Acute hepatitis results from oxidative stress triggered by hepatotoxic drugs causing liver injury and the activation of caspases cascade. The glutathione antioxidant system protects against reactive oxygen species and mitigates development of these processes. The effectiveness of silymarin, a polyphenolic flavonoid, essenthiale, composed of phosphatidyl choline, and melaxen, a melatonin-correcting drug, as hepatoprotectors has been investigated. The variation of 6-sulfatoxymelatonin (aMT6s), resulting from the biotransformation of melatonin, and GSH has been measured. The activities of caspase-1 and caspase-3, glutathione antioxidant system, and NADPH-generating enzymes were determined. The aMT6s decreases in patients with drug hepatitis and recovers with administration of mexalen. GSH increased in the presence of the studied hepatoprotectors. Pathologically activated caspase-1 and caspase-3 decreased their activities in the presence of hepatoprotectors with melaxen showing the highest effect. The positive effect of melatonin appears to be related to the suppression of decompensation of the glutathione antioxidant system functions, recovery of liver redox status, and the attenuation of inhibition of the NADPH supply.
Inflammation and an increase in antioxidant responses mediated by oxidative stress play an important role in the pathogenesis of acute liver injury (ALI). We utilized in silico prediction of biological activity spectra for substances (PASS) analysis to estimate the potential biological activity profile of deethylated ethoxyquin (DEQ) and hypothesized that DEQ exhibits antioxidant and anti-inflammatory effects in a rat model of carbon tetrachloride (CCl4)-induced ALI. Our results demonstrate that DEQ improved liver function which was indicated by the reduction of histopathological liver changes. Treatment with DEQ reduced CCl4-induced elevation of gene expression, and the activity of antioxidant enzymes (AEs), as well as the expression of transcription factors Nfe2l2 and Nfkb2. Furthermore, DEQ treatment inhibited apoptosis, downregulated gene expression of pro-inflammatory cytokines (Tnf and Il6), cyclooxygenase 2 (Ptgs2), decreased glutathione (GSH) level and myeloperoxidase (MPO) activity in rats with ALI. Notably, DEQ treatment led to an inhibition of CCl4-induced NLRP3-inflammasome activation which was indicated by the reduced protein expression of IL-1β, caspase-1, and NLRP3 in the liver. Our data suggest that DEQ has a hepatoprotective effect mediated by redox-homeostasis regulation, NLRP3 inflammasome, and apoptosis inhibition, which makes that compound a promising candidate for future clinical studies.
Ïðè ñàõàðíîì äèàáåòå 2 òèïà, îñëîaeíåííîì ñòåàòîãåïàòèòîì, íàáëþäàëîñü ïàäåíèå àêòèâíîñòè àêîíèòàòãèäðàòàçû, óâåëè÷åíèå ñîäåðaeàíèÿ äèåíîâûõ êîíúþãàòîâ, óìåíü-øåíèå êîíöåíòðàöèè a-òîêîôåðîëà è èçìåíåíèå óðîâíÿ öèòðàòà â ñûâîðîòêå êðîâè áîëüíûõ, ÷òî ñâèäåòåëüñòâóåò î ðàçâèòèè îêèñëèòåëüíîãî ñòðåññà â ðåçóëüòàòå âîçðàñ-òàíèÿ èíòåíñèâíîñòè ñâîáîäíîðàäèêàëüíîãî îêèñëåíèÿ áèîñóáñòðàòîâ è ñíèaeåíèè ñòåïåíè àíòèîêñèäàíòíîé çàùèòû îðãàíèçìà. Êîìáèíèðîâàííàÿ òåðàïèÿ ñ ìåëàêñåíîì ïðèâîäèëà ê áîëåå çíà÷èòåëüíîìó, â ñðåäíåì íà 36 % (ð £ 0,05), ïî ñðàâíåíèþ ñ áàçèñ-íûì ëå÷åíèåì, èçìåíåíèþ èññëåäóåìûõ ïîêàçàòåëåé â íàïðàâëåíèè íîðìû, ÷òî, ïî-âèäèìîìó, ñâÿçàíî ñ ðåàëèçàöèåé àíòèîêñèäàíòíîãî ýôôåêòà ìåëàòîíèíà.Êëþ÷åâûå ñëîâà: ñàõàðíûé äèàáåò 2 òèïà; íåàëêîãîëüíûé ñòåàòîãåïàòèò; ìåëàêñåí; äèåíîâûå êîíúþãàòû; àêîíèòàòãèäðàòàçà; öèòðàò; a-òîêîôåðîë. ÂÂÅÄÅÍÈÅÏî ñâîåé õèìè÷åñêîé ñòðóêòóðå ìåëàòîíèí (N-àöå-òèë-5-ìåòîêñèòðèïòàìèí) ïðåäñòàâëÿåò ñîáîé ïðîèç-âîäíîå ñåðîòîíèíà -áèîãåííîãî àìèíà, êîòîðûé, â ñâîþ î÷åðåäü, ñèíòåçèðóåòñÿ èç àìèíîêèñëîòû òðèï-òîôàíà. Ìåëàòîíèí ó÷àñòâóåò â ôîðìèðîâàíèè ñóòî÷-íûõ áèîðèòìîâ, òîðìîaeåíèè íåêîòîðûõ ôóíêöèé ãè-ïîôèçà, ðåãóëÿöèè èììóííûõ ðåàêöèé [6]. Äàííûé ãîðìîí ñïîñîáåí òàêaeå äåçàêòèâèðîâàòü àêòèâíûå ôîðìû êèñëîðîäà (ÀÔÊ). Ðàíåå íàìè áûëè ïîëó÷åíû äàííûå î òîì, ÷òî ïðè ââåäåíèè ýêçîãåííîãî ìåëàòîíè-íà ïðîèñõîäèò òîðìîaeåíèå ñâîáîäíîðàäèêàëüíîãî îêèñëåíèÿ (ÑÎ) ó êðûñ ñ òîêñè÷åñêèì ãåïàòèòîì [12], ñàõàðíûì äèàáåòîì [1], ãèïåðòèðåîçîì [4].Ïðåäïîëàãàþò, ÷òî íåçàâèñèìî îò ýòèîëîãè÷åñêèõ ôàêòîðîâ â îñíîâå ðàçâèòèÿ âîñïàëèòåëüíî-íåêðîòè-÷åñêèõ èçìåíåíèé â ïå÷åíè ëåaeàò óíèâåðñàëüíûå ìå-õàíèçìû. Ïðè ñàõàðíîì äèàáåòå â ïå÷åíè ïîâûøàåòñÿ ñîäåðaeàíèå ãëþêîçî-6-ôîñôàòàçû, â ñâÿçè ñ ÷åì îáëåã-÷àåòñÿ âûäåëåíèå ãëþêîçû â êðîâü [7]. Èçáûòî÷íîå ïî-ñòóïëåíèå ñâîáîäíûõ aeèðíûõ êèñëîò â ïå÷åíü, îáðà-çîâàíèå èç íèõ òðèãëèöåðèäîâ, ñíèaeåíèå ñêîðîñòè b-îêèñëåíèÿ ñâîáîäíûõ aeèðíûõ êèñëîò, à òàêaeå ñåê-ðåöèÿ ëèïèäîâ â êðîâîòîê ñïîñîáñòâóþò ôîðìèðîâà-íèþ aeèðîâîé äèñòðîôèè ãåïàòîöèòîâ. Ïðè íåàëêî-ãîëüíîì ñòåàòîãåïàòèòå (ÍÀÑÃ) íàáëþäàåòñÿ ïîâû-øåííàÿ àêòèâíîñòü öèòîõðîìà Ð450 2Å1 â ïå÷åíè, ÷òî ÷àñòî ñîïðîâîaeäàåòñÿ îáðàçîâàíèåì àêòèâíûõ ìåòàáî-ëèòîâ, âêëþ÷àÿ ÀÔÊ. Ïðè ýòîì ïðîäóêòû ïåðåêèñíîãî îêèñëåíèÿ ëèïèäîâ (ÏÎË) âûçûâàþò íàáóõàíèå ìèòî-õîíäðèé, ëîìêîñòü ìåìáðàí ëèçîñîì, íàðóøåíèå öåëî-ñòíîñòè êëåòî÷íûõ ìåìáðàí [17].Ê âàaeíåéøèì íåôåðìåíòàòèâíûì àíòèîêñèäàíòàì îòíîñèòñÿ âèòàìèí Å, êîòîðûé çàùèùàåò âíóòðåííèå ìèòîõîíäðèàëüíûå ìåìáðàíû, à òàêaeå ëèçîìû îò ïî-âðåaeäàþùåãî äåéñòâèÿ ïåðåêèñåé, ïîääåðaeèâàåò ôóíêöèîíàëüíóþ öåëîñòíîñòü âíåøíåé öèòîïëàçìàòè-÷åñêîé ìåìáðàíû êëåòîê [15]. a-Òîêîôåðîë ýôôåêòèâ-íî ïðåðûâàåò öåïíûå ñâîáîäíîðàäèêàëüíûå ðåàêöèè â ïðîöåññå ïåðåîêèñëåíèÿ íåíàñûùåííûõ aeèðíûõ êè-ñëîò â ìåìáðàíàõ, ïðåäóïðåaeäàåò àòåðîãåííûå èçìå-íåíèÿ ëèïîïðîòåèíîâ íèçêîé ïëîòíîñòè. Ñóùåñòâóåò ïðÿìàÿ ñâÿçü ìåaeäó óðîâíåì âèòàìèíà Å è èíòåíñèâ-íîñòüþ òêàíåâîãî äûõàíèÿ è îáðàòíàÿ ñâÿçü ñî ñòåïå-íüþ îêèñëåíèÿ ëèïèäîâ [15].Âàaeíåéøåå ìåñòî â íåôåðìåíòàòèâíîì çâåíå àíòè-îêñèäàíòíîé ñèñòåìû (ÀÎÑ) çàíèìàåò öèòðàò, êîòî-ðûé îòíîñè...
Purpose The diabetic nephropathy is associated with oxidative stress and increases in pigment epithelium-derived factor (PEDF) level in the patient's blood. For the first time, authors investigated the effect of methylethylpiridinol addition to the therapy on oxidative status and pigment epithelium-derived factor concentrations, and examined the relationship between these indicators and clinical markers of pathology development. Methods Study design: open label randomized controlled trial study. Authors assessed the effect of methylethylpiridinol addition to the therapy vs basic treatment on antioxidant and NADPH-generating enzymes activity, glutathione's concentration and free radical-induced oxidation's intensity using a spectrophotometric method and iron-induced biochemiluminescence. The pigment epithelium-derived factor concentration in the serum was measured by enzyme-linked immunosorbent assay. Results Patients receiving combination therapy with methylethylpiridinol showed a more substantial increase in activity of glutathione peroxidase (Δ = 0.04 ± 0.11, p = 0.002), glutathione transferase (Δ = 0.12 ± 0.08, p < 0.001) and the concentration of reduced glutathione (Δ = 0.30 ± 0.17, p = 0.039). In addition, there was a significant decrease in PEDF level (Δ = -6.4 ± 5.4, p = 0.004). Correlation analysis showed a negative link between Δ postprandial glucose and Δ NADP-isocitrate dehydrogenase (-0.39, p = 0.033), Δ reduced glutathione and Δ postprandial glucose (-0.372, p = 0.043), Δ glutathione transferase and Δ PEDF (-0.37, p = 0.044). Conclusions The methylethylpiridinol addition to the therapy had a more potent stimulating effect on the patients' oxidative status in comparison with standard treatment, and reliably decreased pigment epithelium-derived factor level in patients' serum. The observed differences seem to be associated with the antioxidant activity of methylethylpiridinol which contributing to the mitigation of oxidative stress reducing at diabetes mellitus.
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