Satoshi Matsubara

Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand

In our previous study, a peroxisome proliferator‐activated receptor γ (PPARγ) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc1309 mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPARγ agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13–15 times higher than those in the wild‐type counterparts at 20 weeks of age. They were reduced dose‐dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6–20 weeks of age with suppression to almost the wild‐type level at the highest dose. Moreover, up‐regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone‐treated animals. Dose‐dependent reduction of intestinal polyps was observed in Min mice given 100–1600 ppm for 14 weeks, total numbers being decreased to 63–9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPARγ agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer.

Cloning of Mongolian gerbil cDNAs encoding inflammatory proteins, and their expression in glandular stomach during H. pylori infection

Mongolian gerbils are considered to be a good animal model for understanding the development of Helicobacter pylori‐associated diseases. However, limitations regarding the genetic information available for this animal species hamper the elucidation of underlying mechanisms. Thus, we have focused on identifying the nu‐cleotide sequences of cDNAs encoding Mongolian gerbil inflammatory proteins, such as interleukin‐1 (IL‐lβ), tumor necrosis factor a (TNF‐α), cyclooxygenase‐2 (COX‐2) and inducible nitric oxide synthase (iNOS). Furthermore, we examined the mRNA expression of these genes in the glandular stomach by RT‐PCR at 1–8 weeks after H. pylori infection. The deduced amino acid homol‐ogies to mouse, rat and human proteins were 86.2%, 83.6% and 67.8% for IL‐1β, 87.2%, 85.1% and 78.4% for TNF‐α, 91.9%, 90.2% and 84.8% for COX‐2 and 90.8%, 89.1% and 80.1% for iNOS, respectively. The average stomach weight of Mongolian gerbils inoculated with H. pylori was increased in a time‐dependent manner at 1, 2, 4 and 8 weeks after inoculation. In the py‐loric region, mRNA expression levels of IL‐1β, TNF‐α and iNOS were increased in H. pylori‐infected animals at the 2 weeks time point, while in the fundic region, expression levels of IL‐1β, TNF‐α and iNOS were elevated at 4 and 8 weeks. The COX‐2 expression level in the fundic region was clearly elevated in infected animals compared with control animals at 4 and 8 weeks, but in the py‐loric region, expression levels were similar in both infected and control animals. Thus, our results indicate that oxidative stress occurs from an early stage of H. pylori infection in the glandular stomach of Mongolian gerbils.

Induction of glandular stomach cancers in Helicobacter pylori-infected Mongolian gerbils by 1-nitrosoindole-3-acetonitrile.

Helicobacter pylori (H. pylori) infection and high intake of various traditional salt‐preserved foods are regarded as risk factors for human gastric cancer. We previously reported that Chinese cabbage contains indole compounds, such as indole‐3‐acetonitrile, a mutagen precursor. 1‐Nitrosoindole‐3‐acetonitrile (NIAN), formed by the treatment of indole‐3‐acetonitrile with nitrite under acidic conditions, shows direct‐acting mutagenicity. In the present study, NIAN administration by gavage to Mongolian gerbils (MGs) at the dose of 100 mg/kg two times a week resulted in three adduct spots (1.6 adducts/108 nucleotides in total), detected in DNA samples from the glandular stomach by 32P‐postlabeling methods. Treatment with six consecutive doses of 100 mg/kg of NIAN, two times a week for 3 weeks, induced well—and moderately—differentiated glandular stomach adenocarcinomas in the MGs at the incidence of 31% under H. pylori infection at 54–104 weeks. Such lesions were not induced in MGs given broth alone, broth + NIAN or infection with H. pylori alone. Thus, endogenous carcinogens formed from nitrosation of indole compounds could be critical risk factors for human gastric cancer development under the influence of H. pylori infection.