BACKGROUND： Proliferation of hepatic stellate cells （HSCs） plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess ...BACKGROUND： Proliferation of hepatic stellate cells （HSCs） plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS： The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin （10, 50 and 100 μmol/L） for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS： Silibinin inhibits LX-2 cell proliferation in doseand time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin- inhibited proliferation of LX-2 cells. CONCLUSION： The anti-proliferative effect of silibinin on LX-2 human steUate cells is via the inhibition of the expres- sions of various cell cycle targets including p27, Akt and sir- tuin signaling.展开更多
AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer(COLO 205) cells.METHODS: MTT assays were performed to quantify cell viability.Western blot assays were applied to i...AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer(COLO 205) cells.METHODS: MTT assays were performed to quantify cell viability.Western blot assays were applied to identify the expression of signaling proteins.RESULTS: The combined treatment of COLO 205 cells with metformin and silibinin decreased cell survival at a dose insufficient to influence the non-malignant cells [Human colonic epithelial cells(HCo Epi C)].Silibinin and metformin increased phosphatase and tensin homolog and 5'-adenosine monophosphate-activated protein kinase expression in COLO 205 cells and inhibited the phosphorylation of mammol/Lalian target of rapamycin.This combined treatment resulted in an increase in the expression of activated caspase 3 and apoptosis inducing factor, indicating apoptosis.CONCLUSION: The combined treatment of human colorectal cancer cells with silibinin and metformin may induce apoptosis at a dose that does not affect HCo Epi C.This finding reveals a potential therapeutic strategy for the treatment of colorectal cancer.展开更多
AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibini...AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined. RESULTS： We demonstrated that silibinin significantly reduced the growth of HUH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly up- regulated p21/CDK4 and p27/CDK4 complexes, down- regulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and upregulated activated caspase-3 and -9. Silibinin＇s antiangiogenic effects were indicated by down-regulated metalloproteinase-2 （MMP2） and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten （PTEN） and decreased p-Akt production, indicating the role of PTEN/ PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 （AC-H3 and AC-H4）, indicating a possible role of altered histone acetylation in silibininreduced HCC cell proliferation. CONCLUSION： Our results defined silibinin＇s in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.展开更多
AIM:To investigate the in vivo effects and mechanisms of silibinin on the growth of hepatocellular carcinoma (HCC) xenografts in nude mice.METHODS: Nude mice bearing HuH7 xenografts were used to assess the anti-HCC ef...AIM:To investigate the in vivo effects and mechanisms of silibinin on the growth of hepatocellular carcinoma (HCC) xenografts in nude mice.METHODS: Nude mice bearing HuH7 xenografts were used to assess the anti-HCC effects and mechanisms of silibinin.RESULTS: Silibinin resulted in a potent dosedependent reduction of HuH7 xenografts in association with a significant decrease in Ki-67 and α-fetoprotein production, nuclear NF-κB content, polo-like kinase 1, Rb phosphorylation, and E2F1/DP1 complex, but increased p27/CDK4 complex and checkpoint kinase 1 expression, suggesting that the in vivo effects of silibinin are mediated by inhibiting G1-S transition of the cell cycle. Silibinin-induced apoptosis of HuH7 xenografts was associated with inhibited survivin phosphorylation. Silibinin-reduced growth of HuH7 xenografts was associated with decreased p-ERK, increased PTEN expression and the activity of silibinin was correlated with decreased p-Akt production, indicating involvement of PTEN/PI3K/Akt and ERK pathways in its in vivo anti-HCC effects. Silibinin-reduced growth of HuH7 xenografts was also associated with a significant increase in AC-H3 and AC-H4 expression and the production of superoxide dismutase (SOD)-1.CONCLUSION: Silibinin reduces HCC xenograft growth through the inhibition of cell proliferation, cell cycle progression and PTEN/P-Akt and ERK signaling, inducing cell apoptosis, and increasing histone acetylation and SOD-1 expression.展开更多
Globally,the risk of colorectal cancer（CRC） as well as the incidence of mortality associated with CRC is increasing.Thus,it is imperative that we look at alternative approaches involving intake of non-toxic natural ...Globally,the risk of colorectal cancer（CRC） as well as the incidence of mortality associated with CRC is increasing.Thus,it is imperative that we look at alternative approaches involving intake of non-toxic natural dietary/non-dietary agents,for the prevention of CRC.The ultimate goal of this approach is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent their progression to more advanced forms of CRC,and use these natural agents as a safe intervention strategy during the clinical course of this deadly malignancy.Over the years,pre-clinical studies have shown that silibinin（a flavonolignan isolated from the seeds of milk thistle,Silybum marianum） has strong preventive and therapeutic efficacy against various epithelial cancers,including CRC.The focus of the present review is to provide a comprehensive tabular summary,categorically for an easy accessibility and referencing,pertaining to the efficacy and associated mechanisms of silibinin against CRC growth and progression.展开更多
Objective:To explore the protective effect and the underlying mechanism of silibinin(SIB),one of the active compounds from Silybum marianum(L.)Gaertn in endotoxemia.Methods:Mouse peritoneal macrophage were isolated vi...Objective:To explore the protective effect and the underlying mechanism of silibinin(SIB),one of the active compounds from Silybum marianum(L.)Gaertn in endotoxemia.Methods:Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium.Cell viability was assessed using the cell counting kit-8,while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay.The protein expressions of interleukin(IL)-1α,IL-1β,and IL-18 were determined by enzyme-linked immunosorbent assay.Intracellular lipopolysaccharide(LPS)levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry.Additionally,proximity ligation assay was employed for the LPS and caspase-11 interaction.Mice were divided into 4 groups:the control,LPS,high-dose-SIB(100 mg/kg),and low-dose-SIB(100 mg/kg)groups(n=8).Zebrafish were divided into 4 groups:the control,LPS,high-dose-SIB(200μmol/L),and low-dose-SIB(100μmol/L)groups(n=30 for survival experiment and n=10 for gene expression analysis).The expression of caspase-11,gasdermin D(GSDMD),and N-GSDMD was determined by Western blot and the expressions of caspy2,gsdmeb,and IL-1βwere detected using quantitative real-time PCR.Histopathological observation was performed through hematoxylineosin staining,and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay.Results:SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1α,IL-1β,and IL-18 induced by LPS(P<0.05).Moreover,SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS(P<0.05).SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD,inhibited the relative cytokines,prolonged the survival time,and up-regulated the survival rate in the endotoxemia models(P<0.05).Conclusions:SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model,at least in part,by inhibiting the caspase-11-mediated cleavage of GSDMD.Additionally,SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression,which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.展开更多
Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK ...Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57 BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h,then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibininsignificantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2 E1 and CYP4 A in vivo.These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity(CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity(CYP2 E1 and CYP4 A) to relieve oxidative stress.展开更多
The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat liver.The liver damage was induced in Wi...The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat liver.The liver damage was induced in Wistar albino rats by repeated administration of DMN(10 mg·kg-1 b.w.,i.p.)on 3 consecutive days per week for 3 weeks.SBN(100 mg·kg-1 b.w.,p.o.)was given daily to the DMN treated rats for two weeks.The marker enzymes of liver toxicity and second-line enzymic and non-enzymic antioxidants were evaluated in serum and liver tissues before and after SBN treatment.Histopathology of the liver was evaluated by H & E staining.The DMN treatment produced a progressive increase in all the serum marker enzymes(AST,ALT,ALP,LDH,and γ-GT),peaking on Day 21.This treatment produced highly significant decreases in all the second-line antioxidant parameters(GSH,GST,GR,GPx,and vitamins C and E).The SBN treatment significantly reversed the DMN-induced damages,towards normalcy.Histopathological studies confirmed the development of liver toxicity in DMN-treated rats,which was reversed by SBN treatment in corroboration with the aforementioned biochemical results,indicating the hepatoprotective and antioxidant properties of SBN.In conclusion,the DMN-induced degenerative changes in the liver were alleviated by SBN treatment and this protective ability may be attributed to its antioxidant,free radical scavenging,and membrane stabilizing properties.展开更多
Aim:Neuroblastoma is a pediatric cancer of the sympathetic nervous system.Using various parameters including stage of the disease,amplification status of N-Myc,DNA index and histopathology,neuroblastoma can be stratif...Aim:Neuroblastoma is a pediatric cancer of the sympathetic nervous system.Using various parameters including stage of the disease,amplification status of N-Myc,DNA index and histopathology,neuroblastoma can be stratified into low-and high-risk groups.Recent advances in treatment have significantly improved the survival rate of lowrisk neuroblastoma patients.However,the overall survival rate of high-risk neuroblastoma group,especially N-Myc amplified patients,is poor.Moreover,the survivors of both low-and high-risk neuroblastoma manifest adverse side effects to chemotherapy and thus their quality of life is impaired.Considering all these factors,there is an urgent need to develop therapeutic strategies with natural compounds to improve the survival rate and to reduce the side effects.In this study,we hypothesised that the mesenchymal nature of neuroblastoma cells is a reason,at least in part,for the aggressive and treatment resistant phenotype.Method:In order to validate our hypothesis,we used publicaly available RNA-Seq data,in vitro assays and xenograft mouse models.Results:Using a combinatorial treatment of mesenchymal-to-epithelial inducers(curcumin or silibinin)with doxorubicin significantly increased the cell death in a panel of neuroblastoma cells in vitro.Follow up analysis in vivo,confirmed the therapeutic benefit of utilising the combination of curcumin with doxorubicin.The combinatorial therapy significantly reduced the tumor burden and increased the survival of mice implanted with high-risk neuroblastoma cells.Conclusion:Taken together,this study shows the efficacy of using curcumin in combination with doxorubicin to improve the survival rate and has the potential to enhance the quality of life of neuroblastoma patients.展开更多
文摘BACKGROUND： Proliferation of hepatic stellate cells （HSCs） plays a pivotal role in the progression of liver fibrosis conse- quent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS： The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin （10, 50 and 100 μmol/L） for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS： Silibinin inhibits LX-2 cell proliferation in doseand time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin- inhibited proliferation of LX-2 cells. CONCLUSION： The anti-proliferative effect of silibinin on LX-2 human steUate cells is via the inhibition of the expres- sions of various cell cycle targets including p27, Akt and sir- tuin signaling.
基金Supported by A grant from the Chi Mei Medical Center in Taiwan(partly),No.CMFHR10302
文摘AIM: To investigate the effect of metformin on silibinin-induced apoptosis in human colorectal cancer(COLO 205) cells.METHODS: MTT assays were performed to quantify cell viability.Western blot assays were applied to identify the expression of signaling proteins.RESULTS: The combined treatment of COLO 205 cells with metformin and silibinin decreased cell survival at a dose insufficient to influence the non-malignant cells [Human colonic epithelial cells(HCo Epi C)].Silibinin and metformin increased phosphatase and tensin homolog and 5'-adenosine monophosphate-activated protein kinase expression in COLO 205 cells and inhibited the phosphorylation of mammol/Lalian target of rapamycin.This combined treatment resulted in an increase in the expression of activated caspase 3 and apoptosis inducing factor, indicating apoptosis.CONCLUSION: The combined treatment of human colorectal cancer cells with silibinin and metformin may induce apoptosis at a dose that does not affect HCo Epi C.This finding reveals a potential therapeutic strategy for the treatment of colorectal cancer.
基金Supported by UCI institutional research grants from GI Division Chao Family Comprehensive Cancer Center(K.-Q.H.)
文摘AIM： To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma （HCC） cell growth, METHODS： Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined. RESULTS： We demonstrated that silibinin significantly reduced the growth of HUH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly up- regulated p21/CDK4 and p27/CDK4 complexes, down- regulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and upregulated activated caspase-3 and -9. Silibinin＇s antiangiogenic effects were indicated by down-regulated metalloproteinase-2 （MMP2） and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten （PTEN） and decreased p-Akt production, indicating the role of PTEN/ PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 （AC-H3 and AC-H4）, indicating a possible role of altered histone acetylation in silibininreduced HCC cell proliferation. CONCLUSION： Our results defined silibinin＇s in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.
文摘AIM:To investigate the in vivo effects and mechanisms of silibinin on the growth of hepatocellular carcinoma (HCC) xenografts in nude mice.METHODS: Nude mice bearing HuH7 xenografts were used to assess the anti-HCC effects and mechanisms of silibinin.RESULTS: Silibinin resulted in a potent dosedependent reduction of HuH7 xenografts in association with a significant decrease in Ki-67 and α-fetoprotein production, nuclear NF-κB content, polo-like kinase 1, Rb phosphorylation, and E2F1/DP1 complex, but increased p27/CDK4 complex and checkpoint kinase 1 expression, suggesting that the in vivo effects of silibinin are mediated by inhibiting G1-S transition of the cell cycle. Silibinin-induced apoptosis of HuH7 xenografts was associated with inhibited survivin phosphorylation. Silibinin-reduced growth of HuH7 xenografts was associated with decreased p-ERK, increased PTEN expression and the activity of silibinin was correlated with decreased p-Akt production, indicating involvement of PTEN/PI3K/Akt and ERK pathways in its in vivo anti-HCC effects. Silibinin-reduced growth of HuH7 xenografts was also associated with a significant increase in AC-H3 and AC-H4 expression and the production of superoxide dismutase (SOD)-1.CONCLUSION: Silibinin reduces HCC xenograft growth through the inhibition of cell proliferation, cell cycle progression and PTEN/P-Akt and ERK signaling, inducing cell apoptosis, and increasing histone acetylation and SOD-1 expression.
文摘Globally,the risk of colorectal cancer（CRC） as well as the incidence of mortality associated with CRC is increasing.Thus,it is imperative that we look at alternative approaches involving intake of non-toxic natural dietary/non-dietary agents,for the prevention of CRC.The ultimate goal of this approach is to reduce the incidence of pre-neoplastic adenomatous polyps and prevent their progression to more advanced forms of CRC,and use these natural agents as a safe intervention strategy during the clinical course of this deadly malignancy.Over the years,pre-clinical studies have shown that silibinin（a flavonolignan isolated from the seeds of milk thistle,Silybum marianum） has strong preventive and therapeutic efficacy against various epithelial cancers,including CRC.The focus of the present review is to provide a comprehensive tabular summary,categorically for an easy accessibility and referencing,pertaining to the efficacy and associated mechanisms of silibinin against CRC growth and progression.
基金Supported by the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515011106)Science and Technology Program of Guangzhou(No.2023A04J1826)。
文摘Objective:To explore the protective effect and the underlying mechanism of silibinin(SIB),one of the active compounds from Silybum marianum(L.)Gaertn in endotoxemia.Methods:Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium.Cell viability was assessed using the cell counting kit-8,while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay.The protein expressions of interleukin(IL)-1α,IL-1β,and IL-18 were determined by enzyme-linked immunosorbent assay.Intracellular lipopolysaccharide(LPS)levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry.Additionally,proximity ligation assay was employed for the LPS and caspase-11 interaction.Mice were divided into 4 groups:the control,LPS,high-dose-SIB(100 mg/kg),and low-dose-SIB(100 mg/kg)groups(n=8).Zebrafish were divided into 4 groups:the control,LPS,high-dose-SIB(200μmol/L),and low-dose-SIB(100μmol/L)groups(n=30 for survival experiment and n=10 for gene expression analysis).The expression of caspase-11,gasdermin D(GSDMD),and N-GSDMD was determined by Western blot and the expressions of caspy2,gsdmeb,and IL-1βwere detected using quantitative real-time PCR.Histopathological observation was performed through hematoxylineosin staining,and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay.Results:SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1α,IL-1β,and IL-18 induced by LPS(P<0.05).Moreover,SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS(P<0.05).SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD,inhibited the relative cytokines,prolonged the survival time,and up-regulated the survival rate in the endotoxemia models(P<0.05).Conclusions:SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model,at least in part,by inhibiting the caspase-11-mediated cleavage of GSDMD.Additionally,SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression,which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.
基金supported by Major Technological Innovation Project of Hubei Province(Grant no.2016ACA140,China)Innovation and Entrepreneurship Training Project for College Students of the Ministry of Education(Grant no.201610512001,China)
文摘Non-alcoholic steatohepatitis(NASH) is a chronic metabolic syndrome and the CFLAR-JNK pathway can reverse the process of NASH. Although silibinin is used for the treatment of NASH in clinical, its effect on CFLAR-JNK pathway in NASH remains unclear. This study aimed to investigate the effect of silibinin on CFLAR-JNK pathway in NASH models both in vivo and in vitro. The in vivo study was performed using male C57 BL/6 mice fed with methionine– choline-deficient diet and simultaneously treated with silibinin for 6 weeks. The in vitro study was performed by using mouse NCTC-1469 cells which were respectively pretreated with oleic acid plus palmitic acid, and adenovirus-down Cflar for 24 h,then treated with silibinin for 24 h. After the drug treatment, the key indicators involved in CFLAR-JNK pathway including hepatic injury, lipid metabolism and oxidative stress were determined. Silibininsignificantly activated CFLAR and inhibited the phosphorylation of JNK, up-regulated the mRNA expression of Pparα, Fabp5, Cpt1α, Acox, Scd-1, Gpat and Mttp, reduced the activities of serum ALT and AST and the contents of hepatic TG, TC and MDA, increased the expression of NRF2 and the activities of CAT, GSH-Px and HO-1, and decreased the activities and expression of CYP2 E1 and CYP4 A in vivo.These effects were confirmed by the in vitro experiments. Silibinin prevented NASH by regulating CFLAR-JNK pathway, and thereby on one hand promoting the β-oxidation and efflux of fatty acids in liver to relieve lipid accumulation, and on the other hand inducing antioxidase activity(CAT, GSH-Px and HO-1) and inhibiting pro-oxidase activity(CYP2 E1 and CYP4 A) to relieve oxidative stress.
基金supported by the DST-INSPIRE(Department of Science and Technology,Government of India Innovation in Science Pursuit for Inspired Research)fellowship(Award No:DST/INSPIRE Fellowship/2010/dated 16.03.2010)
文摘The present study was designed to evaluate the hepatoprotective and antioxidant potentials of silibinin(SBN)against N-nitrosodimethylamine(DMN)-induced toxic insults in the rat liver.The liver damage was induced in Wistar albino rats by repeated administration of DMN(10 mg·kg-1 b.w.,i.p.)on 3 consecutive days per week for 3 weeks.SBN(100 mg·kg-1 b.w.,p.o.)was given daily to the DMN treated rats for two weeks.The marker enzymes of liver toxicity and second-line enzymic and non-enzymic antioxidants were evaluated in serum and liver tissues before and after SBN treatment.Histopathology of the liver was evaluated by H & E staining.The DMN treatment produced a progressive increase in all the serum marker enzymes(AST,ALT,ALP,LDH,and γ-GT),peaking on Day 21.This treatment produced highly significant decreases in all the second-line antioxidant parameters(GSH,GST,GR,GPx,and vitamins C and E).The SBN treatment significantly reversed the DMN-induced damages,towards normalcy.Histopathological studies confirmed the development of liver toxicity in DMN-treated rats,which was reversed by SBN treatment in corroboration with the aforementioned biochemical results,indicating the hepatoprotective and antioxidant properties of SBN.In conclusion,the DMN-induced degenerative changes in the liver were alleviated by SBN treatment and this protective ability may be attributed to its antioxidant,free radical scavenging,and membrane stabilizing properties.
基金Suresh Mathivanan is supported by Australian Research Council Future Fellowship(FT180100333)the project was not funded by the basic science fellowship.Angela Di Giannatale is supported by a Grant from the Italian Ministry of Health(GR-2016-02364088).
文摘Aim:Neuroblastoma is a pediatric cancer of the sympathetic nervous system.Using various parameters including stage of the disease,amplification status of N-Myc,DNA index and histopathology,neuroblastoma can be stratified into low-and high-risk groups.Recent advances in treatment have significantly improved the survival rate of lowrisk neuroblastoma patients.However,the overall survival rate of high-risk neuroblastoma group,especially N-Myc amplified patients,is poor.Moreover,the survivors of both low-and high-risk neuroblastoma manifest adverse side effects to chemotherapy and thus their quality of life is impaired.Considering all these factors,there is an urgent need to develop therapeutic strategies with natural compounds to improve the survival rate and to reduce the side effects.In this study,we hypothesised that the mesenchymal nature of neuroblastoma cells is a reason,at least in part,for the aggressive and treatment resistant phenotype.Method:In order to validate our hypothesis,we used publicaly available RNA-Seq data,in vitro assays and xenograft mouse models.Results:Using a combinatorial treatment of mesenchymal-to-epithelial inducers(curcumin or silibinin)with doxorubicin significantly increased the cell death in a panel of neuroblastoma cells in vitro.Follow up analysis in vivo,confirmed the therapeutic benefit of utilising the combination of curcumin with doxorubicin.The combinatorial therapy significantly reduced the tumor burden and increased the survival of mice implanted with high-risk neuroblastoma cells.Conclusion:Taken together,this study shows the efficacy of using curcumin in combination with doxorubicin to improve the survival rate and has the potential to enhance the quality of life of neuroblastoma patients.
