Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies.

OBJECTIVE: Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA-2 in Japanese children with Type 1 diabetes. SUBJECTS AND MEASUREMENTS: The study group consisted of 125 childhood-onset Japanese subjects (50 males, 75 females) with Type 1 diabetes. The CTLA4 A/G polymorphism at position 49 was analysed using a PCR-restriction fragment length polymorphism (PCR-RFLP) method. The HLA-DRB1 and DQB1 genotypes were defined by DNA analysis using PCR-sequence-specific oligonucleotide (PCR-SSO) probes. The GAD65 autoantibody (GAD65Ab) and IA-2 autoantibody (IA-2Ab) titres were measured using radioimmunoassay. RESULTS: The distribution of genotype frequencies differs between subjects with Type 1 diabetes (GG: 46%, AG: 50%, AA: 5%) and controls (GG: 39%, AG: 44%, AA: 17%) (P < 0.01). The frequency of the G allele is higher in the diabetes group than in the controls (P < 0.05). When the subjects were subdivided according to HLA genotype, the two major HLA high-risk groups, with DR9-DQ9 and DR4-DQ4, that are unique to Japanese populations showed no difference in their CTLA4 polymorphism frequencies. Although no association between the CTLA4 polymorphism and the prevalence of GAD65Ab was found, CTLA4 GG subjects that had been newly diagnosed (< 9 months) had significantly higher levels of autoantibodies than AG subjects (P < 0.01). The prevalence and titres of IA-2Ab were not associated with the CTLA4 polymorphism. CONCLUSIONS: The CTLA4 gene might confer a susceptibility to childhood-onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high-risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.

Inhibitory effects of rebamipide on ENNG-induced duodenal carcinogenesis in mice: a possible strategy for chemoprevention of gastrointestinal cancers.

Rebamipide is a potent antioxidative agent; it increases gastric mucosal PGE2 production and thus protects the gastric mucosa. We hypothesized that the mechanisms of ulcer formation could be extended to carcinogenesis and that an increase in gastric mucosal protection may result in a decrease in gastric carcinogenesis. Therefore, we assessed the inhibitory effects of rebamipide on N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) -induced carcinogenesis in mice. The percentage of tumor-bearing mice in three treatment groups--ENNG + rebamipide 20 mg, ENNG + rebamipide 50 mg, and ENNG alone--was 55%, 42%, and 67%, respectively. The incidence of tumorigenesis tended to decrease with increasing doses of rebamipide. The difference between ENNG + rebamipide 50 mg and ENNG alone was statistically significant (P < 0.05). These results suggest that rebamipide may strengthen the host defense mechanisms related to carcinogenesis in the digestive tract.

Inhibitory effects and toxicity of green tea polyphenols for gastrointestinal carcinogenesis.

BACKGROUND: Recently, and epidemiologic study showed a lower risk of gastrointestinal carcinogenesis in green tea drinkers. An experiment on two-stage skin carcinogenesis in mice showed that (-)-epigallocatechin gallate (EGCG), one of the main constituents of green tea, inhibited tumor formation. METHODS: The inhibitory effects of EGCG and green tea extract (GTE) on N-ethyl-N'-nitro-N-nitroguanidine (ENNG)-induced duodenal carcinogenesis in the mouse, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis of the glandular stomach in the rat, and azoxymethane-induced colon carcinogenesis in the rat were examined. The toxicity of GTE was assessed experimentally and GTE was applied clinically in normal volunteers to determine the effective dose and to assess its harmful effects. RESULTS: EGCG and GRE inhibited chemical carcinogenesis of the gastrointestinal tract in rodents. Judging from the epidemiologic and experimental findings, it was determined that 1 g per day of GTE might be an effective dose. GTE was not toxic and no harmful effect was found during its clinical use. CONCLUSIONS: These findings suggest that EGCG and GTE are useful in preventing gastrointestinal carcinogenesis, and the clinical usefulness of GTE, which has no harmful effects and is inexpensive, should be studied further.

Inhibition of 1,2-dimethylhydrazine-induced oxidative DNA damage by green tea extract in rat.

Following subcutaneous injection of 1,2-dimethylhydrazine (DMH), which is carcinogenic to rat colon and liver, to Sprague-Dawley rats, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) was observed in the DNA of colonic mucosa and liver. The 8-OHdG formation reached the maximal level at about 24 h after the DMII injection. On the other hand, no increase of 8-OHdG was observed in the DNA of the kidney. Drinking green tea extract (GTE) for ten days prior to the DMH injection significantly inhibited the formation of 8-OHdG in the colon. These findings demonstrate that DMH causes oxidative damage to the DNA of its target organ, and that GTE protects colonic mucosa from this oxidative damage.

Risk analysis of carcinogenesis in the remnant stomach with measurement of ornithine decarboxylase activity.

Gastric ornithine decarboxylase (ODC) activity was measured as a biomarker of tumor-promoting activity in the remnant stomach of rats and humans. Gastrectomy of Wistar rats utilizing the Billroth I method caused a significantly high induction of ODC, and use of the Billroth II method caused a significantly higher induction of ODC than the Billroth I method. In humans, ODC activity of remnant gastric cancer tissue, normal-appearing mucosa of remnant gastric cancer patient, and remnant gastric mucosa without cancer after the Billroth II method were significantly higher than that of normal gastric mucosa without gastrectomy. ODC activity of remnant gastric mucosa without cancer after the Billroth II method was significantly higher than that after the Billroth I method. Risk of carcinogenesis was high in the remnant stomach, especially after the Billroth II method.