Genetic variation in the farnesoid X-receptor predicts Crohn's disease severity in female patients
Authors: Wilson, Aze; Wang, Qian; Almousa, Ahmed A.; Jansen, Laura E.; Choi, Yun-hee; Schwarz, Ute I.; Kim, Richard B.
The farnesoid X receptor (FXR) is implicated in Crohn's disease (CD) pathogenesis. It is unclear how genetic variation in FXR impacts CD severity versus genetic variation in nuclear receptors such as pregnane X receptor (PXR) and the multi-drug resistance protein 1 (MDR1, ABCB1). To evaluate FXR-1G>T as a genomic biomarker of severity in CD and propose a plausible molecular mechanism. A retrospective study (n=542) was conducted in a Canadian cohort of CD patients. Genotypic analysis (FXR-1G>T, MDR1 3435C>T and PXR -25385C>T) as well as determination of the FXR downstream product, fibroblast growth factor (FGF) 19 was performed. Primary outcomes included risk and time to first CD-related surgery. The effect of estrogen on wild type and variant FXR activity was assessed in HepG2 cells. The FXR-1GT genotype was associated with the risk of (odds ratio, OR=3.34, 95% CI=1.58-7.05, p=0.002) and earlier progression to surgery (hazard ratio, HR=3.00, 95% CI=1.86-4.83, p<0.0001) in CD. Female carriers of the FXR-1GT genotype had the greatest risk of surgery (OR=14.87 95% CI=4.22-52.38, p<0.0001) and early progression to surgery (HR=6.28, 95% CI=3.62-10.90, p<0.0001). Women carriers of FXR-1GT polymorphism had a three-fold lower FGF19 plasma concentration versus women with FXR-1GG genotype (p<0.0001). In HepG2 cells cotransfected with estrogen receptor (ER) and FXR, presence of estradiol further attenuated variant FXR activity. MDR1 and PXR genotypes were not associated with surgical risk. Unlike MDR1 and PXR, FXR-1GT genetic variation is associated with earlier and more frequent surgery in women with CD. This may be through ER-mediated attenuation of FXR activation.
Photothermal-assisted antibacterial application of graphene oxide-Ag nanocomposites against clinically isolated multi-drug resistant Escherichia coli
ROYAL SOCIETY OPEN SCIENCE
Authors: Chen, Yuqing; Wu, Wei; Xu, Zeqiao; Jiang, Cheng; Han, Shuang; Ruan, Jun; Wang, Yong
In the field of public health, treatment of multidrug-resistant (MDR) bacterial infection is a great challenge. Herein, we provide a solution to this problem with the use of graphene oxide-silver (GO-Ag) nanocomposites as antibacterial agent. Following established protocols, silver nanoparticles were grown on graphene oxide sheets. Then, a series of in vitro studies were conducted to validate the antibacterial efficiency of the GO-Ag nanocomposites against clinical MDR Escherichia coli (E. coli) strains. GO-Ag nanocomposites showed the highest antibacterial efficiency among tested antimicrobials (graphene oxide, silver nanoparticles, GO-Ag), and synergetic antibacterial effect was observed in GO-Ag nanocomposites treated group. Treatment with 14.0 mu g ml(-1) GO-Ag could greatly inhibit bacteria growth; remaining bacteria viabilities were 4.4% and 4.1% for MDR-1 and MDR-2 E. coli bacteria, respectively. In addition, with assistance of photothermal effect, effective sterilization could be achieved using GO-Ag nanocomposites as low as 7.0 mu g ml(-1). Fluorescence imaging and morphology characterization uncovered that bacteria integrity was disrupted after GO-Ag nanocomposites treatment. Cytotoxicity results of GO-Ag using human-derived cell lines (HEK 293T, Hep G2) suggested more than 80% viability remained at 7.0 mu g ml(-1). All the results proved that GO-Ag nanocomposites are efficient antibacterial agent against multidrug-resistant E. coli.