鳖甲煎丸对糖尿病合并动脉粥样硬化大鼠作用的实验研究
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摘要
目的:通过观察鳖甲煎丸对糖尿病合并动脉粥样硬化病变模型的血脂、血糖、内皮因子、炎症因子及抗炎因子的影响,探讨其对糖尿病合并动脉粥样硬化病变的保护作用和防治机制。
方法:将造模成功后雄性SD大鼠随机分为模型组、通心络胶囊对照组(简称通心络组)、鳖甲煎丸低剂量组(简称鳖甲低组)、鳖甲煎丸高剂量组(简称鳖甲高组),另设同周龄SD大鼠作为空白对照组。五组实验动物,灌胃8周后,将大鼠用1%戊巴比妥钠腹腔麻醉后分离腹主动脉,抽取动脉血;取胰腺、胸主动脉、睾丸周围脂肪组织,按照试剂盒说明书要求及组织存放要求保存。检测①血脂:总胆固醇(TC)、甘油三酯(TG);②炎症因子:C-反应蛋白(CRP)、肿瘤坏死因子(TNF-α);③内皮因子:内皮素(ET)、一氧化氮(NO);④抗炎因子:血清脂联素(APN)、脂肪组织脂联素mRNA;⑤病理:HE染色观察胰腺及主动脉内膜动脉粥样硬化病变、免疫组化观察主动脉基质金属蛋白酶-9(MMP-9)。
结果:①对血脂、血糖的影响:实验过程中观察到模型大鼠高血糖无自然缓解现象;在治疗后大鼠血糖水平同治疗前及模型组相比较亦无下降(P>0.05);与空白组比较,模型组大鼠血清TC、TG水平明显升高(P<0.01),鳖甲煎丸高、低剂量组可以降低糖尿病合并动脉粥样硬化病变大鼠血清TG水平(P<0.01),且各治疗组之间没有明显差异;各治疗组对糖尿病合并动脉粥样硬化病变大鼠血清TC水平无明显影响。②对炎症因子的影响:与空白组比较,模型组CRP水平增高(P<0.05);与模型组比较,鳖甲煎丸高、低剂量组CRP水平均有下降(P<0.05);各治疗组组相比较CRP水平未见差异(P>0.05)。与空白组比较,模型组TNF-α水平有显著性差异(P<0.01);与模型组比较,通心络组与鳖甲高组有显著性差异(P<0.01);鳖甲低组有差异(P<0.05);通心络组、鳖甲低组、相比较TNF-α水平未见差异(P>0.05)。免疫组化结果显示MMP-9的表达在模型组较空白组高,差异有显著意义(P<0.01);通心络组、鳖甲低组与模型组比较有差异(P<0.05),鳖甲高组与模型组比较有显著差异(P<0.01);各治疗组比较差异无显著性(P>0.05)。
③对内皮因子的影响:与空白组比较,模型组大鼠ET水平增高、NO水平降低(P<0.05或P<0.01)。与模型组相比,鳖甲低组和通心络组ET降低,有统计学差异(P<0.05),鳖甲高组有显著差异(P<0.01);各治疗组比较未见差异(P>0.05)。与模型组比较,通心络组、鳖甲低组、鳖甲高组NO较模型组升高,有统计学差异(P<0.05),各治疗组比较未见差异(P>0.05)。
④对抗炎因子的影响:与空白组比较,模型组血清APN水平和脂肪组织APN-mRNA表达水平均有显著降低(P<0.01);与模型组相比,各治疗组APN水平均有增高,通心络组和鳖甲高组有显著性差异(P< 0.01);鳖甲低组有差异(P<0.05);鳖甲低组、鳖甲高组与通心络组比较无差异(P>0.05);鳖甲低组与鳖甲高组比较有差异(P< 0.05)。与模型组相比,各治疗组APN-mRNA水平均有增高(P<0.05或P<0.01);各治疗组之间比较没有差异(P>0.05)。
⑤对胰腺、主动脉病理的影响:与空白组比较;模型组及各治疗组胰腺内可见散在胰岛组织,胰岛萎缩,小胰岛多见,胰岛内细胞数目较少,各组未见明显差异。与空白组比较,模型组大鼠主动脉光镜下动脉壁三层结构紊乱、界限不清;内膜明显增厚,内皮下可见较多的泡沫细胞聚集、脂质沉积和增生的平滑肌细胞;中膜平滑肌细胞排列紊乱,间质胶原纤维增生。各治疗组大鼠的上述病变均有不同程度的减轻,而以鳖甲高组和通心络组病理改变明显。
结论:鳖甲煎丸可以降低TG水平;降低CRP、TNF-α、ET水平,降低MMP-9表达水平;升高NO、血清APN水平;升高脂肪组织APN-mRNA表达水平。改善主动脉病理表现。从而起到调脂、改善血管内皮功能、抗炎等作用。鳖甲煎丸对实验性糖尿病大鼠合并动脉粥样硬化病变具有血管保护作用,其作用机制可能与其保护内皮功能和抗炎机制有关。
Objective:To observe the effects of the Biejiajian pill on rats of diabetes with atherosclerosis, blood lipid, blood sugar, vascular endothelial factor, inflam-matory factor, anti-inflammatory factors, etc. and to inve-stigate its possible mechanism of action.
Methods: The modeling male SD rats were divided randomly into: model group, Tongxinluo control group, low dose of Biejiajian pill group, and high dose of Biejiajian pill group. The same week-old rats are blank control group. After 8 weeks, drawing blood and taking surrounding fat tissue of testis, pancreas, and thoracic aorta. Examination:①Blood lipid: TC, TG;②Inflammatory factor: CRP, TNF-α;③Diastolic-systolic Factors of Vascular Endothelium: ET, NO;④Anti-inflammatory factors: serum adiponectin. Measuring the level of adiponectin mRNA in testis white fat by RT-PCR;⑤pathological section: to observe pancreatic gland and atherosclerotic lesion of aortic intima with microscope and to measure the level of MMP-9 by immunohistochemistry.
Results:①The influence on Blood sugar, blood lipid: blood sugar in model rat is higher in all terms; compared with model group , high dose of Biejianjian pill and low dose of Biejianjian pill can decreased the level of TG(P< 0.01), and have no difference among each therapic group(P>0.05); the level of TC have no change among each therapic group compared with model group(P>0.05).
②The influence on inflammatory factor: compared with blank control group, the level of CRP, TNF-αincreased in model rats(P<0.05), decreased in each group of Biejiajian pill group compared with model group and the difference was significant(P<0.05), the level have no difference among each therapic group(P>0.05). Immunohistochemistry indicate that the level of MMP-9 in rats of the model group were higher than blank control group and the difference was significant(P< 0.01). compared with model group, The level of MMP-9 in rats of low and high dose of Biejiajian pill group can be reduced, the difference of high dose was significant(P < 0.01). and the difference were insignificant among each therapic group(P>0.05).
③The influence on diastolic-systolic Factors of vascular endothelium: compared with blank control group, the level of ET increased in model rats(P<0.05), decreased in each group of Biejiajian pill group compared with model group and the difference was significant(P<0.05 or P<0.01), the level have no difference among each therapic group(P>0.05). The level of NO was lower in model group compared with blank control group(P<0.01), increased in high dose and low dose Biejiajian pill group and the difference were markedly(P<0.05), the level have no difference among each therapic group, and the difference was insignificant(P>0.05).
④The influence on anti-inflammatory factors: compared with blank control group, the level of APN and APN mRNA decreased in rats of model group(P<0.01), increased in each group of Biejiajian pill group compared with model group and the difference was significant(P<0.01 or P<0.05), the level have no difference among each therapic group(P>0.05).
⑤The influence on pathological section of pancreatic gland and atherosclerotic lesion of aortic intima: Compared with blank control group, we can see less pancreatic islet, smaller pancreatic islet and less cell in pancreatic islet in the tissue of pancreatic gland among model group and therapic group. Under microscope, aortic intima have xanthoma cell aggregation, aortic intima thickening, lipid deposition, proliferative smooth muscle cell, interstitial collagen hyperplasia, etc in model group and therapic group .But it is more markedly in model group.
Conclusion: Biejiajian pill can reduce the levels of TG, CRP, TNF-α, ET, MMP-9, and increase the level of NO, serum adiponectin, adiponect mRNA, and so improve endothelial function and anti-inflammatory action. Biejiajian pill has effect on experimental rats of diabetes with atherosclerosis in protecting vessel, whose mechanism may be relation to protection of endothlial function and anti-inflammatory mechanism.
方法:将造模成功后雄性SD大鼠随机分为模型组、通心络胶囊对照组(简称通心络组)、鳖甲煎丸低剂量组(简称鳖甲低组)、鳖甲煎丸高剂量组(简称鳖甲高组),另设同周龄SD大鼠作为空白对照组。五组实验动物,灌胃8周后,将大鼠用1%戊巴比妥钠腹腔麻醉后分离腹主动脉,抽取动脉血;取胰腺、胸主动脉、睾丸周围脂肪组织,按照试剂盒说明书要求及组织存放要求保存。检测①血脂:总胆固醇(TC)、甘油三酯(TG);②炎症因子:C-反应蛋白(CRP)、肿瘤坏死因子(TNF-α);③内皮因子:内皮素(ET)、一氧化氮(NO);④抗炎因子:血清脂联素(APN)、脂肪组织脂联素mRNA;⑤病理:HE染色观察胰腺及主动脉内膜动脉粥样硬化病变、免疫组化观察主动脉基质金属蛋白酶-9(MMP-9)。
结果:①对血脂、血糖的影响:实验过程中观察到模型大鼠高血糖无自然缓解现象;在治疗后大鼠血糖水平同治疗前及模型组相比较亦无下降(P>0.05);与空白组比较,模型组大鼠血清TC、TG水平明显升高(P<0.01),鳖甲煎丸高、低剂量组可以降低糖尿病合并动脉粥样硬化病变大鼠血清TG水平(P<0.01),且各治疗组之间没有明显差异;各治疗组对糖尿病合并动脉粥样硬化病变大鼠血清TC水平无明显影响。②对炎症因子的影响:与空白组比较,模型组CRP水平增高(P<0.05);与模型组比较,鳖甲煎丸高、低剂量组CRP水平均有下降(P<0.05);各治疗组组相比较CRP水平未见差异(P>0.05)。与空白组比较,模型组TNF-α水平有显著性差异(P<0.01);与模型组比较,通心络组与鳖甲高组有显著性差异(P<0.01);鳖甲低组有差异(P<0.05);通心络组、鳖甲低组、相比较TNF-α水平未见差异(P>0.05)。免疫组化结果显示MMP-9的表达在模型组较空白组高,差异有显著意义(P<0.01);通心络组、鳖甲低组与模型组比较有差异(P<0.05),鳖甲高组与模型组比较有显著差异(P<0.01);各治疗组比较差异无显著性(P>0.05)。
③对内皮因子的影响:与空白组比较,模型组大鼠ET水平增高、NO水平降低(P<0.05或P<0.01)。与模型组相比,鳖甲低组和通心络组ET降低,有统计学差异(P<0.05),鳖甲高组有显著差异(P<0.01);各治疗组比较未见差异(P>0.05)。与模型组比较,通心络组、鳖甲低组、鳖甲高组NO较模型组升高,有统计学差异(P<0.05),各治疗组比较未见差异(P>0.05)。
④对抗炎因子的影响:与空白组比较,模型组血清APN水平和脂肪组织APN-mRNA表达水平均有显著降低(P<0.01);与模型组相比,各治疗组APN水平均有增高,通心络组和鳖甲高组有显著性差异(P< 0.01);鳖甲低组有差异(P<0.05);鳖甲低组、鳖甲高组与通心络组比较无差异(P>0.05);鳖甲低组与鳖甲高组比较有差异(P< 0.05)。与模型组相比,各治疗组APN-mRNA水平均有增高(P<0.05或P<0.01);各治疗组之间比较没有差异(P>0.05)。
⑤对胰腺、主动脉病理的影响:与空白组比较;模型组及各治疗组胰腺内可见散在胰岛组织,胰岛萎缩,小胰岛多见,胰岛内细胞数目较少,各组未见明显差异。与空白组比较,模型组大鼠主动脉光镜下动脉壁三层结构紊乱、界限不清;内膜明显增厚,内皮下可见较多的泡沫细胞聚集、脂质沉积和增生的平滑肌细胞;中膜平滑肌细胞排列紊乱,间质胶原纤维增生。各治疗组大鼠的上述病变均有不同程度的减轻,而以鳖甲高组和通心络组病理改变明显。
结论:鳖甲煎丸可以降低TG水平;降低CRP、TNF-α、ET水平,降低MMP-9表达水平;升高NO、血清APN水平;升高脂肪组织APN-mRNA表达水平。改善主动脉病理表现。从而起到调脂、改善血管内皮功能、抗炎等作用。鳖甲煎丸对实验性糖尿病大鼠合并动脉粥样硬化病变具有血管保护作用,其作用机制可能与其保护内皮功能和抗炎机制有关。
Objective:To observe the effects of the Biejiajian pill on rats of diabetes with atherosclerosis, blood lipid, blood sugar, vascular endothelial factor, inflam-matory factor, anti-inflammatory factors, etc. and to inve-stigate its possible mechanism of action.
Methods: The modeling male SD rats were divided randomly into: model group, Tongxinluo control group, low dose of Biejiajian pill group, and high dose of Biejiajian pill group. The same week-old rats are blank control group. After 8 weeks, drawing blood and taking surrounding fat tissue of testis, pancreas, and thoracic aorta. Examination:①Blood lipid: TC, TG;②Inflammatory factor: CRP, TNF-α;③Diastolic-systolic Factors of Vascular Endothelium: ET, NO;④Anti-inflammatory factors: serum adiponectin. Measuring the level of adiponectin mRNA in testis white fat by RT-PCR;⑤pathological section: to observe pancreatic gland and atherosclerotic lesion of aortic intima with microscope and to measure the level of MMP-9 by immunohistochemistry.
Results:①The influence on Blood sugar, blood lipid: blood sugar in model rat is higher in all terms; compared with model group , high dose of Biejianjian pill and low dose of Biejianjian pill can decreased the level of TG(P< 0.01), and have no difference among each therapic group(P>0.05); the level of TC have no change among each therapic group compared with model group(P>0.05).
②The influence on inflammatory factor: compared with blank control group, the level of CRP, TNF-αincreased in model rats(P<0.05), decreased in each group of Biejiajian pill group compared with model group and the difference was significant(P<0.05), the level have no difference among each therapic group(P>0.05). Immunohistochemistry indicate that the level of MMP-9 in rats of the model group were higher than blank control group and the difference was significant(P< 0.01). compared with model group, The level of MMP-9 in rats of low and high dose of Biejiajian pill group can be reduced, the difference of high dose was significant(P < 0.01). and the difference were insignificant among each therapic group(P>0.05).
③The influence on diastolic-systolic Factors of vascular endothelium: compared with blank control group, the level of ET increased in model rats(P<0.05), decreased in each group of Biejiajian pill group compared with model group and the difference was significant(P<0.05 or P<0.01), the level have no difference among each therapic group(P>0.05). The level of NO was lower in model group compared with blank control group(P<0.01), increased in high dose and low dose Biejiajian pill group and the difference were markedly(P<0.05), the level have no difference among each therapic group, and the difference was insignificant(P>0.05).
④The influence on anti-inflammatory factors: compared with blank control group, the level of APN and APN mRNA decreased in rats of model group(P<0.01), increased in each group of Biejiajian pill group compared with model group and the difference was significant(P<0.01 or P<0.05), the level have no difference among each therapic group(P>0.05).
⑤The influence on pathological section of pancreatic gland and atherosclerotic lesion of aortic intima: Compared with blank control group, we can see less pancreatic islet, smaller pancreatic islet and less cell in pancreatic islet in the tissue of pancreatic gland among model group and therapic group. Under microscope, aortic intima have xanthoma cell aggregation, aortic intima thickening, lipid deposition, proliferative smooth muscle cell, interstitial collagen hyperplasia, etc in model group and therapic group .But it is more markedly in model group.
Conclusion: Biejiajian pill can reduce the levels of TG, CRP, TNF-α, ET, MMP-9, and increase the level of NO, serum adiponectin, adiponect mRNA, and so improve endothelial function and anti-inflammatory action. Biejiajian pill has effect on experimental rats of diabetes with atherosclerosis in protecting vessel, whose mechanism may be relation to protection of endothlial function and anti-inflammatory mechanism.
引文
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