Results: Result 1. LPS induced live injury with increased FK228 serum ALT, AST, and TNF levels, high histological injury score, apoptosis of hepatocytes, accumulation of macrophage and neutrophil evidenced with increment of CD68 expression and MPO activity

in liver.2. AICAR or compound C treatment decreased ALT, AST, and TNF levels in serum, reduced histological injury score, CD68 expression, MPO activity, apoptosis cell number in liver of mice with endotoxemia. However, combination of AICAR and compound C treatments failed to exhibit the benefit effect of each single treatment.3. In survival experiments, AICAR or compound C treatment improved survival of endotoxemic mice. Conclusion: ConclusionAICAR or compound C treatment attenuates LPS-induced liver dysfunction, indicating that activation of inhibition AMPK signal can inhibit endotoxemia-induced immune response and liver injury. AMPK signal may provide an alternative to the current clinical treatments for endotoxemia. Key Word(s): 1. Endotoxemia; 2. AMPK; 3. AICAR; 4. liver damage; Presenting Author: HUITING GAO Additional Authors: LISHU

XU, LICHANG GUAN, DONGFENG LI, WEIPING DENG Corresponding Author: LISHU XU Affiliations: Guangdong General Nivolumab in vivo Hospital Objective: The aims of the study were to investigate the effect of glucagon-like peptide-1 (GLP-1) on diet induce non-alcoholic fatty liver disease (NAFLD) in rats. Methods: A total of 30 male rats were randomly divided into three groups. Each group contained 10 rats, in which they were fed with normal diet (ND), high-fat diet (HFD), high-fat diet with intraperitoneal injection of liraglutide (HFD+GLP-1, first 12 weeks with HFD, later 4 weeks with liraglutide) for 16 weeks respectively. After 16 weeks’ feeding, the rats were killed ethically and their blood samples and liver tissues were collected. The levels of aminotransferase (ALT), aspartate-aminotransferase (AST), triglyceride (TG), total-cholesterol 上海皓元医药股份有限公司 (TC) were detected by biochemistry automatic analyzer. The levels of superoxide dismutase (SOD)

and malondial-dehyde (MAD), tumor necrosis factor-a (TNF-a), JNK-1 and P-JNK1 in liver homogenates were detected by RIA, ELISA and Western blot respectively. Results: The body weight, liver index, serum and liver homogenates levels of TG, TC, ALT and TG, TC, MAD, TNF-a in the HFD group were apparently higher than those in the normal group, while the level of SOD decreased significantly. When compared with the HFD group, the body weight, liver index, serum and liver homogenates levels of TG, TC, ALT and TG, TC, MAD, TNF-a in the HFD+GLP-1 group decreased apparently, while the level of SOD increased. (P < 0.05) Conclusion: Liraglutide (GLP-1) has an anti-inflammatory effect on NAFLD rats, which is conducted by decreasing blood lipid and liver homogenate inflammation index level. Key Word(s): 1. NAFLD; 2. GLP-1; 3.

The aim of the present study was to identify factor(s) predisposing to reintervention. Methods:  Retrospective review of patients (n = 117) referred to a single major endoscopic referral centre for palliative enteral stenting Lumacaftor supplier from 1999 to 2006. Twelve were excluded due

to inadequate follow-up data (n = 7) or initial radiographic documentation (n = 5). A total of 105 patients (gastroduodenal n = 57, colonic n = 48) were therefore analyzed. The primary outcome of interest was recurrent obstruction necessitating reintervention. Kaplan–Meier analysis of potential factors predisposing to reintervention, including stent angulation (mild [<15°], moderate [15°–90°], severe [>90°]) was completed for 98 patients (technically successful enteral stenting). Results:  Technical and clinical success were achieved in 98 of 105 (93.3%) and 92 of 98 (93.9%) cases, respectively. Post-stenting median survival was 97.5 days (range 3–1054). Eighteen patients (18.4%) required reintervention for stent obstruction at a median time to reintervention of 85 days (range 7–481). Increased stent angulation (severe vs mild hazard ratio 6.73 (95% confidence interval 1.59–27.59), PS341 P = 0.009) was the only statistically significant factor in multivariate analysis predicting reintervention. Conclusions:  Despite its limitation as a retrospective review, this study found that reintervention

for stent obstruction is necessary in almost one in five cases, and increasing severity of stent angulation is the most important risk factor. “
“Background and Aim:  Accumulating evidence suggests that the extracellular

matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett’s esophagus metaplasia-dysplasia-adenocarcinoma sequence. Methods:  A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett’s esophagus intestinal medchemexpress metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. Results:  The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett’s esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett’s esophagus than in the stroma of the normal esophagus (P < 0.0001) and that there were 5.

The aim of the present study was to identify factor(s) predisposing to reintervention. Methods:  Retrospective review of patients (n = 117) referred to a single major endoscopic referral centre for palliative enteral stenting Anti-infection Compound Library from 1999 to 2006. Twelve were excluded due

to inadequate follow-up data (n = 7) or initial radiographic documentation (n = 5). A total of 105 patients (gastroduodenal n = 57, colonic n = 48) were therefore analyzed. The primary outcome of interest was recurrent obstruction necessitating reintervention. Kaplan–Meier analysis of potential factors predisposing to reintervention, including stent angulation (mild [<15°], moderate [15°–90°], severe [>90°]) was completed for 98 patients (technically successful enteral stenting). Results:  Technical and clinical success were achieved in 98 of 105 (93.3%) and 92 of 98 (93.9%) cases, respectively. Post-stenting median survival was 97.5 days (range 3–1054). Eighteen patients (18.4%) required reintervention for stent obstruction at a median time to reintervention of 85 days (range 7–481). Increased stent angulation (severe vs mild hazard ratio 6.73 (95% confidence interval 1.59–27.59), http://www.selleckchem.com/products/forskolin.html P = 0.009) was the only statistically significant factor in multivariate analysis predicting reintervention. Conclusions:  Despite its limitation as a retrospective review, this study found that reintervention

for stent obstruction is necessary in almost one in five cases, and increasing severity of stent angulation is the most important risk factor. “
“Background and Aim:  Accumulating evidence suggests that the extracellular

matrix play important roles in intercellular communications and contribute to the development of a number of diseases, including diseases of the gastrointestinal tract. The present study examined the structural characteristics and alterations of the extracellular matrix of the mucosa stroma in the Barrett’s esophagus metaplasia-dysplasia-adenocarcinoma sequence. Methods:  A total of 41 esophageal tissue specimens (15 esophageal adenocarcinoma, 10 Barrett’s esophagus intestinal MCE公司 metaplasia, seven dysplasia and nine normal esophagus) were studied. The present study used transmission electron microscopy and computerized quantitative electron-microscopic analysis in order to investigate the characteristics of the extracellular matrix of the mucosa. Results:  The study revealed that marked structural alterations of the mucosa stroma, relating to changes in the distribution and appearance of collagen fibers as well as to changes in numbers of matrix microvesicles, occur in Barrett’s esophagus and esophageal adenocarcinoma. It was found that there were 3.1 times more microvesicles in the stroma in Barrett’s esophagus than in the stroma of the normal esophagus (P < 0.0001) and that there were 5.

A lack of response to treatment for WD would be expected for CDG patients as well. In summary, Nicastro et al.’s data6 demonstrate that the approach of the current guidelines of the American Association for the Study of Liver Diseases to the diagnosis of WD, which calls for obtaining a slit lamp examination, a serum ceruloplasmin level, and a 24-hour urine copper level (and then liver biopsy in some) is useful even in young, clinically asymptomatic children. The

WD scoring system makes use of these data and helps clinicians to gauge the degree of certainty of the diagnosis. In addition, WD scores greater than 4 appear find more to be validated. Molecular testing for diagnosis has come of age and is perhaps the

new standard for family screening; at present, it is still expensive and not always obtainable for all patients, although it is commercially available. In the pediatric population with liver ailments, WD should be considered in patients with undefined disease, in those rare young patients with concurrent neurological problems, and in those patients Selleckchem Opaganib with a suboptimal response to therapy directed against another presumed liver disease (especially autoimmune hepatitis). As shown by this study, we can now “mine for copper” and for mutant genes in the very young and use the WD score to be more confident in establishing a correct diagnosis of WD. However, keeping our suspicion high and considering a diagnosis of WD before the “ore” or, more specifically, the copper creates irreversible cellular damage are critical to achieving better outcomes for patients with this treatable disorder. “
“Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, et al. Macrophage-derived Wnt opposes Notch signaling

to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 2012;18:572-579. www.nature.com (Reprinted with permission.) During chronic MCE公司 injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during acute liver injury is promoted.

MELD score is the independent predictive factor of prognosis. Given its overall dismal prognosis, prevention, earlier diagnosis and treatment of HRS should be emphasized. Key Word(s): 1. hepatorenal syndrome; 2. prognostic analysis; Presenting Author: SONG YUHU Additional Authors: DOU DOU, YE JIN, SHANG HAITAO, XU

KESHU, HOU XIAOHUA Corresponding Author: SONG YUHU Affiliations: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Objective: The diagnosis of malignant ascites is a challenging problem in clinical practice. non-invasive Galunisertib clinical trial techniques should be developed to improve diagnostic accuracy. The diagnostic performances of serum-ascites albumin gradient (SAAG), ascitic cholesterol and tumor markers in malignant ascites remained unsettled. Methods: A total of 437 patients were enrolled, and the relevant parameters of the patients were analyzed for the differentiation of benign ascites from malignant ascites. Results: Significant difference in SAAG and ascitic cholesterol was observed between portal hypertension and other causes. At the predetermined buy PLX-4720 cutoff values of tumor makers, tumor markers in ascitic

fluid showed better diagnostic performance than those in serum. combined use of tumor markers and the cytology increased the diagnostic yield of the latter by 37%. The combined ascitic tumor markers in cytologically negative malignant yielded 86% sensitivity, 97% specificity. Conclusion: SAAG and ascitic cholesterol were quiet effective in distinguishing portal hypertension from other causes. Detection of tumor markers may represent a beneficial adjunct to cytology due to improved diagnostic efficacy in malignant ascites, thus guiding the selection of patients who might benefit from further invasive procedures. Key Word(s): 1. albumin gradient; 2. cholesterol; 3. tumor markers;

4. malignant ascites; Presenting Author: LIN SU Additional Authors: ZHIXIA DONG, JIANHUA WANG Corresponding Author: LIN SU Affiliations: Department of Gastroenterology, Peking University People’s Hospital Objective: To clarify the role of hepatocyte senescence in the activation of hepatic stellate cells and try to find a new mechanism of liver fibrosis. Methods: HepG2 cells were cultured in DMEM (1%FCS) with 上海皓元 2 mM H2O2 for 48 h and then in DMEM (10%FCS) for another 7 days. Senescence was confirmed by senescence associated β-GAL staining. P21 protein were assessed by Western-blot and profibrotic cytokine (IL-8) was measured by RT-PCR. Conditioned medium of senescent HepG2 was transferred into LX-2(human hepatic stellate cell line) for 48 h and then CollagenI and SMA in LX-2 were tested by RT-PCR and Western-blot. Results: 90% HepG2 cells became senescent after treated with 2 mM H2O2 confirmed by senescence associated β-GAL staining and increase P21 protein expression (P = 0.025). IL-8 in senescent HepG2 cells increased significantly (P = 0.00004). Collagen I gene (P = 0.03) and SMA protein (P = 0.

Liver tissue was obtained from an archive of paraffin-embedded time-zero liver biopsies stored in the Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK. All liver tissue had been fixed in 10% neutral formalin and subjected to standard processing and paraffin-embedding. Tissue was reviewed Erlotinib by a single histopathologist for features of graft injury including steatosis, reperfusion injury and preexisting liver disease. Time-zero liver samples and subject data were reviewed and sections of adequate size were chosen to reflect normality according to the following criteria: no history of liver or senescence-related disease; a short medical

illness

preceding death (intracranial hemorrhage in 65%, trauma in 26%); no or minimal reperfusion injury; no steatosis; see more and normal recipient posttransplantation liver function at 1 year. Liver sections from 73 subjects aged 5-79 years were selected from over 1,000 cases. Mean cold ischemic time was 675 minutes (SD 155). (Table 1: subject demographics). To determine whether selection criteria for using time-zero liver were valid, archived liver tissue from patients with hyperoxalosis (n = 5) removed at combined liver and kidney transplantation was studied and compared with age-matched time-zero samples. These livers were processed immediately and were not subjected to ischemic insult prior to processing. Six serial

10-μm sections exceeding 1.5 cm in length were cut to stain the major intrahepatic cell lineages. Paraffin sections were deparaffinized with xylene, hydrated through graded ethanol and placed in deionized water. Slides were boiled at 97°C in sodium citrate MCE buffer (pH 6.0) for 30 minutes to enhance target retrieval. Following cooling at room temperature for 20 minutes, slides were transferred into phosphate buffered saline for 5 minutes before fixation in 4% formaldehyde for 5 minutes at room temperature. Enzymatic unmasking was achieved with porcine pepsin solution containing 1 mg/mL pepsin (Sigma, Gillingham, UK) in a 0.84% hydrochloric acid solution (pH 2.0) for 10 minutes at 37°C. Slides were rinsed in deionized water, and 80 μL hybridization mix was added (2.5 μL of 25 μg/mL PNA Cy5-labeled telomere-specific probe [TelC Cy5-oo-(CCCTAA)3 PNA probe with >95% purity; Cambridge Research Biochemicals, Billigham, UK] with 1.5 μL 1 M Tris-Cl [pH 7.2]/10.7 μL MgCl2 [25 mM MgCl2/9 mM citric acid/8.2 mM NaH2PO4 (pH 7.4)/87.5 μL deionized formamide; Sigma, Gillingham, UK]/6.2 μL 10% [wt/wt] blocking reagent [Roche, Welwyn Garden City, UK] /16.6 μL deionized water). Hybridization was performed at room temperature for 2 hours in the dark after denaturation at 80°C.

Liver tissue was obtained from an archive of paraffin-embedded time-zero liver biopsies stored in the Department of Pathology, Addenbrooke’s Hospital, Cambridge, UK. All liver tissue had been fixed in 10% neutral formalin and subjected to standard processing and paraffin-embedding. Tissue was reviewed Selleck SCH727965 by a single histopathologist for features of graft injury including steatosis, reperfusion injury and preexisting liver disease. Time-zero liver samples and subject data were reviewed and sections of adequate size were chosen to reflect normality according to the following criteria: no history of liver or senescence-related disease; a short medical

illness

preceding death (intracranial hemorrhage in 65%, trauma in 26%); no or minimal reperfusion injury; no steatosis; STA-9090 and normal recipient posttransplantation liver function at 1 year. Liver sections from 73 subjects aged 5-79 years were selected from over 1,000 cases. Mean cold ischemic time was 675 minutes (SD 155). (Table 1: subject demographics). To determine whether selection criteria for using time-zero liver were valid, archived liver tissue from patients with hyperoxalosis (n = 5) removed at combined liver and kidney transplantation was studied and compared with age-matched time-zero samples. These livers were processed immediately and were not subjected to ischemic insult prior to processing. Six serial

10-μm sections exceeding 1.5 cm in length were cut to stain the major intrahepatic cell lineages. Paraffin sections were deparaffinized with xylene, hydrated through graded ethanol and placed in deionized water. Slides were boiled at 97°C in sodium citrate MCE buffer (pH 6.0) for 30 minutes to enhance target retrieval. Following cooling at room temperature for 20 minutes, slides were transferred into phosphate buffered saline for 5 minutes before fixation in 4% formaldehyde for 5 minutes at room temperature. Enzymatic unmasking was achieved with porcine pepsin solution containing 1 mg/mL pepsin (Sigma, Gillingham, UK) in a 0.84% hydrochloric acid solution (pH 2.0) for 10 minutes at 37°C. Slides were rinsed in deionized water, and 80 μL hybridization mix was added (2.5 μL of 25 μg/mL PNA Cy5-labeled telomere-specific probe [TelC Cy5-oo-(CCCTAA)3 PNA probe with >95% purity; Cambridge Research Biochemicals, Billigham, UK] with 1.5 μL 1 M Tris-Cl [pH 7.2]/10.7 μL MgCl2 [25 mM MgCl2/9 mM citric acid/8.2 mM NaH2PO4 (pH 7.4)/87.5 μL deionized formamide; Sigma, Gillingham, UK]/6.2 μL 10% [wt/wt] blocking reagent [Roche, Welwyn Garden City, UK] /16.6 μL deionized water). Hybridization was performed at room temperature for 2 hours in the dark after denaturation at 80°C.

Although none of the individual functional variants were shared by all 3 patients, we identified 24 common genes (Table 1) in which the 3 Alvelestat research buy aplastic anemia cases harbor putatively functional

variants. The top 2 functional categories revealed by IPA were developmental disorder (5 genes) and hematological disease (1 gene). One common gene SPTA1, spectrin, alpha, erythrocytic 1 (elliptocytosis 2) – was shared by the 2 categories. Two of the 3 aplastic anemia patients carry at least 1 heterozygous SPTA1 mutation; 1 carries a deleterious missense mutation (rs35237700, PolyPhen-2 score 1.000), and the other,

2 relatively benign mutations (rs150007668 and rs143459302, PolyPhen-2 score 0.249 and 0.001, respectively). Conclusions: We characterized the entire genomes of 3 patients who developed aplastic anemia during antiviral therapy, buy 5-Fluoracil and identified 24 genes possibly associated with drug-induced aplastic anemia. List of 24 genes with possible association with drug-induced aplastic anemia. ALPK3 CLUL1 KIF21A MUC12 OR2T5 RNASE11 SH3TC2 STAB1 CENPJ DNAH9 KLHDC4 NUDT14 OR4C15 R0B04 SLC1A5 STARD9 CHD5 FAM21C MNS1 ODZ3 PPIL2 RP11-529J17. 2 SPTA1 VEZT Disclosure: Jacob George – Advisory Committees or Review Panels: Roche, BMS, MSD, Gilead, Janssen Alexander J. Thompson – Advisory Committees or Review Panels: Merck, Inc, Roche, Janssen (Johnson & Johnson), BMS, GSK Australia, Novartis, GILEAD Sciences, Inc; Consulting: GILEAD Sciences, Inc; Grant/Research Support: Merck, Inc, Roche, GILEAD Sciences, Inc; Speaking and Teaching: Merck, Inc, Roche, BMS Steven L. Flamm – Advisory Committees or Review Panels: Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex; Grant/Research Support: Merck, Vertex, 上海皓元 Gilead, Pfizer,

Anadys, Achillion, Abbott, Tibotec, Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec, Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec, Merck, Vertex, Gilead, Pfizer, Anadys, Achillion, Abbott, Tibotec; Speaking and Teaching: Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex, Merck, Gilead, Vertex Dongliang Ge – Employment: Gilead Sciences, Inc Matthew Paulson – Employment: Gilead Sciences Bittoo Kanwar – Employment: Gilead Sciences Phil S. Pang – Employment: Gilead Sciences Mani Subramanian – Employment: Gilead Sciences John G. McHutchison – Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences David B.

7A-C).8 INT-747 and INT-767 increased the size and amount of bile infarcts, as well as LW/BW ratio, in CBDL mice (Supporting Fig. 12A,B), whereas only INT-767 significantly decreased SW/BW ratio (Supporting Fig. 12C) and showed a trend to reduction of serum ALT (Supporting Fig. 13A). Although histological examination

of H&E-stained livers revealed bile infarcts in all the groups, only INT-747 increased infiltration of inflammatory cells within the portal fields (Supporting Fig. 13B). In line with serum ALT levels, INT-767-fed CBDL mice had reduced expression of proinflammatory genes Tnf-α and Il-1β and less CD-11b- and F4/80-positive cells around bile infarcts (Supporting Fig. 14A,B). However, keratin 19 (K19) and Vcam-1 gene expression remained unchanged in CBDL mice after INT-747, INT-777, and INT-767 feeding (Supporting Fig. 15). In this study, we have addressed the see more therapeutic mechanisms of BA receptor signaling through the nuclear BA receptor, FXR, and the G-protein-coupled membrane BA receptor, TGR5, in the Mdr2−/− mouse cholangiopathy model. We report herein that, in this model, the novel FXR/TGR5 agonist, INT-767, reduces bile toxicity by decreasing biliary BA output and inducing HCO-rich

find more choleresis in an FXR-dependent manner. BAs are important signaling molecules with hormonal actions through dedicated nuclear and G-protein-coupled receptors, such as FXR and TGR5, respectively.8 TGR5 and FXR polymorphisms19, 20 further support the importance

of BA signaling in human cholestastic diseases, such as PSC. Liver injury in Mdr2−/− mice is considered to evolve because of detergent properties of nonmicellar-bound free biliary BAs,29 leaving many open questions for the potential role of BA signaling in modulating biliary pathophysiology. Only the dual FXR/TGR5 agonist, INT-767, MCE公司 was hepatoprotective in the Mdr2−/− model, as reflected by reduced serum ALT, decreased hepatic inflammation, improved reactive cholangiocyte phenotype, and reduced fibrosis. We could neither observe significant direct anti-inflammatory effects of INT-767 in RAW264.7 macrophages (with very low endogenous Fxr and Tgr5 expression), BEC cholangiocytes, or HepG2 hepatocytes (both with high levels of Fxr and very low Tgr5; data not shown) nor direct antifibrotic effects in primary MFBs (with very low endogenous Fxr and Tgr5 expression) as major fibrogenic cells in the Mdr2−/− model. Absent expression of FXR and TGR59, 11 in hepatic stellate cells further indicates that FXR and TGR5 signaling may have no direct antifibrotic effects. These findings led us hypothesize that INT-767 might improve liver injury by directly impacting on bile formation and composition. Indeed, via Fxr activation, INT-767 inhibited BA synthesis (by ileal Fgf15 and hepatic Shp induction), thus resulting in decreased biliary BA output while significantly increasing bile flow and-unexpectedly-HCO output.

7A-C).8 INT-747 and INT-767 increased the size and amount of bile infarcts, as well as LW/BW ratio, in CBDL mice (Supporting Fig. 12A,B), whereas only INT-767 significantly decreased SW/BW ratio (Supporting Fig. 12C) and showed a trend to reduction of serum ALT (Supporting Fig. 13A). Although histological examination

of H&E-stained livers revealed bile infarcts in all the groups, only INT-747 increased infiltration of inflammatory cells within the portal fields (Supporting Fig. 13B). In line with serum ALT levels, INT-767-fed CBDL mice had reduced expression of proinflammatory genes Tnf-α and Il-1β and less CD-11b- and F4/80-positive cells around bile infarcts (Supporting Fig. 14A,B). However, keratin 19 (K19) and Vcam-1 gene expression remained unchanged in CBDL mice after INT-747, INT-777, and INT-767 feeding (Supporting Fig. 15). In this study, we have addressed the selleck products therapeutic mechanisms of BA receptor signaling through the nuclear BA receptor, FXR, and the G-protein-coupled membrane BA receptor, TGR5, in the Mdr2−/− mouse cholangiopathy model. We report herein that, in this model, the novel FXR/TGR5 agonist, INT-767, reduces bile toxicity by decreasing biliary BA output and inducing HCO-rich

KPT-330 order choleresis in an FXR-dependent manner. BAs are important signaling molecules with hormonal actions through dedicated nuclear and G-protein-coupled receptors, such as FXR and TGR5, respectively.8 TGR5 and FXR polymorphisms19, 20 further support the importance

of BA signaling in human cholestastic diseases, such as PSC. Liver injury in Mdr2−/− mice is considered to evolve because of detergent properties of nonmicellar-bound free biliary BAs,29 leaving many open questions for the potential role of BA signaling in modulating biliary pathophysiology. Only the dual FXR/TGR5 agonist, INT-767, 上海皓元医药股份有限公司 was hepatoprotective in the Mdr2−/− model, as reflected by reduced serum ALT, decreased hepatic inflammation, improved reactive cholangiocyte phenotype, and reduced fibrosis. We could neither observe significant direct anti-inflammatory effects of INT-767 in RAW264.7 macrophages (with very low endogenous Fxr and Tgr5 expression), BEC cholangiocytes, or HepG2 hepatocytes (both with high levels of Fxr and very low Tgr5; data not shown) nor direct antifibrotic effects in primary MFBs (with very low endogenous Fxr and Tgr5 expression) as major fibrogenic cells in the Mdr2−/− model. Absent expression of FXR and TGR59, 11 in hepatic stellate cells further indicates that FXR and TGR5 signaling may have no direct antifibrotic effects. These findings led us hypothesize that INT-767 might improve liver injury by directly impacting on bile formation and composition. Indeed, via Fxr activation, INT-767 inhibited BA synthesis (by ileal Fgf15 and hepatic Shp induction), thus resulting in decreased biliary BA output while significantly increasing bile flow and-unexpectedly-HCO output.