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ABSTRACT: Butenolide, a mycotoxin elaborated by several toxigenic Fusarium species, has been implicated as an etiological factor of Kashin-Beck disease and it is always detected in food from endemic Kashin-Beck disease areas. Although butenolide is considered as a potential health risk to humans and animals, its toxicity targets and mechanism of action have not been fully understood and the knowledge of its developmental toxicity is absent. The present study investigated butenolide embryotoxicity via an in vitro whole embryo culture system using rat embryos. Embryos exposed to butenolide at a concentration of 0.625 mg/L showed and differentiation similar to that of the control embryos (=no observed adverse effect concentration; NOAECwec). The embryonic growth and differentiation were affected, represented as reduced crown-rump length and head length, and decreased number of somites from 1.25 mg/L. Total morphological scores decreased significantly at the concentration of butenolide of 2.5 mg/L. All embryos were malformed at 3.75 mg/L and above (=ICMaxWEC), presenting growth retardation with flexion failure and irregular somite differentiation. The IC503T3 of butenolide as calculated from the balb/c 3T3 cytotoxicity test is 6.45 mg/L. Our study shows that butenolide exerts detrimental effects on embryo development in vitro by inducing growth retardation and differentiation inhibition, and the embryotoxicity effect of butenolide should be treated with caution.
Toxicology in Vitro 09/2011; 25(8):1727-32. · 2.78 Impact Factor
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ABSTRACT: To investigate the reproductive toxicity and cytotoxicity of T-2 toxin, which is a mycotoxin, and to explore its potential apoptotic induction mechanism.
Ovarian granulosa cells of rats were treated with T-2 toxin (1-100nM) for 24h. The cytotoxicity was assessed with MTT bioassay; apoptotic cells were identified microscopically by chromatin condensation and nuclear fragmentation with Hoechst 33258; mitochondrial membrane potential with hodamine 123 and reactive reactive oxygen species (ROS) with 2',7'-dichlorofluoresceinacetate (DCFH-DA) was analyzed by fluorometry; p53 and other apoptosis-related proteins such as Bax, Bcl-2, caspase-3, caspase-9 were determined by Western blot analysis, and related mRNA expressions were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The caspase activity was measured by cleavage of the caspase substrate (Ac-DEVD-pNA for caspase-3, Ac-LEHD- pNA for caspase-9).
T-2 toxin inhibited the growth of granulosa cells in a concentration-dependent way. The result of Hoechst 33258 staining indicated that T-2 toxin induces granulosa cells apoptosis based on the typical apoptotic morphological changes. Subsequently, we found that T-2 toxin treatment induced ROS accumulation in granulosa cells, resulting in reduction of mitochondrial transmembrane potential. The induction of cell apoptosis was caused by the upregulation of p53, Bax, Bcl-2, Bax/Bcl-2 ration, and the activation of the caspases pathways. T-2 toxin-induced apoptotic granulosa cells significantly decreased through the use of antioxidant Trolox.
These data suggest a possible underlying molecular mechanism for T-2 toxin that induces the apoptosis signaling pathway in rat granulosa cells by regulation of ROS-mediated mitochondrial pathway.
Toxicology Letters 02/2011; 202(3):168-77. · 3.23 Impact Factor
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ABSTRACT: To investigate the effect of metallothionein (MT) on rifampicin (RFP)-induced hepatotoxicity and the possible mechanisms.
Male MT- I / II null (MT-/-) and wild type (MT+/+) mice were randomly divided into 4 groups, respectively, and were orally administered RFP (50, 100 or 200 mg/kg) or equal volumes of solvent daily for 15 consecutive days. Levels of plasma alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DB) were determined. Liver indexes were calculated and liver histopathologic changes were examined by hematoxylin and eosin (HE) staining. The content of glutathione (GSH) as well as the activities of glutathione peroxydase (GPx) and glutathione reductases (GR) were measured in the liver homogenates.
RFP treatment induced significant increases in plasma ALT, AST and DB, as well as liver index. Significant histopathologic changes which were charactered as fatty degeneration in liver were noteced. Moreover, augmentations of GSH content and GR activity and attenuation of GPx activity were observed. More severe hepatic injuries in MT-/- mice were observed as compared to MT+/+ mice, which were evidenced by higher liver/body weight ratio and GR activity, lower GSH content and GPx activity, and more serious fatty degeneration.
RFP-induced hepatotoxicity was associated with cholestasis and oxidative damage. MT -/- mice were more susceptible than MT +/+ mice to RFP-induced hepatotoxicity and the enhanced hepatotoxicity involves increased oxidative stress.
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 07/2010; 41(4):609-12, 647.
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ABSTRACT: Previous studies revealed butenolide (BUT), a Fusarium mycotoxin distributes extensively, induced myocardial oxidative damage, which could be abated by antioxidants such as glutathione. Metallothionein (MT) has proved to attenuate several oxidative cardiomyopathies via its potent antioxidant property. The present study is therefore undertaken to investigate the protective potential of the endogenous expression of MT against BUT-induced myocardial toxicity. Primary cultures of neonatal cardiomyocytes from MT-I/II null mice along with the corresponding wild-type mice will be utilized to determine the possible mechanistic properties of MT. BUT treatment to the cardiomyocytes evoked significant cytotoxicity as evidenced by morphological changes and concentration- and time-dependent reductions in cell viability. Additionally, BUT treatment remarkably increased reactive oxygen species (ROS) production in the cardiomyocytes of both MT-I/II null and wild-type mice. As a result, noticeable DNA damage in both cardiomyocytes was detected by alkaline comet assay. Furthermore, the comparison between the MT-I/II null and wild-type cardiomyocytes indicated that ROS production in the cardiomyocytes from the MT-I/II null mice was higher than from wild-type mice. DNA damage as evaluated by percentage of comet tail DNA, tail length and tail moment was more severe in the MT-l/II null cardiomyocytes than in wild-type myocytes. And in agreement with those results mentioned above, the MT-l/II null cardiomyocytes were more sensitive to BUT-induced cytotoxicity than wild-type cardiomyocytes. Taken together, these findings clearly show that basal MT can efficiently attenuate BUT-induced cytotoxic injuries in cardiomyocytes via the inhibition of intracellular ROS production, and associated DNA damage.
Toxicon 02/2010; 55(7):1291-6. · 2.51 Impact Factor
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ABSTRACT: In this study, the delayed effect and related mechanism after chlorpyrifos (CPF) withdrawal was studied in primary rat hippocampal neurons. The results showed that 10 muM CPF induced no detectable cytotoxicity during 96 h continuous exposure while its withdrawal after 48 h exposure induced evident cytotoxicity, as indexed by decreased methyl thiazolyl tetrazolium (MTT) metabolism, increased loss of neurons immunostained by neuron-specific enolase (NSE) antibody, and the increased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) positive cell rate in the following 24 h and 48 h incubation in the absence of CPF. Extracellular signal-related kinase (ERK)1/2 activation by phosphorylation was observed and persisted during CPF exposure. However, CPF withdrawal after 48 h exposure led to inhibition of ERK1/2 phosphorylation. Carbacol and nerve growth factor (NGF), which are ERK1/2 activators, protected the neurons after CPF withdrawal, while atropine and PD98059, which are ERK1/2 inhibitors, exacerbated the cytotoxicity, indicating the involvement of inhibition of ERK1/2 phosphorylation in CPF-induced delayed cytotoxicity. In conclusion, CPF withdrawal after exposure induced delayed cytotoxicity in cultured neurons. Inhibition of ERK1/2 phosphorylation was found to be related to the delayed cytotoxicity. This finding may provide a new insight into the toxicological mechanism of organophosphorus pesticides, especially chronic organophosphate-induced neuropsychiatric disorder characterized by delayed occurrence.
Biological & Pharmaceutical Bulletin 10/2009; 32(10):1649-55. · 1.66 Impact Factor
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ABSTRACT: To study the changes of metabolites in rat urine after treatment of Aristolochia fangchi decoction by metabonomic method.
Sixty-four male SD rats were divided into Aristolochia fangchi group and normal control group. Rats in the Aristolochia fangchi group were orally administered with 8.1 g/(kg.d) of Aristolochia fangchi and the normal control group was administered with equal volume of distilled water for 4 weeks. Twenty-four hour urine was collected at different time points (before, after 2- and 4-week administration and 2 weeks after administration) and their H nuclear magnetic resonance (NMR) spectra were acquired and subjected to data process, including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) or orthogonal signal correction (OSC). The contents of blood urea nitrogen (BUN) and serum creatinine (SCr) and histopathological changes of the renal tissues were also detected.
The content of BUN of the Aristolochia fangchi group was markedly higher than that of the normal control group after 2-week administration (P<0.05), and cellular edema in tubular endothelial cells, structure damage of glomeruli and inflammatory cell infiltration were found in the kidney. Along with the lasting of administration to 4-week, the renal injury in the Aristolochia fangchi group became more serious, and the contents of BUN and SCr were all significantly higher as compared with the normal control group (P<0.05). Two weeks after administration, the content of BUN in the Aristolochia fangchi group was still higher than that in the normal control group (P<0.05), and the pathological changes in renal tissues were not different from those on the 4th week. The urine of the Aristolochia fangchi group could be readily discriminated from the normal control group at every time point based on PCA. During the whole administration period, compared with the normal control group, the concentration of urinary taurine was increased time-dependently, while the citrate was decreased in the Aristolochia fangchi group. The concentration of hippurate was increased at the 2nd week and the 6th week (2 weeks after drug withdrawal) but decreased at the 4th week; the concentration of creatinine/creatine was increased at the 4th week but decreased at the 6th week; the concentration of 2-oxo-glutarate was decreased and the concentration of trimethylamine oxide was increased at the 4th and 6th week.
High-dose Aristolochia fangchi can induce renal lesion and its seriousness is correspondent to the lasting of administration. Aristolochia fangchi may also have toxicity on liver.
Journal of Chinese Integrative Medicine 09/2009; 7(8):746-52.
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ABSTRACT: Butenolide is a mycotoxin produced by several toxigenic Fusarium species. It frequently invades many important grains, and evokes a broad spectrum of toxic effects. For these reasons, butenolide poses a health risk to both humans and animals. However, many toxicology issues of butenolide including targets and mechanisms of toxicity remain to be elucidated so far. The present study therefore attempts to reveal the toxic profile of butenolide from a viewpoint of oxidative damage, using chick embryos as an in vitro model. A single in ovo injection of butenolide resulted in significant oxidative injuries in embryonic livers and kidneys, as manifested by a dose-dependent depletion of sulfhydryl groups, reduction of glutathione peroxidase activity, and increase of thiobarbituric acid reactive substances production, an indicator of lipid peroxidation. In contrast, co-injections of butenolide with antioxidants sodium selenite, vitamin C and a representative antioxidative enzyme superoxide dismutase markedly abated these oxidative toxicities. In conclusion, the present study suggests that oxidative damage may serve as a mediator in the toxicity of butenolide, and amelioration of antioxidant defense capacity by exogenous supplementation may play a role in the prevention and treatment of butenolide intoxication.
Toxicology in Vitro 07/2009; 23(7):1354-9. · 2.78 Impact Factor
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ABSTRACT: To investigate the changes of gene expression profile of rat liver tissue by cDNA microarrays.
Twenty Wistar rats in control group (n = 10) and isoniazid (INH) group (n = 10) were orally administrated with normal saline and 400 mg/kg INH for 14 days, respectively. The differentially expressed genes significantly correlated with liver injury were screened and analyzed. The mechanisms of liver injury caused by INH were specifically analyzed at level of gene expression based on the biological functions of those differentially expressed genes.
Thirty-seven differentially expressed genes were found in the rats administrated with INH. Among them, 25 genes were up-regulated, while the other 12 genes were down-regulated. These differentially expressed genes were functionally related to the changes of CYP450-related genes, fatty acid metabolism, and protein metabolism.
INH can cause the remarkable changes of the gene expression profiles in rat liver cells, which is important for further elucidating the mechanisms of liver injury caused by INH.
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 07/2009; 31(3):308-14.
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ABSTRACT: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated biphenyls (PCBs) are persistent environmental contaminants that exist as complex mixtures in the environment, but the possible interactions of TCDD and PCBs have not been systematically investigated. The main objective of this study was to investigate the combined nephrotoxic effects of TCDD and PCBs on rats and to reveal the potential interactions between TCDD and PCBs. Male Sprague-Dawley rats were intragastrically administered TCDD (10 microg/kg), PCBs (Aroclor 1254, 10 mg/kg), or the combination (10 microg/kg TCDD + 10 mg/kg Aroclor 1254). After 12 consecutive days of exposure, all treatments induced nephrotoxicity, as evidenced by significant increases in the levels of serum creatinine and blood urea nitrogen, changes of kidney histopathology, and significant renal oxidative stress. Most of these effects were more remarkable in the combined-exposure group. Furthermore, all treatments induced renal cytochrome P450 1A1 (CYP1A1) protein expression, and the induction was more conspicuous in the combined-exposure group. These findings suggested that the nephrotoxicity induced by TCDD and PCBs in the present study might be attributable to the high expression of CYP1A1. In addition, the result of the two-way analysis of variance revealed that the combined effects of TCDD and PCBs were complicated, being additive, synergistic, or antagonistic depending on the selection of toxicity end points under the present experimental condition. This study demonstrates that combined exposure to TCDD and PCBs induced significant nephrotoxicity in rats, and there were complicated interactions between the two pollutants on the nephrotoxicity.
Archives of Environmental Contamination and Toxicology 05/2009; 57(4):767-76. · 1.93 Impact Factor
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ABSTRACT: Fusarium mycotoxin toxicosis has been implicated in the etiology of Keshan disease, an endemic mitochondrial cardiomyopathy prevailing in certain areas of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is one of the Fusarium mycotoxins which are frequently detected from cereal grains in endemic areas. A recent study indicates that this mycotoxin induces rat cardiotoxicity, but its effect on the myocardial mitochondria remains unclear. The present study is therefore undertaken to explore the toxic effect potential of butenolide on the myocardial mitochondria. Exposure of cultured cardiac myocytes to 50 microg/ml of butenolide provoked dissipation of mitochondrial membrane potential. Incubation of isolated rat myocardial mitochondria with butenolide of 100 microg/ml for 60 min resulted in mitochondrial swelling, indicating the occurrence of mitochondrial permeability transition. Furthermore, marked oxidative damage in myocardial mitochondria was observed after incubation of isolated myocardial mitochondria with butenolide ranging from 0 to 50 microg/ml for 60 min, as manifested by concentration-dependent increases in the production of thiobarbituric acid reactive substances, the indicator of lipid peroxidation. Contrarily, a representative antioxidant glutathione significantly alleviated this oxidative mitochondrial damage induced by butenolide. In conclusion, these observations clearly show that butenolide can induce dysfunction of myocardial mitochondria, and oxidative damage appears to play a crucial role in these deleterious effects. The present study supports the hypothesis that mycotoxin toxicosis is a probable etiological factor of Keshan disease, the mitochondrial cardiomyopathy.
Toxicology mechanisms and methods 02/2009; 19(2):79-85. · 1.03 Impact Factor
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ABSTRACT: Chronic organophosphate-induced neuropsychiatric disorder is a less well-characterized syndrome, which is usually delay-occurred, persists long and is similar to the symptom of cholinergic deficit, its mechanism is unclear. The characteristics of chronic organophosphate-induced neuropsychiatric disorder are somewhat opposite to the direct action of OP pesticide, since withdrawal effect is usually opposite to the original effect of a drug, hypothesis that chronic organophosphate-induced neuropsychiatric disorder is a kind of withdrawal syndrome is suggested.
Medical Hypotheses 02/2009; 72(4):405-6. · 1.39 Impact Factor
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ABSTRACT: Male Wistar rats were exposed to 100ppm Pb(2+) in drinking water for 10 months. Tail blood pressure, serum 5-hydroxytryptamine (5-HT), the expression of 5-HT(2B) receptor in the aorta, the aortic response to 5-HT, and the pathologic changes of aorta were examined. The systolic blood pressure of Pb(2+) exposed group was significantly increased after 2 months of Pb(2+) exposure. After 10 months of Pb(2+) exposure, aortic contractile response to 5-HT was significantly decreased. There was no significant difference in the levels of serum 5-HT and the expression of 5-HT(2B) receptor between these two groups. The aortic media and the media-lumen ratio of Pb(2+) exposed group were significantly increased. These data suggest that long-term Pb(2+) exposure can increase blood pressure, and can alter the function and structure of aortic of rats. The decreased aortic response to 5-HT has little relation to the expression of 5-HT(2B) receptor and the serum level of 5-HT, maybe is a result of the aortic structural alteration.
Toxicology Letters 02/2009; 186(2):78-83. · 3.23 Impact Factor
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ABSTRACT: Butenolide, a mycotoxin elaborated by several toxigenic Fusarium species, frequently contaminates important agricultural products, and has been considered a potential health risk to humans and animals. However, many toxicology issues including toxicity targets and mechanisms of butenolide remain unclear. Previous study indicated that acute butenolide exposure produced hepatic oxidative toxicity, but its chronic toxicity is still unknown. The present study therefore attempted to reveal the adverse effects of repeated butenolide exposure from a viewpoint of oxidative damage focusing on the liver. Intragastic administration of rats with butenolide for seven consecutive weeks resulted in hepatic injury as shown by obvious changes of serum biochemistry parameters indicating liver function. Repeated butenolide exposure also induced oxidative stress as manifested by impairment of antioxidant defenses including depletion of sulfhydryl groups and reduction of glutathione peroxidase activity, and enhancement of lipid peroxidation both in serum and liver. In conclusion, the present study indicated that repeated butenolide exposure induced a significant liver injury, and oxidative damage may serve as a mediator in the toxicity of butenolide. The current findings contribute to the understanding of the toxic profile of butenolide.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 01/2009; 47(3):633-7. · 2.99 Impact Factor
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ABSTRACT: To study the effect of rifampin (RFP) on the metabonomic profile of rat urine and its relationship with traditional toxicity evaluation of blood biochemical indicators and histopathology.
Thirty-six male Wistar rats were randomly divided into control group, 50 mg/kg RFP group, and 100 mg/kg RFP group, with 12 rats in each group. Rats in each group were given intragastric infusion with a daily dose of 0, 50 mg/kg RFP, and 100 mg/kg RFP for 3, 7, and 14 days, respectively. Then 4 rats in each group were killed on the next day of administration to collect blood samples and liver sample for the determination of blood biochemical indicators and for the pathological analysis of the liver. The urine specimens over 24 hours of each rat were collected before and after each treatment until the rat was killed. 1H nuclear magnetic resonance (1H NMR) spectra of these urine specimens were acquired and subjected to data preprocess and principal component analyses (PCA).
The level of serum total bilirubin of the rat administrated with 100 mg/(kg x d) RFP for 7 days was significantly higher than that of control group (P < 0.05). Mild hepatotoxicity to the rat, treated with RFP of higher dosage (100 mg/kg) and longer duration (14 days), was revealed by the traditional histopathological method. The metabonomic spectra of rat urine in different groups differed from each other; a trajectory bias in determination of rat urine by 1H NMR occurred depending on the administration duration. As demonstrated by 1H NMR spectra of urine in rats treated with RFP, the concentration of urinary citrate and 2-oxoglutarate decreased, along with the remarkable increase of the concentrations of urinary taurine and glucose (compared with those of the control group).
Being consistent with the results of traditional toxicity evaluation measurements, metabonomic method is more sensitive. The 1H-NMR metabonomic profile of the rat urine is closely related with the duration of RFP. The hepatic toxicity induced by RFP is related to the reduction of energy metabolism in tricarboxylic acid cycle and the perturbation of glucose and lipid metabolism.
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 12/2008; 30(6):696-702.
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ABSTRACT: Fusarium mycotoxin toxicosis has been implicated as an etiological factor for Keshan disease, an endemic cardiomyopathy prevailing in specific regions of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is one of the Fusarium mycotoxins frequently detected from the foodstuffs of endemic areas and has been shown to possess the potential to induce cardiotoxicity, implying this mycotoxin might play a role in the occurrence of Keshan disease. The present study was undertaken to further investigate the myocardial toxicity of butenolide from a viewpoint of oxidative damage. A single in ovo injection of butenolide to chick embryos, an excellent in vitro toxicology model resulted in significant oxidative injuries to the myocardium, manifested by a dose-dependent depletion of sulfhydryl groups, reduction of glutathione peroxidase (GPx) activity, and increase of thiobarbituric acid reactive substances production, a hallmark of lipid peroxidation. In contrast, co-injections of butenolide to chick embryos with sodium selenite or vitamin C, two potent antioxidants, markedly abated these oxidative injuries. In conclusion, the present study clearly indicated that butenolide could induce significant myocardial oxidative injuries. The current findings reinforce the hypothesis that toxicosis by Fusarium mycotoxins may be one of the etiological factors for Keshan disease, and oxidative damage is involved in the pathogenesis of myocardial toxicity.
Toxicon 09/2008; 52(7):781-6. · 2.51 Impact Factor
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ABSTRACT: To study the effect of different treatment period, of isoniazid (INH) on the metabonomic profile of rat urine and its relationship with traditional toxicity evaluation of blood biochemical indicators and histopathology and to explore the feasibility of metabonomics in the application of drug toxicity.
Sixty male Wistar rats were orally administrated with 0, 50, 100, 200, and 400 mg x kg(-1) INH for 3, 7, and 14 days, respectively. Rat urine was then collected and its 1H nuclear magnetic resonance (NMR) spectra were acquired. All animals underwent traditional toxicity evaluation.
Hepatotoxicity was revealed by traditional toxicity evaluation in rats treated with higher dosage and longer treatment of INH. Time-response relationship existed during the treatment. Time-dependent metabonomics changes conformed with the results of traditional toxicity evaluation. The urine metabonomics showed a trajectory bias from those of the controls or pre-administration, and such bias exaggerated along with the prolongation of treatment, indicating a severer toxic injury. Along with the increase of the concentrations of urinary taurine and glucose and the decrease of the concentrations of urinary citrate and 2-oxoglutarate, the 1H NMR spectra of urine in rats treated with INH also changed.
The metabonomics technique can distinguish the onset and development of toxicity, which helps track and identify biomarkers. The hepatic toxicity induced by INH is related to the injury of mitochondrial function, reduction of energy metabolism in tricarboxylic acid cycle, and perturbations in the metabolism of glucose and lipid. The effect of INH on the rat urine metabonomic profile is related with INH toxicology. Therefore, metabonomics can be recognized as an ideal technique to explore and evaluate the drug toxicities.
Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 01/2008; 29(6):730-7.
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ABSTRACT: Mycotoxin toxicosis has been implicated in the etiopathogenesis of Keshan disease (KD), an endemic cardiomyopathy prevailing in some regions of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone, CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species such as Fusarium tricinctum and Fusarium graminearum, is frequently detected from the cereals in the endemic areas of KD. The present study is undertaken to investigate whether this mycotoxin can induce myocardial damage. Exposure of primary culture of cardiac myocytes to butenolide resulted in significant cytotoxicity, manifested by changes in cell morphology and decreases in cell viability. Consistent with the in vitro findings, distinct myocardial toxicity in vivo was observed after administration of rats by gavage with butenolide (10 and 20 mg/kg/day) for 2 months, and the myocardial injuries were characterized by focal necrosis of myocardium and fragmentation of myofiber. Butenolide also induced significant oxidative damage to the myocardium in vitro evidenced by a concentration-dependent lipid peroxidation in the myocardial homogenates, whereas antioxidants superoxide dismutase (SOD), N-acetylcysteine (NAC) and glutathione (GSH) provided significant protections against this oxidative effect. Taken together, these results clearly reveal that butenolide possesses the potential to induce myocardial toxicity. The present findings may reinforce the hypothesis that toxicosis by mycotoxins is one of the etiological factors for KD.
Toxicon 10/2007; 50(3):357-64. · 2.51 Impact Factor
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ABSTRACT: Butenolide (CAS No. 16275-44-8), a mycotoxin produced by several Fusarium species, has been shown to be a potential risk factor for animal and human health. This study was undertaken to investigate the potential oxidative damage of butenolide to biomembranes in vitro using the erythrocyte membrane model. Following exposure of isolated rat erythrocyte membranes to butenolide, the extent of oxidative damage was assessed by measuring lipid peroxidation, -SH groups content, Ca2+/Mg2+-ATPase and Na+/K+-ATPase activities, and conformational changes in membrane proteins. It was observed that butenolide resulted in a significant lipid peroxidation, revealed by a concentration-dependent increase in the level of thiobarbituric acid reactive substances (TBARS). Similarly, this toxin induced a concentration-dependent decrease in the content of membrane total -SH groups, as well as free -SH groups. Membrane-bound enzymes were also impaired by the toxin, demonstrated by the marked inhibition of the activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase. Conformational changes in membrane proteins were determined using electron paramagnetic resonance (EPR) spin labeling. Butenolide caused an increase in the ratio of weakly to strongly immobilized components (W/S ratio) in a manner of concentration-dependent, indicating conformational changes in membrane proteins occurred. In conclusion, these findings indicate that butenolide is capable of inducing significant oxidative damage to membrane lipids and proteins.
Toxicology in Vitro 09/2007; 21(5):863-9. · 2.78 Impact Factor
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ABSTRACT: To investigate the inhibitive effect of metallothionein (MT) on DOX-induced cardiac apoptosis and the involved possible mechanisms.
Adult male C57BL mice (6-8 weeks old) were randomly assigned into four groups and given the following treatment: Zinc (ZnSO4, 300 micromol/kg, s.c., once a day for 2 days) or equal volume of physiological saline prior to a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and hearts were excised for further studies, including cadmium-hemoglobin affinity assay for MT concentration, ELISA detection of DNA fragmentation and Western blot analysis of Bax and Bcl-2.
DOX administration decreased heart weight by 10% and caused remarkable cardiac apoptosis as demonstrated by DNA fragments, while Zinc pretreatment significantly increased the MT levels and therefore inhibited the cardiac apoptotic effect of DOX. Elevated expression of Bax was obviously observed after DOX treatment, while this elevation was prevented by MT induction by Zinc. On the contrary, Bcl-2 protein level was not altered significantly among each group.
These findings suggest that metallothionein induced by Zinc exhibits protective effects on the cardiac apoptosis of DOX, which might be mediated through the prevention of Bax protein up-regulation by DOX and associated elevation of Bax/Bcl-2 ratio.
Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 08/2007; 38(4):620-3.
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ABSTRACT: To observe cell apoptosis and Bcl-2 and Bax expression changes of chondrocytes induced by butenolide (BUT) and the inhibitory effect of selenium against BUT-induced chondrcyte apoptosis, to gain insights into the mechanism by which BUT induces chondrcyte apoptosis.
Cartilage tissue reestablished from human fetal articular chondrocytes in vitro were treated with BUT at the concentrations of 0.1, 1.0 and 5.0 microg/ml and with the protective factor selenium. TUNEL method was used to detect chondrocyte apoptosis, which was quantified by flow cytometry. Immunohitochemistry was performed to analyze the expression of Bcl-2 and Bax in the reestablished cartilage tissue.
BUT exposure induced chondrocyte apoptosis, and the apoptosis rate increased with the concentration increment of BUT from 0 to 1.0 mg/ml, resulting also increased positive expression rate of Bcl-2 and Bax(P<0.05). The apoptosis rate of chondrocytes in BUT+ selenium group was significantly lower than that of BUT groups (P<0.05), as was the positivity rate of Bcl-2 and Bax expression (P<0.05).
BUT induces chondrocyte apoptosis in positive relation with BUT concentration (from 0 to 1.0 mg/ml) and causes increased expressions of Bcl-2 and Bax. Selenium can inhibit the chondrocyte apoptosis induced by BUT.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University 05/2007; 27(4):414-7.
