Pharmacodynamics and mechanism of Shaoyao Gancao Intragastric Floating Tablets based on unification of medicines and excipients / 中草药

Objective: To study the pharmacodynamic effect of “unification of medicines and excipients” and the mechanism of action about Shaoyao Gancao Intragastric Floating Tablets (SGIFT). Methods: Rabbits were randomly divided into control group and model group, Shenmei Yangwei Granule group (1.0 g/kg), Shaoyao Gancao Decoction extract group (1.0 g/kg), low-dose SGIFT group (1.0 g/kg), high-dose SGIFT group (1.5 g/kg), chitosan blank excipients group (1.0 g/kg). The acute gastric ulcer model was established in the blank excipient group without chitosan (1.0 g/kg). Six rats in each group, fasting for 24 h after 13 d of continuous administration, and gastric administration of anhydrous ethanol (2.5 mL/single). The blood and gastric tissue were taken out after 1.5 h to observe the pathological damage in each group. The expression of GAS, MDA, PG, epidermal growth factor (EGF) in serum and EGF, PGE2, TFF1 in gastric tissue of each group were detected. Results: Compared with the model group, the other groups can improve the gastric histopathology of rabbits with acute gastric ulcer effectively. The content of EGF in serum and EGF, PGE2, and TFF1 in gastric tissue of rabbits was increased in varying degrees, and the content of GAS, MDA, and PG in serum was all decreased in different degrees. Conclusion: SGIFT had certain therapeutic effects on rabbits with anhydrous ethanol gastric ulcer. The mechanism might be related to protecting gastric mucosa, increasing the content of protective factors, and reducing the content of attack factors.

Disruption of the Tff1 gene in mice using CRISPR/Cas9 promotes body weight reduction and gastric tumorigenesis / 한국실험동물학회지

Trefoil factor 1 (TFF1, also known as pS2) is strongly expressed in the gastrointestinal mucosa and plays a critical role in the differentiation of gastric glands. Since approximately 50% of all human gastric cancers are associated with decreased TFF1 expression, it is considered a tumor suppressor gene. TFF1 deficiency in mice results in histological changes in the antral and pyloric gastric mucosa, with severe hyperplasia and dysplasia of epithelial cells, resulting in the development of antropyloric adenoma. Here, we generated TFF1-knockout (KO) mice, without a neomycin resistant (NeoR) cassette, using the clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9 (CRSIPR/Cas9) system. Though our TFF1-KO mice showed phenotypes very similar to the previous embryonic stem (ES)-cell-based KO mice, they differed from the previous reports in that a reduction in body weight was observed in males. These results demonstrate that these newly established TFF1-KO mice are useful tools for investigating genetic and environmental factors influencing gastric cancer, without the effects of artificial gene insertion. Furthermore, these findings suggest a novel hypothesis that TFF1 expression influences gender differences.

Association between Promoter Polymorphisms of TFF1, TFF2, and TFF3 and the Risk of Gastric and Diffuse Gastric Cancers in a Korean Population

Gastric cancer is one of the most common cancers in the world. The aims of this study were to evaluate the association between polymorphisms in TFF gene family, TFF1, TFF2, and TFF3 and the risk of gastric cancer (GC) and GC subgroups in a Korean population via a case-control study. The eight polymorphisms in TFF gene family were identified by sequencing and genotyped with 377 GC patients and 396 controls by using TaqMan genotyping assay. The rs184432 TT genotype of TFF1 was significantly associated with a reduced risk of GC (odds ratio, [OR) = 0.45; 95% confidence interval, [CI] = 0.25-0.82; P = 0.009), more protective against diffuse-type GC (OR = 0.20; 95% CI = 0.05-0.89; P = 0.035) than GC (OR = 0.34; 95% CI = 0.14-0.82; P = 0.017) in subjects aged < 60 yr, and correlated with lymph node metastasis negative GC and diffuse-type GC (OR = 0.44; 95% CI = 0.23-0.86; P = 0.016 and OR = 0.20; 95% CI = 0.05-0.87; P = 0.031, respectively). In addition, a decreased risk of lymph node metastasis negative GC and diffuse-type GC was observed for rs225359 TT genotype of TFF1 (OR = 0.46, 95% CI = 0.24-0.88; P = 0.020 and OR = 0.21, 95% CI = 0.05-0.88; P = 0.033, respectively). These findings suggest that the rs184432 and rs225359 polymorphisms in TFF1 have protective effects for GC and contribute to the development of GC in Korean individuals.

Expression of MUC5AC and Trefoil Peptide 1 (TFF1) in the Subtypes of Intestinal Metaplasia

BACKGROUND/AIMS: Alterations of the expression pattern of mucins and trefoil peptides have been described in gastric adenocarcinomas and in their precursor lesions. The aim of this study was to determine the progression patterns of intestinal metaplasia (IM) subtypes by analyzing the expression patterns of TFF1 and MUC5AC in different subtypes of IM of the stomach. METHODS: Endoscopic gastric biopsies of the antrum and body were obtained from patients with dyspepsia and endoscopic IM. Alcian blue/periodic acid-Schiff staining and the high iron diamine technique were used to classify the subtypes of IM. Immunoreactivity for MUC5AC and TFF1 was estimated in different types of IM. RESULTS: IM was detected in 128 samples from 80 patients; type I was found in 48 samples, type II was found in 37 samples, and type III was found in 43 samples. There was a gradual decrease in MUC5AC and TFF1 expression during the progression of IM from type I to type III via the type II intermediate. CONCLUSIONS: This downregulation of MUC5AC and TFF1 expression may challenge the sequential progression of IM from type I to type III via the type II intermediate, and it might be associated with gastric carcinogenesis.

An Association of C/T Polymorphism in the TFF1 Gene and the Susceptibility to Gastric Cancer

PURPOSE: This study investigated whether a single nucleotide polymorphism (SNP) located at position -2 in the Kozak sequence of the TFF1 gene is associated with H. pylori infection and the development of gastric cancer in Koreans. MATERIALS AND METHODS: We enrolled 167 patients with gastric cancer from January 2000 to December 2003 and also 299 healthy controls during the same period. The genotype of the TFF1 SNP was analyzed by polymerase chain reaction-restriction fragment length polymorphism and single strand conformation polymorphism. We also examined the H. pylori infection by Giemsa staining. RESULTS: No significant difference in the allele or the TFF1 SNP genotype frequency was observed between the patients with gastric cancer and the control subjects (P=0.595 and P=0.715, respectively). When stratified by the histological subtype of gastric cancer and the age of the patients, the risk was not statistically significant between the two study groups (P=0.088 and P=0.551, respectively). H. pylori infection was detected in 39 cases and it was not associated with the TFF1 genotype. CONCLUSION: These findings suggest that this TFF1 gene polymorphism is not associated with H. pylori infection and gastric cancer in Koreans and so it doesn't contribute to the susceptibility to gastric cancer in Koreans.

Expression of pS2/TFF1 Protein in Normal Colonic Mucosa, Adenoma and Adenocarcinoma

BACKGROUND: The trefoil factor 1 protein (pS2/TFF1) is a candidate tumor-suppressor protein, and it is a pleiotropic factor involved in the organization and homeostasis of the gastrointestinal tract and various inflammatory or neoplastic diseases. The purpose of this study was to assess the expression of pS2/TFF1 and its clinicopathologic relationship, including the p53 and Ki-67 labeling index, in colorectal carcinogenesis. METHODS: The expression of pS2/TFF1 protein was evaluated immunohistochemically in 45 samples of normal colonic mucosa, 43 samples of adenoma and 186 samples of colorectal carcinoma. RESULTS: pS2/TFF1 protein was expressed weakly in 37.8% of normal colonic mucosa samples, and it had a weak to strong expression in 48.8% of adenomas and 28% of colorectal adenocarcinomas. pS2/TFF1 expression in carcinoma was slightly increased in the poorly differentiated group compared with the well to moderately differentiated group (p=0.059). Interestingly, mucinous carcinoma (4/4) and signet ring cell carcinoma (2/3) showed significant increase of pS2/TFF1 expression. pS2/TFF1 expression was inversely correlated with the p53 protein expression and the Ki-67 labelling index (p<0.05). There was no significant correlation with the tumor size, metastasis or pathologic staging. CONCLUSIONS: Overexpression of pS2/TFF1 expression in colorectal adenocarcinoma was inversely correlated with the Ki-67 labelling index and the p53 expression in cancer. These results suggest that pS2/TFF1 protein may contribute as tumor suppressor factor in colorectal adenocarcinoma.