| Background and content:Gastric cancer is one of the common gastrointestinal cancers. It is difficult for early detection and treatment. The prognosis of gastric cancer is bad. However the incidence of gastric cancer is a long process. About 10 years are required for the development of inflammation-dysplasia-cancer. Prevention and treatment in the pre-cancerous stage is effective to reverse dysplasia and delay the occurrence of gastric cancer. Traditional Chinese medicine has advantages and characteristics in the treatment of gastric precancerous lesions (PLGC)., Actinidia valvata Dunn (AVD) belongs to the Actinidia family, which could exert detoxifying, dispel wind and dampness, which has been used to treat leprosy, digestive cancers. Through clinical practice, our research group found AVD can improve the pathological states of PLGC. Combined with the literature we find the main active ingredient in AVD can inhibit the growth of gastric cancer cells. This study is to investigate the efficacy and mechanisms of AVD in PLGC rats.This literature includes two parts. The first part summarizes the etiology and pathogenesis, treatment of PLGC between Chinese and Western medicine. It also introduces the research status of AVD. The second part is the experimental study, to establish the rat model of PLGC, to find the molecular mechanism of AVD on the treatment and reversal of PLGC which blocks the development of gastric cancer. Purpose:This study is conducted to assess the effect of AVD extract on an animal model of PLGC on the basis of changes in pathological changes of gastric mucosa, cell proliferation and apoptosis and mTOR signaling pathway. Methods:100 five-week-old male SD rats were divided into two groups. Control group(10 rats) was given normal feed, while module group(90 rats) was treated with 10% sodium chloride in the first six weeks, 100μg/ml of N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) in drinking water and 0.03% ranitidine in feed.22 weeks later, two rats from module group were killed to observe pathological changes in gastric tissue to confirm whether model was succeed every week.24 weeks we found the modeling is successful. The survival of 84 rats were randomly divided into four groups, model group was given normal feed, whereas AVD group was given AVD extract(0.03g/kg/d). High-dose AVD group was given AVD extract(0.06g/kg/d), whereas retinoic acid(RA) group was given retinoic acid(0.04g/kg/d). Model group and control group were given normal saline of the same dose. All rats were sacrificed at the end of 41-week experiment. Pathological changes of gastric mucosa were observed by HE staining. The expression of Bcl-2, Bax, Caspase-3, CyclinD1 gene and mTOR signal transduction pathway was detected by immunohistochemistry and western blot.Results:1. Control group has 10 rats, one died of pulmonary congestion, three normal, six with chronic superficial gastritis (CSG), no intestinal metaplasia (IM) and dysplasia (Dys). Model group has 21 rats, one died of pulmonary congestion, two died of stomach cancer, eight with CSG, five with CAG, six with IM, nine with Dys, the incidence of PLGC is 15 (83.3%). AVD group has 21 rats, one died of pulmonary congestion, one died of unknown causes, eleven with CSG, two with CAG, three with IM, four with Dys, the incidence of PLGC is 7(36.8%). High-dose AVD group has 21 rats, two died of pulmonary congestion, twelve with 12, two with CAG, three with IM, two with Dys, the incidence of PLGC is 5(26.3%). RA group has 21 rats, two died of unknown causes, eight with CSG, four with CAG, four with IM, three with Dys, the incidence of PLGC is 7(36.8%). Compared to control group, model group has higher incidence of PLGC(P<0.01). Compared to treatment group, model group also has higher incidence of PLGC(P<0.05). No significantly difference has been found between treatment groups (P> 0.05).2. The positive reaction of Bcl-2, Bax, Caspase-3, CyclinDl protein is brown. Rats treated with MNNG have increased expression of Bcl-2 and CyclinD1. Compared to control group, the expression of model group was the most obvious (P<0.01), while AVD and RA regulate the expression of Bcl-2 and CyclinDl. Compared to model group, AVD and RA group can reduce the Bcl-2, CyclinD1 expression (P<0.01). However, no significant difference occurs between AVDã€high-dose AVD and RA group(P> 0.05). Rats treated with MNNG have decreased expression of Bax and Caspase-3. And the control group Compared with the control, the model group decreased significantly in expression (P<0.01), while AVD and RA can regulate the expression of Bax. Compared to model group, AVD and RA group can increase the Bax and Caspase-3 expression (P<0.01). However, no significant difference is observed between AVD> high-dose AVD and RA group(P> 0.05).3. Almost no expression of PI3K, p-Akt, mTOR occurs in control group. Compared to control group, AVD^ high-dose AVD and RA group have more expression of PI3K,p-Akt, mTOR(P<0.05). Compared to AVDã€high-dose AVD and RA group, model group has higher expression of PI3K, p-Akt, mTOR(P<0.05).4. There is almost no expression of LKBl on gastric epithelial in every group by immunohistochemistry. Compared to control group, the LKBl expression in model group decreased while AVD and RA have a tendency to enhance the level of LKB1 by Western blot. Conclusions:AVD extract can improve the general condition of PLGC rats, delay the pathological aggravation and reduce the incidence of PLGC. AVD inhibits the expression of Bcl-2 and CyclinD1 protein, at the same time it improves the expression of Bax and Caspase-3; AVD inhibits PI3K/Akt/mTOR pathway and promote the positive expression of LKB1.AVD extract exhibits an obvious effect on treatment and reversal of PLGC, probably by acting on the mTOR signaling pathway to regulate the expression of related proteins and regulating cell proliferation and apoptosis. |
