nitrophenols and Inflammation

Biocompatibility of dentin bonding agents (DBA) and composite resin may affect the treatment outcome (e.g., healthy pulp, pulpal inflammation, pulp necrosis) after operative restoration. Bisphenol-glycidyl methacrylate (BisGMA) is one of the major monomers present in DBA and resin. Prior studies focused on salivary esterase for metabolism and degradation of resin monomers clinically. This study found that human dental pulp cells expressed mainly carboxylesterase-2 (CES2) and smaller amounts of CES1A1 and CES3 isoforms. Exposure to BisGMA stimulated CES isoforms expression of pulp cells, and this event was inhibited by catalase. Exogenous addition of porcine esterase prevented BisGMA- and DBA-induced cytotoxicity. Interestingly, inhibition of CES by bis(p-nitrophenyl) phosphate (BNPP) and CES2 by loperamide enhanced the cytotoxicity of BisGMA and DBA. Addition of porcine esterase or N-acetyl-l-cysteine prevented BisGMA-induced prostaglandin E(2) (PGE(2)) and PGF(2α) production. In contrast, addition of BNPP and loperamide, but not mevastatin, enhanced BisGMA-induced PGE(2) and PGF(2α) production in dental pulp cells. These results suggest that BisGMA may induce the cytotoxicity and prostanoid production of pulp cells, leading to pulpal inflammation or necrosis via reactive oxygen species production. Expression of CES, especially CES2, in dental pulp cells can be an adaptive response to protect dental pulp against BisGMA-induced cytotoxicity and prostanoid release. Resin monomers are the main toxic components in DBA, and the ester group is crucial for monomer toxicity.

Topics: Adolescent; Adult; Animals; Antidiarrheals; Bisphenol A-Glycidyl Methacrylate; Carboxylesterase; Cells, Cultured; Child; Cytotoxins; Dental Pulp; Dentin-Bonding Agents; Dinoprost; Dinoprostone; Enzyme Inhibitors; Female; Gene Expression Regulation, Enzymologic; Humans; Inflammation; Isoenzymes; Loperamide; Male; Materials Testing; Nitrophenols; Reactive Oxygen Species; Swine

Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. Here we show that Prf1

Topics: Animals; Biphenyl Compounds; Cellular Senescence; Drug Evaluation, Preclinical; Female; Immunosenescence; Inflammation; Male; Mice, Inbred C57BL; Mice, Knockout; Nitrophenols; Perforin; Piperazines; Progeria; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Morphological and functional changes have been investigated in the rat model of Crohn's disease. The inflammatory bowel disease was induced by indomethacin (1 × 10 mg/kg s.c. for 3 days). Morphological alterations were evaluated by macroscopic scoring system and on the base of histological changes in the small intestine. Functional activities were studied by determination of the intestinal and hepatic elimination of p-Nitrophenol (PNP) and its metabolites (PNP-glucuronide: PNP-G and PNP-sulfate: PNP-S) during the luminal perfusion of PNP. It was found that the indomethacin induced severe macroscopic changes (hyperaemia, petechia, bleeding, erosions, ulcerations) and significant histological alterations in the small intestine of rats which were definitely inhibited by mesalazine (1000 mg/kg by gastric tube for 3 days). Disappearance of PNP from the luminal perfusion solution was diminished by indomethacin which was corrected by administration of mesalazine. Significant depression was found in the luminal appearance of PNP metabolites by giving of indomethacin and these alterations could not be compensated by mesalazine.Hepatic elimination of PNP (biliary excretion of PNP and its metabolites) was decreased definitely by indomethacin which was - at least partly - compensated by mesalazine.The findings of the present study suggest that the indomethacin-induced inflammation in the small intestine represents a useful rat model of Crohn's disease. Morphological and functional alterations caused by indomethacin can be compensated by mesalazine.

Topics: Animals; Crohn Disease; Disease Models, Animal; Glucuronates; Indomethacin; Inflammation; Inflammatory Bowel Diseases; Intestine, Small; Liver; Male; Mesalamine; Nitrobenzenes; Nitrophenols; Rats; Rats, Wistar

Colorectal cancer (CRC) is the second most common malignant neoplasia in women and men worldwide. The B-cell lymphoma 2 (Bcl-2) protein family is mainly known for its pivotal role in the regulation of the mitochondrial death pathway. Anti-apoptotic Bcl-2 proteins may provide survival benefits and induce therapy resistance in cancer cells. Among anti-apoptotic Bcl-2 proteins, we found solely Bcl-xL strongly upregulated in human CRC specimens. In order to study protein function in the context of tumor initiation and progression in vivo, we generated a mouse model lacking Bcl-xL in intestinal epithelial cells (Bcl-xL(IEC-KO)). If challenged in an inflammation-driven tumor model, Bcl-xL(IEC-KO) mice showed a significantly reduced tumor burden with lower tumor numbers per animal and decreased tumor sizes. Analysis of cell death events by immunohistochemistry and immunoblotting revealed a striking increase of apoptosis in Bcl-xL-negative tumors. qRT-PCR and immunohistochemistry excluded changes in proliferative capacity and immune cell infiltration as reasons for the reduced tumor load and thereby identify apoptosis as key mechanism. Human CRC tissue was cultured ex vivo and treated with the small molecule compound ABT-737, which inhibits Bcl-xL and Bcl-2. Under ABT-737 treatment, the amount of apoptotic tumor cells significantly increased compared with controls, whereas proliferation levels remained unaltered. In summary, our findings identify Bcl-xL as a driver in colorectal tumorigenesis and cancer progression, making it a valuable target for clinical application.

Topics: Animals; Apoptosis; bcl-X Protein; Biphenyl Compounds; Carcinogenesis; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Enterocytes; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Inflammation; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Knockout; Nitrophenols; Oncogenes; Organ Specificity; Phenotype; Piperazines; Sulfonamides; Up-Regulation