate nerve agents and pesticides. Despite all efforts to develop new AChE reactivators, none of these drug candidates replaced conventional clinically used oximes. In addition to the therapeutic efficacy, determining the safety profile is crucial in preclinical drug evaluation. The exact mechanism of oxime toxicity and the structure-toxicity relationship are subjects of ongoing research, with oxidative stress proposed as a possible mechanism. In the present study, we investigated four promising bispyridinium oxime AChE reactivators, K048, K074, K075, and K203, and their ability to induce oxidative stress in vitro. Cultured human hepatoma cells were exposed to oximes at concentrations corresponding to their IC50 values determined by the MTT assay after 24 h. Their potency to generate reactive oxygen species, interfere with the thiol antioxidant system, and induce lipid peroxidation was evaluated at 1, 4, and 24 h of exposure. Reactivators without a double bond in the four-carbon linker, K048 and K074, showed a greater potential to induce oxidative stress compared with K075 and K203, which contain a double bond. Unlike oximes with a three-carbon-long linker, the number of aldoxime groups attached to the pyridinium moieties does not determine the oxidative stress induction for K048, K074, K075, and K203 oximes. In conclusion, our results emphasize that the structure of oximes plays a critical role in inducing oxidative stress, and this relationship does not correlate with their cytotoxicity expressed as the IC50 value. However, it is important to note that oxidative stress cannot be disregarded as a potential contributor to the side effects associated with oximes.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota farmakologie   MeSH
• buňky Hep G2 MeSH
• cholinesterasové inhibitory toxicita   MeSH
• lidé MeSH
• organofosfáty toxicita   MeSH
• oxidační stres MeSH
• oximy farmakologie   chemie   MeSH
• pyridinové sloučeniny farmakologie   chemie   MeSH
• reaktivátory cholinesterasy * farmakologie   chemie   MeSH
• uhlík MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterasy * MeSH
• uhlík MeSH

BACKGROUND: Liver resection is a surgical procedure associated with a high risk of hepatic failure that can be fatal. One of the key mechanisms involves ischemia-reperfusion damage. Building on the well-known positive effects of hydrogen at mitigating this damage, the goal of this work was to demonstrate the antioxidant, anti-inflammatory, and anti-apoptotic effects of inhaled hydrogen in domestic pigs during major liver resection. METHODS: The study used a total of 12 domestic pigs, 6 animals underwent resection with inhaled hydrogen during general anesthesia, and 6 animals underwent the same procedure using conventional, unsupplemented, general anesthesia. Intraoperative preparation of the left branch of the hepatic portal vein and the left hepatic artery was performed, and a tourniquet was applied. Warm ischemia was induced for 120 minutes and then followed by liver reperfusion for another 120 minutes. Samples from the ischemic and non-ischemic halves of the liver were then removed for histological and biochemical examinations. RESULTS: An evaluation of histological changes was based on a numerical expression of damage based on the Suzuki score. Liver samples in the group with inhaled hydrogen showed a statistically significant reduction in histological changes compared to the control group. Biochemical test scores showed no statistically significant difference in hepatic transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LD), and lactate. However, a surprising result was a statistically significant difference in gamma-glutamyl-transferase (GMT). Marker levels of oxidative damage varied noticeably in plasma samples. CONCLUSIONS: In this experimental study, we showed that inhaled hydrogen during major liver resection unquestionably reduced the level of oxidative stress associated with ischemia-reperfusion damage. We confirmed this phenomenon both histologically and by direct measurement of oxidative stress in the organism.

• Klíčová slova
• Ischemia-reperfusion injury, hepatic impairment, oxidative damage markers, oxidative stress, reactive oxygen species (ROS),
• Publikační typ
• časopisecké články MeSH

The purpose of the present study was to employ two methods-square wave voltammetry (SWV) performed on screen printed sensors and ferric reducing antioxidant power (FRAP)-as suitable tools for the assay of low-molecular-weight antioxidants (LMWAs). LMWAs were assayed by both methods and the resulting data were statistically compared. Plasma samples from five Cinereous vultures accidentally intoxicated with lead were used to represent real biological matrices with different levels of LMWAs. Blood was collected from the birds prior to and one month after treatment with Ca-EDTA. SWV resulted in two peaks. The first peak, with the potential value of 466 ± 15 mV, was recognized as ascorbic and uric acids, while the second one (743 ± 30 mV) represented glutathione, tocopherol, ascorbic acid and in a minor effect by uric acid, too. Contribution of individual antioxidants was recognized by separate assays of LMWA standards. Correlation between peaks 1 and 2 as well as the sum of the two peaks and FRAP was analysed. While peak 1 and the sum of peaks were in close correlation to FRAP results (correlation coefficient of 0.97), the relation between peak 2 and FRAP may be expressed using a correlation coefficient of 0.64. The determination of thiols by the Ellman assay confirmed the accuracy of SWV. Levels of glutathione and other similar structures were stable in the chosen model and it may be concluded that SWV is appropriate for assay of LMWAs in plasma samples. The methods employed in the study were advantageous in minimal sample volume consumption and fast acquisition of results.

• Klíčová slova
• Cinereous vultures, analytical methods, ascorbate, glutathione, lead intoxication, uric acid,
• Publikační typ
• časopisecké články MeSH