Objective:To investigation the chemopreventive potential of Fumaria indica（F.indica） extract（FIE） on N-nitrosodiethylamine and CCl<sub>4</sub>-induced hepatocarcinogenesis in Wislar rats.Methods:The ex...Objective:To investigation the chemopreventive potential of Fumaria indica（F.indica） extract（FIE） on N-nitrosodiethylamine and CCl<sub>4</sub>-induced hepatocarcinogenesis in Wislar rats.Methods:The experimental animals were divided into six groups（n=6）.Hepatocellular carcinoma was induced by single intraperitoneal injection of N-nitrosodiethylamine（NDEA） in normal saline at a dose of 200 mg/kg body weight followed by weekly subcutaneous injections of CCl<sub>4</sub>（3 mL/kg/week） for 6 weeks,as the promoter of carcinogenic effect.After administration of the carcinogen,200 and 400 mg/kg of FIE were administered orally once a day throughout the study.At the end of 20 weeks,the body weight,liver weight and relative liver weight were measured.The percentage of nodule incidence and liver cancer markers such as aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,γ-glutamyl transferase（γ-GT）,total bilirubin level（TBL）,α-feto protein（AFP） and carcinoembryonic antigen were estimated along with histopathological investigation in experimental groups of rats. Results:Obtained results demonstrated that the cotreatment with FIE significantly prevented the decrease of the body weight and also increased in relative liver weight caused by NDEA. The treatment with FIE significantly reduced the nodule incidence and nodule multiplicity in the rats after NDEA administration.The levels of liver cancer markers such as AST,ALT,ALP,γ-glutamyl transferase,TBL,AFP and carcinoembryonic antigen were substantially increased by NDEA treatment.However,FIE treatment significantly reduced the liver injury and restored the entire liver cancer markers.Histological observations of liver tissues too correlated with the biochemical observations.Conclusions:These finding powerfully supports that F.indica exert chemopreventive effect by suppressing the tumor burden and restoring the activities of hepatic cancer marker enzymes on NDEA and CCl4-induced hepatocarcinogenesis in Wistar rats.展开更多
AIM: To evaluate the protective effect of diallyl sulfide (DAS) against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis.METHODS: Male Wistar rats received either NDEA or NDEA together with DAS as protection....AIM: To evaluate the protective effect of diallyl sulfide (DAS) against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis.METHODS: Male Wistar rats received either NDEA or NDEA together with DAS as protection.Liver energy metabolism was assessed in terms of lactate,pyruvate,lactate/pyruvate,ATP levels,lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD) activities.In addition,membrane disintegration of the liver cells was evaluated by measuring lipid-peroxidation products,measured as malondialdehyde (MDA); nitric oxide (NO) levels; glucose-6-phosphatase (G6Pase),catalase (CAT) and superoxide dismutase (SOD) activities.Liver DNA level,glutathione-S-transferase (GST) and cytochrome c oxidase activities were used as DNA fragmentation indices.Aldose reductase (AR) activity was measured as an index for cancer cells resistant to chemotherapy and histopathological examination was performed on liver sections from different groups.RESULTS: NDEA significantly disturbed liver functions and most of the aforementioned indices.Treatment with DAS significantly restored liver functions and hepatocellular integrity; improved parameters of energy metabolism and suppressed free-radical generation.CONCLUSION: We provide evidence that DAS exerts a protective role on liver functions and tissue integrity in face of enhanced tumorigenesis caused by NDEA,as well as improving cancer-cell sensitivity to chemotherapy.This is mediated through combating oxidative stress of free radicals,improving the energy metabolic state of the cell,and enhancing the activity of G6Pase,GST and AR enzymes.展开更多
In the present study,we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine（NDEA）.NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcino...In the present study,we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine（NDEA）.NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcinogen.The male rats were exposed to NDEA（0.1 mg/mL） dissolved in drinking water separately and along with 25,50,100 mg/mL of Genistein for 21 days.The activities of serum glutamic oxaloacetic transaminase（SGOT）,serum glutamic pyruvic transaminase（SGPT）.alkaline phosphatase（ALP） and lactate dehydrogenase（LDH） were measured in blood serum.Lipid peroxidation,protein carbonyl content,micronucleus frequency and DNA damage（Comet assay） were performed on rat hepatocytes.The results of the study reveal that the treatment of NDEA along with Genistein showed a significant dose-dependent decrease in the levels of blood serum enzymes i.e.,SGOT,SGPT,ALP and LDH（P〈0.05）.The HE staining of histological sections of the liver also revealed a protective effect of Genistein.A significant dose-dependent reduction in the lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA（0.1 mg/mL） along with Genistein（P〈0.05）.The results obtained for the comet assay in rat hepatocytes showed a significant dose-dependent decrease in the mean tail length（P〈0.05）.Thus the present study supports the hepatoprotective role of Genistein.展开更多
This study aims to evaluate the preventive effects of anthocyanins extracts (MAEs) from mulberry variety PR-01 against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. It was found that 150 mg·k...This study aims to evaluate the preventive effects of anthocyanins extracts (MAEs) from mulberry variety PR-01 against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. It was found that 150 mg·kg-1 MAEs treatment significantly reduced the NDEA-induced hepatic nodules incidence and hepatocellular carcinoma incidence by 58.30% and 41.70% compared to the model group. Meanwhile, MAEs significantly restored the elevated the liver function enzymes, inhibited the tumor necrosis factor alpha and interleukin-6 levels, elevated the serum interleukin-10 and interferon-γ and increased hepatic glutathione-S-transferase and UDP-glucuronosyltransferase 2B1 enzyme activity. Moreover, 150 mg·kg-1 MAEs supplement enhanced glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase activities but reduced the malondialdehyde and thiobarbituric acid-reactive substances content by 37.90% and 44.52%. Furthermore, MAEs pretreatment maintained nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1, heme oxygenase-1, and NAD(P)H: quinine oxidoreductase1 stimulation and inhibited the expression of TNF-α, nuclear factor-kappaB (NF-κB), and cyclooxygenase-2 (COX-2), indicating that MAEs exhibit effectively prevention effects against liver cancer via decreased lipid peroxidation, induced Nrf2-mediated antioxidant enzymes and attenuating the inflammatory mediators COX-2 through NF-κB pathway. Thus, MAEs of mulberry variety PR-01 may be used as a good functional dietary supplement against liver cancer.展开更多
The primary routes of potential human exposure to N-nitrosodiethylamine (NDEA) are ingestion, inhalation, and dermal contact. Air, diet and smoking contribute to potential human exposure at levels of a few μg of NDEA...The primary routes of potential human exposure to N-nitrosodiethylamine (NDEA) are ingestion, inhalation, and dermal contact. Air, diet and smoking contribute to potential human exposure at levels of a few μg of NDEA/day. Potential exposure depends on the ability of the nitrosamines to migrate from the product into the body. The first step in the metabolic degradation of NDEA by cytochrome oxidase (CYPs) enzymes is the introduction of a hydroxyl group and in human esophage and liver CYP2A3 and CYP2E1 participate on this metabolism. Measuring cytotoxicity in female rat primary hepatocytes cultures, were used to understand the CYP induction and metaboli-zation correlated with low NDEA concentrations. We observed that NDEA at different concentrations in the absence of CYPs inducers, was able to induce CYP2B1, CYP2B2, CYP2E1, CYP3A1 and CYP4A3. A positive NDEA synergistic effect on the levels of mRNA, was observed in the presence of pyrazole (300 μM) for CYP2B1 and CYP2B2 and for pregnenolone 16- carbonitrile (0.15 μM) for CYP2E1. Negative NDEA synergistic effects were observed for ethanol (0.3%) for CYP3A1, pyrazol (300 μM) for CYP2A1 and CYP2E1, and phenobarbital (1 mM) for CYP2A1. These facts are extremally important once that these metabolites can be directly related to the primary DNA lesions. We consider that studies to elucidate the biological factors that determine the shape of the dose-response curve are crucial for low-dose extrapolations of risk.展开更多
The effects of exogenously administered ethanolamine (Etn) on the N-nitrosodiethylamine (NDA)-induced formation of hepatic lesions in rats were investigated. Sprague-Dawley rats were intraperitoneally administered NDA...The effects of exogenously administered ethanolamine (Etn) on the N-nitrosodiethylamine (NDA)-induced formation of hepatic lesions in rats were investigated. Sprague-Dawley rats were intraperitoneally administered NDA (100 mg/kg body weight) at 7-day intervals, and the animals were allowed free access to water containing Etn (15 or 50 mg/L) for 35 days. NDA-induced hepatic lesions were assessed according to the number of nodules detectable on the liver surface, areas of clear cell foci observed on histopathological thin sections, hydroxyproline levels in liver homogenates, and blood biochemical marker levels. Compared with those from control rats that were not administered Etn, livers from Etn-exposed rats had significantly fewer surface nodules and smaller areas of clear cell foci, indicating that Etn prevented or delayed the formation of preneoplastic cell alterations. Hydroxyproline levels in livers were significantly lower in Etn-treated rats, indicating that the chemical prevented the formation of fibrotic alterations. The protective effects of Etn on NDA-induced hepatic lesions were demonstrated by changes in blood biochemical marker levels. These results suggest that Etn can protect against cellular alterations induced by a carcinogenic chemical, possibly by enhancing hepatic phospholipid synthesis.展开更多
文摘Objective:To investigation the chemopreventive potential of Fumaria indica（F.indica） extract（FIE） on N-nitrosodiethylamine and CCl<sub>4</sub>-induced hepatocarcinogenesis in Wislar rats.Methods:The experimental animals were divided into six groups（n=6）.Hepatocellular carcinoma was induced by single intraperitoneal injection of N-nitrosodiethylamine（NDEA） in normal saline at a dose of 200 mg/kg body weight followed by weekly subcutaneous injections of CCl<sub>4</sub>（3 mL/kg/week） for 6 weeks,as the promoter of carcinogenic effect.After administration of the carcinogen,200 and 400 mg/kg of FIE were administered orally once a day throughout the study.At the end of 20 weeks,the body weight,liver weight and relative liver weight were measured.The percentage of nodule incidence and liver cancer markers such as aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,γ-glutamyl transferase（γ-GT）,total bilirubin level（TBL）,α-feto protein（AFP） and carcinoembryonic antigen were estimated along with histopathological investigation in experimental groups of rats. Results:Obtained results demonstrated that the cotreatment with FIE significantly prevented the decrease of the body weight and also increased in relative liver weight caused by NDEA. The treatment with FIE significantly reduced the nodule incidence and nodule multiplicity in the rats after NDEA administration.The levels of liver cancer markers such as AST,ALT,ALP,γ-glutamyl transferase,TBL,AFP and carcinoembryonic antigen were substantially increased by NDEA treatment.However,FIE treatment significantly reduced the liver injury and restored the entire liver cancer markers.Histological observations of liver tissues too correlated with the biochemical observations.Conclusions:These finding powerfully supports that F.indica exert chemopreventive effect by suppressing the tumor burden and restoring the activities of hepatic cancer marker enzymes on NDEA and CCl4-induced hepatocarcinogenesis in Wistar rats.
文摘AIM: To evaluate the protective effect of diallyl sulfide (DAS) against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis.METHODS: Male Wistar rats received either NDEA or NDEA together with DAS as protection.Liver energy metabolism was assessed in terms of lactate,pyruvate,lactate/pyruvate,ATP levels,lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD) activities.In addition,membrane disintegration of the liver cells was evaluated by measuring lipid-peroxidation products,measured as malondialdehyde (MDA); nitric oxide (NO) levels; glucose-6-phosphatase (G6Pase),catalase (CAT) and superoxide dismutase (SOD) activities.Liver DNA level,glutathione-S-transferase (GST) and cytochrome c oxidase activities were used as DNA fragmentation indices.Aldose reductase (AR) activity was measured as an index for cancer cells resistant to chemotherapy and histopathological examination was performed on liver sections from different groups.RESULTS: NDEA significantly disturbed liver functions and most of the aforementioned indices.Treatment with DAS significantly restored liver functions and hepatocellular integrity; improved parameters of energy metabolism and suppressed free-radical generation.CONCLUSION: We provide evidence that DAS exerts a protective role on liver functions and tissue integrity in face of enhanced tumorigenesis caused by NDEA,as well as improving cancer-cell sensitivity to chemotherapy.This is mediated through combating oxidative stress of free radicals,improving the energy metabolic state of the cell,and enhancing the activity of G6Pase,GST and AR enzymes.
基金Part of this paper was presented at the 8th Congress of Toxicology in Developing Countries(8CTDC)under the auspices of International Union of Toxicology(IUTOX)September 10-13,2012:at Centara Grand at Central Ladprao,Bangkok,Thailand.
基金Science and Engineering Research Board(SERB),Department of Science & Technology,Technology Bhavan,New Delhi,India,for the sanction of the research project (No.SR/FT/LS-60/2011) to Dr.Yasir Hasan Siddique
文摘In the present study,we studied the effect of Genistein against the hepatotoxicity induced by N-nitrosodiethylamine（NDEA）.NDEA is present in almost all kinds of food stuff and has been reported to be a hepatocarcinogen.The male rats were exposed to NDEA（0.1 mg/mL） dissolved in drinking water separately and along with 25,50,100 mg/mL of Genistein for 21 days.The activities of serum glutamic oxaloacetic transaminase（SGOT）,serum glutamic pyruvic transaminase（SGPT）.alkaline phosphatase（ALP） and lactate dehydrogenase（LDH） were measured in blood serum.Lipid peroxidation,protein carbonyl content,micronucleus frequency and DNA damage（Comet assay） were performed on rat hepatocytes.The results of the study reveal that the treatment of NDEA along with Genistein showed a significant dose-dependent decrease in the levels of blood serum enzymes i.e.,SGOT,SGPT,ALP and LDH（P〈0.05）.The HE staining of histological sections of the liver also revealed a protective effect of Genistein.A significant dose-dependent reduction in the lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA（0.1 mg/mL） along with Genistein（P〈0.05）.The results obtained for the comet assay in rat hepatocytes showed a significant dose-dependent decrease in the mean tail length（P〈0.05）.Thus the present study supports the hepatoprotective role of Genistein.
文摘This study aims to evaluate the preventive effects of anthocyanins extracts (MAEs) from mulberry variety PR-01 against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. It was found that 150 mg·kg-1 MAEs treatment significantly reduced the NDEA-induced hepatic nodules incidence and hepatocellular carcinoma incidence by 58.30% and 41.70% compared to the model group. Meanwhile, MAEs significantly restored the elevated the liver function enzymes, inhibited the tumor necrosis factor alpha and interleukin-6 levels, elevated the serum interleukin-10 and interferon-γ and increased hepatic glutathione-S-transferase and UDP-glucuronosyltransferase 2B1 enzyme activity. Moreover, 150 mg·kg-1 MAEs supplement enhanced glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase activities but reduced the malondialdehyde and thiobarbituric acid-reactive substances content by 37.90% and 44.52%. Furthermore, MAEs pretreatment maintained nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1, heme oxygenase-1, and NAD(P)H: quinine oxidoreductase1 stimulation and inhibited the expression of TNF-α, nuclear factor-kappaB (NF-κB), and cyclooxygenase-2 (COX-2), indicating that MAEs exhibit effectively prevention effects against liver cancer via decreased lipid peroxidation, induced Nrf2-mediated antioxidant enzymes and attenuating the inflammatory mediators COX-2 through NF-κB pathway. Thus, MAEs of mulberry variety PR-01 may be used as a good functional dietary supplement against liver cancer.
文摘The primary routes of potential human exposure to N-nitrosodiethylamine (NDEA) are ingestion, inhalation, and dermal contact. Air, diet and smoking contribute to potential human exposure at levels of a few μg of NDEA/day. Potential exposure depends on the ability of the nitrosamines to migrate from the product into the body. The first step in the metabolic degradation of NDEA by cytochrome oxidase (CYPs) enzymes is the introduction of a hydroxyl group and in human esophage and liver CYP2A3 and CYP2E1 participate on this metabolism. Measuring cytotoxicity in female rat primary hepatocytes cultures, were used to understand the CYP induction and metaboli-zation correlated with low NDEA concentrations. We observed that NDEA at different concentrations in the absence of CYPs inducers, was able to induce CYP2B1, CYP2B2, CYP2E1, CYP3A1 and CYP4A3. A positive NDEA synergistic effect on the levels of mRNA, was observed in the presence of pyrazole (300 μM) for CYP2B1 and CYP2B2 and for pregnenolone 16- carbonitrile (0.15 μM) for CYP2E1. Negative NDEA synergistic effects were observed for ethanol (0.3%) for CYP3A1, pyrazol (300 μM) for CYP2A1 and CYP2E1, and phenobarbital (1 mM) for CYP2A1. These facts are extremally important once that these metabolites can be directly related to the primary DNA lesions. We consider that studies to elucidate the biological factors that determine the shape of the dose-response curve are crucial for low-dose extrapolations of risk.
文摘The effects of exogenously administered ethanolamine (Etn) on the N-nitrosodiethylamine (NDA)-induced formation of hepatic lesions in rats were investigated. Sprague-Dawley rats were intraperitoneally administered NDA (100 mg/kg body weight) at 7-day intervals, and the animals were allowed free access to water containing Etn (15 or 50 mg/L) for 35 days. NDA-induced hepatic lesions were assessed according to the number of nodules detectable on the liver surface, areas of clear cell foci observed on histopathological thin sections, hydroxyproline levels in liver homogenates, and blood biochemical marker levels. Compared with those from control rats that were not administered Etn, livers from Etn-exposed rats had significantly fewer surface nodules and smaller areas of clear cell foci, indicating that Etn prevented or delayed the formation of preneoplastic cell alterations. Hydroxyproline levels in livers were significantly lower in Etn-treated rats, indicating that the chemical prevented the formation of fibrotic alterations. The protective effects of Etn on NDA-induced hepatic lesions were demonstrated by changes in blood biochemical marker levels. These results suggest that Etn can protect against cellular alterations induced by a carcinogenic chemical, possibly by enhancing hepatic phospholipid synthesis.
