New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene.

BACKGROUND: Karyomegalic interstitial nephritis (KIN) is a rare disease entity first described by Burry in 1974. The term KIN was introduced by Mihatsch et al. in 1979. KIN is characterized by chronic tubulointerstitial nephritis associated with enlarged tubular epithelial cell nuclei, which leads to a progressive decline of renal function. The prevalence of this disease is less than 1% of all biopsies, and its pathogenesis is unclear. KIN results from mutations in FAN1 (FANCD2/FANCI-Associated Nuclease 1), a gene involved in the DNA damage response pathway, particularly in the kidney. In this study, we report two Tunisian consanguineous families with KIN caused by mutations in the FAN1 gene. METHODS: Direct sequencing of the coding regions and flanking intronic sequences of the FAN1 gene was performed in three affected members. Three prediction programs (Polyphen-2 software, SIFT, and MutationTaster) were used to predict the functional effect of the detected variations. RESULTS: Two causative frameshift variants in the FAN1 gene were identified in each family: The previously described frameshift mutation c.2616delA (p.Asp873ThrfsTer17) and a novel mutation c.2603delT (p.Leu868ArgfsTer22) classified as "pathogenic" according to the American College of Medical Genetics and Genomics (ACMG) guidelines. CONCLUSION: To our best knowledge, this is the first Tunisian study involving familial cases of KIN with mutations in the FAN1 gene. We hypothesize that these findings can expand the mutational spectrum of KIN and provide valuable information on the genetic cause of KIN.

Eugenol protects against citrinin-induced cytotoxicity and oxidative damages in cultured human colorectal HCT116 cells.

This study aimed to investigate the protective effects of Eugenol (EUG), an effective antioxidant phenolic compound with a radical scavenging activity against citrinin (CTN)-induced toxicity in vitro using HCT116 cells. CTN is a well-known mycotoxin found in different constituents of the food chain. This environmental contaminant produces free radicals which interacts with cellular macromolecules and produces oxidation of protein, lipid, and DNA. The cytotoxic effects were monitored by measuring cell viability, reactive oxygen species (ROS) generation, antioxidant enzyme activities, malondialdehyde (MDA) production, protein oxidation, and DNA fragmentation. Our results have shown that the pretreatment of HCT116 cells with EUG, 2 h prior to citrinin (CTN) exposure, significantly decreased CTN-induced cell death, inhibited ROS generation, modulated activities of both catalase (CAT) and superoxide dismutase (SOD), and reduced MDA production. Level of protein-bound sulfhydryls and DNA fragmentation were also declined as compared with CTN-treated cells. These findings suggest that EUG would be an effective protective agent against CTN-induced oxidative stress, and thereby, it may complement and add to the functions of antioxidant vitamins and enzymes as a protection against the cytotoxicity of this mycotoxin.

Protective effects of kefir against deltamethrin-induced hepatotoxicity in rats.

Deltamethrine (DLM) is a synthetic pyrethroid with broad spectrum activities against acaricides and insects. Widely used for agricultural and veterinary purposes, its human and animal exposure occurs by ingestion of contaminated water and food and leads to serious health problems. Kefir is fermented milk with numerous health favors counting restorative properties of bacterial flora, immune system stimulation, cholesterol reduction, as well as anti-mutagenic and anti-tumor properties. The present study was undertaken to examine the hepatoprotective and antioxidant potential of kefir against DLM toxicity in male Wistar albino rats. DLM-treated animals revealed a significant increase in serum biochemical parameters as well as hepatic protein and lipid oxidations but caused an inhibition in antioxidant enzymes. Additionally, we have observed an increase in hepatocyte DNA damages. This toxic effect was confirmed by histological study. Kefir administration normalized the elevated serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T bilirubin), and cholesterol. It also reduced DLM-induced protein carbonyl (PC) and malondialdehyde (MDA) formations. Furthermore, Kefir treatment restored catalase (CAT) and superoxide dismutase (SOD) activities. The co-treatment as well as the pre-treatment by kefir showed an improvement of oxidative status as well as suppressed inflammation and DNA damages. However, the pre-treatment seems to be the most efficient. Therefore, it could be concluded that kefir is a natural product able to protect against the hepatotoxic effects of DLM by its free radical-scavenging and potent antioxidant activity.

Protective effects of kefir against zearalenone toxicity mediated by oxidative stress in cultured HCT-116 cells.

Kefir is a fermented milk with numerous health favors counting restorative properties of bacterial flora, reduction of the symptoms of lactose intolerance, immune system stimulation, cholesterol reduction, as well as anti-mutagenic and anti-tumor properties. Zearalenone (ZEN) is a mycotoxin produced by some Fusarium species. ZEN often occurs as a contaminant in cereal grains and animal feeds. Human exposure occurs by ingestion of mycotoxin-contaminated products and can cause serious health problems. This study aimed to assess the preventive effect of kefir against ZEN toxicity in cultured HCT-116 colorectal carcinoma cells; by the evaluation of cell viability, oxidative stress status and the initiation of apoptotic cell death pathway. Our results demonstrated that ZEN inhibits cell proliferation which was accompanied by an increase in the generation of free radicals as measured by fluorescent 2,7-dichlorofluorescein (DCF) and Malondialdehyde (MDA). As an adaptive response to this redox status, we showed an induction of heat shock protein expression (Hsp 70) and an activation of antioxidant enzymes; catalase and Superoxide Dismutase (SOD). Moreover, a loss of mitochondrial membrane potential (Δѱm) was observed. The co-treatment as well as the pre-treatment by kefir showed a reduction of ZEN induced damages for all tested markers. However, the pre-treatment seems to be the most efficient, it prevented almost all ZEN hazards. Consequently, oxidative damage appears to be a key determinant of ZEN induced toxicity in cultured HCT-116 cells. In conclusion, we showed that kefir may better exert its virtue on preventive mode rather than on curative one. By this way, kefir as a beverage with highly antioxidant properties could be relevant particularly with the emergent demand for natural products which may counteract the detrimental effects of oxidative stress and therefore prevent multiple human diseases.

Acute triflumuron exposure induces oxidative stress responses in liver and kidney of Balb/C mice.

Triflumuron (TFM) is one of the most widely used insecticides over the world. It is a benzoylphenyl urea that belongs to the class of insect growth regulators. This insecticide acts by inhibiting insect's chitin synthesis and by consequences, making insect more susceptible to pathogens and malformations. TFM effects have been reported in mammalians and crops. However, studies that reveal its toxicity mechanisms are limited. In this line, the current study aimed to determine the implication of oxidative stress in the toxicity induced by TFM and particularly in the perturbation of biochemical parameters in male Balb/C mice. Male Balb/C mice were divided into three groups receiving TFM at doses of 250, 350, and 500 mg/kg bw respectively. The occurrence of oxidative stress in both kidney and liver tissues was monitored by measuring of oxidative stress markers. TFM caused an increase as protein carbonyls generation, malondialdehyde induction (MDA) and catalase (CAT), superoxide dismutase (SOD), glutathion peroxidase (Gpx), as well as glutathion S transferase (GST) activities. In the same conditions, we have evaluated the effect of TFM treatment on biochemical parameters. In response to the three TFM doses, we showed significant dose dependent inductions in all tested oxidative stress markers. However, TFM caused an increase in the liver enzyme activities as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), g-glutamyltranspeptidase (GTT), and total bilirubin (BILT) in a dose-dependent manner. Equally, renal markers as urea, uric acid, albumin, and creatinine were increased in the same manner. We can conclude that oxidative damage seems to be a key determinant of TFM-induced toxicity in both liver and kidney of male Balb/C mice. Moreover, the oxidative stress is more pronounced in the liver than in the kidney. Thus, TFM may be considered as a hepatotoxic insecticide.

Citrinin induces apoptosis in human HCT116 colon cancer cells through endoplasmic reticulum stress.

The mycotoxin citrinin (CTN) is a natural contaminant of various human foods that may produce serious adverse health problems. Several studies demonstrated that citrinin exerts cytotoxic and genotoxic effects in both in vivo and in vitro systems. However, the precise mechanisms of action (MOA), particularly in intestinal cells remain unclear. The aim of the present study was to examine the precise MOA of citrinin in vitro. Data demonstrated that CTN significantly decreased the number of viable human intestinal HCT116 cells and induced apoptotic events including (1) decrease in ΔÑ°m indicative of mitochondrial membrane permeabilization, (2) activation of caspase 3, (3) elevated production of reactive oxygen species (ROS) and (4) relative persistence of plasma membrane integrity. Further, the genetic deficiency of the pro-apoptotic protein Bax protected cells against CTN-induced apoptosis, indicating that Bax is required for CTN-mediated toxicity. It was also found that CTN triggered endoplasmic reticulum (ER) stress and activated different arms of the unfolded protein response (UPR) as demonstrated by increase in expression of GRP78 (glucose-regulated protein-78), GRP94 (glucose-regulated protein-94), GADD34 (growth arrest and DNA damage-inducible protein-34), the protein disulfide isomerase associated 6 (PDIA6), CHOP (C/EBP-homologous protein) and the splicing of XBP1 (X-Box Binding Protein 1). Pretreatment of cells with the chemical chaperone 4-phenylbutyrate (PBA), known to alleviate ER stress, prevented significantly the apoptotic process triggered by CTN. Taken together, these results suggest that CTN exerts its cytotoxic effects in HCT116 cells by inducing apoptosis, at least in part, through induction of ER stress.

SIRT1 protects cardiac cells against apoptosis induced by zearalenone or its metabolites α- and ß-zearalenol through an autophagy-dependent pathway.

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by several species of Fusarium in cereals and agricultural products. The major ZEN metabolites are α-zearalenol (α-ZOL) and ß-zearalenol (ß-ZOL). In the present study, we investigated the underlying mechanism of the toxicity induced by ZEN, α-ZOL and ß-ZOL in cardiac cells (H9c2). We show that treatment with ZEN or its metabolites induces the activation of the mitochondrial pathway of apoptosis as characterized by an increase in ROS generation, a loss of mitochondrial transmembrane potential (ΔΨm) and an activation of caspases. Besides, we demonstrate that these mycotoxins promote the activation of autophagy before the onset of apoptosis. Indeed, we observed that a short-time (6h) treatment with ZEN, α-ZOL or ß-ZOL, increased the level of Beclin-1 and LC3-II and induced the accumulation of the CytoID® autophagy detection probe. Moreover, the inhibition of autophagy by Chloroquine significantly increased cell death induced by ZEN, α-ZOL or ß-ZOL, suggesting that the activation of autophagy serves as a cardioprotective mechanism against these mycotoxins. In addition, we found that the inhibition (EX527) or the knockdown of SIRT1 (siRNA) significantly increased apoptosis induced by ZEN or its derivatives, whereas SIRT1 activation with RSV greatly prevents the cytotoxic effects of these mycotoxins. By contrast, when autophagy was inhibited by CQ, the activation of SIRT1 by RSV had no protection against the cardiotoxicity of ZEN or its metabolites, suggesting that SIRT1 protects cardiac cells by an autophagy-dependent pathway.

Beneficial effects of mycophenolate mofetil on cardiotoxicity induced by tacrolimus in wistar rats.

The immunosuppressive drug tacrolimus (TAC) is used clinically to reduce the rejection rate in transplant patients. TAC has contributed to an increased prevalence of cardiovascular disease in patients receiving solid organ transplantation. Mycophenolate mofetil (MMF), a potent inhibitor of de novo purine synthesis, is known to prevent ongoing rejection in combination with TAC. In the present study, we investigated the antioxidant and antigenotoxic effect of MMF on TAC-induced cardiotoxicity in rats. Oral administration of TAC at 2.4, 24, and 60 mg/kg b.w. corresponding, respectively, to 1, 10, and 25% of LD50 for 24 h caused cardiac toxicity in a dose-dependant manner. TAC increased significantly DNA damage level in hearts of treated rats. Furthermore, it increased malondialdehyde (MDA) and protein carbonyl (PC) levels and decreased catalase (CAT) and superoxide dismutase (SOD) activities. The oral administration of MMF at 50 mg/kg b.w. simultaneously with TAC at 60 mg/kg b.w. proved a significant cardiac protection by decreasing DNA damage, MDA, and PC levels, and by increasing the antioxidant activities of CAT and SOD. Thus, our study showed, for the first time, the protective effect of MMF against cardiac toxicity induced by TAC. This protective effect was mediated via an antioxidant process.

Evaluation of anti-proliferative and anti-inflammatory activities of Pelagia noctiluca venom in Lipopolysaccharide/Interferon-γ stimulated RAW264.7 macrophages.

Components of Pelagia noctiluca (P. noctiluca) venom were evaluated for their anticancer and nitric Oxide (NO) inhibition activities. Three fractions, out of four, obtained by gel filtration on Sephadex G75 of P. noctiluca venom revealed an important selective anti-proliferative activity on several cell lines such as human bladder carcinoma (RT112), human glioblastoma (U87), and human myelogenous leukemia (K562) but not on mitogen-stimulated peripheral blood mononuclear cells. Interestingly, P. noctiluca components showed an important dose-dependent anti-inflammatory activity, through inhibition of NO production via transcriptional regulation of Inducible NO Synthase (iNOS), in IFN-γ/LPS stimulated RAW 264.7 macrophages. These data strongly suggest that P. noctiluca venom could be used as a natural inhibitor of cancer cell lines and a potent anti-inflammatory agent for the treatment of anti-inflammatory diseases.

Combination of tacrolimus and mycophenolate mofetil induces oxidative stress and genotoxicity in spleen and bone marrow of Wistar rats.

Tacrolimus (TAC) and mycophenolate mofetil (MMF) are common immunosuppressive drugs used to avoid immunological rejection of transplanted organs. The risk of developing cancer is the most critical complication in organ transplant recipients undergoing immunosuppressive therapy. This study aims to explore the cytotoxic and genotoxic effects of TAC and MMF alone or combined orally administrated on spleen and bone marrow of Wistar rats. Our results showed that TAC (2.4; 24 and 60mg/kg) and MMF (5; 50 and 125mg/kg) induced a genotoxic effect on rat bone marrow. Moreover, the co-treatment with the TAC/MMF (2.4/5mg/kg b.w.; 2.4/50mg/kg b.w. and 60/50mg/kg b.w.) produce a genotoxicity as measured by micronuclei (MN) frequencies, chromosomal aberrations (CA) rates and DNA damage levels. Furthermore, the TAC and MMF-treated animals developed oxidative stress in spleen, indicated by a significant increase of malondialdehyde (MDA), protein oxidation and decrease of anti-oxidant enzymes levels such as catalase (CAT) and superoxide dismutase (SOD). This damage was associated with an increase of DNA fragmentation. Co-treatment with TAC/MMF synergistically induced markers of oxidative stress in rat splenic tissue. In conclusion, TAC/MMF associated induction in oxidative stress plays a role in the splenic and bone marrow toxicity and enhances the different endpoints of genotoxicity, suggesting its mutagenic action in vivo.

Crocin, the main active saffron constituent, mitigates dichlorvos-induced oxidative stress and apoptosis in HCT-116 cells.

The protective effects of Crocin (CRO), a carotenoid with wide spectrum of pharmacological effects, against the cytotoxicity and the apoptosis produced by exposure to Dichlorvos (DDVP) in HCT116 cells were investigated in this work. The cytotoxicity was monitored by cell viability, ROS generation, antioxidant enzymes activities, malondialdehyde (MDA) production and DNA fragmentation. The apoptosis was assessed through the measurement of the mitochondrial transmembrane potential (ΔΨm) and caspases activation. The results indicated that pretreatment of HCT116 cells with CRO, 2h prior to DDVP exposure, significantly increased the survival of cells, inhibited the ROS generation, modulated the activities of catalase (CAT) and superoxide dismutase (SOD) and reduced the MDA level. The reduction in mitochondrial membrane potential, DNA fragmentation and caspases activation were also inhibited by CRO. These findings suggest that CRO can protect HCT116 cells from DDVP-induced oxidative stress and apoptosis.

Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats

Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF’s possible protective effect. Our results showed that MMF (at 50 mg kg−1 body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg−1 b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process (AU)

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The mycotoxin zearalenone enhances cell proliferation, colony formation and promotes cell migration in the human colon carcinoma cell line HCT116.

Zearalenone (ZEN) and Aflatoxin B1 (AFB1) are fungal secondary metabolites produced by Fusarium and Aspergillus genera, respectively. These mycotoxins are found world-wide as corn and wheat contaminants. AFB1 is probably the most toxic and carcinogenic mycotoxin. It has been demonstrated to be mutagenic, genotoxic, and hepatocarcinogenic. ZEN is a non-steroidal estrogenic mycotoxin that displays hepatotoxicity, immunotoxicity and genotoxicity. Its mutagenic and carcinogenic properties have so far remained controversial and questionable. Using the colon carcinoma cell line HCT116, we will show here that ZEN, at low concentrations, enhances cell proliferation, increases colony formation and fastens cell migration after wound healing. The highest effect of ZEN was observed at a concentration 10 times lower as compared to AFB1. Our findings suggest thus that this mycotoxin exhibits carcinogenesis-like properties in HCT116 cells.

Crocin protects human embryonic kidney cells (HEK293) from α- and ß-Zearalenol-induced ER stress and apoptosis.

α-zearalenol (α-ZOL) and ß-zearalenol (ß-ZOL) are the major metabolites of Zearalenone (ZEN) and are known to induce many toxic effects. In the present study, we investigated the involvement of endoplasmic reticulum (ER) stress in α- and ß-ZOL-mediated toxicity in human kidney cells (HEK293) and evaluated the effect of a common dietary compound Crocin (CRO), from saffron. We show that α- and ß-ZOL treatment induces ER stress as evidenced by the upregulation of the 78 kDa glucose-regulated protein (GRP78) and the Growth arrest and DNA damage-inducible protein (GADD34). Activation of the ER stress response is associated with activation of the mitochondrial pathway of apoptosis. This apoptotic process is characterized by an increase in ROS generation and lipid peroxidation, a loss of mitochondrial transmembrane potential (ΔΨm) and activation of caspases. We also demonstrate that the antioxidant properties of CRO help to prevent ER stress and reduce α- and ß-ZOL-induced apoptosis in HEK293 cells. Our results suggest that saffron consumption might be helpful to prevent α- and ß-ZOL-induced ER stress and toxicity.

Crocin protects the liver and kidney from patulin-induced apoptosis in vivo.

Patulin (PAT) is a mycotoxin mainly produced by Aspergillus, Penicillium, and Bissochlamys. Given the high risk associated with this mycotoxin, its potential effects have been investigated by many studies. It is known to be teratogenic, mutagenic, and genotoxic, and it has been shown to induce damages in several organs in experimental animals. Our aim was to investigate the preventive effect against PAT-induced apoptosis in vivo using natural carotenoid, Crocin (CRO). Mice were divided into six groups: a control group, a "PAT alone" group, a "CRO alone" group, and a "PAT plus CRO" groups (pre-treatment conditions). Our results showed that CRO restored the normal levels of biochemical parameters in the liver and kidney. The analysis of the protein expression in these organs revealed that PAT-induced toxicity promotes the induction of apoptosis via the increase in P53, Bax, and cytochrome C and the decrease in Bcl2 expressions. We also found that PAT triggered caspase 3 activation and DNA fragmentation. However, pre-treatment with CRO demonstrated a reduction in the induction of apoptosis via the regulation of all tested biomarkers demonstrating that CRO is effective in the protection against PAT hazards. This could be relevant, particularly with the emergent demand for natural products which may counteract the detrimental toxic effects and therefore prevents multiple human diseases.

Ochratoxin A and T-2 Toxin Induce Clonogenicity and Cell Migration in Human Colon Carcinoma and Fetal Lung Fibroblast Cell Lines.

T-2 toxin and Ochratoxin A (OTA) are toxic secondary metabolites produced by various fungi, and together they contaminate feedstuffs worldwide. T-2 toxin and OTA may exert carcinogenic action in rodent. Despite the various in vivo experiments, carcinogenicity of these two mycotoxins has not yet been proven for human. In this current study, we proposed to investigate, in Human colon carcinoma cells and fetal lung fibroblast-like cells transfected with MYC, the effect of T-2 toxin and OTA on cell clonogenicity and cell migration. Results of the present investigation showed that T2-toxin as well as OTA has an important clonogenic effect in all cell lines, suggesting that these mycotoxins could promote the transcription of c-myc gene. Furthermore, T-2 toxin and OTA enhanced the migration effect of HCT116 cells at very low concentrations, proposing that these mycotoxins may exhibit carcinogenesis-like properties in the studied cells.

Protective effect of mycophenolate mofetil against nephrotoxicity and hepatotoxicity induced by tacrolimus in Wistar rats.

Tacrolimus (TAC), a calcineurin inhibitor (CNI), is clinically used as an immunosuppressive agent in the transplant recipient; however, the use of TAC is greatly limited by its nephrotoxicity and hepatotoxicity. Mycophenolate mofetil (MMF), an inhibitor of the purine synthesis, has been used in combination with many immunosuppressive drugs such as TAC. The association TAC/MMF was used in organ transplantation to increase the efficiency and reduce acute rejection rates, but the effects of MMF on TAC-induced kidney and liver injuries are still not well investigated. The aims of this study are to explore whether MMF co-administration with TAC has a renoprotective and hepatoprotective effect against TAC-induced renal and hepatic injuries and to check the implication of oxidative stress in the MMF's possible protective effect. Our results showed that MMF (at 50 mg kg(-1) body weight (b.w.)) restored creatinine, in addition to increased AST and ALT levels by TAC (at 60 mg kg(-1) b.w.). Furthermore, MMF decreased DNA damage induced by TAC in the kidney and liver of rats as assessed by comet assay. This renoprotective and hepatoprotective effect of MMF was associated with an antioxidant effect. In fact, MMF co-treatment with TAC decreased oxidative damage induced by TAC. It reduced malondialdehyde (MDA) and protein carbonyl (PC) levels as well as catalase and superoxide dismutase (SOD) activities. We conclude that the co-administration MMF with TAC protect liver and kidney against TAC toxicity via an antioxidant process.

Cytotoxic effects induced by patulin, sterigmatocystin and beauvericin on CHO-K1 cells.

Mycotoxins are produced by different genera of fungi; mainly Aspergillus, Penicillium and Fusarium. The natural co-occurrence of beauvericin (BEA), patulin (PAT) and sterigmatocystin (STE) has been proved in feed and food commodities. This study investigates the cytotoxicity of individual and combined mycotoxins BEA, PAT and STE. The cytotoxicity on immortalized ovarian cells (CHO-K1) was evaluated using the MTT assay. After 24, 48 and 72 h, the IC50 values were 2.9 µM for PAT and ranged from 10.7 to 2.2 µM and from 25.0 to 12.5 µM for BEA and STE, respectively. Cytotoxic interactions were assayed by the isobologram method, which provides a combination index (CI) value as a quantitative measure of the three mycotoxin interaction's degree. Binary and tertiary combinations showed a dose dependent effect. At low fraction affected, mycotoxin combinations were synergetic; whereas, at higher fraction affected, the combinations showed additive effect. Our results indicate that the co-occurrence of low concentrations of mycotoxin in food may increase their toxic effects.

Quercetin protects HCT116 cells from Dichlorvos-induced oxidative stress and apoptosis.

The present study was designed to assess the possible protective effects of Quercetin (QUER), a flavonoid with well-known pharmacological effects, against Dichlorvos (DDVP)-induced toxicity in vitro using HCT116 cells. The cytotoxicity was monitored by cell viability, reactive oxygen species (ROS) generation, anti-oxidant enzyme activities, malondialdehyde (MDA) production, and DNA fragmentation. The apoptosis was assessed through the measurement of the mitochondrial transmembrane potential (ΔΨm) and caspase activation. The results indicated that pretreatment of HCT116 cells with QUER, 2 h prior to DDVP exposure, significantly decreased the DDVP-induced cell death, inhibited the ROS generation, modulated the activities of catalase (CAT) and superoxide dismutase (SOD), and reduced the MDA level. The reductions in mitochondrial membrane potential, DNA fragmentation, and caspase activation were also attenuated by QUER. These findings suggest that dietary QUER can protect HCT116 cells against DDVP-induced oxidative stress and apoptosis.

Tissue oxidative stress induced by patulin and protective effect of crocin.

Patulin (PAT) is a secondary toxic metabolite produced principally by Penicillium expansum. This mycotoxin is known to be teratogenic, mutagenic, immunotoxic and neurotoxic, and it has been shown to cause damage in several organs in laboratory animals. This study focuses on the prevention of experimental murine PAT-induced nephrotoxicity and hepatotoxicity. We investigate the ability of a natural product, crocin (CRO), to counteract the toxic effects of PAT. Pre-treatment of mice with CRO prevented PAT-induced oxidative damage in both liver and kidney. CRO reduced lipid peroxidation, protein oxidation and restored redox status by regulating the endogenous antioxidant enzymatic system. These data corroborate and extend findings in PAT-induced nephrotoxicity and hepatotoxicity, and further suggest that preventive effect of CRO towards other forms of PAT toxicity, including neurotoxicity, may be warranted.