橙皮苷对小鼠免疫性肝损伤的保护作用及部分作用机制研究
摘要
本文采用了免疫性小鼠肝损伤模型,分别从免疫调节和细胞因子水平变化的角度,研究分析了橙皮苷对免疫性肝损伤保护作用的部分机制。
目的研究HDN对ConA诱导的小鼠免疫性肝损伤的保护作用及部分作用机制研究。
方法:采用尾静脉一次性注射给予一定剂量的ConA(20mg/kg),诱导小鼠免疫性肝损伤模型,造模8h后采血,并处死动物,剖腹取肝,制备肝匀浆。称量肝脏重量并计算脏器指数;测定不同剂量的橙皮苷对肝损伤血清中ALT、AST活性、白细胞介素-1(IL-1)、干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)的含量、肝匀浆中ALT、AST活性、丙二醛(MDA)、谷胱甘肽(GSH)、一氧化氮(NO)的含量及超氧化物歧化酶( SOD)活性的影响;RT-PCR检测肝脏中TNF-αmRNA表达水平;同时对肝组织进行病理学检查查并进行病理学分级;免疫组化法检测橙皮苷对小鼠肝细胞中α-SMA、NF-κB p65表达的影响。
结果HDN能降低小鼠免疫性肝损伤血清ALT、AST、TNF-α、IFN-γ和IL-1的水平,降低肝匀浆中ALT、AST、MDA、NO的含量,升高GSH的含量增强SOD的活性,RT-PCR法显示HDN能显著降低模型小鼠肝匀浆中TNF-α水平,从而达到保护肝脏的目的,同时HDN减轻ConA对肝组织的病理损伤,抑制ConA引起的肝脏α-SMA、NF-κB p65的过度表达,从而保护肝脏。
结论HDN对ConA致小鼠免疫性肝损伤具有一定的保护作用,其机制可能与他清除自由基,增强机体抗脂质过氧化能力及降低IL-1、TNF-α和IFN-γ等炎性细胞因子的表达有关。
The essay used the immune hepatic injury models. It investigated the mechanism of its protective effect on immune hepatic injury from modulation of immunological function and the levels of cytokines production .
Objective To study the protective effect of hesperidin against immune hepatic injury induced by concanavalin A in Mice and its mechanism..
Methods All groups were injected with ConA once again with ConA (20mg/kg) from tail vein in order to induce immune hepatic injury except the mice in normal group. Animals were sacrificed at the 8th hour and blood was collected, the liver was harvested for liver homogenate. Index of liver were tested.The levels of ALT, AST, IL-1, IFN-γand TNF-αin serum, the contents of MDA, SOD, NO and GSH in liver homogenate were measured. the levels of TNF-αmRNA expression in liver were tested by reverse transcription polymerase chainreaztion(RT-PCR).Histopathlogical examination was observed. TNF-αand NF-κB p65 in hepatic tissues were determined by the method of immunohistochemistry,
Results Compared with that of model group, the levels of ALT, AST, MDA, NO, IL-1, IFN-γand TNF-αwere significantly lowered by hesperidin whereas the levels of SOD and GSH were markedly increased by hesperidin and the hepatic pathological features were improved. Hesperidin could inhibit the expression of TNF-αand NF-κB p65 and TNF-αmRNA in liver tissue.
Conclusion Hesperidin is effective in protecting hepatic lesions in mice induced by ConA. It is possibity related to removing free radicals, enhancing the antioxidant capacity of lipid peroxidation and reducing the levels of IL-1, TNF-αand IFN-γ.
目的研究HDN对ConA诱导的小鼠免疫性肝损伤的保护作用及部分作用机制研究。
方法:采用尾静脉一次性注射给予一定剂量的ConA(20mg/kg),诱导小鼠免疫性肝损伤模型,造模8h后采血,并处死动物,剖腹取肝,制备肝匀浆。称量肝脏重量并计算脏器指数;测定不同剂量的橙皮苷对肝损伤血清中ALT、AST活性、白细胞介素-1(IL-1)、干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)的含量、肝匀浆中ALT、AST活性、丙二醛(MDA)、谷胱甘肽(GSH)、一氧化氮(NO)的含量及超氧化物歧化酶( SOD)活性的影响;RT-PCR检测肝脏中TNF-αmRNA表达水平;同时对肝组织进行病理学检查查并进行病理学分级;免疫组化法检测橙皮苷对小鼠肝细胞中α-SMA、NF-κB p65表达的影响。
结果HDN能降低小鼠免疫性肝损伤血清ALT、AST、TNF-α、IFN-γ和IL-1的水平,降低肝匀浆中ALT、AST、MDA、NO的含量,升高GSH的含量增强SOD的活性,RT-PCR法显示HDN能显著降低模型小鼠肝匀浆中TNF-α水平,从而达到保护肝脏的目的,同时HDN减轻ConA对肝组织的病理损伤,抑制ConA引起的肝脏α-SMA、NF-κB p65的过度表达,从而保护肝脏。
结论HDN对ConA致小鼠免疫性肝损伤具有一定的保护作用,其机制可能与他清除自由基,增强机体抗脂质过氧化能力及降低IL-1、TNF-α和IFN-γ等炎性细胞因子的表达有关。
The essay used the immune hepatic injury models. It investigated the mechanism of its protective effect on immune hepatic injury from modulation of immunological function and the levels of cytokines production .
Objective To study the protective effect of hesperidin against immune hepatic injury induced by concanavalin A in Mice and its mechanism..
Methods All groups were injected with ConA once again with ConA (20mg/kg) from tail vein in order to induce immune hepatic injury except the mice in normal group. Animals were sacrificed at the 8th hour and blood was collected, the liver was harvested for liver homogenate. Index of liver were tested.The levels of ALT, AST, IL-1, IFN-γand TNF-αin serum, the contents of MDA, SOD, NO and GSH in liver homogenate were measured. the levels of TNF-αmRNA expression in liver were tested by reverse transcription polymerase chainreaztion(RT-PCR).Histopathlogical examination was observed. TNF-αand NF-κB p65 in hepatic tissues were determined by the method of immunohistochemistry,
Results Compared with that of model group, the levels of ALT, AST, MDA, NO, IL-1, IFN-γand TNF-αwere significantly lowered by hesperidin whereas the levels of SOD and GSH were markedly increased by hesperidin and the hepatic pathological features were improved. Hesperidin could inhibit the expression of TNF-αand NF-κB p65 and TNF-αmRNA in liver tissue.
Conclusion Hesperidin is effective in protecting hepatic lesions in mice induced by ConA. It is possibity related to removing free radicals, enhancing the antioxidant capacity of lipid peroxidation and reducing the levels of IL-1, TNF-αand IFN-γ.
引文
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10.张玲,李俊,王建青,等.野菊花总黄酮对四氯化碳致急性肝损伤小鼠的保护作用[J].安徽医科大学学报,2007,42(4):412-4.
11.陈诗慧,黄俊婷.加味四逆散对刀豆蛋白A所致免疫性肝损伤的保护作用[J].中国热带医学,2007,7(5):700-1.
12.鲁玉辉,符林春.叶下珠复方对刀豆蛋白A所致免疫性肝损伤小鼠的保护作用[J].光明中医,2007,22(4):76-9.
13.张秀明,陈科力,李翰明,等.蛇葡萄根的抗肝降酶及抗自由基损伤作用[J].中国药师,1999,2(5):225-8.
14.汪晓军,张奉学,朱宇同,等.黄芩苷对刀豆蛋白A致肝损伤小鼠肝组织NO含量的影响[J].中西医结合肝病杂志,2006,16(2):93-5.
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2. Wilmsen PK,Spada DS,SalvadorM.Antioxidant activity of the flavonoid hesperidin in chemical and biological systems[J]. Agric Food Chem,2005, 53(12):4757-61.
3. Garg A. Chemistry and pharmacology of the citrus bioflavonoid hesperidin[J]. PhytotherRes, 2001,15(2):655.
4. Yeh CC,Kao SJ,Lin CC,et al.The immunomodulation of endotoxin-induced acute lung injury by hesperidin in vivo and in vitro[J]. Life Sciences, 2007,80(20):1821-31.
5. Naveen Tirkey,Sangeeta Pilkhwal,Anurag Kuhad,etal.Hesperidin,a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney[J]. BMC Pharmacology ,2005, 5(2):1-8.
6. Gaganjit Kaur, Naveen Tirkey, Kanwaljit Chopra. Beneficial effect of hesperidin on lipopolysaccharide-induced hepatotoxicity [J]. Toxicology,2006,(2-3):152-60.
7. Cantner F,Leist M,Lohse AW,et al.ConcanavalinA induced T-cell-mediated hepatic injury in mice:the role of tumormecrosisfactor [J].Hepatology, 1995, 21:190-8.
8. Sabine K,Florian G,Gerald K,et al.Interferon gamma plays a critical role in T cell-dependent liver injury in mice initiated by concanavalin A[J]. Castroenterology,1996,111(2):462-71.
9.谭友文,吴建成. IL-18及IL-18抗体对刀豆蛋白A所致急性肝损伤的作用[J].江苏医药,2007,33(4):392-3.
10.张玲,李俊,王建青,等.野菊花总黄酮对四氯化碳致急性肝损伤小鼠的保护作用[J].安徽医科大学学报,2007,42(4):412-4.
11.陈诗慧,黄俊婷.加味四逆散对刀豆蛋白A所致免疫性肝损伤的保护作用[J].中国热带医学,2007,7(5):700-1.
12.鲁玉辉,符林春.叶下珠复方对刀豆蛋白A所致免疫性肝损伤小鼠的保护作用[J].光明中医,2007,22(4):76-9.
13.张秀明,陈科力,李翰明,等.蛇葡萄根的抗肝降酶及抗自由基损伤作用[J].中国药师,1999,2(5):225-8.
14.汪晓军,张奉学,朱宇同,等.黄芩苷对刀豆蛋白A致肝损伤小鼠肝组织NO含量的影响[J].中西医结合肝病杂志,2006,16(2):93-5.
15. Zhao Y,Liu J,Wang J,et al.Fumigaclavine C improves concanavalin A induced liver injury in mice mainly via inhibiting TNF-alpha production and lymphocyte adhesion to extracellular matrices[J].J Pharm pharmacol,2004,56(6):775-82.
16.陈震,吕雄文,李俊,等.咖啡因对小鼠急性酒精性肝损伤的保护作用[J].安徽医科大学学报,2009,44(3):359-62.
17.吴皓,陈丽芳.干扰素的研究进展[J].河南农业科学,2004,12:77-9.
18.张晓岚,王占魁,姜慧卿.氧化应激与肝纤维化[J].临床肝胆病志,2007,23(3):226.
19. Buck M,Kim D J,Honglum K,et a1.C-myb modulates tranaeription of the alpha-smooth muscle actin gene in activated hepatic stllate cells[J].Am J Physiol Gastrointest Liver Phaiol, 2000,278(2):321.
20. Friedman SL.Molecular regulation of hepatic fibrosis,an integrated cellular response to tissue injury[J].j boil Chem,2000,275:2247-50.
21. Van Den Berg R,Haenen C R,Van Den Berg H,etal.Transcription factor NF-κB as a potential biomarker for oxidative stress[J].Br J Nutr,2001,86(suppl I):121-7.
22. Baldwin AS.Control of oncogenesis and cancer therapy resitance by the transcription Factor NF-κB [J].J Clin Invest,2001,107(3):241-246.
23.高立芬,孙汶生,刘君炎,等.刀豆蛋白A活化小鼠巨噬细胞机理的初步探讨[J].基础医学与临床,2003,23(6):661-5
1.邢杰,陈英利,陶淑华等.免疫性肝损伤相关细胞因子研究进展[J].中国病原生物学杂志,2009,4(1):71-2.
2. Higuehi H.Gores G J.Meclumisms of liver injury:An overview[J].current molecul medicine,2003,3:483-90.
3. Nakamoto Y,Kaneko S.Mechanisms of viral hepatitis induced liver injury[J]. Current molecular medicine,2003,3:537-44.
4. Tsutsui H,Adaehi K,Seki E , et a1.Cytokine-induced inflammatory liver injury[J].Current molecular medicine,2003,3:545-9.
5. Yin X M,Ding W X.Death receptor activation-induced hepatocyte apoptosis and liver injury[J].Current molecular medicine,2003,3:491-508.
6. Yin X M.Hot topic:Molecular mehanisnm of liver injury[J].Current molecularmedicine,2003,3:1.
7. Nakamoto Y,Kaneko S.Mechanmnm of Viral Hepatitis Induced liver injury[J]. Current molecular medicine,2003,3:537-44.
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