Effect of recombinant human erythropoietin on mitomycin C-induced oxidative stress and genotoxicity in rat kidney and heart tissues.

Mitomycin C (MMC) is an antineoplastic agent used for the treatment of several human malignancies. Nevertheless, the prolonged use of the drug may result in a serious heart and kidney injuries. Recombinant human erythropoietin (rhEPO) has recently been shown to exert an important cytoprotective effect in experimental brain injury and ischemic acute renal failure. The aim of the present work is to investigate the cardioprotective and renoprotective effects of rhEPO against MMC-induced oxidative damage and genotoxicity. Our results showed that MMC induced oxidative stress and DNA damage. rhEPO administration in any treatment conditions decreased oxidative damage induced by MMC. It reduced malondialdehyde and protein carbonyl levels. rhEPO ameliorated reduced glutathione plus oxidized glutathione modulation and the increased catalase activity after MMC treatment. Furthermore, rhEPO restored DNA damage caused by MMC. We concluded that rhEPO administration especially in pretreatment condition protected rats against MMC-induced heart and renal oxidative stress and genotoxicity.

Zearalenone-induced changes in biochemical parameters, oxidative stress and apoptosis in cardiac tissue: Protective role of crocin.

Zearalenone (ZEN) is a mycotoxin from Fusarium species commonly found in food commodities and is known to cause reproductive disorders. Several in vivo studies have shown that ZEN is haematotoxic and hepatotoxic and causes several alterations of immunological parameters. Meantime, the available information on the cardiotoxic effects of ZEN is very much limited. In the present study, we investigated the toxic effects of ZEN in heart tissues of Balb/c mice. We demonstrated that ZEN (40 mg kg(-1) body weight (b.w.)) increased creatine phosphokinase, lactate dehydrogenase, aspartate transaminase, alanine transaminase, total cholesterol and triglyceride levels and induced oxidative stress as monitored by measuring the malondialdehyde level, the generation of protein carbonyls, the catalase and superoxide dismutase activity and the expression of the heat shock proteins (Hsp 70). We also demonstrated that acute administration of ZEN triggers apoptosis in cardiac tissue. Furthermore, we aimed to evaluate the safety and efficacy of crocin (CRO), a natural carotenoid, to prevent ZEN-induced cardiotoxicity in mice. In fact, combined treatment of ZEN with different doses of CRO (50, 100, and 250 mg kg(-1) b.w.) showed a significant reduction of ZEN-induced toxicity for all tested markers in a dose-dependent manner. It could be concluded that CRO was effective in the protection against ZEN-induced toxicity in cardiac tissue.

Protective effect of aqueous extract of Allium sativum against zearalenone toxicity mediated by oxidative stress.

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium in cereals and agricultural products. It has been implicated in several mycotoxicosis in farm animals and in humans. Several reports suggest that oxidative damage seems to be a key determinant of ZEN induced toxicity in vitro and in vivo. The aim of the current study was to evaluate the protective effects of aqueous extract of Allium sativum (AEA), against ZEN-induced cytotoxicity, reactive oxygen species (ROS) generation and DNA fragmentation in cultured Vero cells. Indeed, cytotoxicity effects were studied using MTT viability assay, ROS generation measurement and catalase activity induction. To check whether the oxidative stress induction was associated to DNA lesions, we looked for DNA fragmentation using Comet test. Our results indicated that ZEN induced several toxic effects and significant alterations mediated by oxidative stress mechanism. Treatment by ZEN combined to the lowest dose of AEA (250 µg/ml) showed a significant reduction of ZEN induced damages for all tested markers and a noticeable reduction of DNA fragmentation. It could be concluded that A. sativum aqueous extracts is effective in the protection against ZEN hazards. This could be relevant, particularly with the emergent demand for natural products which may counteract the detrimental toxic effects mediated by oxidative stress process and therefore prevents multiple human diseases.

Comparative study of toxic effects of zearalenone and its two major metabolites alpha-zearalenol and beta-zearalenol on cultured human Caco-2 cells.

Zearalenone (ZEN) is a fusarotoxin converted predominantly into alpha-zearalenol (alpha-Zol) and beta-zearalenol (beta-Zol) by hepatic hydroxysteroid dehydrogenases. The feeding of naturally contaminated grains with ZEN was associated with hyperestrogenic and adverse effects on humans and animals. There is a lack of information on the attribution of the toxic effects of these toxins. One wonders if these effects are due to the parent molecule (ZEN) or to its major metabolites (alpha-Zol and beta-Zol). Using human Caco-2 cells, we looked for the molecular mechanisms of toxicity of ZEN, alpha-Zol, and beta-Zol. Toxicity effects were studied by MTT viability assay and oxidative stress induction by measuring malondialdehyde (MDA) generation. To check whether the oxidative stress induction was associated to DNA lesions, we looked for DNA fragmentation by means of the Comet and the diphenylamine assays. To specify cell death pathway, we investigated caspase-3 activation, confirmed by poly(ADP-ribose) polymerase cleavage and by Bcl-2 depletion. Our results clearly demonstrated that ZEN as well as its two metabolites presented variable toxic effects. They induced cell death and an increase in MDA generation. These effects were associated to DNA fragmentation as well as caspase-3 activation. The observed toxic effects seem to be relieved by the metabolism of ZEN into alpha-Zol and beta-Zol.

Cytotoxicity and related effects of T-2 toxin on cultured Vero cells.

T-2 toxin belongs to a group of mycotoxins synthesized by Fusarium fungi that are widely encountered as natural contaminants of certain important agricultural commodities particularly, cereals. Upon exposure, T-2 toxin causes severe human and animal diseases. It is considered to be a major causative agent in fatal alimentary toxic aleukia (ATA) in humans. In this study, cytotoxicity and apotosis induction by T-2 toxin was investigated in vitro on Vero cell line using the MTT and the neutral red viability assays, the induction of lipid peroxidation, the decrease of macromolecule levels (protein, DNA and RNA), DNA fragmentation and caspase-3-dependent apoptosis induction. Our results showed that T-2 toxin reduced cell viability correlated to an impairment of macromolecule levels. It also increased MDA formation, induced DNA fragmentation showed by DNA laddering patterns on agarose gel electrophoresis. This fragmentation is in relation with apoptosis induction which was confirmed by activation of caspase-3, and depletion of the mitochondrial membrane potential reflecting a mitochondrial dysfunction.

Cytotoxicity, inhibition of DNA and protein syntheses and oxidative damage in cultured cells exposed to zearalenone.

Mycotoxins are toxic metabolites of various fungi commonly found in feed and foodstuff and can cause very serious health problems in animals as well as in humans. Zearalenone (ZEN), a mycotoxin produced by various Fusarium species has several adverse effects. Indeed, ZEN has strong estrogenic activity associated with hyperestrogenism and several physiological alterations of the reproductive tract. Moreover, ZEN was shown to be hepatotoxic, haematotoxic, immunotoxic and genotoxic. The exact mechanism of ZEN toxicity is not completely established. The observed strong estrogenic effect of ZEN resulting from its competition with 17beta-estradiol in the binding to estrogen receptors is generally considered to underline most toxic effects of ZEN, but estrogenic activity alone cannot explain the diverse and apparent adverse effects. The objective of the present study was to determine the involvement of other possible mechanisms in ZEN induced toxicity. Cytotoxicity, cell cycle perturbation, inhibition of protein and DNA synthesis as well as the presumed later marker of oxidative stress, malondialdehyde, were monitored in Vero and Caco-2 cells exposed to ZEN. Our results showed that ZEN reduces cell viability correlated to cell cycle perturbation, inhibits protein and DNA syntheses and increases MDA formation in both cell lines in concentration-dependant manner. We assumed that cytotoxicity and oxidative damage are additional mechanisms of ZEN mediated toxicity.