OBJECTIVE-Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib.RESEARCH DESIGN AND METHODS-Glucose tolerance and insulin tolerance tests were done after daily intraperitoneal injection of 25 mg/kg imatinib into db/db and C57BL/6 mice for 4 weeks. Insulin signaling and endoplasmic reticulum stress responses were studied by Western blotting. -Cell mass and apoptotic -cell number were determined by combined terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and insulin immunohistochemistry. The in vitro effect of imatinib was studied using HepG2 cells.
RESULTS-Imatinib induced remission of diabetes in db/dbmice and amelioration of insulin resistance. Expression of endoplasmic reticulum stress markers in the liver and adipose tissues of db/db mice, such as phospho-PERK, phospho-eIF2␣, TRB3, CHOP, and phospho-c-Jun NH 2 -terminal kinase, was reduced by imatinib. Insulin receptor substrate-1 tyrosine phosphorylation and Akt phosphorylation after insulin administration were improved by imatinib. Serum aminotransferase levels and hepatic triglyceride contents were decreased by imatinib. Pancreatic -cell mass was increased by imatinib, accompanied by decreased TUNEL ϩ -cell and increased BrdU ϩ -cell numbers. Imatinib attenuated endoplasmic reticulum stress in hepatoma cells in vitro.
CONCLUSIONS-Imatinib
Marine sponges are natural sources of brominated organic compounds, including bromoindoles, bromophenols, and bromopyrroles, that may comprise up to 12% of the sponge dry weight. Aplysina aerophoba sponges harbor large numbers of bacteria that can amount to 40% of the biomass of the animal. We postulated that there might be mechanisms for microbially mediated degradation of these halogenated chemicals within the sponges. The capability of anaerobic microorganisms associated with the marine sponge to transform haloaromatic compounds was tested under different electron-accepting conditions (i.e., denitrifying, sulfidogenic, and methanogenic). We observed dehalogenation activity of sponge-associated microorganisms with various haloaromatics. 2-Bromo-, 3-bromo-, 4-bromo-, 2,6-dibromo-, and 2,4,6-tribromophenol, and 3,5-dibromo-4-hydroxybenzoate were reductively debrominated under methanogenic and sulfidogenic conditions with no activity observed in the presence of nitrate. Monochlorinated phenols were not transformed over a period of 1 year. Debromination of 2,4,6-tribromophenol, and 2,6-dibromophenol to 2-bromophenol was more rapid than the debromination of the monobrominated phenols. Ampicillin and chloramphenicol inhibited activity, suggesting that dehalogenation was mediated by bacteria. Characterization of the debrominating methanogenic consortia by using terminal restriction fragment length polymorphism (TRFLP) and denaturing gradient gel electrophoresis analysis indicated that different 16S ribosomal DNA (rDNA) phylotypes were enriched on the different halogenated substrates. Sponge-associated microorganisms enriched on organobromine compounds had distinct 16S rDNA TRFLP patterns and were most closely related to the ␦ subgroup of the proteobacteria. The presence of homologous reductive dehalogenase gene motifs in the sponge-associated microorganisms suggested that reductive dehalogenation might be coupled to dehalorespiration.
The two major elements in the pathogenesis of type 2 diabetes are insulin resistance and b -cell failure. The biochemical mechanisms underlying these two phenomena are incompletely understood. The plasma FFA level is commonly elevated in type 2 diabetes patients ( 1 ). Furthermore, previous studies have presented evidence suggesting that FFA released from visceral fat is one of the primary culprits in the pathogenesis of insulin resistance, which is a prerequisite for the development of type 2 diabetes ( 2 ). In addition to insulin resistance, relative insulin defi ciency is necessary for the development of type 2 diabetes. In this step of b -cell failure, FFA has also been reported to play an important role as a potential effector of pancreatic b -cell dysfunction or death (lipotoxicity) ( 3, 4 ). Thus, chronically elevated FFA may contribute to both essential steps in the development of type 2 diabetes, and it represents one of the fundamental etiological mechanisms
Ammonia-oxidizing archaea are ubiquitous microorganisms which play important roles in global nitrogen and carbon cycle on earth. Here we present the high-quality draft genome sequence of an ammonia-oxidizing archaeon, “
Candidatus
Nitrosopumilus koreensis” MY1, that dominated an enrichment culture of a soil sample from the rhizosphere. Its genome contains genes for survival in the rhizosphere environment as well as those for carbon fixation and ammonium oxidation to nitrite.
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