Barbara Jodłowska-Jędrych

Different Effects of Resveratrol on Dose-Related Doxorubicin-Induced Heart and Liver Toxicity

The aim of the study was to evaluate the effect of resveratrol in doxorubicin-induced cardiac and hepatic toxicity. Doxorubicin was administered once a week throughout the period of 7 weeks with 1.0 or 2.0 mg/kg body weight or concomitantly with resveratrol (20 mg/kg of feed). Heart and liver toxicity was histologically and biochemically evaluated. Resveratrol protected from the heart lipid peroxidation caused by 1 mg doxorubicin and it sharply diminished superoxide dismutase activity. An insignificant effect of resveratrol on the lipid peroxidation level and the superoxide dismutase activity was observed in the hearts of rats administered a higher dose of doxorubicin. However, resveratrol attenuate necrosis and other cardiac histopathological changes were induced by a high dose of doxorubicin. Interestingly, it slightly intensified adverse cardiac histological changes in rats receiving a lower dose of doxorubicin. Resveratrol did not have any protective effect on the hepatic oxidative stress, while exerting a mild beneficial effect on the morphological changes caused by doxorubicin. All in all, this study has shown different effects of resveratrol on dose-related doxorubicin-induced heart and liver toxicity. Resveratrol may modulate the hepatic and cardiac effect of doxorubicin, depending on the drug dose.

Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer

Alterations in microRNAs expression have been proposed to play role in endometrial cancer pathogenesis. Dicer and Drosha are main regulators of microRNA biogenesis and deregulation of their expression has been indicated as a possible cause of microRNAs alterations observed in various cancers. The objective of this study was to investigate Dicer and Drosha genes expression in endometrial cancer and to analyze the impact of clinicopathological characteristics on their expression. Fresh tissue samples were collected from 44 patients (26 endometroid endometrial carcinoma and 18 controls). Clinical and pathological data were acquired from medical documentation. Dicer and Drosha genes expressions were assessed by qRT-PCR using validated reference genes. Dicer and Drosha expression levels were significantly lower in endometrial cancer samples comparing to controls. Dicer was down-regulated by the factor of 1.54 (p = 0.009) and Drosha gene mean expression value was 1.4 times lower in endometrial cancer group versus control group (p = 0.008). Down-regulation of Dicer significantly correlated with decreased expression of Drosha (coefficient value 0.75). Decreased expression of Drosha correlated with higher histological grade and was influenced by BMI. Lower Dicer expression was found in nulli- and uniparous females comparing to multiparous individuals (p = 0.002). Neither the FIGO stage nor the menstrual status had significant influence on the expression of studied genes. This study revealed for the first time that expression alterations of main regulators of microRNAs biogenesis are present in endometrial cancer tissue and could be potentially responsible for altered microRNAs profiles observed in this malignancy.

The evaluation of the biomedical effectiveness of poly(amido)amine dendrimers generation 4.0 as a drug and as drug carriers: a systematic review and meta-analysis.

The purpose of this study was to investigate the evaluation of the biomedical effectiveness of poly(amido)amine dendrimers generation 4.0 (PAMAM G4) as a drug and as drug carriers by a systematic review of literature and meta-analysis. The results obtained from meta-analysis concluded that drug therapy reduces the change of parameters in relation to the control. The impact of the drug administered to change the test parameters are dependent on the type of tissue. PAMAM G4 may be effective in vitro and in vivo as a drug and drug carriers and may have appropriate applications in various fields of medicine. PAMAM G4 dendrimers hold promises for nanomedicine.

Intensification of Doxorubicin-Related Oxidative Stress in the Heart by Hypothyroidism Is Not Related to the Expression of Cytochrome P450 NADPH-Reductase and Inducible Nitric Oxide Synthase, As Well As Activity of Xanthine Oxidase

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.

EMT promoting transcription factors as prognostic markers in human breast cancer

PurposeBreast cancer is one of the most common female cancers. Moreover, despite the progress in medicine, its mortality rate is still very high. Therefore, researchers are constantly looking for new prognostic factors, which may simplify disease diagnosis and optimize the therapy. Metastases are responsible for the majority of deaths caused by breast cancer. Epithelial-mesenchymal transition is one of the mechanisms of metastasis, which is controlled by specific transcription factors. In the recent years, many researchers studied the prognostic value of factors promoting the epithelial–mesenchymal transition in patients with breast cancer. This work is an attempt to summarize the current state of knowledge on this issue.MethodsA systemic search of peer-reviewed articles published between November 2005 and February 2016 was performed using PubMed/MEDLINE database. Most cited articles constituted original papers, although single review articles were also included.ResultsBased on the so far conducted studies, a promising conclusion can be drawn, that several described factors might serve as a putative negative prognostic marker in breast cancer.ConclusionsObtained results of this review should encourage researchers to conduct further clinical trials on large patient groups which will evaluate the prognostic value of EMT transcription factors in breast cancer course.

The differential effects of green tea on dose-dependent doxorubicin toxicity

Background Doxorubicin (DOX) is an anticancer drug displaying cardiac and hepatic adverse effects mostly dependent on oxidative stress. Green tea (GT) has been reported to play a protective role in diseases resulting from oxidative stress. Objective The objective of this study was to evaluate if GT protects against DOX-induced oxidative stress, heart and liver morphological changes, and metabolic disorders. Methods Male Wistar rats received intraperitoneal injection of DOX (1.0 or 2.0 mg/kg b.w.) for 7 weeks or concomitantly GT extract soluble in drinking water. Results There were multidirectional effects of GT on blood metabolic parameters changed by DOX. Among all tested biochemical parameters, statistically significant protection of GT against DOX-induced changes was revealed in case of blood fatty acid–binding protein, brain natriuretic peptide, and superoxide dismutase. Conclusion DOX caused oxidative stress in both organs. It was inhibited by GT in the heart but remained unchanged in the liver. DOX-induced general toxicity and histopathological changes in the heart and in the liver were mitigated by GT at a higher dose of DOX and augmented in rats treated with a lower dose of the drug.

Tirapazamine-Doxorubicin Interaction Referring to Heart Oxidative Stress and Ca2+ Balance Protein Levels

Doxorubicin (DOX) causes long-term cardiomyopathy that is dependent on oxidative stress and contractility disorders. Tirapazamine (TP), an experimental adjuvant drug, passes the same red-ox transformation as DOX. The aim of the study was to evaluate an effect of tirapazamine on oxidative stress, contractile protein level, and cardiomyocyte necrosis in rats administered doxorubicin. Rats were intraperitoneally injected six times once a week with tirapazamine in two doses, 5 (5TP) and 10 mg/kg (10TP), while doxorubicin was administered in dose 1.8 mg/kg (DOX). Subsequent two groups received both drugs simultaneously (5TP+DOX and 10TP+DOX). Tirapazamine reduced heart lipid peroxidation and normalised RyR2 protein level altered by doxorubicin. There were no significant changes in GSH/GSSG ratio, total glutathione, cTnI, AST, and SERCA2 level between DOX and TP+DOX groups. Cardiomyocyte necrosis was observed in groups 10TP and 10TP+DOX.

Tirapazamine has no Effect on Hepatotoxicity of Cisplatin and 5‐fluorouracil but Interacts with Doxorubicin Leading to Side Changes in Redox Equilibrium

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.

The effect of thyroxin on hepatic redox equilibrium and lipid metabolism in rats treated with doxorubicin

Abstract The main side effects of the administration of doxorubicin, a widely used anticancer drug, is the generation of a reactive oxygen species (ROS) in normal cells. As a result, redox disorders and secondary oxidative stress are developed. Doxorubicin ROS generation is attributed to enzymes that are produced abundantly in hepatocytes. Oxidative stress has been a well-known risk factor of doxorubicin-related toxicity. However, in addition, according to the data collected in the last decade, changes in thyroxin status can propagate ROS generation, and, thus, initiate the doxorubicin hepatic effect. Moreover, both compounds have an impact on the cell metabolism. The aim of the study was to verify the thesis that thyroxin can modulate the effect of doxorubicin with regard to redox status and lipid metabolism disorders. In our work, we determined the ratio of NADP+/ NADPH and NAD+/NADH in liver homogenates, blood ketone bodies and triglycerides in the liver and blood in rats treated with doxorubicin and thyroxin. Our results indicate that thyroxin has an insignificant effect on NAD+/NADH, NADP+/NADPH ratios and on hepatic and blood triglycerides. Moreover, thyroxin administration normalized the level of blood ketone bodies that was disturbed by doxorubicin.

Chronic Variable Stress Is Responsible for Lipid and DNA Oxidative Disorders and Activation of Oxidative Stress Response Genes in the Brain of Rats

Chronic environmental stress is associated with reactive oxygen species (ROS) overproduction and the pathogenesis of depression. The purpose of this study was to evaluate biochemical and molecular changes associated with ROS generation in the brains of rats submitted to chronic variable stress. Male Wistar rats (50–55 days old, weighing 200–250 g) were divided in two groups (n = 10): control and stressed. Rats in the stressed group were exposed to stress conditions for 40 days. The animals were decapitated and the brain samples were collected. In prefrontal cortex, we measured the following biochemical parameters: lipid peroxidation and concentration of glutathione—GSH, GSSG, GSH/GSSG ratio, glutathione peroxidase, and glutathione reductase activities. In the hippocampus marker of DNA, oxidative damage and expression of DNA-repairing genes (Ogg1, MsrA) and gene-encoding antioxidative transcriptional factor (Nrf2) were determined. The results demonstrate indirect evidence of ROS overproduction and presence of oxidative stress. They also reveal disruption of oxidative defense systems (decreased GR activity, diminished GSH/GSSG ratio, and decreased Nrf2 expression) and activation of the oxidative DNA repair system (increased Ogg1 and MsrA expression). Together, the presented data suggest that independent activation of oxidative stress response genes occurs in chronic variable stress conditions.