SIL1,an endoplasmic reticulum(ER)-resident protein,is reported to play a protective role in Alzheimer’s disease(AD).However,the effect of SIL1 on amyloid precursor protein(APP)processing remains unclear.In this study...SIL1,an endoplasmic reticulum(ER)-resident protein,is reported to play a protective role in Alzheimer’s disease(AD).However,the effect of SIL1 on amyloid precursor protein(APP)processing remains unclear.In this study,the role of SIL1 in APP processing was explored both in vitro and in vivo.In the in vitro experiment,SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695.In the in vivo experiment,AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates.Western blotting(WB),immunohistochemistry,RNA sequencing(RNA-seq),and behavioral experiments were performed to evaluate the relevant parameters.Results indicated that SIL1 expression decreased in APP23/PS45 mice.Overexpression of SIL1 significantly decreased the protein levels of APP,presenilin-1(PS1),and C-terminal fragments(CTFs)of APP in vivo and in vitro.Conversely,knockdown of SIL1 increased the protein levels of APP,β-site APP cleavage enzyme 1(BACE1),PS1,and CTFs,as well as APP mRNA expression in 2EB2 cells.Furthermore,SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice.Importantly,Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice.These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.展开更多
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
为避免类似江西九江“3·12”石化企业加氢装置高低压互窜爆炸着火事故的发生,提出了对某炼化企业部分临氢装置紧急切断功能隐患治理项目进行基础设计阶段的危险与可操作性分析(HAZOP,Hazard and Operability Analysis)及安全完整...为避免类似江西九江“3·12”石化企业加氢装置高低压互窜爆炸着火事故的发生,提出了对某炼化企业部分临氢装置紧急切断功能隐患治理项目进行基础设计阶段的危险与可操作性分析(HAZOP,Hazard and Operability Analysis)及安全完整性等级(SIL,Safety Integrity Level)分级应用。HAZOP分析采用基于参数优先选择法的工作流程;SIL分级采用保护层分析(LOPA,Layers of Protection Analysis)方法,遵循“尽可能合理降低”(ALARP,As Low As Reasonably Practical)原则。对某炼化企业焦化汽煤油加氢精制装置、加氢联合柴油加氢精制装置和乙苯装置进行了HAZOP&SIL分级,共识别出事故场景12项,提出了建议措施6条。结果表明,HAZOP&SIL分级能够帮助该炼化企业有效地开展窜压风险隐患治理工作,把握安全生产主动权,将存在的窜压风险控制在可接受水平或及时地消除,预防高低压互窜事故的发生,保证炼化企业本质安全。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
文摘为确保某压气站的安全仪表系统(SIS)的完整性和可靠性,针对该压气站的SIS以及压缩机的 SIS 系统开展安全完整性等级(SIL)评估和验证计算工作。首先对保护层分析法(LOPA)和SIL验证方法进行理论介绍,基于实际案例,应用 LOPA法对站内所有的安全仪表系统进行分析,识别保护层的有效性,对各安全仪表回路的 SIL 等级进行定级和验证。结果表明,站内的SIF回路均满足要求,此次 SIL 定级和验证结果也证明了该定级方法的准确性和保守性。
基金National Natural Science Foundation of China(82230043,82293642)。
文摘SIL1,an endoplasmic reticulum(ER)-resident protein,is reported to play a protective role in Alzheimer’s disease(AD).However,the effect of SIL1 on amyloid precursor protein(APP)processing remains unclear.In this study,the role of SIL1 in APP processing was explored both in vitro and in vivo.In the in vitro experiment,SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695.In the in vivo experiment,AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates.Western blotting(WB),immunohistochemistry,RNA sequencing(RNA-seq),and behavioral experiments were performed to evaluate the relevant parameters.Results indicated that SIL1 expression decreased in APP23/PS45 mice.Overexpression of SIL1 significantly decreased the protein levels of APP,presenilin-1(PS1),and C-terminal fragments(CTFs)of APP in vivo and in vitro.Conversely,knockdown of SIL1 increased the protein levels of APP,β-site APP cleavage enzyme 1(BACE1),PS1,and CTFs,as well as APP mRNA expression in 2EB2 cells.Furthermore,SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice.Importantly,Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice.These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.
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.
文摘为避免类似江西九江“3·12”石化企业加氢装置高低压互窜爆炸着火事故的发生,提出了对某炼化企业部分临氢装置紧急切断功能隐患治理项目进行基础设计阶段的危险与可操作性分析(HAZOP,Hazard and Operability Analysis)及安全完整性等级(SIL,Safety Integrity Level)分级应用。HAZOP分析采用基于参数优先选择法的工作流程;SIL分级采用保护层分析(LOPA,Layers of Protection Analysis)方法,遵循“尽可能合理降低”(ALARP,As Low As Reasonably Practical)原则。对某炼化企业焦化汽煤油加氢精制装置、加氢联合柴油加氢精制装置和乙苯装置进行了HAZOP&SIL分级,共识别出事故场景12项,提出了建议措施6条。结果表明,HAZOP&SIL分级能够帮助该炼化企业有效地开展窜压风险隐患治理工作,把握安全生产主动权,将存在的窜压风险控制在可接受水平或及时地消除,预防高低压互窜事故的发生,保证炼化企业本质安全。
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.
