芪莲舒痞方影响Syk、Survivin、p53表达的实验研究及其治疗CAG癌前病变的临床研究
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摘要
目的:通过观察芪莲舒痞方治疗慢性萎缩性胃炎(chronic atrophic gastritis,简称CAG)癌前病变的临床疗效,及其影响CAG癌前病变大鼠胃黏膜血流量、胃黏膜组织脾酪氨酸激酶(spleen tyrosine kinase,简称Syk)、Survivin、突变型p53表达的实验研究,揭示慢性萎缩性胃炎癌前病变病机与治法的分子生物学内涵,探讨芪莲舒痞方的作用机理。
方法:将72例符合纳入标准的CAG癌前病变患者,按数字表法随机分为芪莲舒痞组36例和胃复春组36例,进行双盲、随机、阳性药对照观察。观察药物对综合疗效、临床症状、HP根除率、胃镜像以及病理的影响;实验研究采用“MNNG+雷尼替丁+乙醇+饥饱失调”的综合方法复制Wistar大鼠CAG癌前病变模型,随机分为正常组、模型组、芪莲舒痞大、中、小剂量组和胃复春对照组,分别给予药物干预后观察:激光多普勒观察胃黏膜血流量的变化;光学显微镜观察胃黏膜病理变化;采用免疫组化S-P法、ELISA法检测Syk的表达;免疫组化S-P法检测突变型p53、Survivin的含量与表达。
结果:临床研究表明:①综合疗效评价:QLSP组显效率38.9%,总有效率88.9%;胃复春组显效率27.8%,总有效率63.9%,两组比较有统计学差异(P<0.05);②QLSP组单项临床症状积分及总积分均有明显下降,与胃复春组比较有显著差异(P<0.01);③QLSP组胃镜像及病理均有明显改善,与胃复春组比较有统计学差异(P<0.05);④QLSP组HP根除率为72%,胃复春组HP根除率为43.5%,二者比较有统计学差异(P<0.05)。实验研究表明:①胃黏膜病理变化:经统计分析,造模各组大鼠胃黏膜炎症、萎缩、肠上皮化生、异型增生发生例数与正常组比较,均显著增加(P<0.01或P<0.05);与模型组相比,QLSP大、中剂量组胃黏膜炎症发生例数均显著减少(P<0.01或P<0.05),QLSP大剂量组萎缩、肠上皮化生的发生例数显著减少(P<0.05),药物干预各组异型增生的发生例数无统计学差异。②胃黏膜血流量:正常组胃黏膜血流量为41.18±6.04PU,模型组为25.65±7.18PU,模型组大鼠的胃黏膜血流量显著下降(P<0.01);QLSP大、中剂量组胃黏膜血流量分别为39.88±5.27PU、38.94±6.69PU,较模型组显著增加(P<0.01),胃复春组胃黏膜血流量为30.84±8.74PU,较模型组亦有所改善(P<0.05)。③胃黏膜厚度:正常组为544.72±34.79μm,模型组为328.14±26.24μm,二者比较有显著差异(P<0.01);胃复春组胃黏膜平均厚度为407.81±33.56μm,QLSP大、中、小剂量组分别为539.20±33.17μm、478.60±38.01μm、347.94±34.41μm;经统计学分析,QLSP大剂量组较模型组、胃复春组显著增厚(P<0.01)。④Syk蛋白:正常组Syk蛋白表达量为6309.6±449.5 pg/ml,模型组为3346.1±315.8 pg/ml,二者比较有显著差异(P<0.01);胃复春组为4078.3±379.2 pg/ml,QLSP大、中、小剂量组分别为5362.7±512.3 pg/ml、4768.6±416.7 pg/ml、4072.1±398.4 pg/ml,经统计学分析,胃复春组、QLSP大、中、小剂量组Syk蛋白表达量较模型组显著增强(P<0.01);QLSP大、中剂量组Syk蛋白表达量较胃复春组显著增强(P<0.01)。⑤Survivin蛋白:正常组Survivin阳性率为0(0/20),模型组为80%(12/15),二者比较有显著差异(P<0.01);胃复春组为40%(6/15),QLSP大、中、小剂量组分别为26.7%(4/15)、40%(6/15)、60%(9/15)。经统计学分析,QLSP大剂量组Survivin阳性表达率较模型组显著减弱(P<0.01)。⑥突变型p53蛋白:正常组p53阳性表达率为0(0/20),模型组为80%(12/15),胃复春组为33.3%(5/15),QLSP大、中、小剂量组分别为20%(3/15)、40%(6/15)、60%(9/15)。经统计学分析,胃复春组、QLSP大剂量组突变型p53阳性表达率较模型组显著减弱(P<0.05或P<0.01)。
结论:芪莲舒痞方治疗CAG癌前病变有较好的临床疗效,脾滞肾虚,瘀毒内蕴是CAG癌前病变的关键病机,运脾益肾、化瘀解毒是治疗CAG癌前病变的有效方法。动物实验表明,芪莲舒痞方能明显增加CAG癌前病变大鼠胃黏膜血流量及胃黏膜厚度,促进抑癌基因Syk的表达,抑制突变型p53、抑凋亡基因Survivin的表达,这可能是其治疗CAG癌前病变的作用机理,芪莲舒痞方是治疗该病的有效中药复方。
Objective:To probe into the pharmacodynamic mechanism of Qilian Shupi recipe by way of researching on its treatment on precancerous lesion of chronic atrophic gastritis (CAG) and experimental research on its effect on expression of Syk、Survivin、p53 in Wistar rats, hoping to bring the molecular biological possible connotation of pathogenesis and treatment method to light.
Methods:72 patients with precancerous lesions of CAG were divided randomly into two groups, 36 of them were treated with QLSP Tablet and the other with Wei Fuchun Tablet. Treated for three months, the total effective rate, clinical symptoms, and gastroscopic images, pathological changes of gastric mucous membranes and Hp-eradicating rates were observed. In experiments, models of precancerous lesions of gastric cancer were induced by cancerogenic agent in Wistar rats, which were divided randomly into six groups (normal group, model group, WeiFuchun group and big, middle and small dose QLSP group) according to their weights. After treated with QLSP and WeiFuchun for 12 weeks, main outcome measures: laser Doppler flowmetry was used to determine gastric mucosal blood flows; optical microscope was used to measure the thickness of gastric mucosal; Immunohistochemical S-P method and ELISA were used to monitor the expression of Syk, immunohistochemical S-P method was used to monitor the expressions of p53 and Survivin.
Results:Data of clinical trial showed that in QLSP group the notable effective rate was 38.9%,and the total effective rate was 88.9%,while the notable effective rate was 27.8% and the total effective rate was 63.9% in Wei Fuchun group, there were notable differences between them(P<0.01); The improvements of clinical symptoms and symptom integral are difference between QLSP group and Wei Fuchun group (P<0.01); QLSP could improve gastroscopic images and pathological results of gastric mucous membrane, they were notable differences to Wei Fuchun group(P<0.01); the HP-eradicating rate of QLSP group was 72%, while Wei Fuchun group was 43.5%, there were notable differences between them(P<0.01). Animal experimental research showed that the gastric mucosal blood flows(GMBF) were increased in big and middle doses QLSP group, with notable differences to model control group and Wei Fuchun group(P<0.01); The gastric mucous membrane thicknesses in big doses QLSP group and Wei Fuchun group were notable more thickened than model group, there were notable differences between them(P<0.01); The expressions of Syk were increased in big and middle doses QLSP group, while they were increased slightly in Wei Fuchun group and lower greatly in model group, there were notable differences among them(P<0.01); The expressions of Survivin and p53 were decreased in big and middle doses QLSP group, while they were decreased slightly in Wei Fuchun group and higher greatly in model group, there were notable differences among them (P<0.01).
Conclusions:Splenogastric asthenia,accumulation of stagnant pathogenic factors in the body, and involvement of the kidney functions at the advanced stage are the main causes leading to the pathogenesis of precancerous lesions of chronic atrophic gastritis. Therefore, invigorating spleen and tonifying kidney, regulating qi to disperse stagnation,and dispersing accumulation of pathogenic factors to resolve masses are the principles in the management of the condition. The excellent clinical effect of QLSP, the index from experimental research reveals its mechanism at the systemic, cellular and molecular levels in treating precancerous lesions of chronic atrophic gastritis. The QLSP recipe acts on many chains and targets of the disease to produce a comprehensive therapeutic effect,the therapeutic mechanism may have much to do with an overall effect of inhibition of expression of Survivin, p53 and inhancing the expression of Syk. And thus the study enriched the knowledge of pathology and treatment of precancerous lesions of chronic atrophic gastritis.
方法:将72例符合纳入标准的CAG癌前病变患者,按数字表法随机分为芪莲舒痞组36例和胃复春组36例,进行双盲、随机、阳性药对照观察。观察药物对综合疗效、临床症状、HP根除率、胃镜像以及病理的影响;实验研究采用“MNNG+雷尼替丁+乙醇+饥饱失调”的综合方法复制Wistar大鼠CAG癌前病变模型,随机分为正常组、模型组、芪莲舒痞大、中、小剂量组和胃复春对照组,分别给予药物干预后观察:激光多普勒观察胃黏膜血流量的变化;光学显微镜观察胃黏膜病理变化;采用免疫组化S-P法、ELISA法检测Syk的表达;免疫组化S-P法检测突变型p53、Survivin的含量与表达。
结果:临床研究表明:①综合疗效评价:QLSP组显效率38.9%,总有效率88.9%;胃复春组显效率27.8%,总有效率63.9%,两组比较有统计学差异(P<0.05);②QLSP组单项临床症状积分及总积分均有明显下降,与胃复春组比较有显著差异(P<0.01);③QLSP组胃镜像及病理均有明显改善,与胃复春组比较有统计学差异(P<0.05);④QLSP组HP根除率为72%,胃复春组HP根除率为43.5%,二者比较有统计学差异(P<0.05)。实验研究表明:①胃黏膜病理变化:经统计分析,造模各组大鼠胃黏膜炎症、萎缩、肠上皮化生、异型增生发生例数与正常组比较,均显著增加(P<0.01或P<0.05);与模型组相比,QLSP大、中剂量组胃黏膜炎症发生例数均显著减少(P<0.01或P<0.05),QLSP大剂量组萎缩、肠上皮化生的发生例数显著减少(P<0.05),药物干预各组异型增生的发生例数无统计学差异。②胃黏膜血流量:正常组胃黏膜血流量为41.18±6.04PU,模型组为25.65±7.18PU,模型组大鼠的胃黏膜血流量显著下降(P<0.01);QLSP大、中剂量组胃黏膜血流量分别为39.88±5.27PU、38.94±6.69PU,较模型组显著增加(P<0.01),胃复春组胃黏膜血流量为30.84±8.74PU,较模型组亦有所改善(P<0.05)。③胃黏膜厚度:正常组为544.72±34.79μm,模型组为328.14±26.24μm,二者比较有显著差异(P<0.01);胃复春组胃黏膜平均厚度为407.81±33.56μm,QLSP大、中、小剂量组分别为539.20±33.17μm、478.60±38.01μm、347.94±34.41μm;经统计学分析,QLSP大剂量组较模型组、胃复春组显著增厚(P<0.01)。④Syk蛋白:正常组Syk蛋白表达量为6309.6±449.5 pg/ml,模型组为3346.1±315.8 pg/ml,二者比较有显著差异(P<0.01);胃复春组为4078.3±379.2 pg/ml,QLSP大、中、小剂量组分别为5362.7±512.3 pg/ml、4768.6±416.7 pg/ml、4072.1±398.4 pg/ml,经统计学分析,胃复春组、QLSP大、中、小剂量组Syk蛋白表达量较模型组显著增强(P<0.01);QLSP大、中剂量组Syk蛋白表达量较胃复春组显著增强(P<0.01)。⑤Survivin蛋白:正常组Survivin阳性率为0(0/20),模型组为80%(12/15),二者比较有显著差异(P<0.01);胃复春组为40%(6/15),QLSP大、中、小剂量组分别为26.7%(4/15)、40%(6/15)、60%(9/15)。经统计学分析,QLSP大剂量组Survivin阳性表达率较模型组显著减弱(P<0.01)。⑥突变型p53蛋白:正常组p53阳性表达率为0(0/20),模型组为80%(12/15),胃复春组为33.3%(5/15),QLSP大、中、小剂量组分别为20%(3/15)、40%(6/15)、60%(9/15)。经统计学分析,胃复春组、QLSP大剂量组突变型p53阳性表达率较模型组显著减弱(P<0.05或P<0.01)。
结论:芪莲舒痞方治疗CAG癌前病变有较好的临床疗效,脾滞肾虚,瘀毒内蕴是CAG癌前病变的关键病机,运脾益肾、化瘀解毒是治疗CAG癌前病变的有效方法。动物实验表明,芪莲舒痞方能明显增加CAG癌前病变大鼠胃黏膜血流量及胃黏膜厚度,促进抑癌基因Syk的表达,抑制突变型p53、抑凋亡基因Survivin的表达,这可能是其治疗CAG癌前病变的作用机理,芪莲舒痞方是治疗该病的有效中药复方。
Objective:To probe into the pharmacodynamic mechanism of Qilian Shupi recipe by way of researching on its treatment on precancerous lesion of chronic atrophic gastritis (CAG) and experimental research on its effect on expression of Syk、Survivin、p53 in Wistar rats, hoping to bring the molecular biological possible connotation of pathogenesis and treatment method to light.
Methods:72 patients with precancerous lesions of CAG were divided randomly into two groups, 36 of them were treated with QLSP Tablet and the other with Wei Fuchun Tablet. Treated for three months, the total effective rate, clinical symptoms, and gastroscopic images, pathological changes of gastric mucous membranes and Hp-eradicating rates were observed. In experiments, models of precancerous lesions of gastric cancer were induced by cancerogenic agent in Wistar rats, which were divided randomly into six groups (normal group, model group, WeiFuchun group and big, middle and small dose QLSP group) according to their weights. After treated with QLSP and WeiFuchun for 12 weeks, main outcome measures: laser Doppler flowmetry was used to determine gastric mucosal blood flows; optical microscope was used to measure the thickness of gastric mucosal; Immunohistochemical S-P method and ELISA were used to monitor the expression of Syk, immunohistochemical S-P method was used to monitor the expressions of p53 and Survivin.
Results:Data of clinical trial showed that in QLSP group the notable effective rate was 38.9%,and the total effective rate was 88.9%,while the notable effective rate was 27.8% and the total effective rate was 63.9% in Wei Fuchun group, there were notable differences between them(P<0.01); The improvements of clinical symptoms and symptom integral are difference between QLSP group and Wei Fuchun group (P<0.01); QLSP could improve gastroscopic images and pathological results of gastric mucous membrane, they were notable differences to Wei Fuchun group(P<0.01); the HP-eradicating rate of QLSP group was 72%, while Wei Fuchun group was 43.5%, there were notable differences between them(P<0.01). Animal experimental research showed that the gastric mucosal blood flows(GMBF) were increased in big and middle doses QLSP group, with notable differences to model control group and Wei Fuchun group(P<0.01); The gastric mucous membrane thicknesses in big doses QLSP group and Wei Fuchun group were notable more thickened than model group, there were notable differences between them(P<0.01); The expressions of Syk were increased in big and middle doses QLSP group, while they were increased slightly in Wei Fuchun group and lower greatly in model group, there were notable differences among them(P<0.01); The expressions of Survivin and p53 were decreased in big and middle doses QLSP group, while they were decreased slightly in Wei Fuchun group and higher greatly in model group, there were notable differences among them (P<0.01).
Conclusions:Splenogastric asthenia,accumulation of stagnant pathogenic factors in the body, and involvement of the kidney functions at the advanced stage are the main causes leading to the pathogenesis of precancerous lesions of chronic atrophic gastritis. Therefore, invigorating spleen and tonifying kidney, regulating qi to disperse stagnation,and dispersing accumulation of pathogenic factors to resolve masses are the principles in the management of the condition. The excellent clinical effect of QLSP, the index from experimental research reveals its mechanism at the systemic, cellular and molecular levels in treating precancerous lesions of chronic atrophic gastritis. The QLSP recipe acts on many chains and targets of the disease to produce a comprehensive therapeutic effect,the therapeutic mechanism may have much to do with an overall effect of inhibition of expression of Survivin, p53 and inhancing the expression of Syk. And thus the study enriched the knowledge of pathology and treatment of precancerous lesions of chronic atrophic gastritis.
引文
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