刺蒺藜总皂苷对雷公藤多苷所致急性肝损伤小鼠保护作用的研究
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摘要
【目的】探讨刺蒺藜总皂苷对雷公藤多苷所致小鼠急性肝损伤的保护作用及对肝细胞凋亡的影响。
【方法】昆明种清洁级小鼠60只,体重18-22g,随机分为6组,分别为空白对照组,模型组,甘利欣组,刺蒺藜总皂苷高、中、低剂量组,每组10只。造模前连续7天给小鼠灌胃,每天1次。高、中、低剂量组分别按1.36g/kg,0.68g/kg,0.34g/kg的剂量灌服刺蒺藜总皂苷溶液;甘利欣组灌服甘利欣混悬液(0.075g/kg);空白对照组和模型组灌服等体积的生理盐水。于第7天末次给药后禁食12h开始造模,除空白对照组外,其余各组均以0.27g/kg按0.2mL/10g体重雷公藤多苷混悬液灌胃1次,空白对照组给予等体积的生理盐水灌胃。给药后禁食18h处死。分别检测血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST),超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-Px),观察肝组织普通病理形态学变化和电镜下超微结构变化,并应用TUNEL法检测细胞凋亡,免疫组化方法检测Caspase-3的表达。
【结果】(1)肝功能变化:模型组小鼠血清ALT、AST活性显著升高;与模型组比较,刺蒺藜总皂苷各给药组小鼠转氨酶明显降低(P<0.05),以高、中剂量组最明显。(2)自由基脂质过氧化改变:模型组小鼠血清SOD、GSH-Px水平明显降低,MDA水平明显升高,与空白对照组比较有统计学意义(P<0.05),刺蒺藜总皂苷各给药组及甘利欣组能明显提高血清GSH-Px水平,降低MDA水平,其中刺蒺藜总皂苷高剂量组提高SOD、GSH-Px水平效果最好。(3)病理学变化:模型组小鼠肝组织病理学改变明显;与模型组比较,各给药组病理学改变减轻(P<0.05),以刺蒺藜总皂苷高剂量组减轻明显。(4)超微结构改变:模型组小鼠肝组织超微结构改变明显;刺蒺藜总皂苷各给药组小鼠超微结构改变较模型组减轻(P<0.05)。(5)细胞凋亡:模型组小鼠肝细胞凋亡程度严重,与空白对照组比较有统计学意义(P<0.05),刺蒺藜总皂苷各给药组及甘利欣组能明显减轻小鼠肝细胞凋亡程度。(6)Caspase-3表达:模型组小鼠肝组织Caspase-3表达高于空白对照组(P<0.05);各给药组均可降低其表达,与模型组比较有明显的差异(P<0.05),以刺蒺藜总皂苷高剂量组和甘利欣组效果最好。
【结论】(1)刺蒺藜总皂苷具有清热燥湿、疏肝理气、健脾和胃之功效,可有效防治药物性肝损伤(Drug-induced liver Injury,DILI)。(2)自由基脂质过氧化和细胞凋亡是雷公藤多苷诱导急性肝损伤的病理机制之一。(3)刺蒺藜总皂苷具有较好的抗雷公藤多苷诱导肝损伤模型的效果。(4)刺蒺藜总皂苷的保肝作用通过清除氧自由基、减轻脂质过氧化反应、抑制肝细胞凋亡、降低Caspase-3表达等环节实现。
Objective:To confirm the protectant mechanism of gross saponins from tribulus terrestrisl on mice induced acute hepatic injury by tripterygium glycosides,and explore its influence to the hepatic apoptosis.
Methods:60 mice of Kunming-strain were randomly divided into blank control group,positive group,model group,big-dosage,medium-dosage and small-dosage group of gross saponins from tribulus terrestrisl.Before establishing models,big-dosage, medium-dosage and small-dosage group were respectively perfused with the dosage of 1.36g/㎏ ,0.68g/㎏ and 0.34g/㎏ for successive 7 days. Positive group was administered by Ganlixin capsule with the dosage of 0.075g/kg. Simultaneously,blank control group and model group were given equivoluminal distilled water. 12 hours after the last dosage, all groups were perfused once to make model with the dosage of 0.27g/kg 0.2mL/10g of tripterygium glycosides except for blank control model. 18 hours after ,the 1evels of ALT ,AST,SOD,MDA and GSH-Px in the serum were measured and pathological morphology of the liver tissue under light microscope、liver cell ultrastucture under electronic microscope and liver cell apoptosis by using the method of TUNEL were observed. Caspase-3 were also observed by using the method of immunohistochemical method.
Results:(1) Hepatic function change: the level of ALT and AST in the serum of model group rised obviously . Compared with model group, each dosage of gross saponins from tribulus terrestrisl could reduce it obviously(P<0.05),especially in big-dosage and medium-dosage groups of gross saponins from tribulus terrestrisl; (2) Lipid peroxidation of free radical: Compared with blank control group ,SOD and GSH-Px in the model group decreased and MDA rised obviously(P<0.05) ,Compared with blank control group,each dosage of groups and Ganlixin group could obviously improve SOD and GSH-Px,reduce MDA in the serum, Big-dosage of gross saponins from tribulus terrestrisl was the most effective one; (3) Pathology change: Compared with model group,each dosage of groups could ameliorate the injured liver cells in different level(P<0.05). Big-dosage of gross saponins from tribulus terrestrisl was the most effective one; (4) Ultrastructure change: the ultrastucture of the liver cell of model group had obvious change, each dosage of groups could ameliorate the ultrastucture of the liver cell in different level(P<0.05). (5) Apoptosis: Compared with blank control group,the mice in model group appeared to be apoptosis of liver cell(P<0.05), each dosage of groups and Ganlixin showed great effect on restraining the apoptosis; (6) Caspase-3 expression: Compared with blank control group, the expression of Caspase-3 in the serum of model group increased obviously(P<0.05). Compared with model group,the expression of Caspase-3 could be degraded in each dosage of groups(P<0.05), Big-dosage of gross saponins from tribulus terrestrisl and Ganlixin groups were most obvious.
Conclusions: (1) Gross saponins from Tribulus terrestrisl has the effects of liminating pathologic heat,damp and detoxification,adjusting the liver and strengthening the spleen and stomach ,can effectively prevent and treat DILI. (2) Lipid peroxidation of free radical and apoptosis induced by tripterygium glycosides is one of the pathological mechanism of acute hepatic injury. (3) Gross saponins from Tribulus terrestrisl can ameliorate the injured liver cells in different levels. (4) The mechanism of its protective effective effect may be related to the antioxidant activity and the influence on regulate metabolism,as well as repressing apoptosis of the liver cells,effectively reduce the level of Caspase-3.
【方法】昆明种清洁级小鼠60只,体重18-22g,随机分为6组,分别为空白对照组,模型组,甘利欣组,刺蒺藜总皂苷高、中、低剂量组,每组10只。造模前连续7天给小鼠灌胃,每天1次。高、中、低剂量组分别按1.36g/kg,0.68g/kg,0.34g/kg的剂量灌服刺蒺藜总皂苷溶液;甘利欣组灌服甘利欣混悬液(0.075g/kg);空白对照组和模型组灌服等体积的生理盐水。于第7天末次给药后禁食12h开始造模,除空白对照组外,其余各组均以0.27g/kg按0.2mL/10g体重雷公藤多苷混悬液灌胃1次,空白对照组给予等体积的生理盐水灌胃。给药后禁食18h处死。分别检测血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST),超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GSH-Px),观察肝组织普通病理形态学变化和电镜下超微结构变化,并应用TUNEL法检测细胞凋亡,免疫组化方法检测Caspase-3的表达。
【结果】(1)肝功能变化:模型组小鼠血清ALT、AST活性显著升高;与模型组比较,刺蒺藜总皂苷各给药组小鼠转氨酶明显降低(P<0.05),以高、中剂量组最明显。(2)自由基脂质过氧化改变:模型组小鼠血清SOD、GSH-Px水平明显降低,MDA水平明显升高,与空白对照组比较有统计学意义(P<0.05),刺蒺藜总皂苷各给药组及甘利欣组能明显提高血清GSH-Px水平,降低MDA水平,其中刺蒺藜总皂苷高剂量组提高SOD、GSH-Px水平效果最好。(3)病理学变化:模型组小鼠肝组织病理学改变明显;与模型组比较,各给药组病理学改变减轻(P<0.05),以刺蒺藜总皂苷高剂量组减轻明显。(4)超微结构改变:模型组小鼠肝组织超微结构改变明显;刺蒺藜总皂苷各给药组小鼠超微结构改变较模型组减轻(P<0.05)。(5)细胞凋亡:模型组小鼠肝细胞凋亡程度严重,与空白对照组比较有统计学意义(P<0.05),刺蒺藜总皂苷各给药组及甘利欣组能明显减轻小鼠肝细胞凋亡程度。(6)Caspase-3表达:模型组小鼠肝组织Caspase-3表达高于空白对照组(P<0.05);各给药组均可降低其表达,与模型组比较有明显的差异(P<0.05),以刺蒺藜总皂苷高剂量组和甘利欣组效果最好。
【结论】(1)刺蒺藜总皂苷具有清热燥湿、疏肝理气、健脾和胃之功效,可有效防治药物性肝损伤(Drug-induced liver Injury,DILI)。(2)自由基脂质过氧化和细胞凋亡是雷公藤多苷诱导急性肝损伤的病理机制之一。(3)刺蒺藜总皂苷具有较好的抗雷公藤多苷诱导肝损伤模型的效果。(4)刺蒺藜总皂苷的保肝作用通过清除氧自由基、减轻脂质过氧化反应、抑制肝细胞凋亡、降低Caspase-3表达等环节实现。
Objective:To confirm the protectant mechanism of gross saponins from tribulus terrestrisl on mice induced acute hepatic injury by tripterygium glycosides,and explore its influence to the hepatic apoptosis.
Methods:60 mice of Kunming-strain were randomly divided into blank control group,positive group,model group,big-dosage,medium-dosage and small-dosage group of gross saponins from tribulus terrestrisl.Before establishing models,big-dosage, medium-dosage and small-dosage group were respectively perfused with the dosage of 1.36g/㎏ ,0.68g/㎏ and 0.34g/㎏ for successive 7 days. Positive group was administered by Ganlixin capsule with the dosage of 0.075g/kg. Simultaneously,blank control group and model group were given equivoluminal distilled water. 12 hours after the last dosage, all groups were perfused once to make model with the dosage of 0.27g/kg 0.2mL/10g of tripterygium glycosides except for blank control model. 18 hours after ,the 1evels of ALT ,AST,SOD,MDA and GSH-Px in the serum were measured and pathological morphology of the liver tissue under light microscope、liver cell ultrastucture under electronic microscope and liver cell apoptosis by using the method of TUNEL were observed. Caspase-3 were also observed by using the method of immunohistochemical method.
Results:(1) Hepatic function change: the level of ALT and AST in the serum of model group rised obviously . Compared with model group, each dosage of gross saponins from tribulus terrestrisl could reduce it obviously(P<0.05),especially in big-dosage and medium-dosage groups of gross saponins from tribulus terrestrisl; (2) Lipid peroxidation of free radical: Compared with blank control group ,SOD and GSH-Px in the model group decreased and MDA rised obviously(P<0.05) ,Compared with blank control group,each dosage of groups and Ganlixin group could obviously improve SOD and GSH-Px,reduce MDA in the serum, Big-dosage of gross saponins from tribulus terrestrisl was the most effective one; (3) Pathology change: Compared with model group,each dosage of groups could ameliorate the injured liver cells in different level(P<0.05). Big-dosage of gross saponins from tribulus terrestrisl was the most effective one; (4) Ultrastructure change: the ultrastucture of the liver cell of model group had obvious change, each dosage of groups could ameliorate the ultrastucture of the liver cell in different level(P<0.05). (5) Apoptosis: Compared with blank control group,the mice in model group appeared to be apoptosis of liver cell(P<0.05), each dosage of groups and Ganlixin showed great effect on restraining the apoptosis; (6) Caspase-3 expression: Compared with blank control group, the expression of Caspase-3 in the serum of model group increased obviously(P<0.05). Compared with model group,the expression of Caspase-3 could be degraded in each dosage of groups(P<0.05), Big-dosage of gross saponins from tribulus terrestrisl and Ganlixin groups were most obvious.
Conclusions: (1) Gross saponins from Tribulus terrestrisl has the effects of liminating pathologic heat,damp and detoxification,adjusting the liver and strengthening the spleen and stomach ,can effectively prevent and treat DILI. (2) Lipid peroxidation of free radical and apoptosis induced by tripterygium glycosides is one of the pathological mechanism of acute hepatic injury. (3) Gross saponins from Tribulus terrestrisl can ameliorate the injured liver cells in different levels. (4) The mechanism of its protective effective effect may be related to the antioxidant activity and the influence on regulate metabolism,as well as repressing apoptosis of the liver cells,effectively reduce the level of Caspase-3.
引文
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