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Ligands for peroxisome proliferator-activated receptor (PPAR) γ γ γ γ have been implicated in growth inhibition and cell differentiation in certain malignancies. In this study, the effects of troglitazone, a PPARγ γ γ γ ligand, given during the postinitiation phase of oral carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO) were investigated in male F344 rats. Rats aged 6 weeks were given 4-NQO at 20 ppm for 8 weeks to induce tongue neoplasms. Starting 1 week after the cessation of 4-NQO exposure, animals were fed diets containing 0, 30 or 100 ppm troglitazone for 22 weeks. At the end of the study (week 32), the incidences of 4-NQO-induced tongue neoplasms and preneoplasms were determined histopathologically and cell proliferation activity was estimated by counting bromodeoxyuridine (BrdU)-labeling indices and cyclin D1-positive cell ratios. In addition, immunohistochemical expression of cyclooxygenase (COX)-2 and PPARγ γ γ γ was assessed in the tongue lesions. Feeding with 100 ppm troglitazone significantly decreased the incidence of squamous cell carcinoma when compared to the group without troglitazone treatment (5.0% vs. 45.8%, P < < < <0.005). Interestingly, the BrdU-labeling index and cyclin D1-positive cell ratio assessed in the non-lesional tongue squamous epithelium were reduced by dietary administration of troglitazone (P < < < <0.0001-0.005). Additionally, the immunoreactivity of COX-2 in the tongue lesions was also decreased by the treatment (P < < < <0.01-0.05). These results clearly showed that dietary troglitazone inhibits 4-NQO-induced tongue carcinogenesis and such inhibition is related to suppression of increased cell proliferation and/or COX-2 expression. This study warrants further investigation on the use of PPARγ γ γ γ ligands as a novel preventive approach for oral malignancy. (Cancer Sci 2003; 94: 365-371) he nuclear receptor superfamily acts as ligand-responsive transcription factors that participate in many processes important for cell and tissue homeostasis. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that includes receptors for steroids, thyroid hormone, vitamin D or retinoic acid.1) At present, several PPARs including PPARα, PPARβ (PPARδ, NUC-1, or FAAR), and PPARγ have been identified.2) Of these, PPARγ was initially shown to have regulatory roles in insulin sensitization. 3,4) The receptor binds to the promoter region of target genes involved in adipocyte differentiation and lipid storage [4][5][6] as a heterodimer with the retinoid X receptor.7) Activation of this receptor has been implicated in glucose metabolism, cell cycle control, and macrophage development and function. [8][9][10][11][12] In addition, recent studies suggest that PPARs play an important role in carcinogenesis. 13) 15-Deoxy-δ-prostaglandin J 2 , a natural-occurring metabolite of prostaglandin D 2 , and troglitazone, a thiazolidinedione analogue and a synthetic anti-diabetic drug, have been reported to be selective ligands for PPARγ.9, 14, 15) Re...

It is now well established that bile acids act as colon tumor promoters. However, a previous study provided conflicting data showing that dietary exposure of cholic acid (CHA), a primary bile acid, inhibits the carcinogen-induced formation of aberrant crypt foci (ACF), possible preneoplastic lesions, in colonic mucosa of rodents. Recently we found beta-catenin-accumulated crypts (BCAC) in colonic mucosa of rats initiated with azoxymethane (AOM) and provided evidence that BCAC might be preneoplastic lesions independent from ACF. In the present study, we investigated the modifying effects of dietary CHA on the formation of BCAC as well as ACF in male F344 rats after exposure to AOM to determine if the differences in the effect of CHA on these lesions could account for this discrepancy. The results indicate that administration of CHA (0.5%) in the diet during the post-initiation phase significantly reduced the total number, multiplicity and size of ACF (P < 0.00001) in AOM-exposed colonic mucosa as reported previously. The number of ACF even with >4 aberrant crypts/focus was also decreased significantly (P < 0.0002), suggesting that the large ACF are little resistant to continuous feeding of 0.5% CHA diet. Interestingly, the dietary CHA significantly enhanced both the multiplicity (P < 0.002) and size (P < 0.00001), but not the incidence, of AOM-induced BCAC when compared with the control diet group. Importantly, the number of large BCAC with >6 crypts/lesion was increased significantly by the dietary CHA (P < 0.003). Our results support the concept that BCAC are precursors of colon tumors and indicate the usefulness of BCAC as intermediate biomarkers for colon carcinogenesis, although the methodology for their detection requires further improvement.

Hypertension is a common complication in patients with gout and/or hyperuricemia. Besides, hyperuricemia is a risk factor of gout as well as ischemic heart disease in hypertensive patients. Moreover, the risk of gout is modified by antihypertensive drugs. However, it remains unclear how antihypertensive agents affect uric acid metabolism. In the present study, we investigated the uric acid metabolism in treated hypertensive patients to find out whether any of them would influence serum levels of uric acid. 751 hypertensive patients (313 men and 438 women) under antihypertensive treatment were selected. Blood pressure (BP), serum uric acid (SUA) and serum creatinine (Scr) were measured and evaluated statistically. In patients treated with diuretics, beta-blockers and/or alpha-1 blockers SUA levels were significantly higher than in patients who were not taking these drugs. Besides, the estimated glomerular filtration rate (eGFR) in patients treated with diuretics, beta-blockers and/or alpha-1 blockers was negatively correlated with SUA level. There were gender differences in the effects of beta-blockers and alpha-1 blockers. Multiple regression analysis indicated that both diuretics and beta-blockers significantly contributed to hyperuricemia in patients with medication for hypertension. Diuretics, beta-blockers and alpha-1 blockers reduced glomerular filtration rate and raised SUA levels. Calcium channel blockers, ACE inhibitors and angiotensin receptor blockers, including losartan, did not increase SUA levels.