Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo

SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response

Preparation of Slow-release Implant of Camellia sinensis Hydroalcoholic Extract for Prevention of Post Laparotomy Intraperitoneal Adhesion in Rat

Intra-abdominal adhesion following surgery imposes excessive costs and complications and finding effective treatment can increase the patient's quality of life. The aim of this study was preparation and evaluation of a slow-release implant containing hydroalcoholic extract of Camellia sinensis (C.s) on post laparotomy intraperitoneal adhesion. Four types of implants were prepared including (1) chi-tosan, (2) chitosan containing C.s extract, (3) chitosan and beta-glycerophosphate (β-GP) and (4) chitosan and β-GP containing C.s. Structural properties, thickness and swelling, pH and disintegration time, adhesion strength and extract release in the extracellular medium were determined. For in vivo evaluation, rats were divided in 6 groups including surgical group (without intervention), heparin and groups receiv-ing four types of implants. Fourteen days later, the amount of adhesions was determined and classified. Data was analyzed by SPSS 16. SEM showed that chitosan and β-GP implants have less porosity than chitosan. FTIR also confirmed the cross-linking of chitosan with β-GP. The implants had normal pH in the range of tissue pH and suitable adhesion, swelling, and disintegration time. In non-cross-linked im-plants, the C.s extract release was faster than cross-linked implants. The rate of fibrosis, inflammation and number of adhesive bands in different groups did not show a significant difference (p > 0.05) but the severity of adhesion was significantly different in the studied groups. Cross-linked chitosan implants containing C.s have suitable structural and physical properties and caused long-term release of C.s extract but it had no effect on intra-abdominal adhesion due to laparotomy. These results are probably because of the chitosan polymer that has been used, which has increased the adhesion

Independent and Interdependent Immunoregulatory Effects of IL-27, IFN-β, and IL-10 in the Suppression of Human Th17 Cells and Murine Experimental Autoimmune Encephalomyelitis

IFN-β, IL-27 and IL-10 have been shown to exert a range of similar immunoregulatory effects in murine and human experimental systems, particularly in Th1 and Th17 mediated models of autoimmune inflammatory disease. In this study we sought to translate some of our previous findings in murine systems to human in vitro models and delineate the inter-dependence of these different cytokines in their immunoregulatory effects. We demonstrate that human IL-27 upregulates IL-10 in T cell-activated PBMC cultures and that IFN-β drives IL-27 production in activated monocytes. IFN-β-driven IL-27 is responsible for the upregulation of IL-10, but not IL-17 suppression, by IFN-β in human PBMCs. Surprisingly, IL-10 is not required for the suppression of IL-17 by either IL-27 or IFN-β in this model or in de novo differentiating Th17 cells. Neither is IL-27 signaling required for the suppression of EAE by IFN-β in vivo. Further, and even more surprisingly, IL-10 is not required for the suppression of Th17-biased EAE by IL-27, in sharp contrast to Th1-biased EAE. In conclusion, IFN-β and IL-27 both induce human IL-10, both suppress human Th17 responses and both suppress murine EAE. However, IL-27 signaling is not required for the therapeutic effect of IFN-β in EAE. Suppression of Th17-biased EAE by IL-27 is IL-10-independent, in contrast to its mechanism of action in Th1-biased EAE. Together, these findings delineate a complex set of inter-dependent and independent immunoregulatory mechanisms of IFN-β, IL-27 and IL-10 in human experimental models and in murine Th1 and Th17-driven autoimmunity