Resolution of Liver Function Tests After Laparoscopic Common Bile Duct Exploration Versus Endoscopic Retrograde Cholangiopancreatography.

Laparoscopic cholecystectomy (LC) with laparoscopic common bile duct exploration (LCBDE) is gaining traction for the management of choledocholithiasis. Liver function tests (LFTs) are often used to determine the success of ductal clearance, yet the impact of differing therapeutic interventions, endoscopic retrograde cholangiopancreatography (ERCP) or LCBDE, have on postprocedure LFT is insufficiently described. We hypothesize that these interventions have different postoperative LFT profiles. The preprocedural and postprocedural total bilirubin (Tbili), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were analyzed of 167 patients who had successful ERCPs (117) or LCBDEs (50). Endoscopic retrograde cholangiopancreatography patients demonstrated a significant decrease in all LFTs postprocedure (n = 117; P = <0.001 for all) with a continued downtrend when a second set of LFTs was obtained (n = 102; P = <0.001 for all). For successful LC+LCBDEs, there was no significant change between preoperative and 1st postoperative Tbili, AST, ALT, and ALP and the 2nd postoperative labs.

Characterization of human pregnane X receptor activators identified from a screening of the Tox21 compound library.

The pregnane X receptor (PXR; NR1I2) is an important nuclear receptor whose main function is to regulate enzymes within drug metabolism. The main drug metabolizing enzyme regulated by PXR, cytochrome P450 (CYP) 3A4, accounts for the metabolism of nearly 50% of all marketed drugs. Recently, PXR has also been identified as playing a role in energy homeostasis, immune response, and cancer. Due to its interaction with these important roles, alongside its drug-drug interaction function, it is imperative to identify compounds which can modulate PXR. In this study, we screened the Tox21 10,000 compound collection to identify hPXR agonists using a stable hPXR-Luc HepG2 cell line. A pharmacological study in the presence of a PXR antagonist was performed to confirm the activity of the chosen potential hPXR agonists in the same cells. Finally, metabolically competent cell lines - HepaRG and HepaRG-PXR-Knockout (KO) - were used to further confirm the potential PXR activators. We identified a group of structural clusters and singleton compounds which included potentially novel hPXR agonists. Of the 21 selected compounds, 11 potential PXR activators significantly induced CYP3A4 mRNA expression in HepaRG cells. All of these compounds lost their induction when treating HepaRG-PXR-KO cells, confirming their PXR activation. Etomidoline presented as a potentially selective agonist of PXR. In conclusion, the current study has identified 11 compounds as potentially novel or not well-characterized PXR activators. These compounds should further be studied for their potential effects on drug metabolism and drug-drug interactions due to the immense implications of being a PXR agonist.

Quantitative Proteomic Profiling of Mitochondrial Toxicants in a Human Cardiomyocyte Cell Line.

Mitochondria are essential cellular organelles that participate in important cellular processes, including bioenergetics, metabolism, and signaling. Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization. Mitochondrial protein machineries with diverse functions such as protein translocation, respiration, metabolite transport, protein quality control and the control of membrane architecture interact with each other in dynamic networks. The goal of this study was to identify protein expression changes in a human cardiomyocyte cell line treated with several mitochondrial toxicants which inhibit mitochondrial membrane potential (MMP) and mitochondrial respiration. AC16 human cardiomyocyte cells were treated with carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), dinoterb, picoxystrobin, pinacyanol, and triclocarban for 18 h around the IC50 values generated from MMP assay. The samples were harvested and labeled with tandem mass tags with different mass isotopes. Peptide assignment was performed in Proteome Discoverer. Each dataset was analyzed in Ingenuity Pathway Analysis (IPA). In the proteomic profile, these compounds showed dysregulation of a group of mitochondrial proteins (e.g., NDUA, NDUB, BCS1, CYB5B, and SDHF2), as well as proteins involved in lipid metabolism (e.g., CPT, MECR, and LPGAT1), cytoskeleton protein changes (e.g., CROCC, LAMC3, FBLN1, and FMN2) and stress response (e.g., IKBKG, IKBB, SYVN1, SOD2, and CPIN1). Proteomic data from the current study provides key insights into chemical induced cellular pathway dysregulation, supporting the use of proteomic profiling as a sensitive method to further explore molecular functions and disease pathogenesis upon exposure to environmental chemicals.