红景天苷抗肝纤维化：涉及ROS相关的TGF-β1，NF-κB，MMPs/TIMPs及NO通路
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摘要
肝硬化是一种世界范围的疾病,严重威胁到人们的身体健康。几乎所有的慢性肝病都伴随着肝纤维化。目前认为肝纤维化是一种疾病,国际疾病分类(ICD-10)中作为一种病名(K74.001)。越来越多的研究表明,合理的治疗能够使纤维化的肝脏恢复,甚至痊愈。目前对于防治肝纤维化的研究还处于基础水平,临床中缺少确切有效干预肝纤维化的药物。红景天属景天科植物,红景天苷是其有效成分之一,研究表明其具有确切抗氧化作用。近年来研究表明,其有较好的抗纤维化作用。但其机制仍不清楚。因此,我们建立CCL4诱导的肝脏纤维化小鼠模型,并通过阻断ROS通路,观察其对肝纤维化小鼠肝脏以及相关信号通路的影响,揭示其可能的作用机制,为红景天苷的临床应用提供一些实验证据。
第一部分Sal对CCL4诱导的小鼠肝纤维化的影响
目的：观察红景天苷(Salidroside. Sal)对肝纤维化的作用,并探讨其对ROS相关的TGF-β1、MMP-TIMP、NF-κB通路的影响。
方法：用CCL4腹腔注射制备小鼠肘纤维化模型,分别给予Sal以及N-乙酰半胱氨酸(NAC)处理,8周后,处死小鼠,收集小鼠血清,肝脏,并检测MDA、 SOD, GSH、TGF-β1含量,肝脏HE,masson, α-SMA染色,提取肝脏组织RNA检测MMP-9/TIMP-1, TGF-β1, mRNA表达水平,提取HSCs原代细胞培养,检测HSCs中MMP-9/TIMP-1, TGF-β1mRNA表达,westernblot检测NF-κB P65蛋白表达水平。
结果：病理与免疫组化染色中可见,Sal、NAC处理组与CCL4模型组相比,肝纤维化程度明显降低。血清中,Sal、NAC处理组相较于CCL4模型组ALT、AST、 MDA、TGF-β1水平下降(P<0.01),SOD水平上升(P<0.01)。肝脏组织中GSH、 GSH-Px与SOD相较于CCL4模型组含量上升(P<0.01),MDA水平下降(P<0.01)。肝脏组织及HSCs原代细胞提取RNA检测,Sal, NAC处理组MMP-9mRNA水平相较CCL4模型组无统计学意义,TIMP-1及TGF-β1mRNA水平下降(P<0.01)；westernblot检测NK-κB核蛋白P65蛋白水平,Sa、NNAC处理组与CCL4模型组相比降低(P<0.01)。
结论：Sal具有明显的抗肝纤维化作用,其作用机制涉及ROS相关的TGF-β1、 MPP/TIMP、NF-κB通路。
第二部分红景天苷通过NO通路抑制LPS诱导的HSC-T6增殖
目的：观察红景天苷(Salidroside, Sal)对大鼠肝星状细胞(hepatic stellate cell, HSCs)-T6增殖的影响,并探讨一氧化氮(NO)在此过程中的作用。
方法：LPS诱导HSCs-T6细胞系,噻唑兰(MTT)比色法检测HSCs-T6增殖；NO荧光探针(DAF-FM DA)检测HSCs细胞内NO浓度；Western-blot检测INOS蛋白水平。
结果：在LPS作用于HSCs-T6细胞24小时后,与对照组相比,细胞增殖增加(P<0.01),在Sal作用下,HSCs-T6细胞增殖与LPS组相比受到抑制(P<0.01),并呈浓度依赖性；在Sal处理HSCs-T6细胞24小时后,细胞内NO水平有所上升,并呈浓度依赖性增加(P<0.01);Sal预处理后的HSCs-T6细胞,iNOS蛋白表达有所升高(P<0.01)。
结论：Sa1对HSCs-T6细胞的增殖具有浓度依赖性的抑制作用,可能是通过NO途径抑制增殖。
Background:Cirrhosis is a worldwide disease which seriously threatens people's health. Almost all chronic liver disease associated with liver fibrosis. Currently consider that liver fibrosis is a kind of disease.As a kind of disease (K74.001) in International Classification of Diseases (ICD-10). A growing body of research suggests that reasonable treatment can restore the fibrosis of the liver, and even to cure. Current research for the prevention and treatment of liver fibrosis is still in the basic level, and lack of specific effective drug intervention of liver fibrosis in clinical. Rhodiola genus crassulaceae plants, and Salidroside is one of the effective components. Studies have shown that it has antioxidant properties. In recent years,studies have shown that it has better anti-fibrosis action,but the mechanism is still unclear. Therefore.we establish a mouse liver fibrosis model induced by CCL4and by blocking the ROS pathway, to observe the effects of salidroside on liver fibrosis and the related signal pathways in mice, then reveal the possible mechanism of action. For the clinical application of salidroside provide some experimental evidence.
Part one:The effects of Sal on CCL4induced liver fibrosis in mice
Objective:To observe the effect of salidroside on liver fibrosis, and investigate the influence of ROS-related pathways involve TGF-β1, NF-kB, MMPs/TIMPs.
Method:the liver-fibrosis model was produced by intraperitoneal injection of CCL4in mice. Respectively given Sal and N-acetylcysteine (NAC) processing. After8weeks, execution the mice and then collect its serum,liver, at the same time detection of MDA, SOD, GSH. Liver were observed in HE and masson staining. Extraction of liver tssue's RNA examination the mRNA expression level of MMP-9/TIMP-1,TGF-β1. Extract the HSCs primary cell culture, detected the MMP-9/TIMP-1,TGF-β1mRNA expression level in HSCs. Western-blot detection the protein expression level of NF-κB P65.
Result:Pathological and immunohistochemical staining observed that the degree of liver fibrosis was significantly reduced in Sal and NAC groups. In serum,the ALT, AST, MDA, TGF-β1levels decreased (P<0.01)and the SOD levels increased (P<0.01)in Sal、NAC treatment groups. Compare with CCL4model groups, GSH, GSH-Px, SOD levels increased(P<0.01), MDA decreased in liver tissue(P<0.01).RNA was extracted from liver tissue and HSCs primary cell detection that Sal, NAC treatment groups compared with CCL4model groups of MMP-9mRNA level without statistical significance and TIMP-1, TGF-β1mRNA level decreased(P<0.01). Western-blot detected the NF-κB P65protein levels, Sal, NAC treatment group compared with CCL4model group decreased(P<0.01).
Conclusion:Sal has obvious anti liver fibrosis effect,its mechanism of action involves the ROS related TGF-beta1, MPP/TIMP, the NF-κB pathway
Part two:Sal inhibits LPS induced proliferation in HSC-T6by NO pathway
Objective:To investigate the effect of Salidroside on proliferation of hepatic stellate Cells(HSCs) and estimate the function of the NO during the procedure.
Methods:Choosing the lipopolysaccharide(LPS)used to activate HSC-T6.Rat HSC-T6activated by LPS were incubated with various concentration of Sal. Then conduct the following experiment after twenty-four hours:MTT colorimetric assay was used to detect the Proliferation of HSC-T6;The intracellular NO was detected using DAF-FM DA.Western blot were used to investigate the expression of iNOS protein.
Results:Compared with the control group, the ratio of cell proliferation increased(P<0.01) after LPS-induced HSC-T6for24h. Compared with the LPS group, the ratio of cell proliferation decreased(P<0.01) after Sal treatment with LPS-induced HSC-T6for24h,and in a dose-dependent manner. In group treated with Sal, the NO concentration and expression level of iNOS in HSC-T6increased (P<0.01), and in a dose-dependent manner(P<0.01).
Conclusion:Sal could inhibit the proliferation of HSC-T6.which could be mediated by NO partially at least.
第一部分Sal对CCL4诱导的小鼠肝纤维化的影响
目的：观察红景天苷(Salidroside. Sal)对肝纤维化的作用,并探讨其对ROS相关的TGF-β1、MMP-TIMP、NF-κB通路的影响。
方法：用CCL4腹腔注射制备小鼠肘纤维化模型,分别给予Sal以及N-乙酰半胱氨酸(NAC)处理,8周后,处死小鼠,收集小鼠血清,肝脏,并检测MDA、 SOD, GSH、TGF-β1含量,肝脏HE,masson, α-SMA染色,提取肝脏组织RNA检测MMP-9/TIMP-1, TGF-β1, mRNA表达水平,提取HSCs原代细胞培养,检测HSCs中MMP-9/TIMP-1, TGF-β1mRNA表达,westernblot检测NF-κB P65蛋白表达水平。
结果：病理与免疫组化染色中可见,Sal、NAC处理组与CCL4模型组相比,肝纤维化程度明显降低。血清中,Sal、NAC处理组相较于CCL4模型组ALT、AST、 MDA、TGF-β1水平下降(P<0.01),SOD水平上升(P<0.01)。肝脏组织中GSH、 GSH-Px与SOD相较于CCL4模型组含量上升(P<0.01),MDA水平下降(P<0.01)。肝脏组织及HSCs原代细胞提取RNA检测,Sal, NAC处理组MMP-9mRNA水平相较CCL4模型组无统计学意义,TIMP-1及TGF-β1mRNA水平下降(P<0.01)；westernblot检测NK-κB核蛋白P65蛋白水平,Sa、NNAC处理组与CCL4模型组相比降低(P<0.01)。
结论：Sal具有明显的抗肝纤维化作用,其作用机制涉及ROS相关的TGF-β1、 MPP/TIMP、NF-κB通路。
第二部分红景天苷通过NO通路抑制LPS诱导的HSC-T6增殖
目的：观察红景天苷(Salidroside, Sal)对大鼠肝星状细胞(hepatic stellate cell, HSCs)-T6增殖的影响,并探讨一氧化氮(NO)在此过程中的作用。
方法：LPS诱导HSCs-T6细胞系,噻唑兰(MTT)比色法检测HSCs-T6增殖；NO荧光探针(DAF-FM DA)检测HSCs细胞内NO浓度；Western-blot检测INOS蛋白水平。
结果：在LPS作用于HSCs-T6细胞24小时后,与对照组相比,细胞增殖增加(P<0.01),在Sal作用下,HSCs-T6细胞增殖与LPS组相比受到抑制(P<0.01),并呈浓度依赖性；在Sal处理HSCs-T6细胞24小时后,细胞内NO水平有所上升,并呈浓度依赖性增加(P<0.01);Sal预处理后的HSCs-T6细胞,iNOS蛋白表达有所升高(P<0.01)。
结论：Sa1对HSCs-T6细胞的增殖具有浓度依赖性的抑制作用,可能是通过NO途径抑制增殖。
Background:Cirrhosis is a worldwide disease which seriously threatens people's health. Almost all chronic liver disease associated with liver fibrosis. Currently consider that liver fibrosis is a kind of disease.As a kind of disease (K74.001) in International Classification of Diseases (ICD-10). A growing body of research suggests that reasonable treatment can restore the fibrosis of the liver, and even to cure. Current research for the prevention and treatment of liver fibrosis is still in the basic level, and lack of specific effective drug intervention of liver fibrosis in clinical. Rhodiola genus crassulaceae plants, and Salidroside is one of the effective components. Studies have shown that it has antioxidant properties. In recent years,studies have shown that it has better anti-fibrosis action,but the mechanism is still unclear. Therefore.we establish a mouse liver fibrosis model induced by CCL4and by blocking the ROS pathway, to observe the effects of salidroside on liver fibrosis and the related signal pathways in mice, then reveal the possible mechanism of action. For the clinical application of salidroside provide some experimental evidence.
Part one:The effects of Sal on CCL4induced liver fibrosis in mice
Objective:To observe the effect of salidroside on liver fibrosis, and investigate the influence of ROS-related pathways involve TGF-β1, NF-kB, MMPs/TIMPs.
Method:the liver-fibrosis model was produced by intraperitoneal injection of CCL4in mice. Respectively given Sal and N-acetylcysteine (NAC) processing. After8weeks, execution the mice and then collect its serum,liver, at the same time detection of MDA, SOD, GSH. Liver were observed in HE and masson staining. Extraction of liver tssue's RNA examination the mRNA expression level of MMP-9/TIMP-1,TGF-β1. Extract the HSCs primary cell culture, detected the MMP-9/TIMP-1,TGF-β1mRNA expression level in HSCs. Western-blot detection the protein expression level of NF-κB P65.
Result:Pathological and immunohistochemical staining observed that the degree of liver fibrosis was significantly reduced in Sal and NAC groups. In serum,the ALT, AST, MDA, TGF-β1levels decreased (P<0.01)and the SOD levels increased (P<0.01)in Sal、NAC treatment groups. Compare with CCL4model groups, GSH, GSH-Px, SOD levels increased(P<0.01), MDA decreased in liver tissue(P<0.01).RNA was extracted from liver tissue and HSCs primary cell detection that Sal, NAC treatment groups compared with CCL4model groups of MMP-9mRNA level without statistical significance and TIMP-1, TGF-β1mRNA level decreased(P<0.01). Western-blot detected the NF-κB P65protein levels, Sal, NAC treatment group compared with CCL4model group decreased(P<0.01).
Conclusion:Sal has obvious anti liver fibrosis effect,its mechanism of action involves the ROS related TGF-beta1, MPP/TIMP, the NF-κB pathway
Part two:Sal inhibits LPS induced proliferation in HSC-T6by NO pathway
Objective:To investigate the effect of Salidroside on proliferation of hepatic stellate Cells(HSCs) and estimate the function of the NO during the procedure.
Methods:Choosing the lipopolysaccharide(LPS)used to activate HSC-T6.Rat HSC-T6activated by LPS were incubated with various concentration of Sal. Then conduct the following experiment after twenty-four hours:MTT colorimetric assay was used to detect the Proliferation of HSC-T6;The intracellular NO was detected using DAF-FM DA.Western blot were used to investigate the expression of iNOS protein.
Results:Compared with the control group, the ratio of cell proliferation increased(P<0.01) after LPS-induced HSC-T6for24h. Compared with the LPS group, the ratio of cell proliferation decreased(P<0.01) after Sal treatment with LPS-induced HSC-T6for24h,and in a dose-dependent manner. In group treated with Sal, the NO concentration and expression level of iNOS in HSC-T6increased (P<0.01), and in a dose-dependent manner(P<0.01).
Conclusion:Sal could inhibit the proliferation of HSC-T6.which could be mediated by NO partially at least.
引文
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