Cytochrome P450 NADPH-reductase (P450R), inducible synthase (iNOS) and xanthine oxidase play an important role in the antracycline-related cardiotoxicity. The expression of P450R and iNOS is regulated by triiodothyronine. The aim of this study was to evaluate the effect of methimazole-induced hypothyreosis on oxidative stress secondary to doxorubicin administration. 48 hours after methimazole giving cessation, rats were exposed to doxorubicin (2.0, 5.0 and 15 mg/kg). Blood and heart were collected 4, 48 and 96 h after the drug administration. Animals exposed exclusively to doxorubicin or untreated ones were also assessed. The hypothyreosis (0.025% of methimazole) significantly increased the doxorubicin effect on the cardiac carbonyl group and they may increase the glutathione level. An insignificant effect of methimazole was noticed in case of the cardiac lipid peroxidation product, the amount of DNA oxidative damages, iNOS and xanthine oxidase-enzymes responsible for red-ox activation of doxorubicin. However, the concentration of P450R was affected by a lower dose of methimazole in rats administered with doxorubicin. Since in rats receiving doxorubicin changes in oxidative stress caused by methimazole were not accompanied by elevation of bioreductive enzymes, it may be concluded that these changes in the oxidative stress were not related to the tested enzymes.
Tirapazamine is a hypoxia-activated prodrug which was shown to exhibit up to 300 times greater cytotoxicity under anoxic in comparison with aerobic conditions. Thus, the combined anticancer therapy of tirapazamine with a routinely used anticancer drug seems to be a promising solution. Because tirapazamine undergoes redox cycle transformation in this study, the effect of tirapazamine on redox hepatic equilibrium, lipid status and liver morphology was evaluated in rats exposed to cisplatin, doxorubicin and 5-fluorouracil. Rats were intraperitoneally injected with tirapazamine and a particular cytostatic. The animals were killed, and blood and liver were collected. Hepatic glucose, total cholesterol, triglycerides, NADH, NADPH glutathione and the activity of glucose-6-phosphate dehydrogenase were determined. Liver morphology and the immune expression of HMG-CoA-reductase were also assessed. Glucose, total cholesterol, triglycerides, bilirubin concentrations and the activity of aspartate and alanine aminotransferases were determined in the plasma. Tirapazamine displayed insignificant interactions with cisplatin and 5-fluorouracil referring to hepatic morphology and biochemical parameters. However, tirapazamine interacts with doxorubicin, thus leading to side changes in redox equilibrium and lipid peroxidation, but those effects are not severe enough to exclude that drug combination from further studies. Thus, tirapazamine seems to be a promising agent in successive studies on anticancer activity in similar schedules.
Unusual expression of interleukin-1alpha, -1beta and -6 was previously found in the epiphyseal cartilage of rat fetuses prenatally exposed to various non-steroidal anti-inflammatory drugs (NSAID, i.e., ibuprofen, piroxicam, tolmetin) and selective cyclooxygenase-2 inhibitor (DFU). The aim of the present study was to evaluate the role of placenta in such phenomenon. Morphology of the organ, thickness of basal and labyrinth layer, immunoexpression of COX isoenzymes were examined, and confronted with maternal biochemical data and fetal developmental parameters. Higher maternal urea level, as well as lower placental weight and labyrinth thickness were found in the group of fetuses who revealed expression of genes coded the selected interleukins, when compared with the xenobiotic-exposed pups without the selected genes expression and untreated control. A significant correlation between placental weight and maternal total protein or urea level was revealed. Histological changes like inflammatory infiltration and calcification were observed sporadically. Location and intensity of COX-1 staining was similar in all cases. However, more intense COX-2 staining for majority of cells of the basal zone and in dispersed giant cells of the labyrinth was found in inflamed organs. It could be concluded that abnormal expression of the selected interleukins is associated with low placental weight and decrease of its thickness, especially labyrinth zone, as well as with high maternal urea level.
Reumatologia 2013; 51/5 S t r e s z c z e n i e Układowa postać (o uogólnionym początku) młodzieńczego idiopatycznego zapalenia stawów (MIZS) występuje u 10% ogółu chorych na MIZS, charakteryzuje się hektycznymi gorączkami, typowymi wysypkami (rash), objawami układowymi, zapaleniem stawów oraz wysokimi wskaźnikami stanu zapalnego. Niektórzy chorzy z układową postacią MIZS źle odpowiadają na zastosowane standardowe leczenie, w tym leczenie biologiczne preparatami blokującymi czynnik martwicy nowotworów (tumor necrosis factor -TNF). Efektywność terapii zależy od szybkiego wdrożenia właściwego postępowania. Leczenie inhibitorami interleukiny 1 i 6 (IL-1 i IL-6) jest skuteczną alternatywą terapeutyczną w przypadkach opornych na standardowe leczenie. S u m m a r ySystemic onset juvenile idiopathic arthritis (sJIA) occurs in 10% of patients with juvenile idiopathic arthritis and is manifested by hectic fever, typical rash, systemic symptoms, arthritis and high levels of inflammatory laboratory markers. In some cases of sJIA, response to treatment with standard therapy, including use of biologic medications blocking tumor necrosis factor (TNF), is poor. The efficacy of treatment depends on the rapid implementation of an appropriate therapeutic option. Treatment with interleukin 1 (IL-1) and interleukin 6 (IL-6) blockers is an effective alternative therapy in cases refractory to the most often used therapy.
Background Etanercept interferes with the tumor necrosis factor (TNF) and is widely used in various autoimmune diseases. However, its developmental toxicity has not been fully established. Objectives To analyze the effects of etanercept, new generation biological agent used in the therapy of rheumatoid arthritis, on the selected parameters of rat placenta – both in healthy females and in animals with experimentally induced arthritis. Methods This study included seven groups of Wistar rats: 1) with experimentally induced arthritis (group R), 2-3) with the arthritis treated with etanercept (0.4 or 4.0 mg/kg b.w.; groups RE1 and RE2), 4-5) receiving etanercept despite the lack of arthritis (E1, E2), and 6-7) controls receiving placebo (C1, C2). Female rats were immunized according to the Trentham's method. The drug (0.4 and 4.0 mg/kg) was subcutaneously injected to animals that exhibited one or higher severity score in the visual system for evaluation of CIA rodent model. After the last injection all the females were inseminated and pregnant animals were kept without any xenobiotics until gestational day 21 when cesarean section was performed. Parallel CIA, etanercept-exposed animals without CIA and untreated (sham operated) females were also examined. Morphological and histological structure of placenta, immunohistochemical reaction of placental homogenates to genes encoding tumor necrosis factor (TNF), cyclooxygenase 1 (COX-1), and proliferating cells nuclear antigen (PCNA), concentration of TNF in placental homogenates, placental expression of interleukin encoding genes: IL1α, IL1β, LTβ, IL6, COX-1, and TNF. Results Concentrations of TNF were significantly higher in placental homogenates from females with experimentally induced arthritis (groups R, RE1, and RE2). On detailed analysis of these three groups, the concentration of examined cytokine proved significantly higher in animals that did not receive etanercept (group R). The only significant intergroup difference in qualitative expression of examined genes pertained to IL1α gene, the presence of which could be observed solely in placentas of rats from group R. Conclusions Experimentally induced arthritis causes inflammatory response within the placenta. This effect is partially reversed by etanercept administration; the application of this agent does not negatively affect placental function and morphology. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5644
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