Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the β β β β-catenin gene in its GSK-3β β β β phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of β β β β-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of β β β β-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of β β β β-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (iNOS) and the inducible type of cyclooxygenase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of iNOS is an early and important event occurring in step with β β β β-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of iNOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E 2 (PGE 2 ) receptors may be altered in colon cancers. For example, the EP 1 and EP 2 subtypes have been shown to be up-regulated and EP 3 down-regulated in AOM-induced colon cancers in rats and mice. EP 1 and EP 4 appear to be involved in ACF formation, while alteration in EP 2 and EP 3 is considered to contribute to later steps in colon carcinogenesis. n recent years, colorectal cancer has increasingly become a major cause of cancer mortality in Japan. Therefore, elucidation of the mechanisms of colon carcinogenesis and the search for chemopreventive agents are important and urgent tasks. Screening of colon cancer preventive agents has been carried out using several in vivo animal models, the majority using azoxymethane (AOM), a very potent carcinogen which induces colorectal cancers at high incidence in rats and mice. In relatively short-term experiments, aberrant crypt foci (ACF) induced by treatment with AOM in rats and mice can be used as biomarkers, since the formation and growth of these putative preneoplastic lesions are thought to be useful indices of the effects of carcinogens and agents promoting or preventing carcinogenesis in the colon.1, 2) Recently, other pre-neoplastic lesions such as β-catenin-accumulated crypts and mucin-depleted foci have also been reported as specific biomarkers for colon carcinogenesis. [3][4][5] Compounds which appear to be effec...

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The O-glycan side chains in the hinge of the glomerular IgA1 were highly underglycosylated in IgAN. These results indicate that the decreased sialylation and galactosylation of the IgA1 hinge glycopeptides play a crucial role in its glomerular deposition in IgAN.

mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in Apc Min/1 mice. Apc Min/1 and Apc 1/1 mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase-2, inducible nitric oxide synthase, b-catenin, p53, and nitrotyrosine, and mutations of b-catenin and K-ras and loss of wild-type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female ApcMin/1 mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female Apc Min/1 mice but did not develop in Apc 1/1 mice. Adenocarcinomas developed in Apc Min/1 mice that received DSS showed loss of heterozygosity of Apc and no mutations in the b-catenin and K-ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female Apc Min/1 mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of b-catenin, cyclooxygenase-2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of Apc Min/1 mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of Apc Min/1 mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS-induced inflammation may contribute to the colonic neoplasms development. ' 2005 Wiley-Liss, Inc.

Aims/hypothesis Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods Bscl2−/− mice were generated and phenotyped. X. Prieur, L. Dollet and M. Takahashi contributed equally to this study.Electronic supplementary material The online version of this article