红景天苷对对乙酰氨基酚诱导肝损伤模型小鼠Keap1—Nrf2信号通路的影响(1)
中圖分类号 R285.5 文献标志码 A 文章编号 1001-0408(2018)11-1487-04
DOI 10.6039/j.issn.1001-0408.2018.11.12
摘 要 目的：探讨红景天苷(SALD)对对乙酰氨基酚(APAP)诱导肝脏损伤模型小鼠的保护作用及机制。方法：将60只小鼠随机分为正常组(生理盐水)、模型组(生理盐水)、阳性组(乙酰半胱氨酸，150 mg/kg)和SALD低、中、高剂量组(100、200、300 mg/kg)，每组10只。除正常组外，其余各组小鼠均灌胃500 mg/kg的APAP复制肝损伤模型。造模前1 h，各组小鼠灌胃相应药物，连续5 d。给药结束后，测定小鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、乳酸脱氢酶(LDH)含量，苏木精-伊红(HE)染色观察肝组织病理学改变，Western blot法检测肝组织中Kelch样环氧氯丙烷相关蛋白1(Keap1)(细胞核内)、核转录因子NF-E2相关因子(Nrf2)(细胞核内)、血红素氧合酶1(HO-1)(细胞质中)、还原型辅酶/醌氧化还原酶(NQO1)(细胞质中)以及谷氨酸半胱氨酸连接酶(GCLC)(细胞质中)蛋白表达。结果：与正常组比较，模型组小鼠血清中ALT、AST、ALP和LDH含量显著增加(P<0.01)，肝组织发生肝小叶结构紊乱辨别不清、肝细胞嗜酸性坏死等病变，肝组织中Nrf2、Keap1、HO-1、GCLC蛋白表达水平显著降低(P<0.05)。与模型组比较，除SALD低剂量组小鼠血清中LDH含量减少和阳性组小鼠肝组织中Nrf2、Keap1表达水平升高不显著外，其余各组小鼠上述指标均显著改善(P<0.05或P<0.01)，且各给药组小鼠肝组织中NQO1蛋白表达水平均显著升高(P<0.05或P<0.01)；各给药组小鼠肝组织病理变化均得到不同程度好转。结论：SALD对APAP诱导的肝损伤具有保护作用；其机制可能与促进Keap1、Nrf2入核，增强肝组织中NO-1、NQO1和GCLC蛋白表达有关。
关键词 红景天苷；对乙酰氨基酚；肝损伤；小鼠；Kelch样环氧氯丙烷相关蛋1；核转录因子NF-E2相关因子
Effects of Salidroside on Keap1-Nrf2 Signal Pathway in Acetaminophen-induced Liver Injury Model Mice
ZUO Wei，ZHANG Bo，MEI Dan(Dept. of Pharmacy/Union Translational Medicine Center， Peking Union Medical College Hospital， Chinese Academy of Medical Sciences， Beijing 100730， China)
ABSTRACT OBJECTIVE： To investigate the protection role and mechanisms of salidroside (SALD) on acetaminophen (APAP)-induced liver injury model mice. METHODS： 60 mice were randomly divided into normal group (normal saline)， model group (normal saline)， positive group (acetylcysteine， 150 mg/kg)， SALD low-dose， medium-dose and high-dose groups (100， 200， 300 mg/kg)， with 10 mice in each group. Except for normal group， other groups were given APAP 500 mg/kg intragastrically to induce liver injury model. 1 h before modeling， mice were given relevant medicine intrgastrically for consecutive 5 d. After medication， the serum contents of ALT， AST， ALP and LDH were determined， and the pathohistological changes of the liver tissue were observed by HE staining. The protein expressions of Keap1 (in tranuclear)， Nrf2 (in tranuclear)， HO-1 (in tracytoplasm)， NQO1 (in tracytoplasm) and GCLC (in tracytoplasm) in liver tissue were determined by Western blot assay. RESULTS： Compared with normal group， serum contents of ALT， AST， ALP and LDH in model group were increased significantly (P<0.01). The liver lobuli hepatis disorder and difficult to recognize， liver cell eosinophilic necrosis and other lesions were found in liver tissue. The protein expressions of Nrf2， Keap1， HO-1 and GCLC in liver tissue were decreased significantly (P<0.05). Compared with model group， above indexes of all groups were improved significantly (P<0.05 or P<0.01)， except that the decrease of LDH content in serum of mice in SALD low-dose group and the expression improvement of Nrf2 and Keap1 in liver tissue were not significant in positive group. The expression of NQO1 protein in liver tissue of mice was increased significantly in administration groups (P<0.05 or P<0.01)； pathohistological exchange of liver tissue in mice was improved in adminstration groups to different extent. CONCLUSIONS： SALD can protect APAP-induced liver injury； the mechanism of which may be associated with promoting Keap1， Nrf2 into the of nucleu and strengthening the protein expression HO-1， NQO1， GCLC in liver tissue., 百拇医药(左玮 张波 梅丹)
DOI 10.6039/j.issn.1001-0408.2018.11.12
摘 要 目的：探讨红景天苷(SALD)对对乙酰氨基酚(APAP)诱导肝脏损伤模型小鼠的保护作用及机制。方法：将60只小鼠随机分为正常组(生理盐水)、模型组(生理盐水)、阳性组(乙酰半胱氨酸，150 mg/kg)和SALD低、中、高剂量组(100、200、300 mg/kg)，每组10只。除正常组外，其余各组小鼠均灌胃500 mg/kg的APAP复制肝损伤模型。造模前1 h，各组小鼠灌胃相应药物，连续5 d。给药结束后，测定小鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、乳酸脱氢酶(LDH)含量，苏木精-伊红(HE)染色观察肝组织病理学改变，Western blot法检测肝组织中Kelch样环氧氯丙烷相关蛋白1(Keap1)(细胞核内)、核转录因子NF-E2相关因子(Nrf2)(细胞核内)、血红素氧合酶1(HO-1)(细胞质中)、还原型辅酶/醌氧化还原酶(NQO1)(细胞质中)以及谷氨酸半胱氨酸连接酶(GCLC)(细胞质中)蛋白表达。结果：与正常组比较，模型组小鼠血清中ALT、AST、ALP和LDH含量显著增加(P<0.01)，肝组织发生肝小叶结构紊乱辨别不清、肝细胞嗜酸性坏死等病变，肝组织中Nrf2、Keap1、HO-1、GCLC蛋白表达水平显著降低(P<0.05)。与模型组比较，除SALD低剂量组小鼠血清中LDH含量减少和阳性组小鼠肝组织中Nrf2、Keap1表达水平升高不显著外，其余各组小鼠上述指标均显著改善(P<0.05或P<0.01)，且各给药组小鼠肝组织中NQO1蛋白表达水平均显著升高(P<0.05或P<0.01)；各给药组小鼠肝组织病理变化均得到不同程度好转。结论：SALD对APAP诱导的肝损伤具有保护作用；其机制可能与促进Keap1、Nrf2入核，增强肝组织中NO-1、NQO1和GCLC蛋白表达有关。
关键词 红景天苷；对乙酰氨基酚；肝损伤；小鼠；Kelch样环氧氯丙烷相关蛋1；核转录因子NF-E2相关因子
Effects of Salidroside on Keap1-Nrf2 Signal Pathway in Acetaminophen-induced Liver Injury Model Mice
ZUO Wei，ZHANG Bo，MEI Dan(Dept. of Pharmacy/Union Translational Medicine Center， Peking Union Medical College Hospital， Chinese Academy of Medical Sciences， Beijing 100730， China)
ABSTRACT OBJECTIVE： To investigate the protection role and mechanisms of salidroside (SALD) on acetaminophen (APAP)-induced liver injury model mice. METHODS： 60 mice were randomly divided into normal group (normal saline)， model group (normal saline)， positive group (acetylcysteine， 150 mg/kg)， SALD low-dose， medium-dose and high-dose groups (100， 200， 300 mg/kg)， with 10 mice in each group. Except for normal group， other groups were given APAP 500 mg/kg intragastrically to induce liver injury model. 1 h before modeling， mice were given relevant medicine intrgastrically for consecutive 5 d. After medication， the serum contents of ALT， AST， ALP and LDH were determined， and the pathohistological changes of the liver tissue were observed by HE staining. The protein expressions of Keap1 (in tranuclear)， Nrf2 (in tranuclear)， HO-1 (in tracytoplasm)， NQO1 (in tracytoplasm) and GCLC (in tracytoplasm) in liver tissue were determined by Western blot assay. RESULTS： Compared with normal group， serum contents of ALT， AST， ALP and LDH in model group were increased significantly (P<0.01). The liver lobuli hepatis disorder and difficult to recognize， liver cell eosinophilic necrosis and other lesions were found in liver tissue. The protein expressions of Nrf2， Keap1， HO-1 and GCLC in liver tissue were decreased significantly (P<0.05). Compared with model group， above indexes of all groups were improved significantly (P<0.05 or P<0.01)， except that the decrease of LDH content in serum of mice in SALD low-dose group and the expression improvement of Nrf2 and Keap1 in liver tissue were not significant in positive group. The expression of NQO1 protein in liver tissue of mice was increased significantly in administration groups (P<0.05 or P<0.01)； pathohistological exchange of liver tissue in mice was improved in adminstration groups to different extent. CONCLUSIONS： SALD can protect APAP-induced liver injury； the mechanism of which may be associated with promoting Keap1， Nrf2 into the of nucleu and strengthening the protein expression HO-1， NQO1， GCLC in liver tissue., 百拇医药(左玮 张波 梅丹)
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