中药不同组方对胃癌前病变模型大鼠胃粘膜组织细胞凋亡的影响
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摘要
慢性萎缩性胃炎是由多种因素所致的消化系统常见病,尤其是胃窦萎缩性胃炎与胃癌关系密切[1,2],所以又称为胃癌前状态性疾病。胃癌前病变系一病理学概念,是指胃粘膜上皮不典型增生(异型增生、上皮内瘤变)。不典型增生分为轻度(低级别)、重度(高级别)二级,异型增生(上皮内瘤变)是重要的胃癌癌前病变。2006年中国慢性胃炎共识意见中指出“小肠型和完全性肠化亚型无明显癌前病变的意义,临床实践显示单从肠化亚型的病理形态学难以作出胃癌危险性的预测,而且十多年来,从大肠型肠化发展成胃癌的报道较为少见。所以,胃癌前病变的真正病理学特征性变化是异型增生(或称上皮内瘤)。”所以,针对慢性萎缩性胃炎伴不典型增生的研究,对于胃癌的二级预防具有更加重要的意义。
目的:中药治疗慢性萎缩性胃炎伴不典型增生有着较为理想的疗效,而且大量研究表明慢性萎缩性胃炎伴不典型增生以脾虚、血瘀为主要中医临床证型。我们采用热盐水合并化学药物刺激的方法复制了慢性萎缩性胃炎伴不典型增生的大鼠模型,应用益气化瘀、健脾益气、活血化瘀中药及西药维霉素预防和治疗给药,探讨不同组方中药对慢性萎缩性胃炎伴不典型增生大鼠胃粘膜形态、组织学改变的影响,以其探讨不同组方中药的作用机制,及它们之间的相互关系。
材料与方法:
1.采用化学药物刺激的方法复制了复制了慢性萎缩性胃炎癌前病变动物模型及分组治疗。普通级,健康Wister大鼠120只,雌雄各半,体重160±5 g,将大鼠随机分为11组,分别为正常组、造模组、健脾益气方药预防组、活血化瘀方药预防组、健脾化瘀方药预防组、西药预防组、造模空白组、健脾益气方药治疗组、活血化瘀方药治疗组、健脾化瘀方药治疗组、西药治疗组。除正常组10只外,其余各组均11只。150g/L、55℃热盐水,10ml·Kg~(-1)·d~(-1) ,灌胃;2%水杨酸溶液10ml·Kg~(-1)·d~(-1) ,灌胃;均为1次/d;20mmol/L脱氧胆酸钠溶液,自由饮用;配以饥饱失常处理,即2d饱食,1d禁食。按上述方法造模12周。健脾益气方药预防组、活血化瘀方药预防组、健脾化瘀方药预防组均同时灌服中药制剂6g/kg、4g/kg、8g/kg,西药预防组同时灌服灌服西药维酶素1g/kg,连续给药12周,12周后模型组、健脾益气方药预防组、活血化瘀方药预防组、健脾化瘀方药预防组、西药预防组处死大鼠取材处理。造模空白组、健脾益气方药治疗组、活血化瘀方药治疗组、健脾化瘀方药治疗组、西药治疗组开始分别给予双蒸水(3ml/只)、中药制剂、西药维霉素,剂量同上,满24周后,处死全部大鼠,取材处理。
2.观察了大鼠模型胃粘膜病理形态变化。
3.用免疫组化的方法检测胃粘膜组织bcl-2的表达的变化,用流式细胞仪检测胃组织中活性氧(ROS)、Ca~(2+)含量的变化,用酶标仪检测胃组织中Caspase-3表达的变化。
结果:
1.造模对照组异型增生发病率100%,要高于健脾益气预防组、活血化淤预防组、健脾化淤预防组、西药预防组不典型增生发生率(71.4%、66.6%、12.5%、62.5%),且中药及西药预防组不典型增生病例多发生在轻度不典型增生,健脾益气预防组、活血化淤预防组、健脾化淤预防组、西药组轻度不典型增生发生率分别为分别为80%、50%、100%、60%,而病理对照组全部为中、重度不典型增生。健脾益气预防组、活血化瘀预防组、健脾化瘀预防组与西药预防组之间比较无显著性差异(P>0.05)。健脾化瘀中药组中有87.5%都未发病,要好于其他几组,但是统计学处理时与其他几组无显著差异,考虑系例数较少造成的。在治疗给药过程中,造模空白组大鼠胃粘膜不典型增生经12周的正常饲养,病理损伤无改善,经中药及维酶素连续12周的灌胃治疗,胃粘膜不典型增生发生率明显低于造模对照组(P<0.05),且治疗组病变程度均较轻,各组多为轻度不典型增生(62.5%、55.6%、100%、50%),而造模对照组中、重度不典型增生发病率为100%,中药治疗各组及维酶素组间无显著性差异(P>0.05)。健脾化淤治疗组中有75%都已经正常,要高于其他各组,但在统计学处理时与其他几组比较无显著性差异,考虑系样本数量较小造成的。
2. BCL-2基因在正常胃粘膜、轻、中、重度不典型增生中,其表达率随病变加重逐级增高。在正常胃粘膜中,Bcl-2阳性率为12.5%,在造模组及造模空白组中,中、重度不典型增生的发生率均为100%,Bcl-2的阳性率分别为90%、87.5%,经各组方中药和西药预防、治疗给药后,随着不典型增生程度的下降,Bcl-2表达的阳性率亦在下降,在预防给药组,健脾、化瘀、健脾化瘀、西药组的不典型增生率分别为71.4%、66.6%、12.5%、62.5%,且多集中在轻度不典型增生(80%、50%、100%、60%),与之相伴的Bcl-2表达阳性率也下降(57.1%、55.5%、12.5%、50%)。在治疗给药组,健脾、化瘀、健脾化瘀、西药组的不典型增生发生率分别为(88.8%、90%、25%、75%),轻度不典型增生的发生率为62.5%、55.6%、100%、50%,与之相应的Bcl-2表达阳性率分别为55.5%、60%、25%、50%。而且无论是预防给药还是治疗给药,中药各组及维酶素组,BCL-2基因的表达均较造模组及造模空白组减少。而且无论是预防给药还是治疗给药,健脾化瘀组领的疗效要好于益气健脾和活血化瘀。
3.造模组及造模空白组大鼠胃粘膜细胞中的Caspase– 3明显减少,与正常组比较有显著差异(P﹤0.05),在预防组中,健脾化瘀组、健脾益气组、活血化瘀组及西药组均可以使Caspase– 3的表达增加,与造模组比较有显著差异(P﹤0.05),健脾化瘀组要好于其他组,而健脾益气组、活血化瘀组、西药组之间没有显著差异(P﹥0.05)。在治疗组中,健脾化瘀组、健脾益气组、活血化瘀组及西药组也均可以使Caspase– 3的表达增加,与造模空白组比较有显著差异(P﹤0.05),健脾化瘀组要好于其他组,而健脾益气组、活血化瘀组、西药组之间没有显著差异(P﹥0.05)。
4.模型组大鼠ROS及Ca~(2+)含量明显下降,与空白对照组之间有显著差异(P﹤0.05),而无论是预防给药,还是治疗给药,中药组和西药组均可以提高ROS及Ca~(2+)含量,与造模组大鼠之间有显著性差异(P﹤0.05),无论是预防给药还是治疗给药,健脾化瘀组、西药组之间的疗效无差别(P﹥0.05),两组与正常组之间亦无显著性差异(P﹥0.05),而两组与健脾组、化瘀组比较有显著性差异(P﹤0.05),前者的疗效要好于后者,健脾组与化瘀组比较无显著性差异(P﹥0.05)。通过结果,我们不难发现,随着不典型增生程度的下降,ROS及Ca~(2+)含量均出现相应的减少。在正常胃粘膜中ROS及Ca~(2+)的含量最多,在造模组及造模空白组中,中、重度不典型增生的发生率为100%,而相应的ROS及Ca~(2+)的含量也降至最低。在预防给药和治疗给药过程中,健脾化瘀组的作用要好于健脾益气组和活血化瘀组(P﹤0.05),而健脾益气组和活血化瘀组无论是预防给药还是治疗给药之间没有显著性差异(P﹥0.05)。
结论:
无论是预防给药还是治疗给药,健脾化瘀、健脾益气、活血化瘀中药均具有较显著的预防和治疗胃粘膜上皮不典型增生作用。其疗效机理主要是通过调低胃组织中的Bcl-2的基因表达、增加胃组织中活性氧(ROS)、Ca~(2+)的含量,增加胃组织中Caspase-3的表达,在整个细胞凋亡的各个环节产生作用,从而使细胞凋亡增加,减轻细胞增殖状态,达到治疗萎缩性胃炎癌前病变,防止癌变的作用。在这个过程中,在检测的三个环节中,健脾化瘀、健脾、化瘀中药均可以发挥作用,说明在中药治疗萎缩性胃炎癌前病变的过程中具有相同的作用节点。健脾化瘀中药的治疗萎缩性胃炎癌前病变的作用要明显好于其它两种治则的中药,而健脾、化瘀中药之间的治疗作用没有显著差异。
Chronic atrophic gastritis is a common disease of digestive system caused by multiple factors, especially Antral atrophic gastritis and Gastric Cancer have a very close relationship[1,2], therefore it is called Gastric Precancerous conditions diseases. Gastric precancerous lesions is a pathological concept,refers to the gastric epithelial dysplasia (dysplasia, intraepithelial neoplasia). Dysplasia is divided into two levels: mild (low level) and severe (high level), dysplasia (intraepithelial neoplasia) is an important Gastric precancerous lesions. China Consensus of Chronic Gastritis in 2006 indicate that Small Intestinal metaplasia types and complete intestinal metaplasia subtypes have no obvious significance of precancerous lesions. Clinical practice shows that just from the pathological subtypes of intestinal metaplasia we are difficult to predict cancer risk. And in more than a decade, reports of Gastric cancer developed from the Large Intestinal metaplasia types are rare.So the real characteristic pathological changes is dysplasia (or intraepithelial neoplasia). In short, Research on chronic atrophic gastritis with dysplasia has a greater significance for the secondary prevention of gastric cancer.
Objective: Treatment of chronic atrophic gastritis with dysplasia by traditional Chinese medicine have a relatively good efficacy. And many studies have shown that the main TCM syndromes of Chronic atrophic gastritis with dysplasia are spleen-deficiency syndrome and blood-stasis syndrome. We use the method of hot salt water combined chemical substances to stimulate the rat model of chronic atrophic gastritis with dysplasia,use Traditional Chinese medicine (YiqiHuayu drugs groups、JianpiYiqi drugs groups and HuoxueHuayu drugs groups )and western medicine(Vitacoenzyme groups) for prevention and treatment. All these measures were hoped to explore effects of different traditional Chinese herbs on gastritic morphological and histological changes in rats with chronic atrophic gastritis with dysplasia, and explore the TCM mechanism of different traditional Chinese herbs and the relationships among different herbs.
Materials and methods:1.Take the method that using chemical substances to stimulate animal to replicate the animal models with precancerous lesions of chronic atrophic gastritis and divide them into different groups to therapy. 120 cases of healthy Wisterrats of Ordinary Level with body weight: 160±5 g (60 males and 60 females) were randomly divided into 11 groups,include the normal group, the model group, the Yiqi herbs Prevention group,the Huayu herbs Prevention group,the JianpiHuayu herbs Prevention group, the Western medicine group, the blank group of models,the Yiqi herbs Treatment group, the Huayu herbs Treatment group, the JianpiHuayu herbs Treatment group,the Western medicine Treatment group. Each group has 11 rats except the normal group with 10 rats.
Gavage the rats 10ml?kg -1?d -1 hot-salt water (150g/L、55℃) and salicylic acid solution(2%) once a day. Provide 20mmol/l sodium deoxycholate for rats to drink freely. Feed them with the method of saturating 2 days and the turn to fasting 1 day. Model the rats as above methods and operation steps for 12 weeks.At the same time gavage corresponding herbs to the rats of Yiqi herbs prevention group(6g/kg),Huayu herbs prevention group(4g/kg),Jianpi herbs prevention group(8g/kg) and Western medicine prevention group(Vitacoenzyme,1g/kg) .a12 weeks later,,all the rats of model group and prevention groups are executed to procure the specimens. On the other hand, Double distilled water(3ml per rat ) , Yiqi herbs (6g/kg),Huayu herbs (4g/kg),Jianpi herbs (8g/kg) and Vitacoenzyme(1g/kg) are gavaged correspondingly to model-control group,Yiqi herbs treatment group, Huayu herbs treatment group, JianpiHuayu herbs treatment group, Western medicine treatment group,12 weeks later, all the rats of model-control group and treatment groups are executed to procure the specimens.
2. Observe the pathological changes of rat gastric mucosa
3. Assay the changes of the expression of bcl-2 in gastric mucosa by immunohistochemical methods;Assay the reactive oxygen species(ROS)and the content of Ca~(2+) in gastric tissue by flow cytometry; Detect the changes of the expression of Caspase-3 in gastric tissue by microplate reader for enzyme activity
Results:
1. The incidence of Dysplasia in the model-control group (100%) is more than that in the Jianpi herbs Prevention group(71.4%),the Huayu herbs Prevention group (66.6%), the JianpiHuayu herbs Prevention group (12.5%)and the Western medicine prevention group(62.5%).The cases of Dysplasia in Chinese medicine and Western medicine prevention group are mainly mild dysplasia,but All of the cases in Pathologic-Control group belong to moderate and severe dysplasia.The incidence of mild dysplasia in the Jianpi herbs Prevention group is 80%, in the Huayu herbs Prevention group is 50%,in the JianpiHuayu herbs Prevention group is 100%,in the Western medicine prevention group is 60%. Although 87.5% of rats in the JianpiHuayu herbs Prevention group are not sick, The incidence of mild dysplasia in each groups(the Jianpi herbs Prevention group、the Huayu herbs Prevention group and the JianpiHuayu herbs Prevention group) has no significant difference compared with the Western medicine prevention group(P>0.05).We believe that may caused by too few rats in each groups.In the process of treatment, after 12 weeks of normal feeding,the Pathological damage of gastric mucosal dysplasia in the Model-Control group have no improvement,but after 12 weeks of Gavage treatment by herbs and Vitacoenzyme, the incidence of gastric mucosal dysplasia are lower than which in the Model-Control group(P<0.05).What in each treatment groups(62.5%、55.6%、100%、50%) are mainly mild dysplasia cases, but All of the cases in Model-Control group belong to moderate and severe dysplasia(100%). Although 75% of rats in the JianpiHuayu herbs treatment group pull through, the incidence of each groups has no significant difference compared with each other in statistics(P>0.05). We believe that may caused by too few rats in each groups.
2. The expression of BCL-2 gene in normal gastricmucosa and light, moderate ,severe dysplasia of gastricmucosa increased progressively with the illness grew worse. In the normal gastric mucosa, positive rate of Bcl-2 was 12.5%;In the model group and the model-control group, positive rate of Bcl-2 were 90%、87.5%,but the incidence of moderate and severe dysplasia are 100% in them. After prevention and treatment of each group by Chinese medicine or western medicine, with the decline in the degree of dysplasia, the rate of Bcl-2’s expression is declining. In the prevention groups, the dysplasia’s rate of Jianpi herbs group,Huayu herbs group,JianpiHuayu herbs group,and Western group are 71.4%、66.6%、12.5%、62.5%,and most concentrated in mild dysplasia,the rate are 80%, 50%, 100%, 60%.Accompanying the positive rate of the expression of Bcl-2 decline with the rate 57.1%, 55.5%, 12.5%, 50%. In the treatment group, the dysplasia’s rate of Jianpi herbs group,Huayu herbs group,JianpiHuayu herbs group,and Western group are 88.8%、90%、25%、75%, mild dysplasia’s rate are 62.5%, 55.6%, 100%, 50%, accompanying the positive rate of the expression of Bcl-2 are 55.5%,60%,25%,50%. And no matter prevention or treatment groups, the expression of Bcl-2 in Chinese groups and Vitacoenzyme group are less than the model group and the model-control group.And no matter prevention or treatment groups, effect of JianpiHuayu herbs group is better than YiqiJianpi herbs group and HuoxueHuayu herbs group.
3. Caspase-3 of gastric mucosal cells in model group and control-model group significantly reduce, compare with the normal group are significantly different (P <0.05). In the prevention groups, the expressions of Caspase-3 increase in JianpiHuayu herbs group, JianpiYiqi herbs group, HuoxueHuayu herbs group and
Western medicine Group, compare with the model group are significantly different (P <0.05). JianpiHuayu herbs group is better than other groups,but JianpiYiqi herbs group, HuoxueHuayu herbs group and Western medicine Group compare with each other are no significantly different (P>0.05)In the treatment group, the expressions of Caspase-3 increase in JianpiHuayu herbs group, JianpiYiqi herbs group, HuoxueHuayu herbs group and Western medicine Group, compare with the model-control group are significantly different (P <0.05). JianpiHuayu herbs group is better than other groups,but JianpiYiqi herbs group, HuoxueHuayu herbs group and Western medicine Group compare with each other are no significantly different (P>0.05)
4. The content of ROS and Ca~(2+) of model group obviously declined, which has significant difference compared with blank-control group (p<0.05). Either prophylaxis or treatment of drug delivery, Chinese medicine group and modern medicine group can increase the content of ROS and Ca~(2+), significantly different compared with model group(p<0.05); the effect between JianpiHuayu herbs group and modern medicine group is no difference(p>0.05), and the two groups have no significant difference compared with blank-control group(p>0.05), while the two groups have significant difference compared with Jianpi herb group and Huayu herb group (p<0.05) and get better effect than them; the effect between Jianpi herb group and Huayu herb group has no significant difference (p>0.05). From the results, it shows that the content of ROS and Ca~(2+) is the highest in the normal gastric mucosa, but the ROS and Ca~(2+) content is correspondingly minimized in model group and blank-model group in which the moderate and severe dysplasia rate is 100%. In the prophylaxis or treatment of drug delivery process, the effect of Jianpihuayu herb group is better than Jianpiyiqi herb group and Huoxuehuayu herb group (P<0.05), while Jianpiyiqi herb group and Huoxuehuayu herb group have no significant difference (P>0.05) either prophylaxis or treatment of drug delivery.
Conclusion:Either prophylaxis or treatment of drug delivery, TCM with the function of Jianpihuatan, Jianpi and Huayu shows a more significant role in prevention and treatment of the gastric epithelial dysplasia. The effecting mechanism works by reducing Bcl-2 gene expression of gastric tissue, increasing reactive oxygen species (ROS), the content of Ca~(2+) and the expression of Caspase-3 in gastric tissue, effects in all aspects of apoptosis in order to increase the apoptosis and reduce cell proliferation state to achieve the treatment of atrophic gastritis with precancerous lesions of gastric cancer and prevent the canceration. In this process, that TCM with the function of Jianpihuatan, Jianpi and Huayu effect in the three segments of this test, proves TCM can take the same place in treating atrophic gastritis with precancerous lesions of gastric cancer. TCM with the function of Jianpihuatan are significantly better than the other two treating principles in the treatment of atrophic gastritis with precancerous lesions of gastric cancer, while TCM with the function of Jianpi and TCM with the function of Huayu have no significant difference in the treatment.
目的:中药治疗慢性萎缩性胃炎伴不典型增生有着较为理想的疗效,而且大量研究表明慢性萎缩性胃炎伴不典型增生以脾虚、血瘀为主要中医临床证型。我们采用热盐水合并化学药物刺激的方法复制了慢性萎缩性胃炎伴不典型增生的大鼠模型,应用益气化瘀、健脾益气、活血化瘀中药及西药维霉素预防和治疗给药,探讨不同组方中药对慢性萎缩性胃炎伴不典型增生大鼠胃粘膜形态、组织学改变的影响,以其探讨不同组方中药的作用机制,及它们之间的相互关系。
材料与方法:
1.采用化学药物刺激的方法复制了复制了慢性萎缩性胃炎癌前病变动物模型及分组治疗。普通级,健康Wister大鼠120只,雌雄各半,体重160±5 g,将大鼠随机分为11组,分别为正常组、造模组、健脾益气方药预防组、活血化瘀方药预防组、健脾化瘀方药预防组、西药预防组、造模空白组、健脾益气方药治疗组、活血化瘀方药治疗组、健脾化瘀方药治疗组、西药治疗组。除正常组10只外,其余各组均11只。150g/L、55℃热盐水,10ml·Kg~(-1)·d~(-1) ,灌胃;2%水杨酸溶液10ml·Kg~(-1)·d~(-1) ,灌胃;均为1次/d;20mmol/L脱氧胆酸钠溶液,自由饮用;配以饥饱失常处理,即2d饱食,1d禁食。按上述方法造模12周。健脾益气方药预防组、活血化瘀方药预防组、健脾化瘀方药预防组均同时灌服中药制剂6g/kg、4g/kg、8g/kg,西药预防组同时灌服灌服西药维酶素1g/kg,连续给药12周,12周后模型组、健脾益气方药预防组、活血化瘀方药预防组、健脾化瘀方药预防组、西药预防组处死大鼠取材处理。造模空白组、健脾益气方药治疗组、活血化瘀方药治疗组、健脾化瘀方药治疗组、西药治疗组开始分别给予双蒸水(3ml/只)、中药制剂、西药维霉素,剂量同上,满24周后,处死全部大鼠,取材处理。
2.观察了大鼠模型胃粘膜病理形态变化。
3.用免疫组化的方法检测胃粘膜组织bcl-2的表达的变化,用流式细胞仪检测胃组织中活性氧(ROS)、Ca~(2+)含量的变化,用酶标仪检测胃组织中Caspase-3表达的变化。
结果:
1.造模对照组异型增生发病率100%,要高于健脾益气预防组、活血化淤预防组、健脾化淤预防组、西药预防组不典型增生发生率(71.4%、66.6%、12.5%、62.5%),且中药及西药预防组不典型增生病例多发生在轻度不典型增生,健脾益气预防组、活血化淤预防组、健脾化淤预防组、西药组轻度不典型增生发生率分别为分别为80%、50%、100%、60%,而病理对照组全部为中、重度不典型增生。健脾益气预防组、活血化瘀预防组、健脾化瘀预防组与西药预防组之间比较无显著性差异(P>0.05)。健脾化瘀中药组中有87.5%都未发病,要好于其他几组,但是统计学处理时与其他几组无显著差异,考虑系例数较少造成的。在治疗给药过程中,造模空白组大鼠胃粘膜不典型增生经12周的正常饲养,病理损伤无改善,经中药及维酶素连续12周的灌胃治疗,胃粘膜不典型增生发生率明显低于造模对照组(P<0.05),且治疗组病变程度均较轻,各组多为轻度不典型增生(62.5%、55.6%、100%、50%),而造模对照组中、重度不典型增生发病率为100%,中药治疗各组及维酶素组间无显著性差异(P>0.05)。健脾化淤治疗组中有75%都已经正常,要高于其他各组,但在统计学处理时与其他几组比较无显著性差异,考虑系样本数量较小造成的。
2. BCL-2基因在正常胃粘膜、轻、中、重度不典型增生中,其表达率随病变加重逐级增高。在正常胃粘膜中,Bcl-2阳性率为12.5%,在造模组及造模空白组中,中、重度不典型增生的发生率均为100%,Bcl-2的阳性率分别为90%、87.5%,经各组方中药和西药预防、治疗给药后,随着不典型增生程度的下降,Bcl-2表达的阳性率亦在下降,在预防给药组,健脾、化瘀、健脾化瘀、西药组的不典型增生率分别为71.4%、66.6%、12.5%、62.5%,且多集中在轻度不典型增生(80%、50%、100%、60%),与之相伴的Bcl-2表达阳性率也下降(57.1%、55.5%、12.5%、50%)。在治疗给药组,健脾、化瘀、健脾化瘀、西药组的不典型增生发生率分别为(88.8%、90%、25%、75%),轻度不典型增生的发生率为62.5%、55.6%、100%、50%,与之相应的Bcl-2表达阳性率分别为55.5%、60%、25%、50%。而且无论是预防给药还是治疗给药,中药各组及维酶素组,BCL-2基因的表达均较造模组及造模空白组减少。而且无论是预防给药还是治疗给药,健脾化瘀组领的疗效要好于益气健脾和活血化瘀。
3.造模组及造模空白组大鼠胃粘膜细胞中的Caspase– 3明显减少,与正常组比较有显著差异(P﹤0.05),在预防组中,健脾化瘀组、健脾益气组、活血化瘀组及西药组均可以使Caspase– 3的表达增加,与造模组比较有显著差异(P﹤0.05),健脾化瘀组要好于其他组,而健脾益气组、活血化瘀组、西药组之间没有显著差异(P﹥0.05)。在治疗组中,健脾化瘀组、健脾益气组、活血化瘀组及西药组也均可以使Caspase– 3的表达增加,与造模空白组比较有显著差异(P﹤0.05),健脾化瘀组要好于其他组,而健脾益气组、活血化瘀组、西药组之间没有显著差异(P﹥0.05)。
4.模型组大鼠ROS及Ca~(2+)含量明显下降,与空白对照组之间有显著差异(P﹤0.05),而无论是预防给药,还是治疗给药,中药组和西药组均可以提高ROS及Ca~(2+)含量,与造模组大鼠之间有显著性差异(P﹤0.05),无论是预防给药还是治疗给药,健脾化瘀组、西药组之间的疗效无差别(P﹥0.05),两组与正常组之间亦无显著性差异(P﹥0.05),而两组与健脾组、化瘀组比较有显著性差异(P﹤0.05),前者的疗效要好于后者,健脾组与化瘀组比较无显著性差异(P﹥0.05)。通过结果,我们不难发现,随着不典型增生程度的下降,ROS及Ca~(2+)含量均出现相应的减少。在正常胃粘膜中ROS及Ca~(2+)的含量最多,在造模组及造模空白组中,中、重度不典型增生的发生率为100%,而相应的ROS及Ca~(2+)的含量也降至最低。在预防给药和治疗给药过程中,健脾化瘀组的作用要好于健脾益气组和活血化瘀组(P﹤0.05),而健脾益气组和活血化瘀组无论是预防给药还是治疗给药之间没有显著性差异(P﹥0.05)。
结论:
无论是预防给药还是治疗给药,健脾化瘀、健脾益气、活血化瘀中药均具有较显著的预防和治疗胃粘膜上皮不典型增生作用。其疗效机理主要是通过调低胃组织中的Bcl-2的基因表达、增加胃组织中活性氧(ROS)、Ca~(2+)的含量,增加胃组织中Caspase-3的表达,在整个细胞凋亡的各个环节产生作用,从而使细胞凋亡增加,减轻细胞增殖状态,达到治疗萎缩性胃炎癌前病变,防止癌变的作用。在这个过程中,在检测的三个环节中,健脾化瘀、健脾、化瘀中药均可以发挥作用,说明在中药治疗萎缩性胃炎癌前病变的过程中具有相同的作用节点。健脾化瘀中药的治疗萎缩性胃炎癌前病变的作用要明显好于其它两种治则的中药,而健脾、化瘀中药之间的治疗作用没有显著差异。
Chronic atrophic gastritis is a common disease of digestive system caused by multiple factors, especially Antral atrophic gastritis and Gastric Cancer have a very close relationship[1,2], therefore it is called Gastric Precancerous conditions diseases. Gastric precancerous lesions is a pathological concept,refers to the gastric epithelial dysplasia (dysplasia, intraepithelial neoplasia). Dysplasia is divided into two levels: mild (low level) and severe (high level), dysplasia (intraepithelial neoplasia) is an important Gastric precancerous lesions. China Consensus of Chronic Gastritis in 2006 indicate that Small Intestinal metaplasia types and complete intestinal metaplasia subtypes have no obvious significance of precancerous lesions. Clinical practice shows that just from the pathological subtypes of intestinal metaplasia we are difficult to predict cancer risk. And in more than a decade, reports of Gastric cancer developed from the Large Intestinal metaplasia types are rare.So the real characteristic pathological changes is dysplasia (or intraepithelial neoplasia). In short, Research on chronic atrophic gastritis with dysplasia has a greater significance for the secondary prevention of gastric cancer.
Objective: Treatment of chronic atrophic gastritis with dysplasia by traditional Chinese medicine have a relatively good efficacy. And many studies have shown that the main TCM syndromes of Chronic atrophic gastritis with dysplasia are spleen-deficiency syndrome and blood-stasis syndrome. We use the method of hot salt water combined chemical substances to stimulate the rat model of chronic atrophic gastritis with dysplasia,use Traditional Chinese medicine (YiqiHuayu drugs groups、JianpiYiqi drugs groups and HuoxueHuayu drugs groups )and western medicine(Vitacoenzyme groups) for prevention and treatment. All these measures were hoped to explore effects of different traditional Chinese herbs on gastritic morphological and histological changes in rats with chronic atrophic gastritis with dysplasia, and explore the TCM mechanism of different traditional Chinese herbs and the relationships among different herbs.
Materials and methods:1.Take the method that using chemical substances to stimulate animal to replicate the animal models with precancerous lesions of chronic atrophic gastritis and divide them into different groups to therapy. 120 cases of healthy Wisterrats of Ordinary Level with body weight: 160±5 g (60 males and 60 females) were randomly divided into 11 groups,include the normal group, the model group, the Yiqi herbs Prevention group,the Huayu herbs Prevention group,the JianpiHuayu herbs Prevention group, the Western medicine group, the blank group of models,the Yiqi herbs Treatment group, the Huayu herbs Treatment group, the JianpiHuayu herbs Treatment group,the Western medicine Treatment group. Each group has 11 rats except the normal group with 10 rats.
Gavage the rats 10ml?kg -1?d -1 hot-salt water (150g/L、55℃) and salicylic acid solution(2%) once a day. Provide 20mmol/l sodium deoxycholate for rats to drink freely. Feed them with the method of saturating 2 days and the turn to fasting 1 day. Model the rats as above methods and operation steps for 12 weeks.At the same time gavage corresponding herbs to the rats of Yiqi herbs prevention group(6g/kg),Huayu herbs prevention group(4g/kg),Jianpi herbs prevention group(8g/kg) and Western medicine prevention group(Vitacoenzyme,1g/kg) .a12 weeks later,,all the rats of model group and prevention groups are executed to procure the specimens. On the other hand, Double distilled water(3ml per rat ) , Yiqi herbs (6g/kg),Huayu herbs (4g/kg),Jianpi herbs (8g/kg) and Vitacoenzyme(1g/kg) are gavaged correspondingly to model-control group,Yiqi herbs treatment group, Huayu herbs treatment group, JianpiHuayu herbs treatment group, Western medicine treatment group,12 weeks later, all the rats of model-control group and treatment groups are executed to procure the specimens.
2. Observe the pathological changes of rat gastric mucosa
3. Assay the changes of the expression of bcl-2 in gastric mucosa by immunohistochemical methods;Assay the reactive oxygen species(ROS)and the content of Ca~(2+) in gastric tissue by flow cytometry; Detect the changes of the expression of Caspase-3 in gastric tissue by microplate reader for enzyme activity
Results:
1. The incidence of Dysplasia in the model-control group (100%) is more than that in the Jianpi herbs Prevention group(71.4%),the Huayu herbs Prevention group (66.6%), the JianpiHuayu herbs Prevention group (12.5%)and the Western medicine prevention group(62.5%).The cases of Dysplasia in Chinese medicine and Western medicine prevention group are mainly mild dysplasia,but All of the cases in Pathologic-Control group belong to moderate and severe dysplasia.The incidence of mild dysplasia in the Jianpi herbs Prevention group is 80%, in the Huayu herbs Prevention group is 50%,in the JianpiHuayu herbs Prevention group is 100%,in the Western medicine prevention group is 60%. Although 87.5% of rats in the JianpiHuayu herbs Prevention group are not sick, The incidence of mild dysplasia in each groups(the Jianpi herbs Prevention group、the Huayu herbs Prevention group and the JianpiHuayu herbs Prevention group) has no significant difference compared with the Western medicine prevention group(P>0.05).We believe that may caused by too few rats in each groups.In the process of treatment, after 12 weeks of normal feeding,the Pathological damage of gastric mucosal dysplasia in the Model-Control group have no improvement,but after 12 weeks of Gavage treatment by herbs and Vitacoenzyme, the incidence of gastric mucosal dysplasia are lower than which in the Model-Control group(P<0.05).What in each treatment groups(62.5%、55.6%、100%、50%) are mainly mild dysplasia cases, but All of the cases in Model-Control group belong to moderate and severe dysplasia(100%). Although 75% of rats in the JianpiHuayu herbs treatment group pull through, the incidence of each groups has no significant difference compared with each other in statistics(P>0.05). We believe that may caused by too few rats in each groups.
2. The expression of BCL-2 gene in normal gastricmucosa and light, moderate ,severe dysplasia of gastricmucosa increased progressively with the illness grew worse. In the normal gastric mucosa, positive rate of Bcl-2 was 12.5%;In the model group and the model-control group, positive rate of Bcl-2 were 90%、87.5%,but the incidence of moderate and severe dysplasia are 100% in them. After prevention and treatment of each group by Chinese medicine or western medicine, with the decline in the degree of dysplasia, the rate of Bcl-2’s expression is declining. In the prevention groups, the dysplasia’s rate of Jianpi herbs group,Huayu herbs group,JianpiHuayu herbs group,and Western group are 71.4%、66.6%、12.5%、62.5%,and most concentrated in mild dysplasia,the rate are 80%, 50%, 100%, 60%.Accompanying the positive rate of the expression of Bcl-2 decline with the rate 57.1%, 55.5%, 12.5%, 50%. In the treatment group, the dysplasia’s rate of Jianpi herbs group,Huayu herbs group,JianpiHuayu herbs group,and Western group are 88.8%、90%、25%、75%, mild dysplasia’s rate are 62.5%, 55.6%, 100%, 50%, accompanying the positive rate of the expression of Bcl-2 are 55.5%,60%,25%,50%. And no matter prevention or treatment groups, the expression of Bcl-2 in Chinese groups and Vitacoenzyme group are less than the model group and the model-control group.And no matter prevention or treatment groups, effect of JianpiHuayu herbs group is better than YiqiJianpi herbs group and HuoxueHuayu herbs group.
3. Caspase-3 of gastric mucosal cells in model group and control-model group significantly reduce, compare with the normal group are significantly different (P <0.05). In the prevention groups, the expressions of Caspase-3 increase in JianpiHuayu herbs group, JianpiYiqi herbs group, HuoxueHuayu herbs group and
Western medicine Group, compare with the model group are significantly different (P <0.05). JianpiHuayu herbs group is better than other groups,but JianpiYiqi herbs group, HuoxueHuayu herbs group and Western medicine Group compare with each other are no significantly different (P>0.05)In the treatment group, the expressions of Caspase-3 increase in JianpiHuayu herbs group, JianpiYiqi herbs group, HuoxueHuayu herbs group and Western medicine Group, compare with the model-control group are significantly different (P <0.05). JianpiHuayu herbs group is better than other groups,but JianpiYiqi herbs group, HuoxueHuayu herbs group and Western medicine Group compare with each other are no significantly different (P>0.05)
4. The content of ROS and Ca~(2+) of model group obviously declined, which has significant difference compared with blank-control group (p<0.05). Either prophylaxis or treatment of drug delivery, Chinese medicine group and modern medicine group can increase the content of ROS and Ca~(2+), significantly different compared with model group(p<0.05); the effect between JianpiHuayu herbs group and modern medicine group is no difference(p>0.05), and the two groups have no significant difference compared with blank-control group(p>0.05), while the two groups have significant difference compared with Jianpi herb group and Huayu herb group (p<0.05) and get better effect than them; the effect between Jianpi herb group and Huayu herb group has no significant difference (p>0.05). From the results, it shows that the content of ROS and Ca~(2+) is the highest in the normal gastric mucosa, but the ROS and Ca~(2+) content is correspondingly minimized in model group and blank-model group in which the moderate and severe dysplasia rate is 100%. In the prophylaxis or treatment of drug delivery process, the effect of Jianpihuayu herb group is better than Jianpiyiqi herb group and Huoxuehuayu herb group (P<0.05), while Jianpiyiqi herb group and Huoxuehuayu herb group have no significant difference (P>0.05) either prophylaxis or treatment of drug delivery.
Conclusion:Either prophylaxis or treatment of drug delivery, TCM with the function of Jianpihuatan, Jianpi and Huayu shows a more significant role in prevention and treatment of the gastric epithelial dysplasia. The effecting mechanism works by reducing Bcl-2 gene expression of gastric tissue, increasing reactive oxygen species (ROS), the content of Ca~(2+) and the expression of Caspase-3 in gastric tissue, effects in all aspects of apoptosis in order to increase the apoptosis and reduce cell proliferation state to achieve the treatment of atrophic gastritis with precancerous lesions of gastric cancer and prevent the canceration. In this process, that TCM with the function of Jianpihuatan, Jianpi and Huayu effect in the three segments of this test, proves TCM can take the same place in treating atrophic gastritis with precancerous lesions of gastric cancer. TCM with the function of Jianpihuatan are significantly better than the other two treating principles in the treatment of atrophic gastritis with precancerous lesions of gastric cancer, while TCM with the function of Jianpi and TCM with the function of Huayu have no significant difference in the treatment.
引文
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