ABSTRACT:The

The environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) is known to cause a wide variety of toxic effects, including hepatotoxicity, by way of the aryl hydrocarbon receptor (AHR). Although inducible expression of cytochrome P450 (CYP) 1A1 and CYP1A2 is associated with liver injury caused by high-dose TCDD, the specific role of the AHR-CYP1 cascade in hepatotoxicity remains unclear. We investigated the effects of AHR activation under conditions of cholestasis. We administered oral TCDD to mice at a dose that can effectively induce Cyp1 gene expression without overt liver toxicity and then ligated their bile ducts. TCDD pretreatment enhanced bile duct ligation (BDL)-induced increases in liver and plasma bile acids, bilirubin, and aminotransferases. Histology of TCDD-pretreated BDL mice revealed massive hepatic necrosis without any increase in number of apoptotic cells. Whereas induction of AHRtarget genes by TCDD was observed similarly in sham-operated as well as in BDL mice, TCDD pretreatment of BDL mice altered the expression of hepatic genes involved in bile acid synthesis and transport. Increased plasma proinflammatory cytokines, tumor necrosis factor and interleukin-1β, in BDL mice were further elevated by TCDD pretreatment. Liver injury by TCDD plus BDL, such as increased plasma bile acids, bilirubin and aminotransferases, liver necrosis, and increased tumor necrosis factor production, was exaggerated in Cyp1a1/1a2(−/−) double knockout mice. These findings indicate that TCDD aggravates cholestatic liver damage and that the presence of CYP1A1 and CYP1A2 plays a protective role in liver damage caused by TCDD and BDL.

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Background Breast augmentation has been linked to various complications, including cancerous tumors. The majority type of breast cancer associated with breast augmentation is adenocarcinoma. Primary squamous cell carcinoma (SCC) of the breast is extremely rare in both augmented and non-augmented women. Due to the low incidence, the possible origin and the mechanism of carcinogenesis of the breast SCC are not well understood. Here, we report a rare case of pure SCC 16 years after breast augmentation with liquid silicone injection. Case presentation A 51-year-old Japanese woman was suffered from prolonged breast fluid retention in her left breast. Multiple unknown foreign bodies caused difficulties to investigate the inflammatory focus with ultrasonography. After unsuccessful surgical drainage and antibiotics treatments, the long-standing fluid retention was surgically removed and pathologically investigated. SCC was found in the removed tissue, and the patient underwent a total left mastectomy followed by postoperative chemotherapy. Pathological analysis revealed multiple cystic structures with a hard shell which enclosed high viscous liquid. A qualitative analysis using a Fourier transform infrared spectroscope defined the liquid as pure silicon, which possibly caused the squamous cell carcinogenesis. Conclusions Although liquid silicone injection is not a current option for breast augmentation, the injected silicone could result in cancerous tumor generation after years. This case revealed that unphysiological substances could lead to unexpected biological reactions, which caused difficulties in diagnosis with our routine examination. It will be required that accumulate information from more cases and develop novel diagnostic equipment and biomarkers to address these artificial substance-derived tumors.

Peptide YY (PYY) is a peptide hormone secreted from L cells in the intestine after food intake and regulates appetite and intestinal function. PYY is also expressed in the pancreas, but the mechanisms of regulation of pancreatic PYY expression have not been elucidated. The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D(3) and regulates numerous physiological processes. Because VDR is expressed in the pancreas, we investigated the role of pancreatic VDR activation and found that Pyy is a VDR target gene in the mouse pancreas. Treatment of mice with 1α-hydroxyvitamin D(3) increased plasma PYY levels. VDR activation increased mRNA and protein expression of PYY in the pancreatic islets of mice and pancreatic endocrine cell lines but did not change intestinal PYY expression. 1α-Hydroxyvitamin D(3)-dependent induction of pancreatic and plasma PYY was abolished in VDR-null mice. We identified a functional vitamin D-responsive element in the mouse Pyy promoter using chromatin immunoprecipitation assay, EMSA, and luciferase promoter assay. Thus, Pyy is a tissue-specific VDR target gene. The pancreatic VDR-PYY pathway may mediate a regulatory function of vitamin D in the neuroendocrine system.