贯叶连翘提取物对甲型流感病毒的作用及免疫调节机制的研究
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摘要
金丝桃素和金丝桃苷是贯叶连翘提取物中最主要有效成分,药理实验证明具有抗病毒、抗肿瘤、抗抑郁、抗炎、抗氧化以及提高免疫功能等作用。本文分别进行了贯叶连翘提取物的制备、其有效成分金丝桃素和金丝桃苷的定性及定量的研究;贯叶连翘提取物抗甲型流感病毒的体内外试验研究;在此基础上,从病理形态学、抗氧化能力、免疫功能以及免疫炎症相关因子的分泌情况来探讨贯叶连翘提取物对流感病毒感染小鼠的抗病毒机制。
采用薄层色谱法进行贯叶连翘提取物中主要药物成分金丝桃素和金丝桃苷的定性研究,并应用高效液相色谱法进行上述成分的定量研究。试验结果表明:贯叶连翘提取物中金丝桃素含量为1.45 %,金丝桃苷含量为4.72 %。
以细胞存活率和抑制率为指标,采用噻唑蓝(MTT)比色法检测贯叶连翘提取物体外对甲型流感病毒活性的抑制效应;并通过其对甲型流感病毒在MDCK细胞中增殖的影响来评价贯叶连翘提取物体外对甲型流感病毒的作用效果。试验结果表明:最大无毒浓度范围内,贯叶连翘提取物体外对甲型流感病毒直接灭活作用不明显,与达菲对照组相比差异显著(P<0.01,P<0.05);对甲型流感病毒感染细胞的阻断作用和对已进入细胞的甲型流感病毒的抑制作用明显,与病毒对照组比较差异极显著(P<0.01),与达菲药物对照组相比差异不显著(P>0.05),且抗病毒效果与药物浓度(12.5μg/mL -100μg/mL)呈剂量依赖关系;不同浓度的贯叶连翘提取物均能使甲型流感病毒的TCID50降低,最大可使TCID50由4.6降低到3.5。
体内试验应用鼻腔感染流感病毒,复制流感病毒小鼠模型4小时后,分别灌胃给药(贯叶连翘提取物高剂量组100 mg·kg-1、低剂量组50 mg·kg-1和利巴韦林组10 mg·kg-1),0.2 mL/次,2次/d,连续5 d。通过观察其对流感病毒感染小鼠的死亡保护作用、肺指数及肺组织病毒血凝滴度的影响,从整体水平上考察贯叶连翘提取物抗甲型流感病毒的作用效果。为进一步探讨此提取物对甲型流感病毒治疗效果的机制,本实验又对病毒性肺炎标本进行病理形态学观察,测定小鼠脾脏指数、胸腺指数的改变,初步探讨其作用机制;采用黄嘌呤氧化酶法和硫代巴比妥酸(TBA)比色分析法,通过小鼠肺组织中MDA和SOD的改变,观察贯叶连翘提取物对流感病毒感染小鼠的清除氧自由基及抗氧化的能力;通过MTT比色法,测定其对流感病毒感染小鼠脾淋巴细胞增殖功能的改变,从细胞水平探讨其作用机制;采用ELISA法和RT-PCR法,于贯叶连翘提取物干预后第3、5天动态观察肺组织和血清中细胞因子IL-6、IL-10、TNF-α及IFN-γ的蛋白表达及其第5天以上各细胞因子mRNA在肺组织中的转录水平的变化,进一步探讨贯叶连翘提取物抗流感病毒的作用机制。
研究结果表明:感染模型组的小鼠死亡率为80 %,生存时间为8.8天;而高、低剂量贯叶连翘提取物的小鼠死亡率分别为40 %和50 %,生存时间分别为12.1天和11.3天,与感染模型组相比有统计学意义(P<0.05,P<0.01),说明贯叶连翘提取物可降低流感病毒感染小鼠的病死率,延长存活时间;感染模型组与正常空白组相比,小鼠的肺指数增加,肺组织的病毒血凝滴度上升,肺组织显示病毒性肺炎的改变;贯叶连翘提取物治疗后,小鼠肺指数和病毒血凝滴度明显下降(P<0.05,P<0.01),病毒性肺炎的病变较模型组明显减轻,感染模型组肺脏大体病变呈实变,出血等病灶;光镜下呈重度间质性肺炎病变,而贯叶连翘提取物组与感染模型组相比,肺泡间隔较薄,肺泡壁和细支气管壁单核细胞浸润数量较少,腔内无渗出,病变明显减轻;流感病毒感染小鼠后肺组织SOD降低,MDA升高明显,与正常空白组比较,P<0.01,差异极显著;贯叶连翘提取物干预后,小鼠肺组织SOD升高,MDA降低,与感染模型组比较,P<0.01,有显著性差异;而利巴韦林组与感染模型组相比,P<0.05,差异显著;感染模型组的脾脏指数和胸腺指数均较正常空白组下降,P<0.01,而贯叶连翘提取物组的胸腺指数较模型组升高,P<0.01,有显著性差异,脾脏指数与模型对照比较无统计学意义(P>0.05);感染模型组T、B淋巴细胞的增殖功能较正常空白组下降,P<0.01,贯叶连翘提取物促进了T、B淋巴细胞的增殖,与感染模型组比较,P<0.01,差异显著;感染模型组肺组织和血清中IL-6和TNF-α的蛋白表达在两时间点均较正常空白组有所升高,两组比较,差异显著(P<0.01,P<0.05);IFN-γ和IL-10的蛋白表达在两时间点均较正常空白组下降,两组比较,差异极显著(P<0.01)。灌服贯叶连翘提取物后,小鼠肺组织和血清中IL-6和TNF-α蛋白含量下降,仅第5天的与感染模型组相比,P<0.05,有显著性差异;IFN-γ和IL-10的蛋白表达升高,两组比较,差异显著(P<0.05,P<0.01);观察以上细胞因子在第5天时mRNA转录情况,IL-6、TNF-α、IL-10及IFN-γ的mRNA转录与其蛋白表达趋势一致。
综上所述,贯叶连翘提取物通过降低小鼠肺组织中MDA的含量减轻了流感病毒感染小鼠肺组织脂质过氧化所致的肺损伤,提高SOD活力来增强了抗氧自由基的能力;通过提高胸腺指数和淋巴细胞增殖,提高了流感病毒感染小鼠的免疫功能;通过抑制促炎性细胞因子的分泌,提高抗炎性细胞因子的分泌,控制了炎症反应,进而起到抗流感病毒感染造成的免疫损伤。
Hypericin and hyperoside are the major effective components in Hypericum perforatum L. Extract (HPE). The pharmacological experiments showed that they had the effects of anti-viral, anti-tumor, anti-depression, anti-inflammation, anti-oxidation and raise immune function. The studies on preparation of Hypericum perforatum L. extract, determine of qualitation and quantitation of hypericin and hyperoside. Anti-viral effects of HPE against influenza A virus (IAV) in vitro and in vivo were carried out respectively in this paper. Anti-viral mechanism was approached according to pathomorphism, anti-oxidation, immune function and secretion of immune-inflammation correlation factor.
Thin-layer chromatography (TLC) was used to detect effective components qualitatively in HPE. High performance liquid chromatography (HPLC) was applied to detect the content of hypericin and hyperoside in HPE. The experiment results showed that the content of hypericin was 1.45 % and hyperoside was 4.72 %.
Cell survival rate and inhibition rate were served as target to evaluate antiviral activity of HPE against IAV in vitro by method thiazolyl tetrazolium (MTT) and the influence of HPE against proliferation of IAV in MDCK cell. The experiment results indicated that within the scope of biggest nontoxic concentration, the effect of HPE in deactivating IAV is not obvious as compared with oseltamivir and the difference was significan(tP<0.01,P<0.05). But the effects of preventing IAV from adsorbing target cell and inhibiting its replication were obvious as compared with the virus control and differences were significant(P<0.01,P<0.05). The anti-viral effect was dose-dependent with drug concentrations (12.5μg/mL -100μg/mL). HPE could decrease maximally the TCID50 of IAV from 4.6 to 3.5.
This study was performed to investigate anti-viral effect of HPE by mouse model in whole level. Mice were infected with IAV through nasal cavity to make model mice. After 4 hours, mice infected with IAV were treated with HPE 100 mg·kg-1, HPE 50 mg·kg -1 and ribavirin 10 mg·kg-1 respectively by mouth for 5 days, twice daily. The major criteria for evaluating the effects of HPE on mice infected with IAV in whole level including influence on the mortality rate, life-prolong rate of mice, lung index and the change of viral pneumonia. Pathomorphology of the lung tissue, spleen index and thymus index of mice were observed to approach further the mechanism of HPE on mice infected with IAV. The changes of SOD and MDA in lung tissues were detected by XO and TBA colorimetric analysis antigenic to observe the effect of removing free radicle and anti-oxidation of HPE. The change of T, B leukomonocyte cells multiplication were determined by MTT in order to understand the mechanism of HPE on mice infected with IAV in cellular level. The contents of cytokine IL-6, IL-10, TNF-αand IFN-γin the lung tissues and serum were observed dynamically in two phases (the third day and the fifth day) using ELISA to research on the influence of HPE. And their mRNA in the lung tissue (the fifth day) were observed by RT-PCR to probe further into mechanism of action of HPE.
The research results showed that the death rate of infectious model group was 80 %, survival time was 8.8 days. But the death rate of two HPE groups were respectively 40 % and 50 %, survival time were 12.1 and 11.3 days. There were significant differences as compared with the infectious model group(P<0.01,P<0.05).Therefore HPE could decrease the mortality rate and prolong life-time of the mice infected with IAV. The lung index and virus hemagglutinin titre of the infectious model group were increaser than those of the normal group. The lung index and virus hemagglutinin titre of HPE groups decreased and the change of viral pneumonia lessened as compared with the infectious model group (P<0.05,P<0.01).The lung pathohistology results showed that the lungs were consolidation, bleed and the changes of interstitial pneumonia in the infectious model group by microscope. But the catabatic interstitial pneumonia were showed in two HPE groups, alveolar septum were thinner and the number of mononuclear cell was less in alveolar and bronchiole wall than those of the infectious model group. The content of SOD and MDA in the infectious model group decreased and increased respectively than those of the normal group (P<0.01). But the content of SOD and MDA in the HPE groups increased and decreased respectively than those of the infectious model group (P<0.01). The spleen index and thymus index of the infectious model group lowered than those of the normal group ( P<0.01). But the thymus of HPE increaser than those of the infectious model group ( P<0.01). T, B leukomonocyte cells multiplication function of the infectious model group were decreased as compared with the normal group (P<0.01). T, B leukomonocyte cell multiplication function of the HPE groups were increased as compared with the infectious model group (P<0.01). The contents of cytokines IL-6 and TNF-αof the lung tissues and serum in infectious model group in two phases were higher than those of the normal group and the differences were significant (P<0.05,P<0.01). But the contents of cytokines IFN-γand IL-10 of lung tissues in infectious model group in two phases were lower than those of the normal group and the difference were significant(P<0.05,P<0.01). The amounts of protein expression of IL-6 and TNF-αof HPE groups decreased and the differences were only significant on the fifth day (P<0.05). The content of IFN-γand IL-10 of HPE groups were decreased and the difference were significant (P<0.05,P<0.01) as compared with those of the infectious model group. As for the mRNA transcription level of IL-6, IL-10, TNF-αand IFN-γon the fifth day shared the same tendency as their protein expression.
To sum up, HPE could lessen the lung damage caused by the lung tissues lipid peroxidation and strengthen anti-oxidation through raising the content of SOD and decreasing the content of MDA. It could improve the immune function of mice infected with IAV by improving the thymus index and the multiplication of lymphocytes. It could hold the inflammatory reaction under control by inhibiting the secretion of pro-inflammatory cytokines and promoting that of anti-inflammatory factors, so it could recover the immune damage caused by IAV.
采用薄层色谱法进行贯叶连翘提取物中主要药物成分金丝桃素和金丝桃苷的定性研究,并应用高效液相色谱法进行上述成分的定量研究。试验结果表明:贯叶连翘提取物中金丝桃素含量为1.45 %,金丝桃苷含量为4.72 %。
以细胞存活率和抑制率为指标,采用噻唑蓝(MTT)比色法检测贯叶连翘提取物体外对甲型流感病毒活性的抑制效应;并通过其对甲型流感病毒在MDCK细胞中增殖的影响来评价贯叶连翘提取物体外对甲型流感病毒的作用效果。试验结果表明:最大无毒浓度范围内,贯叶连翘提取物体外对甲型流感病毒直接灭活作用不明显,与达菲对照组相比差异显著(P<0.01,P<0.05);对甲型流感病毒感染细胞的阻断作用和对已进入细胞的甲型流感病毒的抑制作用明显,与病毒对照组比较差异极显著(P<0.01),与达菲药物对照组相比差异不显著(P>0.05),且抗病毒效果与药物浓度(12.5μg/mL -100μg/mL)呈剂量依赖关系;不同浓度的贯叶连翘提取物均能使甲型流感病毒的TCID50降低,最大可使TCID50由4.6降低到3.5。
体内试验应用鼻腔感染流感病毒,复制流感病毒小鼠模型4小时后,分别灌胃给药(贯叶连翘提取物高剂量组100 mg·kg-1、低剂量组50 mg·kg-1和利巴韦林组10 mg·kg-1),0.2 mL/次,2次/d,连续5 d。通过观察其对流感病毒感染小鼠的死亡保护作用、肺指数及肺组织病毒血凝滴度的影响,从整体水平上考察贯叶连翘提取物抗甲型流感病毒的作用效果。为进一步探讨此提取物对甲型流感病毒治疗效果的机制,本实验又对病毒性肺炎标本进行病理形态学观察,测定小鼠脾脏指数、胸腺指数的改变,初步探讨其作用机制;采用黄嘌呤氧化酶法和硫代巴比妥酸(TBA)比色分析法,通过小鼠肺组织中MDA和SOD的改变,观察贯叶连翘提取物对流感病毒感染小鼠的清除氧自由基及抗氧化的能力;通过MTT比色法,测定其对流感病毒感染小鼠脾淋巴细胞增殖功能的改变,从细胞水平探讨其作用机制;采用ELISA法和RT-PCR法,于贯叶连翘提取物干预后第3、5天动态观察肺组织和血清中细胞因子IL-6、IL-10、TNF-α及IFN-γ的蛋白表达及其第5天以上各细胞因子mRNA在肺组织中的转录水平的变化,进一步探讨贯叶连翘提取物抗流感病毒的作用机制。
研究结果表明:感染模型组的小鼠死亡率为80 %,生存时间为8.8天;而高、低剂量贯叶连翘提取物的小鼠死亡率分别为40 %和50 %,生存时间分别为12.1天和11.3天,与感染模型组相比有统计学意义(P<0.05,P<0.01),说明贯叶连翘提取物可降低流感病毒感染小鼠的病死率,延长存活时间;感染模型组与正常空白组相比,小鼠的肺指数增加,肺组织的病毒血凝滴度上升,肺组织显示病毒性肺炎的改变;贯叶连翘提取物治疗后,小鼠肺指数和病毒血凝滴度明显下降(P<0.05,P<0.01),病毒性肺炎的病变较模型组明显减轻,感染模型组肺脏大体病变呈实变,出血等病灶;光镜下呈重度间质性肺炎病变,而贯叶连翘提取物组与感染模型组相比,肺泡间隔较薄,肺泡壁和细支气管壁单核细胞浸润数量较少,腔内无渗出,病变明显减轻;流感病毒感染小鼠后肺组织SOD降低,MDA升高明显,与正常空白组比较,P<0.01,差异极显著;贯叶连翘提取物干预后,小鼠肺组织SOD升高,MDA降低,与感染模型组比较,P<0.01,有显著性差异;而利巴韦林组与感染模型组相比,P<0.05,差异显著;感染模型组的脾脏指数和胸腺指数均较正常空白组下降,P<0.01,而贯叶连翘提取物组的胸腺指数较模型组升高,P<0.01,有显著性差异,脾脏指数与模型对照比较无统计学意义(P>0.05);感染模型组T、B淋巴细胞的增殖功能较正常空白组下降,P<0.01,贯叶连翘提取物促进了T、B淋巴细胞的增殖,与感染模型组比较,P<0.01,差异显著;感染模型组肺组织和血清中IL-6和TNF-α的蛋白表达在两时间点均较正常空白组有所升高,两组比较,差异显著(P<0.01,P<0.05);IFN-γ和IL-10的蛋白表达在两时间点均较正常空白组下降,两组比较,差异极显著(P<0.01)。灌服贯叶连翘提取物后,小鼠肺组织和血清中IL-6和TNF-α蛋白含量下降,仅第5天的与感染模型组相比,P<0.05,有显著性差异;IFN-γ和IL-10的蛋白表达升高,两组比较,差异显著(P<0.05,P<0.01);观察以上细胞因子在第5天时mRNA转录情况,IL-6、TNF-α、IL-10及IFN-γ的mRNA转录与其蛋白表达趋势一致。
综上所述,贯叶连翘提取物通过降低小鼠肺组织中MDA的含量减轻了流感病毒感染小鼠肺组织脂质过氧化所致的肺损伤,提高SOD活力来增强了抗氧自由基的能力;通过提高胸腺指数和淋巴细胞增殖,提高了流感病毒感染小鼠的免疫功能;通过抑制促炎性细胞因子的分泌,提高抗炎性细胞因子的分泌,控制了炎症反应,进而起到抗流感病毒感染造成的免疫损伤。
Hypericin and hyperoside are the major effective components in Hypericum perforatum L. Extract (HPE). The pharmacological experiments showed that they had the effects of anti-viral, anti-tumor, anti-depression, anti-inflammation, anti-oxidation and raise immune function. The studies on preparation of Hypericum perforatum L. extract, determine of qualitation and quantitation of hypericin and hyperoside. Anti-viral effects of HPE against influenza A virus (IAV) in vitro and in vivo were carried out respectively in this paper. Anti-viral mechanism was approached according to pathomorphism, anti-oxidation, immune function and secretion of immune-inflammation correlation factor.
Thin-layer chromatography (TLC) was used to detect effective components qualitatively in HPE. High performance liquid chromatography (HPLC) was applied to detect the content of hypericin and hyperoside in HPE. The experiment results showed that the content of hypericin was 1.45 % and hyperoside was 4.72 %.
Cell survival rate and inhibition rate were served as target to evaluate antiviral activity of HPE against IAV in vitro by method thiazolyl tetrazolium (MTT) and the influence of HPE against proliferation of IAV in MDCK cell. The experiment results indicated that within the scope of biggest nontoxic concentration, the effect of HPE in deactivating IAV is not obvious as compared with oseltamivir and the difference was significan(tP<0.01,P<0.05). But the effects of preventing IAV from adsorbing target cell and inhibiting its replication were obvious as compared with the virus control and differences were significant(P<0.01,P<0.05). The anti-viral effect was dose-dependent with drug concentrations (12.5μg/mL -100μg/mL). HPE could decrease maximally the TCID50 of IAV from 4.6 to 3.5.
This study was performed to investigate anti-viral effect of HPE by mouse model in whole level. Mice were infected with IAV through nasal cavity to make model mice. After 4 hours, mice infected with IAV were treated with HPE 100 mg·kg-1, HPE 50 mg·kg -1 and ribavirin 10 mg·kg-1 respectively by mouth for 5 days, twice daily. The major criteria for evaluating the effects of HPE on mice infected with IAV in whole level including influence on the mortality rate, life-prolong rate of mice, lung index and the change of viral pneumonia. Pathomorphology of the lung tissue, spleen index and thymus index of mice were observed to approach further the mechanism of HPE on mice infected with IAV. The changes of SOD and MDA in lung tissues were detected by XO and TBA colorimetric analysis antigenic to observe the effect of removing free radicle and anti-oxidation of HPE. The change of T, B leukomonocyte cells multiplication were determined by MTT in order to understand the mechanism of HPE on mice infected with IAV in cellular level. The contents of cytokine IL-6, IL-10, TNF-αand IFN-γin the lung tissues and serum were observed dynamically in two phases (the third day and the fifth day) using ELISA to research on the influence of HPE. And their mRNA in the lung tissue (the fifth day) were observed by RT-PCR to probe further into mechanism of action of HPE.
The research results showed that the death rate of infectious model group was 80 %, survival time was 8.8 days. But the death rate of two HPE groups were respectively 40 % and 50 %, survival time were 12.1 and 11.3 days. There were significant differences as compared with the infectious model group(P<0.01,P<0.05).Therefore HPE could decrease the mortality rate and prolong life-time of the mice infected with IAV. The lung index and virus hemagglutinin titre of the infectious model group were increaser than those of the normal group. The lung index and virus hemagglutinin titre of HPE groups decreased and the change of viral pneumonia lessened as compared with the infectious model group (P<0.05,P<0.01).The lung pathohistology results showed that the lungs were consolidation, bleed and the changes of interstitial pneumonia in the infectious model group by microscope. But the catabatic interstitial pneumonia were showed in two HPE groups, alveolar septum were thinner and the number of mononuclear cell was less in alveolar and bronchiole wall than those of the infectious model group. The content of SOD and MDA in the infectious model group decreased and increased respectively than those of the normal group (P<0.01). But the content of SOD and MDA in the HPE groups increased and decreased respectively than those of the infectious model group (P<0.01). The spleen index and thymus index of the infectious model group lowered than those of the normal group ( P<0.01). But the thymus of HPE increaser than those of the infectious model group ( P<0.01). T, B leukomonocyte cells multiplication function of the infectious model group were decreased as compared with the normal group (P<0.01). T, B leukomonocyte cell multiplication function of the HPE groups were increased as compared with the infectious model group (P<0.01). The contents of cytokines IL-6 and TNF-αof the lung tissues and serum in infectious model group in two phases were higher than those of the normal group and the differences were significant (P<0.05,P<0.01). But the contents of cytokines IFN-γand IL-10 of lung tissues in infectious model group in two phases were lower than those of the normal group and the difference were significant(P<0.05,P<0.01). The amounts of protein expression of IL-6 and TNF-αof HPE groups decreased and the differences were only significant on the fifth day (P<0.05). The content of IFN-γand IL-10 of HPE groups were decreased and the difference were significant (P<0.05,P<0.01) as compared with those of the infectious model group. As for the mRNA transcription level of IL-6, IL-10, TNF-αand IFN-γon the fifth day shared the same tendency as their protein expression.
To sum up, HPE could lessen the lung damage caused by the lung tissues lipid peroxidation and strengthen anti-oxidation through raising the content of SOD and decreasing the content of MDA. It could improve the immune function of mice infected with IAV by improving the thymus index and the multiplication of lymphocytes. It could hold the inflammatory reaction under control by inhibiting the secretion of pro-inflammatory cytokines and promoting that of anti-inflammatory factors, so it could recover the immune damage caused by IAV.
引文
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