Окислительный стресс в митохондриях мозга при алюминиевом нейротоксикозе и введении модуляторов биосинтеза глутатиона и кофермента А

oai:oai.dan.elpub.ru:article/857Using an experimental model of aluminum neurotoxicosis, it was established that under conditions of chronic administration of aluminum chloride to rats, oxidative stress develops and inhibits the redox potential of the glutathione system in the mitochondrial and postmitochondrial fractions of the cerebral hemispheres. It was shown that the ingestion of N-acetylcysteine, as well as its combined use with coenzyme A biosynthesis precursors (D-panthenol or D-pantetin) against the background of aluminum neurotoxicosis, leads to a marked decrease in the production of reactive oxygen species by mitochondria, a decrease in the production of thiobarbituric acid reactive substances, and normalization of GSH content and its biosynthesis in brain tissue. The results indicate a high efficiency of the biosynthesis precursor of glutathione N-acetylcysteine in the prevention of oxidative stress in the chronic model of aluminum neurotoxicosis, which may be the rationale for its use as a modulator of mitochondrial redox status in the development of neurodegenerative pathology.На экспериментальной модели алюминиевого нейротоксикоза установлено, что в условиях хронического введения хлорида алюминия у крыс развиваются явления окислительного стресса и угнетение восстановительного потенциала системы глутатиона в митохондриальной и постмитохондриальной фракциях больших полушарий мозга. Показано, что введение N-ацетилцистеина, а также сочетанного назначения его с модуляторами биосинтеза кофермента А (D-пантенолом или D-пантетином) на фоне алюминиевого нейротоксикоза приводят к выраженному снижению продукции активных форм кислорода митохондриями, снижению наработки тиобарби-турат-реагирующих соединений, нормализации содержания глутатиона и его биосинтеза в ткани мозга. Полученные результаты указывают на высокую эффективность предшественника биосинтеза глутатиона N-ацетилцистеина в предупреждении окислительного стресса в хронической модели алюминиевого нейротоксикоза, что может быть обоснованием для его применения как модулятора редокс-статуса митохондрий при развитии нейродегенеративной патологии

Temperature- and field-induced transformation of the magnetic state in Co2.5Ge0.5BO5

A tetravalent-substituted cobalt ludwigite Co2.5Ge0.5BO5 has been synthesized using the flux method. The compound undergoes two magnetic transitions: a long-range antiferromagnetic transition at TN1 = 84 K and a metamagnetic one at TN2 = 36 K. The sample-oriented magnetization measurements revealed a fully compensated magnetic moment along the a- and c-axes and an uncompensated one along the b-axis leading to high uniaxial anisotropy. A field-induced enhancement of the ferromagnetic correlations at TN2 is observed in specific heat measurements. The DFT+GGA calculation predicts the spin configuration of (↑↓↓↑) as a ground state with a magnetic moment of 1.37 μB/f.u. The strong hybridization of Ge(4s, 4p) with O (2p) orbitals resulting from the high electronegativity of Ge4+ is assumed to cause an increase in the interlayer interaction, contributing to the long-range magnetic order. The effect of two super–superexchange pathways Co2+-O-B-O-Co2+ and Co2+-O-M4-O-Co2+ on the magnetic state is discussed.This work has been financed by the Russian Foundation for Basic Research (project no. 20-02-00559). The authors acknowledge financial support from the Spanish Agencia Estatal de Investigación, through projects MAT2017-83468-R (AEI/FEDER, UE) and PID2020-115159GB-I00/AEI/10.13039/501100011033, the Aragonese project RASMIA E12_20R (co-funded by Fondo Social Europeo), and of the European Union FEDER (ES).Peer reviewe

Theoretical principles of organic chemistry /

Mw. Wed. AnnoLEIDSSTELSELOPLADEN-RUG0

Antioxidants selenomethionine and D-pantethine differentially affect doxorubicin’s action on glutathione system in human leukemia cells varying in their resistance to chemotherapy in vitro

Rapid development of multiple drug resistance and occurrence of negative side effects in cancer patients arising at the treatment belong to the main problems in cancer chemotherapy. Recently, it was shown that specific antioxidants (selenomethionine – SeMet and D-pantethine – D-Pt) possessed nephro-, myelo- and hepatoprotective activity at doxorubicin’s (Dx) action in tumor-bearing mice. Besides, these antioxidants inhibited a cytotoxic action of Dx toward chemotherapy-sensitive tumor cells, and enhanced the cytotoxic effect of this drug toward selected drug-resistant tumor cell lines (e.g. HL-60/vinc, HL-60/adr), while in other such lines (e.g. HCT-116/Bax(−/−), HCT-116/p53), it was not effective. The aim of present study was to investigate the molecular mechanisms of the revealed difference in the action of SeMet and D-Pt toward cytotoxic effects of Dx in tumor cells varying in drug resistance. Human leukemia cells of HL-60/wt line and its drug-resistant sublines HL-60/adr (overexpression of MRP-1) and HL-60/vinc (overexpression of P-gp) were used in this study. Treatment of cells with Dx led to the versatile action of this drug on the level of glutathione in each of the studied cell line and sublines. HL-60/wt cells were characterized by 8-fold lower GSH level under Dx treatment compared to control, while in HL-60/vinc and HL-60/adr cells GSH level was increased 2.2- and 8.2-fold (compared to untreated cells), correspondingly. The use of doxorubicin also led to significant rearrangement of GSSG/GSH ratio in these cell lines, leading to 2-fold elevation of GSSG level HL-60/vinc cells, and 2.5-fold decrease of this index in HL-60/adr cells. We have shown that a combined effect of SeMet or D-Pt on the background of the cytotoxic action of doxorubicin on HL-60/vinc cells is accompanied by a 2-fold decrease in both oxidized and reduced glutathione levels. Such an effect of these antioxidants can serve as an explanation of their sensitizing effect on the cells of the HL-60/vinc subline under Dx’s action which we observed earlier. It should be noted that treatment with Dx led to a 2.5-fold increase in the activity of glutathione-S-transferase in the leukemia cells of HL-60/vinc subline. The antioxidants effectively reduced this indicator. SeMet and D-Pt differentialy affected the activity of glutathione-S-transferase in HL-60/adr cells. In conclusion, our data demonstrate an important role of the antioxidants on the functional state of the glutathione system in tumor cells that differ in their drug resistance. The obtained results suggest an important role of glutathione-S-transferase in modulation of cancer drug resistance that is caused by P-glycoprotein overexpression, but not by the overexpression of MRP-1 protein. Selenomethionine and D-pantethine effectively inhibit this enzyme, thus, sensitizing P-gp overexpressing cells towards the action of doxorubicin. This event is accompanied by further decrease in GSH and GSSG levels in these cells, thus sensitizing them to Dx action. Further studies of the molecular mechanisms underlying this phenomenon are in progress

Modeling the Acquisition of English: an Intelligent CALL Approach

In this paper, we present a methodology for the development of a user model for CALL which captures various levels of language acquisition using individualized overlays supported with stereotypes. Our current focus is the empirical analysis of the order of written English grammatical structure acquisition in our learner population used to develop stereotype layers in our model

Decreased renal expression of PAQR5 is associated with the absence of a nephroprotective effect of progesterone in a rat UUO model

Abstract Fibrosis is a severe complication of chronic kidney disease (CKD). Progesterone, like other sex hormones, plays an important role in renal physiology, but its role in CKD is poorly understood. We investigated progesterone effect on renal fibrosis progression in the rat model of unilateral ureteral obstruction (UUO). Female rats were exposed to UUO, ovariectomy and progesterone administration after UUO with ovariectomy. Expression of key fibrosis markers, proinflammatory cytokines, levels of membrane-bound (PAQR5) and nuclear (PGR) progesterone receptors, and matrix metalloproteinase (MMP) activity were analyzed in the obstructed and intact rat kidney. In all groups exposed to UUO, decreased PAQR5 expression was observed in the obstructed kidney while in the contralateral kidney, it remained unaffected. We found increased mRNA levels for profibrotic COL1A1, FN1, MMP2, TIMP1, TIMP2, proinflammatory IL1α, IL1β, and IL18, as well as elevated α-SMA and MMP9 proteins, collagen deposition, and MMP2 activity in all UUO kidneys. Progesterone had slight or no effect on the change in these markers. Thus, we demonstrate for the first time diminished sensitivity of the kidney to progesterone associated with renal fibrosis due to a severe decrease in PAQR5 expression that was accompanied by the lack of nephroprotection in a rat UUO model