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Sample records for bile acid-induced activation

  1. Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways.

    Science.gov (United States)

    Chen, Bi; Cai, Hou-Rong; Xue, Shan; You, Wen-Jie; Liu, Bin; Jiang, Han-Dong

    2016-08-01

    The roles of bile acid microaspiration and bile acid-activated farnesoid X receptor (FXR) in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear. We hypothesized that bile acids activate alveolar epithelial cells (AECs) and lung fibroblasts, which may be regulated by FXR activation. Human AECs and normal or IPF-derived lung fibroblast cells were incubated with the three major bile acids: lithocholic acid (LCA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). The AECs injury indices, epithelial-mesenchymal transition (EMT) and lung fibroblast activation were evaluated. FXR expression in IPF lungs and the roles of FXR and FXR-independent pathways in bile acid-induced profibrotic effects were also investigated. LCA, DCA and CDCA reduced cell viability and increased intracellular reactive oxygen species (ROS) production in A549 cells. They all induced EMT, as shown by enhanced α-SMA and vimentin and decreased E-cadherin levels. LCA directly induced differentiation of lung fibroblasts to myofibroblasts. All three bile acids promoted cellular migration but not proliferation of lung fibroblasts. FXR expression was upregulated in IPF lungs, and inhibition of FXR restrained the bile acid-induced EMT and lung fibroblast activation. Differentiation and proliferation were enhanced in lung fibroblasts exposed to conditioned medium from bile acid-stimulated A549 cells, which contained increased levels of profibrotic factors. TGF-β/Smad3 signaling was also involved in the bile acid-induced EMT and lung fibroblast differentiation. Bile acid microaspiration may promote the development of pulmonary fibrosis by inducing activation of AECs and lung fibroblasts via FXR-dependent and independent pathways. © 2016 Asian Pacific Society of Respirology.

  2. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    NARCIS (Netherlands)

    Svegliati-Baroni, G; Ridolfi, F; Hannivoort, R; Saccomanno, S; Homan, M; De Minicis, S; Jansen, PLM; Candelaresi, C; Benedetti, A; Moshage, H

    Background B Aims: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to

  3. Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor

    NARCIS (Netherlands)

    Svegliati-Baroni, Gianluca; Ridolfi, Francesco; Hannivoort, Rebekka; Saccomanno, Stefania; Homan, Manon; de Minicis, Samuele; Jansen, Peter L. M.; Candelaresi, Cinzia; Benedetti, Antonio; Moshage, Han

    2005-01-01

    BACKGROUND & AIMS: Hepatic stellate cell (HSC) proliferation is a key event in the development of liver fibrosis. In many liver diseases, HSCs are exposed to inflammatory cytokines, reactive oxygen species, and bile acids. Although inflammatory cytokines and reactive oxygen species are known to

  4. Metformin protects rat hepatocytes against bile acid-induced apoptosis.

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    Titia E Woudenberg-Vrenken

    Full Text Available BACKGROUND: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD. Metformin activates AMP-activated protein kinase (AMPK, the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR. Both AMPK and mTOR are able to modulate cell death. AIM: To evaluate the effects of metformin on hepatocyte cell death. METHODS: Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA or TNFα in combination with actinomycin D (actD. AMPK, mTOR and phosphoinositide-3 kinase (PI3K/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively. RESULTS: Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation. CONCLUSION: Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.

  5. Metformin Protects Rat Hepatocytes against Bile Acid-Induced Apoptosis

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    Woudenberg-Vrenken, Titia E.; Conde de la Rosa, Laura; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han

    2013-01-01

    Background Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD). Metformin activates AMP-activated protein kinase (AMPK), the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR). Both AMPK and mTOR are able to modulate cell death. Aim To evaluate the effects of metformin on hepatocyte cell death. Methods Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA) or TNFα in combination with actinomycin D (actD). AMPK, mTOR and phosphoinositide-3 kinase (PI3K)/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively. Results Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation. Conclusion Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation. PMID:23951244

  6. Role of mitogen-activated protein kinases in tauroursodeoxycholic acid-induced bile formation in cholestatic rat liver

    NARCIS (Netherlands)

    Denk, Gerald Ulrich; Hohenester, Simon; Wimmer, Ralf; Boehland, Claudia; Rust, Christian; Beuers, Ulrich

    2008-01-01

    Aim: Ursodeoxycholic acid exerts anticholestatic effects in various cholestatic disorders and experimental models of cholestasis. Its taurine conjugate (TUDCA) stimulates bile salt secretion in isolated perfused rat livers (IPRL) under physiological, non-cholestatic conditions, in part by

  7. Bile acid-induced inflammatory signaling in mice lacking Foxa2 in the liver leads to activation of mTOR and age-onset obesity★

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    Bochkis, Irina Mikhailovna; Shin, Soona; Kaestner, Klaus Hermann

    2013-01-01

    Cytokine signaling has been connected to regulation of metabolism and energy balance. Numerous cytokine gene expression changes are stimulated by accumulation of bile acids in livers of young Foxa2 liver-conditional null mice. We hypothesized that bile acid-induced inflammation in young Foxa2 mutants, once chronic, affects metabolic homeostasis. We found that loss of Foxa2 in the liver results in a premature aging phenotype, including significant weight gain, reduced food intake, and decreased energy expenditure. We show that Foxa2 antagonizes the mammalian target of rapamycin (mTOR) pathway, resulting in increased hepatic lipogenesis and adiposity. While much prior work has focused on adipose tissue in obesity, we discovered a novel age-onset obesity phenotype in a model where gene deletion occurs only in the liver, underscoring the importance of the role hepatic lipogenesis plays in the development of obesity. PMID:24327960

  8. Bile Acid-induced Apoptosis in Hepatocytes Is Caspase-6-dependent

    NARCIS (Netherlands)

    Rust, Christian; Wild, Nadine; Bernt, Carina; Vennegeerts, Timo; Wimmer, Ralf; Beuers, Ulrich

    2009-01-01

    Apoptosis induced by hydrophobic bile acids is thought to contribute to liver injury during cholestasis. Caspase-6 is an executioner caspase that also appears to have regulatory functions in hematopoetic cell lines. We aimed to elucidate the role of caspase-6 in bile acid-induced apoptosis. The

  9. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion

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    Kårhus, Martin L; Brønden, Andreas; Sonne, David P

    2017-01-01

    Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have...... current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid...... sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism....

  10. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

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    Woolbright, Benjamin L.; Dorko, Kenneth [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Antoine, Daniel J.; Clarke, Joanna I. [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Gholami, Parviz [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Li, Feng [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS (United States); Fan, Fang [Department of Pathology, University of Kansas Medical Center, Kansas City, KS (United States); Jenkins, Rosalind E.; Park, B. Kevin [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Hagenbuch, Bruno [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Olyaee, Mojtaba [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2015-03-15

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  11. Bile acid-induced virulence gene expression of Vibrio parahaemolyticus reveals a novel therapeutic potential for bile acid sequestrants.

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    Kazuyoshi Gotoh

    Full Text Available Vibrio parahaemolyticus, a bacterial pathogen, causes human gastroenteritis. A type III secretion system (T3SS2 encoded in pathogenicity island (Vp-PAI is the main contributor to enterotoxicity and expression of Vp-PAI encoded genes is regulated by two transcriptional regulators, VtrA and VtrB. However, a host-derived inducer for the Vp-PAI genes has not been identified. Here, we demonstrate that bile induces production of T3SS2-related proteins under osmotic conditions equivalent to those in the intestinal lumen. We also show that bile induces vtrA-mediated vtrB transcription. Transcriptome analysis of bile-responsive genes revealed that bile strongly induces expression of Vp-PAI genes in a vtrA-dependent manner. The inducing activity of bile was diminished by treatment with bile acid sequestrant cholestyramine. Finally, we demonstrate an in vivo protective effect of cholestyramine on enterotoxicity and show that similar protection is observed in infection with a different type of V. parahaemolyticus or with non-O1/non-O139 V. cholerae strains of vibrios carrying the same kind of T3SS. In summary, these results provide an insight into how bacteria, through the ingenious action of Vp-PAI genes, can take advantage of an otherwise hostile host environment. The results also reveal a new therapeutic potential for widely used bile acid sequestrants in enteric bacterial infections.

  12. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury.

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    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W; Flanders, Kathleen C; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M; Gonzalez, Frank J

    2012-12-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury.

  13. Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice.

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    Beilke, Lisa D; Aleksunes, Lauren M; Holland, Ricky D; Besselsen, David G; Beger, Rick D; Klaassen, Curtis D; Cherrington, Nathan J

    2009-05-01

    Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the hepatoprotection observed during LCA-induced liver injury.

  14. Bile acid-induced arrhythmia is mediated by muscarinic M2 receptors in neonatal rat cardiomyocytes.

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    Siti H Sheikh Abdul Kadir

    Full Text Available BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP is a common disease affecting up to 5% of pregnancies and which can cause fetal arrhythmia and sudden intrauterine death. We previously demonstrated that bile acid taurocholate (TC, which is raised in the bloodstream of ICP, can acutely alter the rate and rhythm of contraction and induce abnormal calcium destabilization in cultured neonatal rat cardiomyocytes (NRCM. Apart from their hepatic functions bile acids are ubiquitous signalling molecules with diverse systemic effects mediated by either the nuclear receptor FXR or by a recently discovered G-protein coupled receptor TGR5. We aim to investigate the mechanism of bile-acid induced arrhythmogenic effects in an in-vitro model of the fetal heart. METHODS AND RESULTS: Levels of bile acid transporters and nuclear receptor FXR were studied by quantitative real time PCR, western blot and immunostaining, which showed low levels of expression. We did not observe functional involvement of the canonical receptors FXR and TGR5. Instead, we found that TC binds to the muscarinic M(2 receptor in NRCM and serves as a partial agonist of this receptor in terms of inhibitory effect on intracellular cAMP and negative chronotropic response. Pharmacological inhibition and siRNA-knockdown of the M(2 receptor completely abolished the negative effect of TC on contraction, calcium transient amplitude and synchronisation in NRCM clusters. CONCLUSION: We conclude that in NRCM the TC-induced arrhythmia is mediated by the partial agonism at the M(2 receptor. This mechanism might serve as a promising new therapeutic target for fetal arrhythmia.

  15. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury[S

    OpenAIRE

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W.; Flanders, Kathleen C.; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M.; Gonzalez, Frank J.

    2012-01-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohisto...

  16. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury[S

    Science.gov (United States)

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W.; Flanders, Kathleen C.; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M.; Gonzalez, Frank J.

    2012-01-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. PMID:23034213

  17. Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via β1-Integrin- and Protein Kinase A-Dependent Mechanisms

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    Annika Sommerfeld

    2015-05-01

    Full Text Available Background/Aims: Ursodeoxycholic acid, which in vivo is rapidly converted into its taurine conjugate, is frequently used for the treatment of cholestatic liver disease. Apart from its choleretic effects, tauroursodeoxycholate (TUDC can protect hepatocytes from bile acid-induced apoptosis, but the mechanisms underlying its anti-apoptotic effects are poorly understood. Methods: These mechanisms were investigated in perfused rat liver and isolated rat hepatocytes. Results: It was found that TUDC inhibited the glycochenodeoxycholate (GCDC-induced activation of the CD95 death receptor at the level of association between CD95 and the epidermal growth factor receptor. This was due to a rapid TUDC-induced β1-integrin-dependent cyclic AMP (cAMP signal with induction of the dual specificity mitogen-activated protein (MAP kinase phosphatase 1 (MKP-1, which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4 and c-jun-NH2-terminal kinase (JNK activation. Furthermore, TUDC induced a protein kinase A (PKA-mediated serine/threonine phosphorylation of the CD95, which was recently identified as an internalization signal for CD95. Furthermore, TUDC inhibited GCDC-induced CD95 targeting to the plasma membrane in a β1-integrin-and PKA-dependent manner. In line with this, the β1-integrin siRNA knockdown in sodium taurocholate cotransporting polypeptide (Ntcp-transfected HepG2 cells abolished the protective effect of TUDC against GCDC-induced apoptosis. Conclusion: TUDC exerts its anti-apoptotic effect via a β1-integrin-mediated formation of cAMP, which prevents CD95 activation by hydrophobic bile acids at the levels of JNK activation and CD95 serine/threonine phosphorylation.

  18. Agonist of farnesoid X receptor protects against bile acid induced damage and oxidative stress in mouse placenta--a study on maternal cholestasis model.

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    Wu, W B; Xu, Y Y; Cheng, W W; Wang, Y X; Liu, Y; Huang, D; Zhang, H J

    2015-05-01

    Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, which is characterized by raised serum bile acid level and potential adverse fetal outcome. Farnesoid X receptor (FXR), also known as a bile acid receptor, was found to be expressed in placenta with low level. Whether activation of FXR by specific agonists could regulate the pathogenesis of ICP is still unclear. A model of maternal cholestasis was induced by administration of 17α-ethynylestradiol (E2) in pregnant mice for 6 days. We explored the regulatory effect of WAY-362450 (W450), a highly selective and potent FXR agonist on placenta. In this study, we demonstrated that administration of E2 increased bile acid levels in mouse serum, liver and amniotic fluid. Bile acid levels were significantly decreased after W450 treatment. W450 protected against the impairment of placentas induced by E2, including severe intracellular edema and apoptosis of trophoblasts. Moreover, W450 significantly induced the expressions of FXR target bile acid transport gene ATP-binding cassette, sub-family B (MDR/TAP), member 11 (Abcb11;Bsep) in placenta. W450 could also attenuate placental oxidative stress and increase the expressions of antioxidant enzymes Prdx1 and Prdx3. In conclusion, our data demonstrated that FXR agonist W450 modulated bile acid balance and protected against placental oxidative stress. Thus, our results support that potent FXR agonists might represent promising drugs for the treatment of ICP. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Factors regulating nuclear factor-kappa B activation in esophageal cancer cells: Role of bile acids and acid

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    Mohamed Mahmoud M Abdel-Latif

    2016-01-01

    Conclusions: Our data demonstrate that bile and acid induce NF-κB activation in esophageal cells qualitatively and quantitatively. The induction of COX-2 promoter activity by DCA and acid was mediated via NF-κB and AP-1 transcription. The activation of NF-κB signaling pathway in esophageal cells may contribute to the development of esophageal cancer, and, therefore, modulating of NF-κB pathway may uncover new therapeutic strategies.

  20. Lipid-activated transcription factors control bile acid glucuronidation.

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    Barbier, Olivier; Trottier, Jocelyn; Kaeding, Jenny; Caron, Patrick; Verreault, Mélanie

    2009-06-01

    Bile acids subserve important physiological functions in the control of cholesterol homeostasis. Indeed, hepatic bile acid synthesis and biliary excretion constitute the main route for cholesterol removal from the human body. On the other hand, bile acids serve as natural detergents for the intestinal absorption of dietary cholesterol. However, due to their detergent properties, bile acids are inherently cytotoxic, and their cellular level may be tightly controlled to avoid pathological situations such as cholestasis. Recent investigations have illustrated the crucial roles that a series of ligand-activated transcription factors has in the control of hepatic bile acids synthesis, transport and metabolism. Thus, the lipid-activated nuclear receptors, farnesoid X-receptor (FXR), liver X-receptor (LXR), pregnane X-receptor (PXR) and peroxisome proliferator-activated receptor alpha (PPAR alpha), modulate the expression and activity of genes controlling bile acid homeostasis in the liver. Several members of the UDP-glucuronosyltransferase (UGT) enzymes family are among the bile acid metabolizing enzymes regulated by these receptors. UGTs catalyze glucuronidation, a major phase II metabolic reaction, which converts hydrophobic bile acids into polar and urinary excretable metabolites. This article summarizes our recent observations on the regulation of bile acid conjugating UGTs upon pharmacological activation of lipid-activated receptors, with a particular interest for the role of PPAR alpha and LXRalpha in controlling human UGT1A3 expression.

  1. [Structure and Activity of Fungal Lipases in Bile Salt Solutions].

    Science.gov (United States)

    Bogdanova, L R; Bakirova, D R; Valiullina, Yu A; Idiyatullin, B Z; Faizullin, D A; Zueva, O S; Zuev, Yu F

    2016-01-01

    The changes in structure and catalytic properties of fungal lipases (Candida rugosa, Rhizomucor miehei, Mucor javanicus) were investigated in micellar solutions of bile salts that differ in hydrophilic-lypophilic balance and reaction medium properties. The methods of circular dichroism and tryptophan fluorescence were applied to estimate the changes in peptide structure within complexes with bile salt micelles. Bile salts do not exert a significant influence on the structure of the enzymes under study: in Rh. miehei and M. javanicus lipases the alpha helix content slightly decreased, the influence of bile salts on the C. rugosa structure was not revealed. Despite negligible structural modifications in the enzymes, in bile salt solutions a considerable change in their catalytic properties was observed: an abrupt decrease in catalytic effectiveness. Substrate-bile salts micelles complex formation was demonstrated by the NMR self-diffusion method. The model of a regulation of fungal lipase activity was proposed.

  2. Caffeic Acid Induced Apoptosis in MG63 Osteosarcoma Cells Through Activation of Caspases

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    Ferry Sandra

    2017-03-01

    Full Text Available Background: Caffeic acid has been reported that when it is combined with all-trans retinoic acid, it can inhibit proliferation activity of SaOS-2 or OSA-01 cells. In addition, caffeic acid merely could reduce cell viability of SaOS-2 cells. However, there is not any study in caffeic acid's possible effect to induce apoptosis in osteosarcoma cell. Materials and Methods: MG-63 cells were cultured in Dulbecco’s Modified Eagle Medium containing 10% fetal bovine serum. Cells were treated with various concentrations of caffeic acid. Apoptosis were analyzed with Sub-G1 assay and activation of caspase-8, -9, and -3 were analyzed with immunoblotting. Caffeic acid-induced percentage of apoptotic cells and cleaved-8, -9, -3 were then statistically analyzed. Results: Sub-G1 results showed that caffeic acid significantly induced apoptosis in MG-63 osteosarcoma cells in concentration dependent manner. Immunoblotting results showed that caffeic acid induced cleavage of caspase-8, -9 and -3. Cleaved-caspase-8 and -9 were increased at 1-hour treatment of caffeic acid, while cleaved-caspase 3 was increased markedly at 6-hours treatment of caffeic acid. Conclusions: Caffeic acid induces apoptosis significantly in concentration dependent manner through caspase-dependent intrinsic apoptotic pathway. Keywords: caffeic acid, osteosarcoma, MG-63, apoptosis, caspase

  3. Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

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    Zhou, Yang; Fang, Li; Jiang, Lei; Wen, Ping; Cao, Hongdi; He, Weichun; Dai, Chunsun; Yang, Junwei

    2012-01-01

    Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling. PMID:22761883

  4. Single-Dose Metformin Enhances Bile Acid-Induced Glucagon-Like Peptide-1 Secretion in Patients With Type 2 Diabetes

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2017-01-01

    -controlled, and double-blinded crossover study. Setting: This study was conducted at Center for Diabetes Research, Gentofte Hospital, Denmark. Patients: Fifteen metformin-treated patients with type 2 diabetes; all participants completed the study. Interventions: Four experimental study days in randomized order...... with administration of either 1500 mg metformin or placebo in combination with intravenous infusion of cholecystokinin (0.4 pmol × kg-1 × min-1) or saline. Main Outcome Measure: Plasma GLP-1 excursions as measured by baseline-subtracted area under the curve. Results: Single-dose metformin further enhanced bile acid...

  5. Fusobacterium nucleatum activates the immune response through retinoic acid-inducible gene I.

    Science.gov (United States)

    Lee, P; Tan, K S

    2014-02-01

    Retinoic acid-inducible gene I (RIG-I) is a cytosolic pattern recognition receptor involved in the sensing of RNA viruses and the initiation of antiviral responses. Fusobacterium nucleatum, a Gram-negative anaerobic bacterium associated with periodontal disease, is capable of invading cells. We hypothesized that F. nucleatum's ability to invade cells allows the microorganism to activate the immune response through RIG-I. Bacterial invasion was found to be necessary for F. nucleatum-induced nuclear factor kappa B (NF-κB) activation. Following invasion of the human periodontal ligament fibroblast (PDLF), F. nucleatum was located in the cytosol. F. nucleatum infection led to an 80-fold increase in RIG-I expression. Silencing RIG-I in PDLF by siRNA led to a significant decrease of NF-κB activation and expression of proinflammatory genes. Additionally, F. nucleatum was able to secrete nucleic acids, and introduction of F. nucleatum RNA into PDLF led to a RIG-I-dependent activation of NF-κB. Our findings showed RIG-I to be involved in the recognition of F. nucleatum. The function of RIG-I is likely to be broad and not limited to sensing of viruses only. Hence, this receptor may play an important role in detecting invasive forms of oral pathogens and contribute to inflammation in periodontal tissues.

  6. Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

  7. Acid-induced autophagy protects human lung cancer cells from apoptosis by activating ER stress.

    Science.gov (United States)

    Xie, Wen-Yue; Zhou, Xiang-Dong; Li, Qi; Chen, Ling-Xiu; Ran, Dan-Hua

    2015-12-10

    An acidic tumor microenvironment exists widely in solid tumors. However, the detailed mechanism of cell survival under acidic stress remains unclear. The aim of this study is to clarify whether acid-induced autophagy exists and to determine the function and mechanism of autophagy in lung cancer cells. We have found that acute low pH stimulated autophagy by increasing LC3-positive punctate vesicles, increasing LC3 II expression levels and reducing p62 protein levels. Additionally, autophagy was inhibited by the addition of Baf or knockdown of Beclin 1, and cell apoptosis was increased markedly. In mouse tumors, the expression of cleaved caspase3 and p62 was enhanced by oral treatment with sodium bicarbonate, which can raise the intratumoral pH. Furthermore, the protein levels of ER stress markers, including p-PERK, p-eIF2α, CHOP, XBP-1s and GRP78, were also increased in response to acidic pH. The antioxidant NAC, which reduces ROS accumulation, alleviated acid-mediated ER stress and autophagy, and knocking down GRP78 reduced autophagy activation under acidic conditions, which suggests that autophagy was induced by acidic pH through ER stress. Taken together, these results indicate that the acidic microenvironment in non-small cell lung cancer cells promotes autophagy by increasing ROS-ER stress, which serves as a survival adaption in this setting. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Effect of cholesterol nucleation-promoting activity on cholesterol solubilization in model bile

    NARCIS (Netherlands)

    Groen, A. K.; Ottenhoff, R.; Jansen, P. L.; van Marle, J.; Tytgat, G. N.

    1989-01-01

    Human bile contains a factor with cholesterol nucleation-promoting activity that binds to concanavalin A-Sepharose. In this study we have investigated the effect of this activity on the dynamics of lipid solubilization in supersaturated model bile. A concanavalin A binding protein fraction of human

  9. Dietary omega-3 polyunsaturated fatty acids induce plasminogen activator activity and DNA damage in rabbit spermatozoa.

    Science.gov (United States)

    Kokoli, A N; Lavrentiadou, S N; Zervos, I A; Tsantarliotou, M P; Georgiadis, M P; Nikolaidis, E A; Botsoglou, N; Boscos, C M; Taitzoglou, I A

    2017-12-01

    The aim of this study was to determine the effect(s) of dietary omega-3 polyunsaturated fatty acids (ω-3 PUFA) on rabbit semen. Adult rabbit bucks were assigned to two groups that were given two diets, a standard diet (control) and a diet supplemented with ω-3 PUFA. Sperm samples were collected from all bucks with the use of an artificial vagina in 20-day intervals, for a total period of 120 days. The enrichment of membranes in ω-3 PUFA was manifested by the elevation of the 22:5 ω-3 (docosapentaenoic acid [DPA]) levels within 40 days. This increase in DPA content did not affect semen characteristics (i.e., concentration, motility and viability). However, it was associated with the induction of lipid peroxidation in spermatozoa, as determined on the basis of the malondialdehyde content. Lipid peroxidation was associated with DNA fragmentation in ω-3 PUFA-enriched spermatozoa and a concomitant increase in plasminogen activator (PA) activity. The effects of ω-3 PUFA on sperm cells were evident within 40 days of ω-3 PUFA dietary intake and exhibited peack values on day 120. Our findings suggest that an ω-3 PUFA-rich diet may not affect semen characteristics; however, it may have a negative impact on the oxidative status and DNA integrity of the spermatozoa, which was associated with an induction of PAs activity. © 2017 Blackwell Verlag GmbH.

  10. In Vitro Antibacterial Activity of Unconjugated and Conjugated Bile Salts on Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Thippeswamy H. Sannasiddappa

    2017-08-01

    Full Text Available Bile salts are potent antimicrobial agents and are an important component of innate defenses in the intestine, giving protection against invasive organisms. They play an important role in determining microbial ecology of the intestine and alterations in their levels can lead to increased colonization by pathogens. We have previously demonstrated survival of the opportunistic pathogen Staphylococcus aureus in the human colonic model. Thus investigating the interaction between S. aureus and bile salts is an important factor in understanding its ability to colonize in the host intestine. Harnessing bile salts may also give a new avenue to explore in the development of therapeutic strategies to control drug resistant bacteria. Despite this importance, the antibacterial activity of bile salts on S. aureus is poorly understood. In this study, we investigated the antibacterial effects of the major unconjugated and conjugated bile salts on S. aureus. Several concentration-dependent antibacterial mechanisms were found. Unconjugated bile salts at their minimum inhibitory concentration (cholic and deoxycholic acid at 20 and 1 mM, respectively killed S. aureus, and this was associated with increased membrane disruption and leakage of cellular contents. Unconjugated bile salts (cholic and deoxycholic acid at 8 and 0.4 mM, respectively and conjugated bile salts (glycocholic and taurocholic acid at 20 mM at their sub inhibitory concentrations were still able to inhibit growth through disruption of the proton motive force and increased membrane permeability. We also demonstrated that unconjugated bile salts possess more potent antibacterial action on S. aureus than conjugated bile salts.

  11. The Bile Acid-Sensitive Ion Channel (BASIC) Is Activated by Alterations of Its Membrane Environment

    Science.gov (United States)

    Schmidt, Axel; Lenzig, Pia; Oslender-Bujotzek, Adrienne; Kusch, Jana; Dias Lucas, Susana; Gründer, Stefan; Wiemuth, Dominik

    2014-01-01

    The bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC family of ion channels. Channels of this family are characterized by a common structure, their physiological functions and modes of activation, however, are diverse. Rat BASIC is expressed in brain, liver and intestinal tract and activated by bile acids. The physiological function of BASIC and its mechanism of bile acid activation remain a puzzle. Here we addressed the question whether amphiphilic bile acids activate BASIC by directly binding to the channel or indirectly by altering the properties of the surrounding membrane. We show that membrane-active substances other than bile acids also affect the activity of BASIC and that activation by bile acids and other membrane-active substances is non-additive, suggesting that BASIC is sensitive for changes in its membrane environment. Furthermore based on results from chimeras between BASIC and ASIC1a, we show that the extracellular and the transmembrane domains are important for membrane sensitivity. PMID:25360526

  12. Diverticular bile duct lesion in chronic active hepatitis

    DEFF Research Database (Denmark)

    Vyberg, M

    1989-01-01

    of a not previously described diverticular type were revealed. The diverticuli were of varying shape with a diameter of 30 to 110 microns and a length of 75 to 150 microns budding from small (12 to 25 microns), slightly ectatic bile ducts. The diverticular epithelium was disordered. Some cells appeared as bile duct...... cells, but most were larger, with rounded nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, sometimes with periodic acid-Schiff-positive, diastase-resistant granules. The lesions were only partly surrounded by a basement membrane. They were all embedded in a tight mononuclear inflammatory...

  13. Deconjugated bile salts produced by extracellular bile-salt hydrolase-like activities from the probiotic Lactobacillus johnsonii La1 inhibit Giardia duodenalis in vitro growth

    Directory of Open Access Journals (Sweden)

    Marie-Agnès Travers

    2016-09-01

    Full Text Available Giardiasis, currently considered a neglected disease, is caused by the intestinal protozoan parasite Giardia duodenalis and is widely spread in human as well as domestic and wild animals. The lack of appropriate medications and the spread of resistant parasite strains urgently call for the development of novel therapeutic strategies. Host microbiota or certain probiotic strains have the capacity to provide some protection against giardiasis. By combining biological and biochemical approaches, we have been able to decipher a molecular mechanism used by the probiotic strain Lactobacillus johnsonii La1 to prevent Giardia growth in vitro. We provide evidence that the supernatant of this strain contains active principle(s not directly toxic to Giardia but able to convert non-toxic components of bile into components highly toxic to Giardia. By using bile acid profiling, these components were identified as deconjugated bile-salts. A bacterial bile-salt-hydrolase of commercial origin was able to mimic the properties of the supernatant. Mass spectrometric analysis of the bacterial supernatant identified two of the three bile-salt-hydrolases encoded in the genome of this probiotic strain. These observations document a possible mechanism by which L. johnsonii La1, by secreting or releasing BSH-like activity(ies in the vicinity of replicating Giardia in an environment where bile is present and abundant, can fight this parasite. This discovery has both fundamental and applied outcomes to fight giardiasis, based on local delivery of deconjugated bile salts, enzyme deconjugation of bile components, or natural or recombinant probiotic strains that secrete or release such deconjugating activities in a compartment where both bile salts and Giardia are present.

  14. Effects of ionizing radiation on the activity of the major hepatic enzymes implicated in bile acid biosynthesis in the rat

    International Nuclear Information System (INIS)

    Souidi, M.; Scanff, P.; Grison, St.; Gourmelon, P.; Aigueperse, J.

    2007-01-01

    In the days following high-dose radiation exposure, damage to small intestinal mucosa is aggravated by changes in the bile acid pool reaching the gut. Intestinal bile acid malabsorption, as described classically, may be associated with altered hepatic bile acid biosynthesis, which was the objective of this work. The activity of the main rate-limiting enzymes implicated in the bile acid biosynthesis were evaluated in the days following an 8-Gy γ Co 60 total body irradiation of rats, with concomitant determination of biliary bile acid profiles and intestinal bile acid content. Modifications of biliary bile acid profiles, observed as early as the first post-irradiation day, were most marked at the third and fourth day, and resulted in an increased hydrophobicity index. In parallel, the intestinal bile acids' content was enhanced and hepatic enzymatic activities leading to bile acids were changed. A marked increase of sterol 12-hydroxylase and decrease of oxy-sterol 7-hydroxylase activity was observed at day 3, whereas both cholesterol 7-hydroxylase and oxy-sterol 7-hydroxylase activities were decreased at day 4 after irradiation. These results show, for the first time, radiation-induced modifications of hepatic enzymatic activities implicated in bile acid biosynthesis and suggest that they are mainly a consequence of radiation-altered intestinal absorption, which induces a physiological response of the entero-hepatic bile acid recirculation. (authors)

  15. Bile salt receptor complex activates a pathogenic type III secretion system

    Science.gov (United States)

    Li, Peng; Rivera-Cancel, Giomar; Kinch, Lisa N; Salomon, Dor; Tomchick, Diana R; Grishin, Nick V; Orth, Kim

    2016-01-01

    Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered that Vibrio parahaemolyticus VtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment. DOI: http://dx.doi.org/10.7554/eLife.15718.001 PMID:27377244

  16. Bile salt receptor complex activates a pathogenic type III secretion system

    Energy Technology Data Exchange (ETDEWEB)

    Li, Peng; Rivera-Cancel, Giomar; Kinch, Lisa N.; Salomon, Dor; Tomchick, Diana R.; Grishin, Nick V.; Orth, Kim

    2016-07-05

    Bile is an important component of the human gastrointestinal tract with an essential role in food absorption and antimicrobial activities. Enteric bacterial pathogens have developed strategies to sense bile as an environmental cue to regulate virulence genes during infection. We discovered thatVibrio parahaemolyticusVtrC, along with VtrA and VtrB, are required for activating the virulence type III secretion system 2 in response to bile salts. The VtrA/VtrC complex activates VtrB in the presence of bile salts. The crystal structure of the periplasmic domains of the VtrA/VtrC heterodimer reveals a β-barrel with a hydrophobic inner chamber. A co-crystal structure of VtrA/VtrC with bile salt, along with biophysical and mutational analysis, demonstrates that the hydrophobic chamber binds bile salts and activates the virulence network. As part of a family of conserved signaling receptors, VtrA/VtrC provides structural and functional insights into the evolutionarily conserved mechanism used by bacteria to sense their environment.

  17. Activation of BK(Ca channels in zoledronic acid-induced apoptosis of MDA-MB-231 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Yu-Guang Ma

    Full Text Available BACKGROUND: Zoledronic acid, one of the most potent nitrogen-containing biphosphonates, has been demonstrated to have direct anti-tumor and anti-metastatic properties in breast cancer in vitro and in vivo. In particular, tumor-cell apoptosis has been recognized to play an important role in the treatment of metastatic breast cancer with zoledronic acid. However, the precise mechanisms remain less clear. In the present study, we investigated the specific role of large conductance Ca(2+-activated potassium (BK(Ca channel in zoledronic acid-induced apoptosis of estrogen receptor (ER-negative MDA-MB-231 breast cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: The action of zoledronic acid on BK(Ca channel was investigated by whole-cell and cell-attached patch clamp techniques. Cell apoptosis was assessed with immunocytochemistry, analysis of fragmented DNA by agarose gel electrophoresis, and flow cytometry assays. Cell proliferation was investigated by MTT test and immunocytochemistry. In addition, such findings were further confirmed with human embryonic kidney 293 (HEK293 cells which were transfected with functional BK(Ca α-subunit (hSloα. Our results clearly indicated that zoledronic acid directly increased the activities of BK(Ca channels, and then activation of BK(Ca channel by zoledronic acid contributed to induce apoptosis in MDA-MB-231 cells. The possible mechanisms were associated with the elevated level of intracellular Ca(2+ and a concomitant depolarization of mitochondrial membrane potential (Δψm in MDA-MB-231 cells. CONCLUSIONS: Activation of BK(Ca channel was here shown to be a novel molecular pathway involved in zoledronic acid-induced apoptosis of MDA-MB-231 cells in vitro.

  18. Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242.

    Science.gov (United States)

    Martoni, Christopher J; Labbé, Alain; Ganopolsky, Jorge G; Prakash, Satya; Jones, Mitchell L

    2015-01-01

    The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia.

  19. Oleic Acid Induces Lung Injury in Mice through Activation of the ERK Pathway

    Directory of Open Access Journals (Sweden)

    Cassiano Felippe Gonçalves-de-Albuquerque

    2012-01-01

    Full Text Available Oleic acid (OA can induce acute lung injury in experimental models. In the present work, we used intratracheal OA injection to show augmented oedema formation, cell migration and activation, lipid mediator, and cytokine productions in the bronchoalveolar fluids of Swiss Webster mice. We also demonstrated that OA-induced pulmonary injury is dependent on ERK1/2 activation, since U0126, an inhibitor of ERK1/2 phosphorylation, blocked neutrophil migration, oedema, and lipid body formation as well as IL-6, but not IL-1β production. Using a mice strain carrying a null mutation for the TLR4 receptor, we proved that increased inflammatory parameters after OA challenges were not due to the activation of the TLR4 receptor. With OA being a Na/K-ATPase inhibitor, we suggest the possible involvement of this enzyme as an OA target triggering lung inflammation.

  20. Citric acid induced promoted dispersion of Pt on the support and enhanced catalytic activities for a Pt-based catalyst

    Science.gov (United States)

    Cheng, Tianqiong; Wang, Jianli; Wang, Suning; Cui, Yajuan; Zhang, Hailong; Yan, Shuang; Yuan, Shandong; Chen, Yaoqiang

    2017-12-01

    Citric acid (CA), as the chelating agent, was introduced to obtain the enhanced Pt dispersion and catalytic activities for the Pt-based catalysts supported on oxygen-storage material. The role and content of CA were investigated systematically. It was found that the citric acid-assisted catalysts showed better Pt dispersion and smaller nanoparticle size of Pt. Thus, the catalyst had lower reduction temperature, preferable thermostability and possessed more oxidation state of Pt species under the oxidation atmosphere. The citric acid-induced fresh catalysts were excellent to convert CO and the corresponding aged ones exhibited higher activities for the elimination of all the target pollutants. Among the aged catalysts, P2-a (the mole ratio of Pt/CA is 2:1) presented the best performance. Particularly, compared with the reference sample (Pc-a), the light-off temperatures (T50) of NO, HC and CO for P2-a decreased by 39 °C, 42 °C and 72 °C, respectively, and the full-conversion temperatures (T90) of NO, HC and CO for P2-a decreased by 44 °C, 44 °C and 48 °C, respectively. Therefore, this work provides a facile and valid method to manufacture advanced catalysts for purification of the vehicle exhaust in the future.

  1. Photo-activated 5-hydroxyindole-3-acetic acid induces apoptosis of prostate and bladder cancer cells.

    Science.gov (United States)

    Jeong, Yun-Mi; Li, Hailan; Kim, Su Yeon; Park, Woo-Jae; Yun, Hye-Young; Baek, Kwang Jin; Kwon, Nyoun Soo; Jeong, Ji Hoon; Myung, Soon Chul; Kim, Dong-Seok

    2011-04-04

    5-Hydroxyindole-3-acetic acid (5-HIAA), an indole derivative, is the main metabolite of serotonin in the human body. We determined whether or not ultraviolet B (UVB)-activated 5-HIAA (5-HIAA(UVB)) affects the viability of human prostate (LnCaP and PC-3) and bladder cancer cells (TCCSUP). While 5-HIAA alone had no cytotoxic effect at led to phosphorylation of stress-activated signaling proteins, such as c-Jun N-terminal kinase (JNK) and/or p38 mitogen-activated protein kinase (MAPK). Furthermore, 5-HIAA(UVB) activated caspase-8, -9, and -3 and cleaved poly(ADP-ribose) polymerase (PARP), which are indicators of apoptosis. From these findings, the present study demonstrated that 5-HIAA(UVB) induces apoptotic cell death of prostate and bladder cancer cells via stress-mediated signaling and apoptotic pathways. Therefore, we suggest that 5-HIAA might be used as a new photosensitizer for photodynamic cancer therapy. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Gallic acid induces necroptosis via TNF-α signaling pathway in activated hepatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Ya Ju Chang

    Full Text Available Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA, a natural phenolic acid widely found in gallnuts, tea leaves and various fruits, possesses several bioactivities against inflammation, oxidation, and carcinogenicity. The beneficial effect of GA on the reduction of animal hepatofibrosis has been indicated due to its antioxidative property. However, the cytotoxicity of GA autoxidation causing cell death has also been reported. Herein, we postulated that GA might target activated hepatic stellate cells (aHSCs, the cell type responsible for hepatofibrosis, to mitigate the process of fibrosis. The molecular cytotoxic mechanisms that GA exerted on aHSCs were then analyzed. The results indicated that GA elicited aHSC programmed cell death through TNF-α-mediated necroptosis. GA induced significant oxidative stress through the suppression of catalase activity and the depletion of glutathione (GSH. Elevated oxidative stress triggered the production of TNF-α facilitating the undergoing of necroptosis through the up-regulation of key necroptotic regulatory proteins TRADD and receptor-interacting protein 3 (RIP3, and the inactivation of caspase-8. Calmodulin and calpain-1 activation were engaged, which promoted subsequent lysosomal membrane permeabilization (LMP. The TNF-α antagonist (SPD-304 and the RIP1 inhibitor (necrostatin-1, Nec-1 confirmed GA-induced TNFR1-mediated necroptosis. The inhibition of RIP1 by Nec-1 diverted the cell death from necroptosis to apoptosis, as the activation of caspase 3 and the increase of cytochrome c. Collectively, this is the first report indicating that GA induces TNF signaling-triggered necroptosis in aHSCs, which may offer an alternative strategy for the amelioration of liver fibrosis.

  3. Polyunsaturated fatty acids induce ovarian cancer cell death through ROS-dependent MAP kinase activation.

    Science.gov (United States)

    Tanaka, Aiko; Yamamoto, Akane; Murota, Kaeko; Tsujiuchi, Toshifumi; Iwamori, Masao; Fukushima, Nobuyuki

    2017-11-04

    Free fatty acids not only play a role in cell membrane construction and energy production but also exert diverse cellular effects through receptor and non-receptor mechanisms. Moreover, epidemiological and clinical studies have so far suggested that polyunsaturated fatty acids (PUFAs) could have health benefits and the advantage as therapeutic use in cancer treatment. However, the underlying mechanisms of PUFA-induced cellular effects remained to be cleared. Here, we examined the effects of ω-3 and ω-6 PUFAs on cell death in ovarian cancer cell lines. ω-3 PUFA, docosahexaenoic acid (DHA) and ω-6 PUFA, γ-linolenic acid (γ-LNA) induced cell death in KF28 cells at the levels of physiological concentrations, but not HAC2 cells. Pharmacological and biochemical analyses demonstrated that cell death induced by DHA and γ-LNA was correlated with activation of JNK and p38 MAP kinases, and further an upstream MAP kinase kinase, apoptosis signal-regulating kinase 1, which is stimulated by reactive oxygen species (ROS). Furthermore, an antioxidant vitamin E attenuated PUFA-induced cell death and MAP kinase activation. These findings indicate that PUFA-induced cell death involves ROS-dependent MAP kinase activation and is a cell type-specific action. A further study of the underlying mechanisms for ROS-dependent cell death induced by PUFAs will lead to the discovery of a new target for cancer therapy or diagnosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Diabetic cognitive dysfunction is associated with increased bile acids in liver and activation of bile acid signaling in intestine.

    Science.gov (United States)

    Wang, Xue; Wang, Fangyu; Zhang, Yidan; Xiong, Hui; Zhang, Yanjun; Zhuang, Pengwei; Zhang, Youcai

    2018-05-01

    Impaired regulation of bile acid (BA) homeostasis has been suggested to be associated with adverse metabolic consequences. However, whether BA homeostasis is altered in diabetes-induced cognitive dysfunction (DCD) remains unknown. In the present study, mice were divided into four groups, namely normal control (NC) group, high-fat diet (HFD) group, diabetes without cognitive dysfunction (unDCD) group, and DCD group. Compared to HFD mice, the concentration of total BAs in liver was higher in unDCD and DCD mice, due to increased intestinal BA absorption. DCD mice tended to have higher BA concentrations in both liver and ileum than unDCD mice. Consequently, DCD mice had increased basolateral BA efflux (Ostα, Ostβ, and Mrp4) and decreased BA synthesis (Cyp7a1, Cyp8b1, and Cyp7b1) in the liver as well as activated Fxr-Fgf15 signaling in the ileum. DCD mice also had increased BA hydroxylation (Cyp3a11) and BA sulfation (Sult2a1) in the liver compared to HFD mice. Furthermore, the bacterial community composition was altered in the cecum of DCD mice, characterized with a marked increase in Defferribacteres and Candidatus Saccharibacteria. In summary, the present study provides the first comprehensive analysis of BA homeostasis in DCD mice, and revealed a potential role of BAs in DCD development. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Salicylic acid induced cysteine protease activity during programmed cell death in tomato plants.

    Science.gov (United States)

    Kovács, Judit; Poór, Péter; Szepesi, Ágnes; Tari, Irma

    2016-06-01

    The hypersensitive response (HR), a type of programmed cell death (PCD) during biotic stress is mediated by salicylic acid (SA). The aim of this work was to reveal the role of proteolysis and cysteine proteases in the execution of PCD in response of SA. Tomato plants were treated with sublethal (0.1 mM) and lethal (1 mM) SA concentrations through the root system. Treatment with 1 mM SA increased the electrolyte leakage and proteolytic activity and reduced the total protein content of roots after 6 h, while the proteolytic activity did not change in the leaves and in plants exposed to 0.1 mM SA. The expression of the papain-type cysteine protease SlCYP1, the vacuolar processing enzyme SlVPE1 and the tomato metacaspase SlMCA1 was induced within the first three hours in the leaves and after 0.5 h in the roots in the presence of 1 mM SA but the transcript levels did not increase significantly at sublethal SA. The Bax inhibitor-1 (SlBI-1), an antiapoptotic gene was over-expressed in the roots after SA treatments and it proved to be transient in the presence of sublethal SA. Protease inhibitors, SlPI2 and SlLTC were upregulated in the roots by sublethal SA but their expression remained low at 1 mM SA concentration. It is concluded that in contrast to leaves the SA-induced PCD is associated with increased proteolytic activity in the root tissues resulting from a fast up-regulation of specific cysteine proteases and down-regulation of protease inhibitors.

  6. Vinpocetine Ameliorates Acetic Acid-Induced Colitis by Inhibiting NF-κB Activation in Mice.

    Science.gov (United States)

    Colombo, Bárbara B; Fattori, Victor; Guazelli, Carla F S; Zaninelli, Tiago H; Carvalho, Thacyana T; Ferraz, Camila R; Bussmann, Allan J C; Ruiz-Miyazawa, Kenji W; Baracat, Marcela M; Casagrande, Rúbia; Verri, Waldiceu A

    2018-04-10

    The idiopathic inflammatory bowel diseases (IBD) comprise two types of chronic intestinal disorders: Crohn's disease and ulcerative colitis. Recruited neutrophils and macrophages contribute to intestinal tissue damage via production of ROS and NF-κB-dependent pro-inflammatory cytokines. The introduction of anti-TNF-α therapies in the treatment of IBD patients was a seminal advance. This therapy is often limited by a loss of efficacy due to the development of adaptive immune response, underscoring the need for novel therapies targeting similar pathways. Vinpocetine is a nootropic drug and in addition to its antioxidant effect, it is known to have anti-inflammatory and analgesic properties, partly by inhibition of NF-κB and downstream cytokines. Therefore, the present study evaluated the effect of the vinpocetine in a model of acid acetic-induced colitis in mice. Treatment with vinpocetine reduced edema, MPO activity, microscopic score and macroscopic damage, and visceral mechanical hyperalgesia. Vinpocetine prevented the reduction of colonic levels of GSH, ABTS radical scavenging ability, and normalized levels of anti-inflammatory cytokine IL-10. Moreover, vinpocetine reduced NF-κB activation and thereby NF-κB-dependent pro-inflammatory cytokines IL-1β, TNF-α, and IL-33 in the colon. Thus, we demonstrate for the first time that vinpocetine has anti-inflammatory, antioxidant, and analgesic effects in a model of acid acetic-induced colitis in mice and deserves further screening to address its suitability as an approach for the treatment of IBD.

  7. Ursodeoxycholic acid reduces protein levels and nucleation-promoting activity in human gallbladder bile

    NARCIS (Netherlands)

    van Erpecum, K. J.; Portincasa, P.; Eckhardt, E.; Go, P. M.; vanBerge-Henegouwen, G. P.; Groen, A. K.

    1996-01-01

    Background & Aims: Ursodeoxycholic acid prevents gallstone formation in selected patients. The aim of this study was to examine whether decreased concentration and nucleation-promoting activity of various proteins contribute to this beneficial effect. Methods: Gallbladder bile of 13 patients with

  8. Impaired activity of bile bile canalicular organic anion transporter (Mrp2/cmoat) is not the main cause of ethinylestradiol-induced cholestasis in the rat

    NARCIS (Netherlands)

    Koopen, NR; Wolters, H; Havinga, R; Vonk, RJ; Jansen, PLM; Muller, M; Kuipers, F

    To test the hypothesis that impaired activity of the bile canalicular organic anion transporting system mrp2 (cmoat) is a key event in the etiology of 17 alpha-ethinylestradiol (EE)-induced intrahepatic cholestasis in rats, EE (5 mg/kg subcutaneously daily) was administered to male normal Wistar

  9. Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification.

    Science.gov (United States)

    Mostarda, Serena; Passeri, Daniela; Carotti, Andrea; Cerra, Bruno; Colliva, Carolina; Benicchi, Tiziana; Macchiarulo, Antonio; Pellicciari, Roberto; Gioiello, Antimo

    2018-01-20

    Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  10. Biochemical basis for activation of virulence genes by bile salts in Vibrio parahaemolyticus.

    Science.gov (United States)

    Rivera-Cancel, Giomar; Orth, Kim

    2017-07-04

    Bile salts act as a stressor to bacteria that transit the intestinal tract. Enteric pathogens have hijacked bile as an intestinal signal to regulate virulence factors. We recently demonstrated that Vibrio parahemolyticus senses bile salts via a heterodimeric receptor formed by the periplasmic domains of inner-membrane proteins VtrA and VtrC. Crystal structures of the periplasmic complex reveal that VtrA and VtrC form a β-barrel that binds bile salts in its hydrophobic interior to activate the VtrA cytoplasmic DNA-binding domain. Proteins with the same domain arrangement as VtrA and VtrC are widespread in Vibrio and related bacteria, where they are involved in regulating virulence and other unknown functions. Here we discuss our findings and review current knowledge on VtrA and VtrC homologs. We propose that signaling by these membrane-bound transcription factors can be advantageous for the regulation of membrane and secretory proteins.

  11. PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells.

    Science.gov (United States)

    Wu, Liping; Oshima, Tadayuki; Shan, Jing; Sei, Hiroo; Tomita, Toshihiko; Ohda, Yoshio; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

    2015-10-15

    Esophageal visceral hypersensitivity has been proposed to be the pathogenesis of heartburn sensation in nonerosive reflux disease. Protease-activated receptor-2 (PAR-2) is expressed in human esophageal epithelial cells and is believed to play a role in inflammation and sensation. PAR-2 activation may modulate these responses through adenosine triphosphate (ATP) release, which is involved in transduction of sensation and pain. The transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs) are both acid-sensitive nociceptors. However, the interaction among these molecules and the mechanisms of heartburn sensation are still not clear. We therefore examined whether ATP release in human esophageal epithelial cells in response to acid is modulated by TRPV1 and ASICs and whether PAR-2 activation influences the sensitivity of TRPV1 and ASICs. Weak acid (pH 5) stimulated the release of ATP from primary human esophageal epithelial cells (HEECs). This effect was significantly reduced after pretreatment with 5-iodoresiniferatoxin (IRTX), a TRPV1-specific antagonist, or with amiloride, a nonselective ASIC blocker. TRPV1 and ASIC3 small interfering RNA (siRNA) transfection also decreased weak acid-induced ATP release. Pretreatment of HEECs with trypsin, tryptase, or a PAR-2 agonist enhanced weak acid-induced ATP release. Trypsin treatment led to the phosphorylation of TRPV1. Acid-induced ATP release enhancement by trypsin was partially blocked by IRTX, amiloride, or a PAR-2 antagonist. Conversely, acid-induced ATP release was augmented by PAR-2 activation through TRPV1 and ASICs. These findings suggested that the pathophysiology of heartburn sensation or esophageal hypersensitivity may be associated with the activation of PAR-2, TRPV1, and ASICs. Copyright © 2015 the American Physiological Society.

  12. Bile Salts Modulate the Mucin-Activated Type VI Secretion System of Pandemic Vibrio cholerae.

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    Verena Bachmann

    Full Text Available The causative agent of cholera, Vibrio cholerae, regulates its diverse virulence factors to thrive in the human small intestine and environmental reservoirs. Among this pathogen's arsenal of virulence factors is the tightly regulated type VI secretion system (T6SS. This system acts as an inverted bacteriophage to inject toxins into competing bacteria and eukaryotic phagocytes. V. cholerae strains responsible for the current 7th pandemic activate their T6SS within the host. We established that T6SS-mediated competition occurs upon T6SS activation in the infant mouse, and that this system is functional under anaerobic conditions. When investigating the intestinal host factors mucins (a glycoprotein component of mucus and bile for potential regulatory roles in controlling the T6SS, we discovered that once mucins activate the T6SS, bile acids can further modulate T6SS activity. Microbiota modify bile acids to inhibit T6SS-mediated killing of commensal bacteria. This interplay is a novel interaction between commensal bacteria, host factors, and the V. cholerae T6SS, showing an active host role in infection.

  13. Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice.

    Science.gov (United States)

    Yu, Su Jong; Bae, Seyeon; Kang, Jae Seung; Yoon, Jung-Hwan; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Yoon Jun; Lee, Wang Jae; Kim, Chung Yong; Lee, Hyo-Suk

    2015-09-05

    Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.

    Science.gov (United States)

    Han, Shuxin; Li, Tiangang; Ellis, Ewa; Strom, Stephen; Chiang, John Y L

    2010-06-01

    Vitamin D receptor (VDR) is activated by natural ligands, 1alpha, 25-dihydroxy-vitamin D(3) [1alpha,25(OH)(2)-D(3)] and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1alpha,25(OH)(2)-D(3) activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1alpha, 25(OH)(2)-D(3) induced intracellular translocation of VDR from the cytosol to the nucleus and also plasma membrane where VDR colocalized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/extracellular signal-regulated kinase (ERK) 1/2 pathway, which stimulates serine phosphorylation of VDR and hepatocyte nuclear factor-4alpha, and their interaction. Mammalian two-hybrid assays showed a VDR ligand-dependent interaction of nuclear receptor corepressor-1 and silencing mediator of retinoid and thyroid with VDR/retinoid X receptor-alpha (RXRalpha). Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRalpha, and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRalpha recruitment of corepressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR-signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.

  15. Bile acid sequestrants

    DEFF Research Database (Denmark)

    Hansen, Morten; Sonne, David P; Knop, Filip K

    2014-01-01

    Bile acids are synthesized in the liver from cholesterol and have traditionally been recognized for their role in absorption of lipids and in cholesterol homeostasis. In recent years, however, bile acids have emerged as metabolic signaling molecules that are involved in the regulation of lipid...... and glucose metabolism, and possibly energy homeostasis, through activation of the bile acid receptors farnesoid X receptor (FXR) and TGR5. Bile acid sequestrants (BASs) constitute a class of drugs that bind bile acids in the intestine to form a nonabsorbable complex resulting in interruption...... of the enterohepatic circulation. This increases bile acid synthesis and consequently reduces serum low-density lipoprotein cholesterol. Also, BASs improve glycemic control in patients with type 2 diabetes. Despite a growing understanding of the impact of BASs on glucose metabolism, the mechanisms behind their glucose...

  16. "Theranostic" role of bile salt-capped silver nanoparticles - gall stone/pigment stone disruption and anticancer activity.

    Science.gov (United States)

    Mandal, Ranju Prasad; Mandal, Gunjan; Sarkar, Sudeshna; Bhattacharyya, Arindam; De, Swati

    2017-10-01

    Silver nanoparticles (AgNPs) have been synthesized in situ in micelles formed by the bile salt sodium deoxycholate (NaDC). The AgNPs exhibit "green" fluorescence. It has been shown in the present study that they can disrupt the components of gall stones/pigment stones. This unique ability of the AgNPs has been observed upon detailed study of the interaction between the endobiotic pigment bilirubin (BR) and bile salt (NaDC). In addition, these AgNPs show significant cytotoxicity towards the breast cancer cells (MCF-7). Thus the AgNPs synthesized in this work show important physiological activity and can serve as prospective "Theranostic Materials" in future. Their green fluorescence bears relevance to future diagnostic applications while their anticancer activity and disruptive action upon BR aggregates in bile salt micelles is extremely important for therapeutic purpose. This is the first report of the use of metal nanoparticles in disruption of components of gall stones/pigment stones and thus the present work has very important physiological significance. The detailed spectral studies indicate that bile salts increase the dimerization of BR which could be linked to increased solubilisation of BR in bile salt media and consequent bile stone/pigment stone formation. Importantly, an increase in red fluorescence was observed (upon dimerization of BR), which is important for cancer detection and studying the metabolism of biological tissues. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Synergistic effect of natural compounds on the fatty acid-induced autophagy of activated hepatic stellate cells.

    Science.gov (United States)

    Lee, Kuan-Wei; Thiyagarajan, Varadharajan; Sie, Huei-Wun; Cheng, Ming-Fan; Tsai, May-Jywan; Chia, Yi-Chen; Weng, Ching-Feng

    2014-09-01

    Autophagy, a lysosomal pathway to maintain cellular homeostasis, is mediated via the mammalian target of rapamycin (mTOR)-dependent pathways. Hepatic stellate cells (HSCs), previously termed fat- or vitamin A-storing cells, can transdifferentiate into myofibroblast-like cells and are the most relevant cell type for overproduction of extracellular matrix (ECM) and development of liver fibrosis during injury. However, the role of autophagy in fat metabolism of HSCs remains unclear. This study investigates the regulatory effect of natural compounds on fatty acid-induced autophagy pathways of nonchemical-induced HSC (NHSC) and thioacetamide-induced HSC. Oleic acid (OA) and palmitic acid (PA) have shown a significant effect on cell proliferation with oil red O staining and Western blot confirming that OA and PA induce fat storage ability and autophagy protein expression in NHSC. Natural compounds rutin, curcumin, antroquinonol and benzyl cinnamate treatment have shown no effect on the autophagy protein expression. Nevertheless, cells pretreated with OA and PA then treated with rutin, curcumin, antroquinonol and benzyl cinnamate could significantly induce the light chain I/II (LC3 I/II) protein expression. In mTOR-dependent pathway, the PI3K-Class I, Akt, and p-mTOR proteins were decreased with PA treatment. However, there were no significant changes in PI3K-Class III and Beclin-1 protein expressions found to imply that this autophagy is unrelated to the mTOR-independent pathway. Taken together, the present study unveils rutin and curcumin as a possible effective stimulation for fatty acid-induced autophagy via mTOR-dependent pathways in NHSC. We further suggest the benefits of these natural compounds for alleviating liver fibrosis. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells.

    Directory of Open Access Journals (Sweden)

    Soung-Hoon Lee

    Full Text Available Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA, a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo.Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP. VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX, a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl(2 also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice.Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth.

  19. Bile acids exert negative feedback control on bile acid synthesis in cultured pig hepatocytes by suppression of cholesterol 7α-hydroxylase activity

    NARCIS (Netherlands)

    Kwekkeboom, J.; Princen, H.M.G.; Voorthuizen, E.M. van; Kempen, H.J.M.

    1990-01-01

    Feedback regulation of bile acid synthesis by its end products was studied in cultured hepatocytes of young weaned pigs. We previously showed that conversion of exogenous [14C] cholesterol into bile acids was suppressed by addition of bile acids to the culture medium. In the present study, the

  20. Membranolytic Activity of Bile Salts: Influence of Biological Membrane Properties and Composition

    Directory of Open Access Journals (Sweden)

    Alfred Blume

    2007-10-01

    Full Text Available The two main steps of the membranolytic activity of detergents: 1 the partitioning of detergent molecules in the membrane and 2 the solubilisation of the membrane are systematically investigated. The interactions of two bile salt molecules, sodium cholate (NaC and sodium deoxycholate (NaDC with biological phospholipid model membranes are considered. The membranolytic activity is analysed as a function of the hydrophobicity of the bile salt, ionic strength, temperature, membrane phase properties, membrane surface charge and composition of the acyl chains of the lipids. The results are derived from calorimetric measurements (ITC, isothermal titration calorimetry. A thermodynamic model is described, taking into consideration electrostatic interactions, which is used for the calculation of the partition coefficient as well as to derive the complete thermodynamic parameters describing the interaction of detergents with biological membranes (change in enthalpy, change in free energy, change in entropy etc. The solubilisation properties are described in a so-called vesicle-to-micelle phase transition diagram. The obtained results are supplemented and confirmed by data obtained from other biophysical techniques (DSC differential scanning calorimetry, DLS dynamic light scattering, SANS small angle neutron scattering.

  1. Isolation, Identification and Partial Characterization of a Lactobacillus casei Strain with Bile Salt Hydrolase Activity from Pulque.

    Science.gov (United States)

    González-Vázquez, R; Azaola-Espinosa, A; Mayorga-Reyes, L; Reyes-Nava, L A; Shah, N P; Rivera-Espinoza, Y

    2015-12-01

    The aim of this study was to isolate, from pulque, Lactobacillus spp. capable of survival in simulated gastrointestinal stress conditions. Nine Gram-positive rods were isolated; however, only one strain (J57) shared identity with Lactobacillus and was registered as Lactobacillus casei J57 (GenBank accession: JN182264). The other strains were identified as Bacillus spp. The most significant observation during the test of tolerance to simulated gastrointestinal conditions (acidity, gastric juice and bile salts) was that L. casei J57 showed a rapid decrease (p ≤ 0.05) in the viable population at 0 h. Bile salts were the stress condition that most affected its survival, from which deoxycholic acid and the mix of bile salts (oxgall) were the most toxic. L. casei J57 showed bile salt hydrolase activity over primary and secondary bile salts as follows: 44.91, 671.72, 45.27 and 61.57 U/mg to glycocholate, taurocholate, glycodeoxycholate and taurodeoxycholate. In contrast, the control strain (L. casei Shirota) only showed activity over tauroconjugates. These results suggest that L. casei J57 shows potential for probiotic applications.

  2. Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARδ Activation.

    Science.gov (United States)

    Tumova, Jana; Malisova, Lucia; Andel, Michal; Trnka, Jan

    2015-10-01

    Unsaturated free fatty acids (FFA) are able to prevent deleterious effects of saturated FFA in skeletal muscle cells although the mechanisms involved are still not completely understood. FFA act as endogenous ligands of peroxisome proliferator-activated receptors (PPAR), transcription factors regulating the expression of genes involved in lipid metabolism. The aim of this study was to determine whether activation of PPARδ, the most common PPAR subtype in skeletal muscle, plays a role in mediating the protective effect of unsaturated FFA on saturated FFA-induced damage in skeletal muscle cells and to examine an impact on mitochondrial respiration. Mouse C2C12 myotubes were treated for 24 h with different concentrations of saturated FFA (palmitic acid), unsaturated FFA (oleic, linoleic and α-linolenic acid), and their combinations. PPARδ agonist GW501516 and antagonist GSK0660 were also used. Both mono- and polyunsaturated FFA, but not GW501516, prevented palmitic acid-induced cell death. Mono- and polyunsaturated FFA proved to be effective activators of PPARδ compared to saturated palmitic acid; however, in combination with palmitic acid their effect on PPARδ activation was blocked and stayed at the levels observed for palmitic acid alone. Unsaturated FFA at moderate physiological concentrations as well as GW501516, but not palmitic acid, mildly uncoupled mitochondrial respiration. Our results indicate that although unsaturated FFA are effective activators of PPARδ, their protective effect on palmitic acid-induced toxicity is not mediated by PPARδ activation and subsequent induction of lipid regulatory genes in skeletal muscle cells. Other mechanisms, such as mitochondrial uncoupling, may underlie their effect.

  3. Priming by Hexanoic acid induce activation of mevalonic and linolenic pathways and promotes the emission of plant volatiles.

    Directory of Open Access Journals (Sweden)

    Eugenio eLlorens

    2016-04-01

    Full Text Available Hexanoic acid is a short natural monocarboxylic acid present in some fruits and plants. Previous studies reported that soil drench application of this acid induces effective resistance in tomato plants against Botrytis cinerea and Pseudomonas syringae and in citrus against Alternaria alternata and Xanthomonas citri. In this work, we performed an in deep study of the metabolic changes produced in citrus by the application of hexanoic acid in response to the challenge pathogen Alternaria alternata, focusing on the response of the plant. Moreover, we used 13C labeled hexanoic to analyze its behavior inside the plants. Finally, we studied the volatile emission of the treated plants after the challenge inoculation. Drench application of 13C labeled hexanoic demonstrated that this molecule stays in the roots and is not mobilized to the leaves, suggesting long distance induction of resistance. Moreover, the study of the metabolic profile showed an alteration of more than two hundred molecules differentially induced by the application of the compound and the inoculation with the fungus. Bioinformatics analysis of data showed that most of these altered molecules could be related with the mevalonic and linolenic pathways suggesting the implication of these pathways in the induced resistance mediated by hexanoic acid. Finally, the application of this compound showed an enhancement of the emission of 17 volatile metabolites. Taken together, this study indicates that after the application of hexanoic acid this compound remains in the roots, provoking molecular changes that may trigger the defensive response in the rest of the plant mediated by changes in the mevalonic and linolenic pathways and enhancing the emission of volatile compounds, suggesting for the first time the implication of mevalonic pathway in response to hexanoic application.

  4. Bark Extracts of Ceylon Cinnamon Possess Antilipidemic Activities and Bind Bile Acids In Vitro

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    Walimuni Prabhashini Kaushalya Mendis Abeysekera

    2017-01-01

    Full Text Available Ethanol (95% and dichloromethane : methanol (1 : 1 bark extracts of authenticated Ceylon cinnamon were investigated for range of antilipidemic activities (ALA: HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities and bile acids binding in vitro. Individual compounds in bark extracts were also evaluated. Bark extracts showed ALA in all the assays studied. The IC50 (μg/mL values ranged within 153.07±8.38–277.13±32.18, 297.57±11.78–301.09±4.05, 30.61±0.79–34.05±0.41, and 231.96±9.22–478.89±9.27, respectively, for HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities. The bile acids binding (3 mg/mL for taurocholate, glycodeoxycholate, and chenodeoxycholate ranged within 19.74±0.31–20.22±0.31, 21.97±2.21–26.97±1.61, and 16.11±1.42–19.11±1.52%, respectively. The observed ALA were moderate compared to the reference drugs studied. Individual compounds in bark extracts ranged within 2.14±0.28–101.91±3.61 and 0.42±0.03–49.12±1.89 mg/g of extract. Cinnamaldehyde and gallic acid were the highest and the lowest among the tested compounds. The ethanol extract had highest quantity of individual compounds and ALA investigated. Properties observed indicate usefulness of Ceylon cinnamon bark in managing hyperlipidemia and obesity worldwide. Further, this study provides scientific evidence for the traditional claim that Ceylon cinnamon has antilipidemic activities.

  5. Bark Extracts of Ceylon Cinnamon Possess Antilipidemic Activities and Bind Bile Acids In Vitro

    Science.gov (United States)

    Abeysekera, Walimuni Prabhashini Kaushalya Mendis; Ratnasooriya, Wanigasekera Daya

    2017-01-01

    Ethanol (95%) and dichloromethane : methanol (1 : 1) bark extracts of authenticated Ceylon cinnamon were investigated for range of antilipidemic activities (ALA): HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities and bile acids binding in vitro. Individual compounds in bark extracts were also evaluated. Bark extracts showed ALA in all the assays studied. The IC50 (μg/mL) values ranged within 153.07 ± 8.38–277.13 ± 32.18, 297.57 ± 11.78–301.09 ± 4.05, 30.61 ± 0.79–34.05 ± 0.41, and 231.96 ± 9.22–478.89 ± 9.27, respectively, for HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities. The bile acids binding (3 mg/mL) for taurocholate, glycodeoxycholate, and chenodeoxycholate ranged within 19.74 ± 0.31–20.22 ± 0.31, 21.97 ± 2.21–26.97 ± 1.61, and 16.11 ± 1.42–19.11 ± 1.52%, respectively. The observed ALA were moderate compared to the reference drugs studied. Individual compounds in bark extracts ranged within 2.14 ± 0.28–101.91 ± 3.61 and 0.42 ± 0.03–49.12 ± 1.89 mg/g of extract. Cinnamaldehyde and gallic acid were the highest and the lowest among the tested compounds. The ethanol extract had highest quantity of individual compounds and ALA investigated. Properties observed indicate usefulness of Ceylon cinnamon bark in managing hyperlipidemia and obesity worldwide. Further, this study provides scientific evidence for the traditional claim that Ceylon cinnamon has antilipidemic activities. PMID:28808476

  6. Effect of chenodeoxycholic acid and the bile acid sequestrant colesevelam on glucagon-like peptide-1 secretion

    DEFF Research Database (Denmark)

    Hansen, Morten; Scheltema, Matthijs J; Sonne, David P

    2016-01-01

    of the primary human bile acid, chenodeoxycholic acid (CDCA), and the BAS, colesevelam, instilled into the stomach, on plasma levels of GLP-1, glucose-dependent insulinotropic polypeptide, glucose, insulin, C-peptide, glucagon, cholecystokinin and gastrin as well as gastric emptying, gallbladder volume, appetite......AIMS: In patients with type 2 diabetes, rectal administration of bile acids increases glucagon-like peptide-1 (GLP-1) secretion and reduces plasma glucose. In addition, oral bile acid sequestrants (BASs) reduce blood glucose by an unknown mechanism. In this study we evaluated the effects......, and delayed gastric emptying. We speculate that bile acid-induced activation of TGR5 on L cells increases GLP-1 secretion, which in turn may result in amplification of glucose-stimulated insulin secretion. Furthermore our data suggest that colesevelam does not have an acute effect on GLP-1 secretion in humans....

  7. ENZYME MARKERS ACTIVITY AND BILE FORMATION FUNCTION OF LIVER IN CASES OF TUBERCULOSTATICS AND HEXAVALENT CHROMIUM COMPOUNDS AFFECTION IN RATS

    Directory of Open Access Journals (Sweden)

    N. I. Burmas

    2016-05-01

    Full Text Available Background. Currently, the growing incidence of toxic lesions of the liver is associated with industrial chemicalization and uncontrolled use of hepatotoxic drugs in everyday life. There are about one thousand drugs with high or low hepatotoxicity, such as anti-TB drugs. Objective. In this research we studied the intracellular enzymes activity and bile formation function of the liver in rats of different ages in cases of tuberculostatic (isoniazid and rifampicin affection and chromium (potassium dichromate intoxication. Methods. The experimental affection of rats of different ages was performed by combined injection of hexavalent chromium compounds (a solution of potassium dichromate, 3 mg/kg, isoniazid (0.05 g/kg and rifampicin (0.25 g/kg. On the 7th and 14th days the rats were injected with enterosorbent Sorbex (150 mg/kg. Enzyme markers activity of the liver was evaluated due to alanine and aspartate aminotransferases (ALT and AST and alkaline phosphatase (ALP rates. Bile formation function of the liver was evaluated by total bilirubin and bile acids content in blood. Results. The disorders in hepatocytes plasma membranes permeability were defined by the increased rates of ALT, AST and alkaline phosphatase in blood serum which were decreased in the liver. It was determined that total bilirubin and bile acids content in blood serum of the affected animals increased. It influenced hepatocytes excretion in bile capillaries and caused cholestasis and revenues decrease in bile. Conclusions. The most significant metabolic disorders in cases of chrome-isoniazid-rifampicin affection were defined in immature and senior animals in comparison with mature animals.

  8. Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats

    NARCIS (Netherlands)

    Bolder, U.; Trang, N. V.; Hagey, L. R.; Schteingart, C. D.; Ton-Nu, H. T.; Cerrè, C.; Elferink, R. P.; Hofmann, A. F.

    1999-01-01

    BACKGROUND & AIMS: Dihydroxy bile acids induce a bicarbonate-rich hypercholeresis when secreted into canalicular bile in unconjugated form; the mechanism is cholehepatic shunting. The aim of this study was to identify a xenobiotic that induces hypercholeresis by a similar mechanism. METHODS: Five

  9. Defective bile salt biosynthesis and hydroxylation in mice with reduced cytochrome P450 activity

    NARCIS (Netherlands)

    Kunne, Cindy; Acco, Alexandra; Hohenester, Simon; Duijst, Suzanne; de Waart, Dirk R.; Zamanbin, Alaleh; Oude Elferink, Ronald P. J.

    2013-01-01

    The difference in bile salt (BS) composition between rodents and humans is mainly caused by formation of muricholate in rodents as well as by efficient rehydroxylation of deoxycholic acid. The aim of this study was to characterize bile formation in a mouse model (Hrn mice) with hepatic disruption of

  10. Bile acid synthesis in man. In vivo activity of the 25-hydroxylation pathway

    International Nuclear Information System (INIS)

    Duane, W.C.; Pooler, P.A.; Hamilton, J.N.

    1988-01-01

    During biosynthesis of bile acid, carbons 25-26-27 are removed from the cholesterol side-chain. Side-chain oxidation begins either with hydroxylation at the 26-position, in which case the three-carbon fragment is released as propionic acid, or with hydroxylation at the 25-position, in which case the three-carbon fragment is released as acetone. We have previously shown in the rat that the contribution of the 25-hydroxylation pathway can be quantitated in vivo by measuring production of [ 14 C]acetone from [ 14 C]26-cholesterol. In the present study, we adapted this method to human subjects. 4 d after oral administration of 100 microCi of [ 14 C]26-cholesterol and 1 d after beginning a constant infusion of 16.6 mumol/min unlabeled acetone, three men and two women underwent breath collections. Expired acetone was trapped and purified as the 2,4 dinitrophenylhydrazine derivative. 14 CO 2 was trapped quantitatively using phenethylamine. Specific activity of breath acetone was multiplied by the acetone infusion rate to calculate production of [ 14 C]acetone. [ 14 C]Acetone production averaged 4.9% of total release of 14 C from [ 14 C]26-cholesterol, estimated by 14 CO2 output. The method was validated by showing that [ 14 C]acetone production from [ 14 C]isopropanol averaged 86.9% of the [ 14 C]-isopropanol infusion rate. We conclude that in man, as in the rat, the 25-hydroxylation pathway accounts for less than 5% of bile acid synthesis

  11. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression

    NARCIS (Netherlands)

    Post, SM; Duez, H; Gervois, PP; Staels, B; Kuipers, F; Princen, HMG

    2001-01-01

    Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased

  12. Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-α-mediated downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase expression

    NARCIS (Netherlands)

    Post, S.M.; Duez, H.; Gervois, P.P.; Staels, B.; Kuipers, F.; Princen, H.M.G.

    2001-01-01

    Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased

  13. Bile acid increases expression of the histamine-producing enzyme, histidine decarboxylase, in gastric cells.

    Science.gov (United States)

    Ku, Hye Jin; Kim, Hye Young; Kim, Hyeong Hoe; Park, Hee Ju; Cheong, Jae Hun

    2014-01-07

    To investigate the effect of bile acid on the expression of histidine decarboxylase (HDC), which is a major enzyme involved in histamine production, and gene expression of gastric transcription factors upon cooperative activation. HDC expression was examined by immunohistochemistry, reverse transcriptase polymerase chain reaction, and promoter assay in human gastric precancerous tissues, normal stomach tissue, and gastric cancer cell lines. The relationship between gastric precancerous state and HDC expression induced by bile acid was determined. The association between the expression of HDC and various specific transcription factors in gastric cells was also evaluated. MKN45 and AGS human gastric carcinoma cell lines were transfected with farnesoid X receptor (FXR), small heterodimer partner (SHP), and caudal-type homeodomain transcription factor (CDX)1 expression plasmids. The effects of various transcription factors on HDC expression were monitored by luciferase-reporter promoter assay. Histamine production and secretion in the stomach play critical roles in gastric acid secretion and in the pathogenesis of gastric diseases. Here, we show that bile acid increased the expression of HDC, which is a rate-limiting enzyme of the histamine production pathway. FXR was found to be a primary regulatory transcription factor for bile acid-induced HDC expression. In addition, the transcription factors CDX1 and SHP synergistically enhanced bile acid-induced elevation of HDC gene expression. We confirmed similar expression patterns for HDC, CDX1, and SHP in patient tissues. HDC production in the stomach is associated with bile acid exposure and its related transcriptional regulation network of FXR, SHP, and CDX1.

  14. Anti-inflammatory, antioxidant and anti-apoptotic activity of diosmin in acetic acid-induced ulcerative colitis.

    Science.gov (United States)

    Shalkami, A S; Hassan, Mia; Bakr, A G

    2018-01-01

    Ulcerative colitis (UC) is a chronic inflammatory disease affecting colon. The primary symptoms of UC are diarrhoea with blood and mucus and sometimes associated with pain. This study aimed to evaluate the effects of diosmin (DIO) on UC. UC was induced in rats by rectal administration of acetic acid (AA). The degree of mucosal ulceration and damage was determined by evaluating the disease activity index (DAI) and colon damage index scores. Inflammation, oxidative stress and apoptotic responses were determined by measuring the levels of tumour necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-II), malondialdehyde (MDA) and reduced glutathione (GSH) in addition to myeloperoxidase (MPO) activity and caspase-3 expression. The results of this study indicate that AA caused increase in DAI and colon damage index scores. Also, markers of inflammation (TNF-α, COX-II and MPO) and oxidative stress (MDA and reduced GSH) were significantly elevated. These changes were associated with increases in colon caspase-3 expression. Treatment of rats with two doses of DIO produced a dose-dependent decline in DAI and colon damage index scores. Also, DIO resulted in significant reduction of inflammatory and oxidative stress markers as well as reduced the expression of caspase-3. DIO therapy decreased UC development depending on its ability to decreases inflammation, oxidative stress and apoptosis in rat colon.

  15. Sulforaphane Ameliorates Okadaic Acid-Induced Memory Impairment in Rats by Activating the Nrf2/HO-1 Antioxidant Pathway.

    Science.gov (United States)

    Dwivedi, Subhash; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2016-10-01

    Okadaic acid (OKA) causes memory impairment and attenuates nuclear factor erythroid 2-related factor 2 (Nrf2) along with oxidative stress and neuroinflammation in rats. Sulforaphane (dietary isothiocyanate compound), an activator of Nrf2 signaling, exhibits neuroprotective effects. However, the protective effect of sulforaphane in OKA-induced neurotoxicity remains uninvestigated. Therefore, in the present study, the role of sulforaphane in OKA-induced memory impairment in rats was explored. A significant increased Nrf2 expression in the hippocampus and cerebral cortex was observed in trained (Morris water maze) rats, and a significant decreased Nrf2 expression in memory-impaired (OKA, 200 ng icv) rats indicated its involvement in memory function. Sulforaphane administration (5 and 10 mg/kg, ip, days 1 and 2) ameliorates OKA-induced memory impairment in rats. The treatment also restored Nrf2 and its downstream antioxidant protein expression (GCLC, HO-1) and attenuated oxidative stress (ROS, nitrite, GSH), neuroinflammation (NF-κB, TNF-α, IL-10), and neuronal apoptosis in the cerebral cortex and hippocampus of OKA-treated rats. Further, to determine whether modulation of Nrf2 signaling is responsible for the protective effect of sulforaphane, in vitro, Nrf2 siRNA and its downstream HO-1 inhibition studies were carried out in a rat astrocytoma cell line (C6). The protective effects of sulforaphane were abolished with Nrf2 siRNA and HO-1 inhibition in astrocytes. The results suggest that Nrf2-dependent activation of cellular antioxidant machinery results in sulforaphane-mediated protection against OKA-induced memory impairment in rats. Graphical Abstract ᅟ.

  16. Free fatty acids induce ER stress and block antiviral activity of interferon alpha against hepatitis C virus in cell culture

    Directory of Open Access Journals (Sweden)

    Gunduz Feyza

    2012-08-01

    Full Text Available Abstract Background Hepatic steatosis is recognized as a major risk factor for liver disease progression and impaired response to interferon based therapy in chronic hepatitis C (CHC patients. The mechanism of response to interferon-alpha (IFN-α therapy under the condition of hepatic steatosis is unexplored. We investigated the effect of hepatocellular steatosis on hepatitis C virus (HCV replication and IFN-α antiviral response in a cell culture model. Methods Sub-genomic replicon (S3-GFP and HCV infected Huh-7.5 cells were cultured with a mixture of saturated (palmitate and unsaturated (oleate long-chain free fatty acids (FFA. Intracytoplasmic fat accumulation in these cells was visualized by Nile red staining and electron microscopy then quantified by microfluorometry. The effect of FFA treatment on HCV replication and IFN-α antiviral response was measured by flow cytometric analysis, Renilla luciferase activity, and real-time RT-PCR. Results FFA treatment induced dose dependent hepatocellular steatosis and lipid droplet accumulation in the HCV replicon cells was confirmed by Nile red staining, microfluorometry, and by electron microscopy. Intracellular fat accumulation supports replication more in the persistently HCV infected culture than in the sub-genomic replicon (S3-GFP cell line. FFA treatment also partially blocked IFN-α response and viral clearance by reducing the phosphorylation of Stat1 and Stat2 dependent IFN-β promoter activation. We show that FFA treatment induces endoplasmic reticulum (ER stress response and down regulates the IFNAR1 chain of the type I IFN receptor leading to defective Jak-Stat signaling and impaired antiviral response. Conclusion These results suggest that intracellular fat accumulation in HCV cell culture induces ER stress, defective Jak-Stat signaling, and attenuates the antiviral response, thus providing an explanation to the clinical observation regarding how hepatocellular steatosis influences IFN

  17. Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro.

    Science.gov (United States)

    Yoshino, Hironori; Iwabuchi, Miyu; Kazama, Yuka; Furukawa, Maho; Kashiwakura, Ikuo

    2018-04-01

    Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern-recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell-derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non-small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non-small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non-small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase-dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non-small cell lung cancer through caspase-mediated apoptosis.

  18. Manuka Honey Exerts Antioxidant and Anti-Inflammatory Activities That Promote Healing of Acetic Acid-Induced Gastric Ulcer in Rats

    Science.gov (United States)

    Almasaudi, Saad B.; Al-Hindi, Rashad R.; Abdel-dayem, Umama A.; Ali, Soad S.; Saleh, Rasha M.; Al Jaouni, Soad K.

    2017-01-01

    Gastric ulcers are a major problem worldwide with no effective treatment. The objective of this study was to evaluate the use of manuka honey in the treatment of acetic acid-induced chronic gastric ulcers in rats. Different groups of rats were treated with three different concentrations of honey. Stomachs were checked macroscopically for ulcerative lesions in the glandular mucosa and microscopically for histopathological alterations. Treatment with manuka honey significantly reduced the ulcer index and maintained the glycoprotein content. It also reduced the mucosal myeloperoxidase activity, lipid peroxidation (MDA), and the inflammatory cytokines (TNF-α, IL-1β, and IL-6) as compared to untreated control group. In addition, honey-treated groups showed significant increase in enzymatic (GPx and SOD) and nonenzymatic (GSH) antioxidants besides levels of the anti-inflammatory cytokine IL-10. Flow cytometry studies showed that treatment of animals with manuka honey has normalized cell cycle distribution and significantly lowered apoptosis in gastric mucosa. In conclusion, the results indicated that manuka honey is effective in the treatment of chronic ulcer and preservation of mucosal glycoproteins. Its effects are due to its antioxidant and anti-inflammatory properties that resulted in a significant reduction of the gastric mucosal MDA, TNF-α, IL-1β, and IL-6 and caused an elevation in IL-10 levels. PMID:28250794

  19. Fluorescence properties and sequestration of peripheral anionic site specific ligands in bile acid hosts: Effect on acetylcholinesterase inhibition activity.

    Science.gov (United States)

    Islam, Mullah Muhaiminul; Aguan, Kripamoy; Mitra, Sivaprasad

    2016-05-01

    The increase in fluorescence intensity of model acetyl cholinesterase (AChE) inhibitors like propidium iodide (PI) and ethidium bromide (EB) is due to sequestration of the probes in primary micellar aggregates of bile acid (BA) host medium with moderate binding affinity of ca. 10(2)-10(3)M(-1). Multiple regression analysis of solvent dependent fluorescence behavior of PI indicates the decrease in total nonradiative decay rate due to partial shielding of the probe from hydrogen bond donation ability of the aqueous medium in bile acid bound fraction. Both PI and EB affects AChE activity through mixed inhibition and consistent with one site binding model; however, PI (IC50=20±1μM) shows greater inhibition in comparison with EB (IC50=40±3μM) possibly due to stronger interaction with enzyme active site. The potency of AChE inhibition for both the compounds is drastically reduced in the presence of bile acid due to the formation of BA-inhibitor complex and subsequent reduction of active inhibitor fraction in the medium. Although the inhibition mechanism still remains the same, the course of catalytic reaction critically depends on equilibrium binding among several species present in the solution; particularly at low inhibitor concentration. All the kinetic parameters for enzyme inhibition reaction are nicely correlated with the association constant for BA-inhibitor complex formation. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Vitamin A active metabolite, all-trans retinoic acid, induces spinal cord sensitization. II. Effects after intrathecal administration

    Science.gov (United States)

    Alique, M; Lucio, F J; Herrero, J F

    2006-01-01

    Background and purpose: In our previous study (see accompanying paper) we observed that all-trans retinoic acid (ATRA) p.o. induces changes in spinal cord neuronal responses similar to those observed in inflammation-induced sensitization. In the present study we assessed the it. effects of ATRA, and its mechanisms of action. Experimental approach: The effects of all drugs were studied after it. administration in nociceptive withdrawal reflexes using behavioural tests in awake male Wistar rats. Key results: The administration of ATRA in normal rats induced a dose-dependent enhancement of nociceptive responses to noxious mechanical and thermal stimulation, as well as responses to innocuous stimulation. The intensity of the responses was similar to that observed in non-treated animals after carrageenan-induced inflammation. The effect induced by ATRA was fully prevented by the previous administration of the retinoic acid receptor (RAR) pan-antagonist LE540 but not by the retinoid X receptor (RXR) pan-antagonist HX531, suggesting a selective action on spinal cord RARs. The COX inhibitor dexketoprofen and the interleukin-1 receptor antagonist IL-1ra inhibited ATRA effect. The results indicate that COX and interleukin-1 are involved in the effects of ATRA in the spinal cord, similar to that seen in inflammation. Conclusions and implications: In conclusion, ATRA induces changes in the spinal cord similar to those observed in inflammation. The sensitization-like effect induced by ATRA was mediated by RARs and associated with a modulation of COX-2 and interleukin-1 activities. ATRA might be involved in the mechanisms underlying the initiation and/or maintenance of sensitization in the spinal cord. PMID:16847438

  1. A comparative study of the antitussive activity of levodropropizine and dropropizine in the citric acid-induced cough model in normal subjects.

    Science.gov (United States)

    Fumagalli, G; Cordaro, C I; Vanasia, M; Balzarotti, C; Camusso, L; Caiazzo, G; Maghini, L; Mazzocchi, M; Zennaro, M

    1992-01-01

    Levodropropizine is the levo-rotatory (S)-enantiomer of dropropizine, a racemic non-opiate antitussive agent which has been used clinically for many years. Compared with the racemic drug, levodropropizine exhibits in animal models similar antitussive activity but considerably lower central nervous system (CNS) depressant effects. It is also less likely to cause sedation in treated patients. Since the comparative antitussive potency of the two drugs in clinical experimental models has not been evaluated, the authors performed a randomized, double blind, cross over investigation in which the effects of single oral doses (60 and 90 mg) of levodropropizine and dropropizine were assessed by using the citric acid-induced cough model in eight normal volunteers. Stimulation tests involved inhalation of individual cumulative doses of citric acid (6.3 to 53.3 mg) which at pre-study assessment had been found to induce reproducibly at least ten coughs over a 30 sec period. Each subject was studied by repeating the citric acid stimulation test four times (0 h, 1 h, 2 h and 6 h) on each of five different days separated by intervals of at least three days. In the absence of drug administration (control session), cough response to citric inhalation was remarkably reproducible throughout the 6 h period of observation. A marked and statistically significant reduction in cough response (to about one third--one sixth of the pre-drug values) was observed 1 h after intake for both compounds. At subsequent testing 2 h and 6 h after dosing, cough response was still depressed and did not differ significantly from that observed at 1 h.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Bile culture

    Science.gov (United States)

    Culture - bile ... is placed in a special dish called a culture medium to see if bacteria, viruses, or fungi ... Chernecky CC, Berger BJ. Body fluid - anaerobic culture. In: ... . 6th ed. St Louis, MO: Elsevier Saunders; 2013:225-226. Kim AY, ...

  3. Detection of active bile leak with Gd-EOB-DTPA enhanced MR cholangiography: comparison of 20-25 min delayed and 60-180 min delayed images.

    Science.gov (United States)

    Cieszanowski, Andrzej; Stadnik, Anna; Lezak, Aleksandra; Maj, Edyta; Zieniewicz, Krzysztof; Rowinska-Berman, Katarzyna; Grudzinski, Ireneusz P; Krawczyk, Marek; Rowiński, Olgierd

    2013-12-01

    The purpose of this study was to assess the value of contrast-enhanced magnetic resonance cholangiography (MRC) performed in different time delays after injection of gadoxetic acid disodium (Gd-EOB-DTPA) for the diagnosis of active bile leak. This retrospective analysis included Gd-EOB-DTPA enhanced MR images of 34 patients suspected of bile leak. Images were acquired 20-25 min after Gd-EOB-DTPA injection. If there was inadequate contrast in the bile ducts then delayed images after 60-90 min and 150-180 min were obtained. Results were correlated with intraoperative findings, ERCP results, clinical data, laboratory tests, and follow-up examinations. Gd-EOB-DTPA enhanced MRC yielded an overall sensitivity of 96.4%, specificity of 100% and accuracy of 97.1% for the diagnosis of an active bile leak. The sensitivity of 20-25 min delayed MR images was 42.9%, of combined 20-25 min and 60-90 min delayed images was 92.9% and of combined 20-25 min, 60-90 min and 150-180 min delayed images was 96.4%. Gd-EOB-DTPA enhanced MRC utilizing delayed phase images was effective for detecting the presence and location of active bile leaks. The images acquired 60-180 min post-injection enabled identification of bile leaks even in patients with a dilated biliary system or moderate liver dysfunction. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  4. Polymeric bile acid sequestrants: review of design, in vitro binding activities, and hypocholesterolemic effects

    Czech Academy of Sciences Publication Activity Database

    Heřmánková, Eva; Žák, A.; Poláková, Lenka; Hobzová, Radka; Hromádka, R.; Širc, Jakub

    2018-01-01

    Roč. 144, 20 January (2018), s. 300-317 ISSN 0223-5234 R&D Projects: GA MPO(CZ) FV10380; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 Keywords : review * bile acid sequestrant * pleiotropic effect Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Medicinal chemistry Impact factor: 4.519, year: 2016

  5. Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress

    Directory of Open Access Journals (Sweden)

    Klingelhoeffer Christoph

    2012-05-01

    against oxidative stress mediated by ascorbic acid induced hydrogen peroxide production. The antioxidative enzyme catalase is important to protect cancer cells against cytotoxic hydrogen peroxide. Silenced catalase expression increased the susceptibility of the formerly resistant cancer cell line BT-20 to oxidative stress.

  6. Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress

    Science.gov (United States)

    2012-01-01

    Background Ascorbic acid demonstrates a cytotoxic effect by generating hydrogen peroxide, a reactive oxygen species (ROS) involved in oxidative cell stress. A panel of eleven human cancer cell lines, glioblastoma and carcinoma, were exposed to serial dilutions of ascorbic acid (5-100 mmol/L). The purpose of this study was to analyse the impact of catalase, an important hydrogen peroxide-detoxifying enzyme, on the resistance of cancer cells to ascorbic acid mediated oxidative stress. Methods Effective concentration (EC50) values, which indicate the concentration of ascorbic acid that reduced the number of viable cells by 50%, were detected with the crystal violet assay. The level of intracellular catalase protein and enzyme activity was determined. Expression of catalase was silenced by catalase-specific short hairpin RNA (sh-RNA) in BT-20 breast carcinoma cells. Oxidative cell stress induced apoptosis was measured by a caspase luminescent assay. Results The tested human cancer cell lines demonstrated obvious differences in their resistance to ascorbic acid mediated oxidative cell stress. Forty-five percent of the cell lines had an EC50 > 20 mmol/L and fifty-five percent had an EC50 ascorbic acid was observed. To study the possible protective role of catalase on the resistance of cancer cells to oxidative cell stress, the expression of catalase in the breast carcinoma cell line BT-20, which cells were highly resistant to the exposure to ascorbic acid (EC50: 94,9 mmol/L), was silenced with specific sh-RNA. The effect was that catalase-silenced BT-20 cells (BT-20 KD-CAT) became more susceptible to high concentrations of ascorbic acid (50 and 100 mmol/L). Conclusions Fifty-five percent of the human cancer cell lines tested were unable to protect themselves against oxidative stress mediated by ascorbic acid induced hydrogen peroxide production. The antioxidative enzyme catalase is important to protect cancer cells against cytotoxic hydrogen peroxide

  7. Non-Alcoholic Fatty Liver Disease: The Bile Acid-Activated Farnesoid X Receptor as an Emerging Treatment Target

    Directory of Open Access Journals (Sweden)

    Michael Fuchs

    2012-01-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects.

  8. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice.

    Science.gov (United States)

    Beilke, Lisa D; Aleksunes, Lauren M; Olson, Erik R; Besselsen, David G; Klaassen, Curtis D; Dvorak, Katerina; Cherrington, Nathan J

    2009-07-10

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR(+/+) (WT) and CAR(-/-) (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16alpha-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-x(L) was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.

  9. Possible protective role of pregnenolone-16 alpha-carbonitrile in lithocholic acid-induced hepatotoxicity through enhanced hepatic lipogenesis.

    Science.gov (United States)

    Miyata, Masaaki; Nomoto, Masahiro; Sotodate, Fumiaki; Mizuki, Tomohiro; Hori, Wataru; Nagayasu, Miho; Yokokawa, Shinya; Ninomiya, Shin-ichi; Yamazoe, Yasushi

    2010-06-25

    Lithocholic acid (LCA) feeding causes both liver parenchymal and cholestatic damages in experimental animals. Although pregnenolone-16 alpha-carbonitrile (PCN)-mediated protection against LCA-induced hepatocyte injury may be explained by induction of drug metabolizing enzymes, the protection from the delayed cholestasis remains incompletely understood. Thus, the PCN-mediated protective mechanism has been studied from the point of modification of lipid metabolism. At an early stage of LCA feeding, an imbalance of biliary bile acid and phospholipid excretion was observed. Co-treatment with PCN reversed the increase in serum alanine aminotransferase (ALT) as well as alkaline phosphatase (ALP) activities and hepatic hydrophobic bile acid levels. LCA feeding decreased hepatic mRNA levels of several fatty acid- and phospholipid-related genes before elevation of serum ALT and ALP activities. On the other hand, PCN co-treatment reversed the decrease in the mRNA levels and hepatic levels of phospholipids, triglycerides and free fatty acids. PCN co-treatment also reversed the decrease in biliary phospholipid output in LCA-fed mice. Treatment with PCN alone increased hepatic phospholipid, triglyceride and free fatty acid concentrations. Hepatic fatty acid and phosphatidylcholine synthetic activities increased in mice treated with PCN alone or PCN and LCA, compared to control mice, whereas these activities decreased in LCA-fed mice. These results suggest the possibility that PCN-mediated stimulation of lipogenesis contributes to the protection from lithocholic acid-induced hepatotoxicity. (c) 2010 Elsevier B.V. All rights reserved.

  10. Mefenamic Acid Induced Nephrotoxicity: An Animal Model

    Directory of Open Access Journals (Sweden)

    Muhammad Nazrul Somchit

    2014-12-01

    Full Text Available Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs are used for the treatment of many joint disorders, inflammation and to control pain. Numerous reports have indicated that NSAIDs are capable of producing nephrotoxicity in human. Therefore, the objective of this study was to evaluate mefenamic acid, a NSAID nephrotoxicity in an animal model. Methods: Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day. Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN and creatinine activities were measured. Results: Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine. Conclusion: Results from this study suggest that mefenamic acid as with other NSAIDs capable of producing nephrotoxicity. Therefore, the study of the exact mechanism of mefenamic acid induced severe nephrotoxicity can be done in this animal model.

  11. Biosynthesis and biotransformation of bile acids

    Directory of Open Access Journals (Sweden)

    Šarenac Tanja M.

    2017-01-01

    Full Text Available Bile acids are steroidal compounds, which contain 24 carbon atoms. They can be classified into two major groups: primary and secondary. The most abundant bile acids: The primary bile acids include cholic acid and chenodeoxycholic acid, while the major secondary bile acids are deoxycholic acid and litocholic acid. Bile acids are important physiological agents for intestinal absorption of nutrients and are used for biliary lipid secretion, toxic metabolites and xenobiotics. The aim of this paper is to analyze biosynthesis and biotransformation of bile acids, as preparation for practical usage in laboratory and clinical conditions. Topic: Biosynthesis and biotransformation of bile acids: The biosynthesis of bile acids is the dominant metabolic pathway for catabolism of cholesterol in humans. The classical route of biosynthesis of bile acids is embarking on the conversion of cholesterol into 7α-hydroxycholesterol using enzyme 7α-cholesterol hydroxylase (CYP7A1. This enzyme is one of the microsomal cytochrome P450 enzyme is localized exclusively in the liver. Classical road is the main road in the biosynthesis of bile acids, and its total contribution amounts to 90% for people, and 75% in mice. CYP 7A1 enzyme is considered to be sensitive to the inhibition of carbon monoxide, and the condition for the effect of NADPH, the oxygen, lecithin, and the NADPH-cytochrome P450 reductase. Bile acids are important signaling molecules and metabolic controls which activate the nuclear receptor and the G protein-coupled receptors (GPCR, a signaling lipid regulation of the liver, glucose and energy homeostasis. Also, bile acids maintain metabolic homeostasis. Biotransformation of bile acids: The conversion of cholesterol into bile acids just important for maintenance of cholesterol homeostasis, but also to prevent the accumulation of cholesterol, triglycerides and toxic metabolites as well as violations of the liver and other organs. Enterohepatic circulation of

  12. Caffeic Acid Induces Apoptosis in Human Cervical Cancer Cells Through the Mitochondrial Pathway

    Directory of Open Access Journals (Sweden)

    Wei-Chun Chang

    2010-12-01

    Conclusion: Caffeic acid induces apoptosis by inhibiting Bcl-2 activity, leading to release of cytochrome c and subsequent activation of caspase-3, indicating that caffeic acid induces apoptosis via the mitochondrial apoptotic pathway. This also suggests that caffeic acid has a strong anti-tumor effect and may be a promising chemopreventive or chemotherapeutic agent.

  13. Beyond intestinal soap-bile acids in metabolic control

    NARCIS (Netherlands)

    Kuipers, Folkert; Bloks, Vincent W.; Groen, Albert K.

    Over the past decade, it has become apparent that bile acids are involved in a host of activities beyond their classic functions in bile formation and fat absorption. The identification of the farnesoid X receptor (FXR) as a nuclear receptor directly activated by bile acids and the discovery that

  14. Effect of dietary fibers on cholic acid induced cell proliferation in the colonic epithelium of C57BL/6J mice

    International Nuclear Information System (INIS)

    Robblee, N.M.; Bruce, W.R.; Bird, R.P.

    1986-01-01

    It has been postulated that high fat diets promote tumorigenesis by increasing the level of secondary bile acids in the colonic lumen. Dietary fibers are thought to be protective perhaps through their interaction with bile acids. In the present study, animals were fed diets containing either 0%, 5%, or 10% cellulose (C), pectin (P), or wheat bran (WB). The diets were formulated to contain either 0% (control) or 0.2% cholic acid (test). After two weeks of dietary treatment the animals were injected with [ 3 H]-thymidine and their colons were processed for autoradiography. The number of labeled cells (LC) in the colonic crypts was determined. Among the control diets, 10%P induced a two-fold increase in the LC. All the test groups had significantly higher LC than in their controls. However, the C group excited a higher LC than the P or WB groups (5.2 +/- 0.8 vs 3.9 +/- 0.8 or 3.9 +/- 0.6). These results were substantiated by metaphase arrest technique. The authors results show that nonfermentable fiber does not alleviate bile acid induced cell proliferative activity in the colon whereas fermentable fibers will counteract the promotional effect of a high fat diet

  15. Pharmacological activation of the bile acid nuclear farnesoid X receptor is feasible in patients with quiescent Crohn's colitis.

    Directory of Open Access Journals (Sweden)

    Fiona D M van Schaik

    Full Text Available BACKGROUND: The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC. METHODS: Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF 19. Since FGF19 induces gallbladder (GB refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined. RESULTS: At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups. CONCLUSIONS: Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients. TRIAL REGISTRATION: TrialRegister.nl NTR2009.

  16. Unique inhibition of bile salt-induced apoptosis by lecithins and cytoprotective bile salts in immortalized mouse cholangiocytes.

    Science.gov (United States)

    Komichi, Daisuke; Tazuma, Susumu; Nishioka, Tomoji; Hyogo, Hideyuki; Une, Mizuho; Chayama, Kazuaki

    2003-12-01

    Bile duct epithelium is physiologically exposed to high concentrations of bile salts, suggesting the presence of a cytoprotective mechanism(s). The aim of this study was to clarify whether bile salts cause bile duct cell damage and to elucidate the mechanism(s) providing protection against such an action of bile salts. Immortalized mouse cholangiocytes were incubated with taurocholate, taurochenodeoxycholate, glycochenodeoxycholate (GCDC), taurodeoxycholate, and tauroursodeoxycholate (TUDC), followed by flow-cytometric analysis and caspase activity assay to evaluate the induction of apoptosis. GCDC time-dependently induced caspase 3 (3.4-fold)- and caspase 9 (1.4-fold)-mediated apoptosis of cholangiocytes, but this was inhibited by lecithins and TUDC. Further, expression of cholangiocyte bile salt transporters (apical sodium-dependent bile salt transporter [Asbt] and multidrug resistance protein 3 [Mrp3]) was examined by RT-PCR and western blotting, and cholangiocyte bile salt uptake was determined using radiolabeled bile salts. Expression of cholangiocyte Asbt and Mrp3 was increased by bile salts, whereas lecithins interestingly reduced bile salt uptake to inhibit cholangiocyte apoptosis. In conclusion, bile salts themselves cause cholangiocyte apoptosis when absorbed by and retained inside the cell, but this is inhibited by washing out cytotoxic bile salts according to Mrp3, a rescue exporting molecule. Biliary lecithin is seemingly another cytoprotective player against cytotoxic bile salts, reducing their uptake, and this is associated with a reduced expression of Mrp3.

  17. Spironolactone lowers portal hypertension by inhibiting liver fibrosis, ROCK-2 activity and activating NO/PKG pathway in the bile-duct-ligated rat.

    Directory of Open Access Journals (Sweden)

    Wei Luo

    Full Text Available OBJECTIVE: Aldosterone, one of the main peptides in renin angiotensin aldosterone system (RAAS, has been suggested to mediate liver fibrosis and portal hypertension. Spironolactone, an aldosterone antagonist, has beneficial effect on hyperdynamic circulation in clinical practice. However, the mechanisms remain unclear. The present study aimed to investigate the role of spionolactone on liver cirrhosis and portal hypertension. METHODS: Liver cirrhosis was induced by bile duct ligation (BDL. Spironolactone was administered orally (20 mg/kg/d after bile duct ligation was performed. Liver fibrosis was assessed by histology, Masson's trichrome staining, and the measurement of hydroxyproline and type I collagen content. The activation of HSC was determined by analysis of alpha smooth muscle actin (α-SMA expression. Protein expressions and protein phosphorylation were determined by immunohistochemical staining and Western blot analysis, Messenger RNA levels by quantitative real time polymerase chain reaction (Q-PCR. Portal pressure and intrahepatic resistance were examined in vivo. RESULTS: Treatment with spironolactone significantly lowered portal pressure. This was associated with attenuation of liver fibrosis, intrahepatic resistance and inhibition of HSC activation. In BDL rat liver, spironolactone suppressed up-regulation of proinflammatory cytokines (TNFα and IL-6. Additionally, spironolactone significantly decreased ROCK-2 activity without affecting expression of RhoA and Ras. Moreover, spironolactone markedly increased the levels of endothelial nitric oxide synthase (eNOS, phosphorylated eNOS and the activity of NO effector-protein kinase G (PKG in the liver. CONCLUSION: Spironolactone lowers portal hypertension by improvement of liver fibrosis and inhibition of intrahepatic vasoconstriction via down-regulating ROCK-2 activity and activating NO/PKG pathway. Thus, early spironolactone therapy might be the optional therapy in cirrhosis and

  18. The bile acid sensor FXR is required for immune-regulatory activities of TLR-9 in intestinal inflammation.

    Directory of Open Access Journals (Sweden)

    Barbara Renga

    Full Text Available BACKGROUND: Toll like receptors (TLRs sense the intestinal microbiota and regulate the innate immune response. A dysregulation of TLRs function participates into intestinal inflammation. Farnesoid X Receptor (FXR is a nuclear receptor and bile acid sensor highly expressed in entero-hepatic tissues. FXR regulates lipid metabolism and innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: In this study we have investigated whether FXR gene expression/function in the intestine is modulated by TLRs. We found that in human monocytes activation of membrane TLRs (i.e. TLR2, 4, 5 and 6 downregulates, while activation of intracellular TLRs (i.e. TLR3, 7, 8 and 9 upregulates the expression of FXR and its target gene SHP, small heterodimer partner. This effect was TLR9-dependent and TNFα independent. Intestinal inflammation induced in mice by TNBS downregulates the intestinal expression of FXR in a TLR9-dependent manner. Protection against TNBS colitis by CpG, a TLR-9 ligand, was lost in FXR(-/- mice. In contrast, activation of FXR rescued TLR9(-/- and MyD88(-/- mice from colitis. A putative IRF7 response element was detected in the FXR promoter and its functional characterization revealed that IRF7 is recruited on the FXR promoter under TLR9 stimulation. CONCLUSIONS/SIGNIFICANCE: Intestinal expression of FXR is selectively modulated by TLR9. In addition to its role in regulating type-I interferons and innate antiviral immunity, IRF-7 a TLR9-dependent factor, regulates the expression of FXR, linking microbiota-sensing receptors to host's immune and metabolic signaling.

  19. Cholesterol-Lowering Potentials of Lactic Acid Bacteria Based on Bile-Salt Hydrolase Activity and Effect of Potent Strains on Cholesterol Metabolism In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Cheng-Chih Tsai

    2014-01-01

    Full Text Available This study collected different probiotic isolates from animal and plant sources to evaluate the bile-salt hydrolase activity of probiotics in vitro. The deconjugation potential of bile acid was determined using high-performance liquid chromatography. HepG2 cells were cultured with probiotic strains with high BSH activity. The triglyceride (TG and apolipoprotein B (apo B secretion by HepG2 cells were evaluated. Our results show that the BSH activity and bile-acid deconjugation abilities of Pediococcus acidilactici NBHK002, Bifidobacterium adolescentis NBHK006, Lactobacillus rhamnosus NBHK007, and Lactobacillus acidophilus NBHK008 were higher than those of the other probiotic strains. The cholesterol concentration in cholesterol micelles was reduced within 24 h. NBHK007 reduced the TG secretion by 100% after 48 h of incubation. NBHK002, NBHK006, and NBHK007 could reduce apo B secretion by 33%, 38%, and 39%, respectively, after 24 h of incubation. The product PROBIO S-23 produced a greater decrease in the total concentration of cholesterol, low-density lipoprotein, TG, and thiobarbituric acid reactive substance in the serum or livers of hamsters with hypercholesterolemia compared with that of hamsters fed with a high-fat and high-cholesterol diet. These results show that the three probiotic strains of lactic acid bacteria are better candidates for reducing the risk of cardiovascular disease.

  20. Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation.

    Science.gov (United States)

    Magen, I; Avraham, Y; Ackerman, Z; Vorobiev, L; Mechoulam, R; Berry, E M

    2010-02-01

    We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice. Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin. Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL. The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.

  1. [Correlations of bile acids in the bile of rats in conditions of alloxan induced diabetes melitus].

    Science.gov (United States)

    Danchenko, N M; Vesel'skyĭ, S P; Tsudzevych, B O

    2014-01-01

    The ratio of bile acids in the bile of rats with alloxan diabetes was investigated using the method of thin-layer chromatography. Changes of coefficients of conjugation and hydroxylation of bile acids were calculated and analyzed in half-hour samples of bile obtained during the 3-hour experiment. It has been found that the processes of conjugation of cholic acid with glycine and taurine are inhibited in alloxan diabetes. At the same time a significant increase of free threehydroxycholic and dixydroxycholic bile acids and conjugates of the latter ones with taurine has been registered. Coefficients of hydroxylation in alloxan diabetes show the domination of "acidic" pathway in bile acid biosynthesis that is tightly connected with the activity of mitochondrial enzymes.

  2. Preparation of [3beta-3H] labeled bile acids and bile alcohols

    International Nuclear Information System (INIS)

    Dayal, B.; Baga, E.; Tint, G.S.; Shefer, S.; Salen, G.

    1979-01-01

    [3beta-3H]-bile acids and bile alcohols may be useful for metabolic studies in man and animals because the 3-position is invulnerable to bacterial attack. A number of tritium labeled bile acids and bile alcohols were prepared by selective oxidation of the hydroxyl group at carbon-3 followed by reduction with NaBT4. In each case, the bile acids and bile alcohols epimeric at carbon-3 were resolved by analytical and preparative thin-layer chromatography and characterized by gas liquid chromatography. The average yield was 60 to 65% and specific activities of the final products were in the range of 7.4 x 10 7 dpm/mg

  3. Bile acid-binding activity of young persimmon (Diospyros kaki) fruit and its hypolipidemic effect in mice.

    Science.gov (United States)

    Matsumoto, Kenji; Yokoyama, Shin-ichiro; Gato, Nobuki

    2010-02-01

    The hypolipidemic effects and bile acid-binding properties of young persimmon (Diospyros kaki) fruit were examined. In an animal experiment, male C57BL/6.Cr mice (n = 5) were fed an AIN-76-modified high fat diet supplemented with 2% or 5% (w/w) dried young persimmon fruit (YP) for 10 weeks. The intake of YP significantly enhanced fecal bile acid excretion and lowered the concentration of hepatic lipids and plasma cholesterol. Analysis of gene expression in liver tissue showed that 2% or 5% YP up-regulated the expression of the sterol regulatory element-binding protein-2 gene. In the 5% group, there were increased expressions of the genes for cholesterol 7alpha-hydroxylase and the low-density lipoprotein receptor. Next, the bile acid-binding ability of YP was analysed in vitro using cholic acid (CA). In 100-2000 microM CA solutions, 1% (w/v) YP adsorbed approximately 60% of CA, while dried mature persimmon fruit adsorbed approximately 20% of CA. The positive control, cholestyramine, adsorbed approximately 80% of CA in the 100-2000 microM CA solutions. A crude tannin extract from YP, which contained 54.7% condensed tannins, adsorbed approximately 78% of CA in the 2000 microM CA solutions. These results suggest that the ability of YP to bind bile acid contributes to its hypolipidemic effect in mice. (c) 2009 John Wiley & Sons, Ltd.

  4. Protective effects of nonionic tri-block copolymers on bile acid-mediated epithelial barrier disruption.

    Energy Technology Data Exchange (ETDEWEB)

    Edelstein, A.; Fink, D.; Musch, M.; Valuckaite, V.; Zabornia, O.; Grubjesic, S.; Firestone, M. A.; Matthews, J. B.; Alverdy, J. C. (Materials Science Division); (Univ. of Chicago)

    2011-11-01

    Translocation of bacteria and other luminal factors from the intestine following surgical injury can be a major driver of critical illness. Bile acids have been shown to play a key role in the loss of intestinal epithelial barrier function during states of host stress. Experiments to study the ability of nonionic block copolymers to abrogate barrier failure in response to bile acid exposure are described. In vitro experiments were performed with the bile salt sodium deoxycholate on Caco-2 enterocyte monolayers using transepithelial electrical resistance to assay barrier function. A bisphenol A coupled triblock polyethylene glycol (PEG), PEG 15-20, was shown to prevent sodium deoxycholate-induced barrier failure. Enzyme-linked immunosorbent assay, lactate dehydrogenase, and caspase 3-based cell death detection assays demonstrated that bile acid-induced apoptosis and necrosis were prevented with PEG 15-20. Immunofluorescence microscopic visualization of the tight junctional protein zonula occludens 1 (ZO-1) demonstrated that PEG 15-20 prevented significant changes in tight junction organization induced by bile acid exposure. Preliminary transepithelial electrical resistance-based studies examining structure-function correlates of polymer protection against bile acid damage were performed with a small library of PEG-based copolymers. Polymer properties associated with optimal protection against bile acid-induced barrier disruption were PEG-based compounds with a molecular weight greater than 10 kd and amphiphilicity. The data demonstrate that PEG-based copolymer architecture is an important determinant that confers protection against bile acid injury of intestinal epithelia.

  5. Abscisic Acid Induced Changes in Production of Primary and Secondary Metabolites, Photosynthetic Capacity, Antioxidant Capability, Antioxidant Enzymes and Lipoxygenase Inhibitory Activity of Orthosiphon stamineus Benth.

    Directory of Open Access Journals (Sweden)

    Mohd Hafiz Ibrahim

    2013-07-01

    Full Text Available An experiment was conducted to investigate and distinguish the relationships in the production of total phenolics, total flavonoids, soluble sugars, H2O2, O2−, phenylalanine ammonia lyase (PAL activity, leaf gas exchange, antioxidant activity, antioxidant enzyme activity [ascorbate peroxidase (APX, catalase (CAT, superoxide dismutase (SOD and Lipoxygenase inhibitory activity (LOX] under four levels of foliar abscisic acid (ABA application (0, 2, 4, 6 µM for 15 weeks in Orthosiphon stamineus Benth. It was found that the production of plant secondary metabolites, soluble sugars, antioxidant activity, PAL activity and LOX inhibitory activity was influenced by foliar application of ABA. As the concentration of ABA was increased from 0 to 6 µM the production of total phenolics, flavonoids, sucrose, H2O2, O2−, PAL activity and LOX inhibitory activity was enhanced. It was also observed that the antioxidant capabilities (DPPH and ORAC were increased. This was followed by increases in production of antioxidant enzymes APX, CAT and SOD. Under high application rates of ABA the net photosynthesis and stomatal conductance was found to be reduced. The production of primary and secondary metabolites displayed a significant positive relationship with H2O2 (total phenolics, r2 = 0.877; total flavonoids, r2 = 0.812; p ≤ 0.05 and O2− (total phenolics, r2 = 0.778; total flavonoids, r2 = 0.912; p ≤ 0.05. This indicated that increased oxidative stress at high application rates of ABA, improved the production of phytochemicals.

  6. The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Brønden, Andreas; Albér, Anders; Rohde, Ulrich

    2018-01-01

    of the present study was to assess the GLP-1 secretory and gluco-metabolic effects of endogenously released bile, with and without concomitant administration of the bile acid-sequestering resin, sevelamer, in patients with type 2 diabetes. MATERIALS AND METHODS: We performed a randomized, placebo......-controlled, and double-blinded cross-over study including 15 metformin-treated patients with type 2 diabetes. Four experimental study days in randomized order with administration of either sevelamer 3,200 mg or placebo in combination with intravenous infusion of cholecystokinin (CCK) (0.4 pmol sulfated CCK-8/kg...... was shown to eliminate the acute bile acid-induced increase in plasma GLP-1 excursions. CONCLUSIONS: Single-dose administration of sevelamer eliminated bile acid-mediated GLP-1 secretion in patients with type 2 diabetes, which could be explained by reduced bile acid stimulation of the basolaterally...

  7. Recent advances in understanding bile acid homeostasis [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    John YL Chiang

    2017-11-01

    Full Text Available Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5 to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

  8. Nuclear Factor-Kappa B Activity Regulates Brain Expression of P-Glycoprotein in the Kainic Acid-Induced Seizure Rats

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    Nian Yu

    2011-01-01

    Full Text Available This study was aimed to investigate the effect of NF-κB activity on the seizure susceptibility, brain damage, and P-gp expression in kainic acid- (KA- induced seizure rats. Male SD rats were divided into saline control group (NS group, KA induced epilepsy group (EP group, and epilepsy group intervened with NF-κB inhibitor-pyrrolidine dithiocarbamate salt (PDTC group or with dexamethasone (DEX group. No seizures were observed in the rats of NS group. Compared with NS group, increased P-gp expression and NF-κB activation in the rat brain of the EP group were observed after KA micro-injection. Both PDTC and DEX pre-treatment significantly increased the latency to grade III or V seizure onset compared to EP group but failed to show neuron-protective effect as the number of survival neurons didn't significantly differ from that in EP group. Furthermore, PDTC pre-treatment significantly decreased P-gp expression along with NF-κB activation in the hippocampus CA3 area and amygdala complex of rats compared with the EP group, implying that NF-κB activation involved in the seizure susceptibility and seizure induced brain P-gp over-expression. Additionally, DEX pre-treatment only decreased P-gp expression level without inhibition of NF-κB activation, suggesting NF-κB independent pathway may also participate in regulating seizure induced P-gp over-expression.

  9. Allelic variation of bile salt hydrolase genes in Lactobacillus salivarius does not determine bile resistance levels.

    LENUS (Irish Health Repository)

    Fang, Fang

    2009-09-01

    Commensal lactobacilli frequently produce bile salt hydrolase (Bsh) enzymes whose roles in intestinal survival are unclear. Twenty-six Lactobacillus salivarius strains from different sources all harbored a bsh1 allele on their respective megaplasmids. This allele was related to the plasmid-borne bsh1 gene of the probiotic strain UCC118. A second locus (bsh2) was found in the chromosomes of two strains that had higher bile resistance levels. Four Bsh1-encoding allele groups were identified, defined by truncations or deletions involving a conserved residue. In vitro analyses showed that this allelic variation was correlated with widely varying bile deconjugation phenotypes. Despite very low activity of the UCC118 Bsh1 enzyme, a mutant lacking this protein had significantly lower bile resistance, both in vitro and during intestinal transit in mice. However, the overall bile resistance phenotype of this and other strains was independent of the bsh1 allele type. Analysis of the L. salivarius transcriptome upon exposure to bile and cholate identified a multiplicity of stress response proteins and putative efflux proteins that appear to broadly compensate for, or mask, the effects of allelic variation of bsh genes. Bsh enzymes with different bile-degrading kinetics, though apparently not the primary determinants of bile resistance in L. salivarius, may have additional biological importance because of varying effects upon bile as a signaling molecule in the host.

  10. Differential activation of diverse glutathione transferases of Clonorchis sinensis in response to the host bile and oxidative stressors.

    Directory of Open Access Journals (Sweden)

    Young-An Bae

    Full Text Available BACKGROUND: Clonorchis sinensis causes chronic cumulative infections in the human hepatobiliary tract and is intimately associated with cholangiocarcinoma. Approximately 35 million people are infected and 600 million people are at risk of infections worldwide. C. sinensis excretory-secretory products (ESP constitute the first-line effector system affecting the host-parasite interrelationship by interacting with bile fluids and ductal epithelium. However, the secretory behavior of C. sinensis in an environment close to natural host conditions is unclear. C. sinensis differs from Fasciola hepatica in migration to, and maturation in, the hepatic bile duct, implying that protein profile of the ESP of these two trematodes might be different from each other. METHODOLOGY/PRINCIPAL FINDINGS: We conducted systemic approaches to analyze the C. sinensis ESP proteome and the biological reactivity of C. sinensis glutathione transferases (GSTs, such as global expression patterns and induction profiles under oxidative stress and host bile. When we observed ex host excretion behavior of C. sinensis in the presence of 10% host bile, the global proteome pattern was not significantly altered, but the amount of secretory proteins was increased by approximately 3.5-fold. Bioactive molecules secreted by C. sinensis revealed universal/unique features in relation to its intraluminal hydrophobic residing niche. A total of 38 protein spots identified abundantly included enzymes involved in glucose metabolism (11 spots, 28.9% and diverse-classes of glutathione transferases (GSTs; 10 spots, 26.3%. Cathepsin L/F (four spots, 10.5% and transporter molecules (three spots, 7.9% were also recognized. The universal secretory proteins found in other parasites, such as several enzymes involved in glucose metabolism and oxygen transporters, were commonly detected. C. sinensis secreted less cysteine proteases and fatty acid binding proteins compared to other tissue-invading or

  11. Differential Activation of Diverse Glutathione Transferases of Clonorchis sinensis in Response to the Host Bile and Oxidative Stressors

    Science.gov (United States)

    Bae, Young-An; Ahn, Do-Whan; Lee, Eung-Goo; Kim, Seon-Hee; Cai, Guo-Bin; Kang, Insug; Sohn, Woon-Mok; Kong, Yoon

    2013-01-01

    Background Clonorchis sinensis causes chronic cumulative infections in the human hepatobiliary tract and is intimately associated with cholangiocarcinoma. Approximately 35 million people are infected and 600 million people are at risk of infections worldwide. C. sinensis excretory-secretory products (ESP) constitute the first-line effector system affecting the host-parasite interrelationship by interacting with bile fluids and ductal epithelium. However, the secretory behavior of C. sinensis in an environment close to natural host conditions is unclear. C. sinensis differs from Fasciola hepatica in migration to, and maturation in, the hepatic bile duct, implying that protein profile of the ESP of these two trematodes might be different from each other. Methodology/Principal Findings We conducted systemic approaches to analyze the C. sinensis ESP proteome and the biological reactivity of C. sinensis glutathione transferases (GSTs), such as global expression patterns and induction profiles under oxidative stress and host bile. When we observed ex host excretion behavior of C. sinensis in the presence of 10% host bile, the global proteome pattern was not significantly altered, but the amount of secretory proteins was increased by approximately 3.5-fold. Bioactive molecules secreted by C. sinensis revealed universal/unique features in relation to its intraluminal hydrophobic residing niche. A total of 38 protein spots identified abundantly included enzymes involved in glucose metabolism (11 spots, 28.9%) and diverse-classes of glutathione transferases (GSTs; 10 spots, 26.3%). Cathepsin L/F (four spots, 10.5%) and transporter molecules (three spots, 7.9%) were also recognized. The universal secretory proteins found in other parasites, such as several enzymes involved in glucose metabolism and oxygen transporters, were commonly detected. C. sinensis secreted less cysteine proteases and fatty acid binding proteins compared to other tissue-invading or intravascular

  12. Bile Acid-regulated Peroxisome Proliferator-activated Receptor-α (PPARα) Activity Underlies Circadian Expression of Intestinal Peptide Absorption Transporter PepT1/Slc15a1*

    Science.gov (United States)

    Okamura, Ayako; Koyanagi, Satoru; Dilxiat, Adila; Kusunose, Naoki; Chen, Jia Jun; Matsunaga, Naoya; Shibata, Shigenobu; Ohdo, Shigehiro

    2014-01-01

    Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor α (PPARα). Nocturnally active mice mainly consumed their food during the dark phase. PPARα activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co-transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARα-mediated transactivation of Slc15a1. The time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal peptide transporter. PMID:25016014

  13. Bile acid-regulated peroxisome proliferator-activated receptor-α (PPARα) activity underlies circadian expression of intestinal peptide absorption transporter PepT1/Slc15a1.

    Science.gov (United States)

    Okamura, Ayako; Koyanagi, Satoru; Dilxiat, Adila; Kusunose, Naoki; Chen, Jia Jun; Matsunaga, Naoya; Shibata, Shigenobu; Ohdo, Shigehiro

    2014-09-05

    Digested proteins are mainly absorbed as small peptides composed of two or three amino acids. The intestinal absorption of small peptides is mediated via only one transport system: the proton-coupled peptide transporter-1 (PepT1) encoded from the soluble carrier protein Slc15a1. In mammals, intestinal expression of PepT1/Slc15a1 oscillates during the daily feeding cycle. Although the oscillation in the intestinal expression of PepT1/Slc15a1 is suggested to be controlled by molecular components of circadian clock, we demonstrated here that bile acids regulated the oscillation of PepT1/Slc15a1 expression through modulating the activity of peroxisome proliferator-activated receptor α (PPARα). Nocturnally active mice mainly consumed their food during the dark phase. PPARα activated the intestinal expression of Slc15a1 mRNA during the light period, and protein levels of PepT1 peaked before the start of the dark phase. After food intake, bile acids accumulated in intestinal epithelial cells. Intestinal accumulated bile acids interfered with recruitment of co-transcriptional activator CREB-binding protein/p300 on the promoter region of Slc15a1 gene, thereby suppressing PPARα-mediated transactivation of Slc15a1. The time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the intestinal expression of PepT1/Slc15a1 during the daily feeding cycle that led to circadian changes in the intestinal absorption of small peptides. These findings suggest a molecular clock-independent mechanism by which bile acid-regulated PPARα activity governs the circadian expression of intestinal peptide transporter. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Blocking TGF-β Signaling Pathway Preserves Mitochondrial Proteostasis and Reduces Early Activation of PDGFRβ+ Pericytes in Aristolochic Acid Induced Acute Kidney Injury in Wistar Male Rats.

    Directory of Open Access Journals (Sweden)

    Agnieszka A Pozdzik

    Full Text Available The platelet-derived growth factor receptor β (PDGFRβ+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ inhibition in a rat model of AAN.Neutralizing anti-TGFβ antibody (1D11 and its control isotype (13C4 were administered (5 mg/kg, i.p. at Days -1, 0, 2 and 4; AA (15 mg/kg, sc was injected daily.At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation.

  15. Foliar spraying of salicylic acid induced accumulation of phenolics, increased radical scavenging activity and modified the composition of the essential oil of water stressed Thymus vulgaris L.

    Science.gov (United States)

    Khalil, Noha; Fekry, Mostafa; Bishr, Mokhtar; El-Zalabani, Soheir; Salama, Osama

    2018-02-01

    Polyphenolic compounds are considered valuable secondary plant metabolites owing to the myriad of biological activities they exert. This study aimed to investigate the effect of applying various concentrations of the plant growth regulator, salicylic acid (SA), on Thymus vulgaris L. while subjecting the plant to decreasing amounts of irrigation water. The following parameters were monitored; total polyphenolic and flavonoid content, yield and composition of the essential oil, and antioxidant activity of the alcoholic extracts. Drought alone significantly (P < 0.05) increased the polyphenolic and flavonoid content, yield of the essential oil and antioxidant activity. The total flavonoid content in control plants was 6.1 ± 0.3 mg/gm dry weight calculated in terms of rutin equivalent. However, in drought stressed plants, (irrigated at 25% of the field capacity) sprayed with 3 mM SA, the flavonoid content increased to 32.1 ± 0.1 mg/gm dry weight calculated in terms of rutin equivalent. Moreover, the total phenolic content increased from 8.5 ± 0.3 to 68.5 ± 1.2 mg/gm dry weight calculated in terms of gallic acid in the same test plants. Radical scavenging activity, using DPPH assay, was measured for the different plant treatments. A decrease from 74.4 ± 0.4 μg/ml to 36.6 ± 0.9 μg/ml of IC 50 was recorded in the drought stressed plants (25% FC) sprayed with 3 mM SA compared with the control plants. The variability in polyphenolic composition between the control plants and plants with the highest total polyphenolic content was investigated by UPLC-ESI-MS/MS. Rosmarinic acid was detected as the major component in samples from both treatments, with a higher percentage observed upon subjecting the plant to the test conditions (25% FC and sprayed with 3 mM SA). The highest yield of the essential oil (1 ± 0.06 %v/w) was obtained from drought stressed plants (25% FC) sprayed with 2 mM SA. GC/MS analysis of oil samples revealed that the Thymol

  16. The human UDP-glucuronosyltransferase UGT2A1 and UGT2A2 enzymes are highly active in bile acid glucuronidation

    Science.gov (United States)

    Perreault, Martin; Gauthier-Landry, Louis; Trottier, Jocelyn; Verreault, Mélanie; Caron, Patrick; Finel, Moshe; Barbier, Olivier

    2013-01-01

    Bile acids (BA) are essential modulators of lipid, glucose and cholesterol homeostasis, but exert cytotoxic effects in the cholestatic liver. Glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT) enzymes is a pharmacologically-relevant BA detoxification process. The present study aimed at characterizing the BA-conjugating activity of the little-studied human UGTs of subfamily 2A, UGT2A1, 2A2 and 2A3. Recombinant UGT2As, expressed in baculovirus-infected insect cells, were assayed for the glucuronidation of 6 major bile acids, chenodeoxycholic (CDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA), hyocholic (HCA) and hyodeoxycholic (HDCA) acids. UGT2A3 exhibited detectable, but very low, activity with all the tested BAs substrates. UGT2A1 was highly efficient in forming LCA-3 and -24G, CDCA-24, DCA-24, HCA-24 and HDCA-24G, while UGT2A2 was the most active enzyme for CA-24G and CDCA-24G formation, and was also able to generate HDCA-6G, HDCA-24G, LCA-24G and HCA-24G. The Km values of UGT2A1 varied between 102.2 ± 14.3 μM and 2.4 ± 1.2 mM. With the exception of CA-24G, a low affinity substrate for UGT2A2, all the Km values for UGT2A2 were in the 100 to 400 μM range. In conclusion, the present study demonstrates the high reactivity of the human UGT2A1 and UGT2A2 for bile acid glucuronidation. The physiological importance of these reactions to BA disposition remains, however, to be clarified in vivo. PMID:23756265

  17. Docosahexaenoic acid induces apoptosis in MCF-7 cells in vitro and in vivo via reactive oxygen species formation and caspase 8 activation.

    Directory of Open Access Journals (Sweden)

    Ki Sung Kang

    Full Text Available BACKGROUND: The present study sought to further investigate the in vitro and in vivo anticancer effects of a representative omega-3 fatty acid, docosahexaenoic acid (DHA, with a focus on assessing the induction of oxidative stress and apoptosis as an important mechanism for its anticancer actions. METHODOLOGY/PRINCIPAL FINDINGS: In vitro studies showed that DHA strongly reduces the viability and DNA synthesis of MCF-7 human breast cancer cells in culture, and also promotes cell death via apoptosis. Mechanistically, accumulation of reactive oxygen species and activation of caspase 8 contribute critically to the induction of apoptotic cell death. Co-presence of antioxidants or selective inhibition or knockdown of caspase 8 each effectively abrogates the cytotoxic effect of DHA. Using athymic nude mice as an in vivo model, we found that feeding animals the 5% fish oil-supplemented diet for 6 weeks significantly reduces the growth of MCF-7 human breast cancer cells in vivo through inhibition of cancer cell proliferation as well as promotion of cell death. Using 3-nitrotyrosine as a parameter, we confirmed that the fish oil-supplemented diet significantly increases oxidative stress in tumor cells in vivo. Analysis of fatty acid content in plasma and tissues showed that feeding animals a 5% fish oil diet increases the levels of DHA and eicosapentaenoic acid in both normal and tumorous mammary tissues by 329% and 300%, respectively. CONCLUSIONS/SIGNIFICANCE: DHA can strongly induce apoptosis in human MCF-7 breast cancer cells both in vitro and in vivo. The induction of apoptosis in these cells is selectively mediated via caspase 8 activation. These observations call for further studies to assess the effectiveness of fish oil as a dietary supplement in the prevention and treatment of human breast cancer.

  18. Differential feedback regulation of cholesterol 7α-hydroxylase mRNA and transcriptional activity by rat bile acids in primary monolayer cultures of rat hepatocytes

    NARCIS (Netherlands)

    Twisk, J.; Lehmann, E.M.; Princen, H.M.G.

    1993-01-01

    We have used primary monolayer cultures of rat hepatocytes to study the effects of physiological concentrations of various bile acids, commonly found in bile of normal rats, on the mechanism of regulation of cholesterol 7α-hydroxylase and bile acid synthesis. Addition of taurocholic acid, the most

  19. Zanthoxylum ailanthoides Suppresses Oleic Acid-Induced Lipid Accumulation through an Activation of LKB1/AMPK Pathway in HepG2 Cells

    Directory of Open Access Journals (Sweden)

    Eun-Bin Kwon

    2018-01-01

    Full Text Available Zanthoxylum ailanthoides (ZA has been used as folk medicines in East Asian and recently reported to have several bioactivity; however, the studies of ZA on the regulation of triacylglycerol (TG biosynthesis have not been elucidated yet. In this study, we examined whether the methanol extract of ZA (ZA-M could reduce oleic acid- (OA- induced intracellular lipid accumulation and confirmed its mode of action in HepG2 cells. ZA-M was shown to promote the phosphorylation of AMPK and its upstream LKB1, followed by reduction of lipogenic gene expressions. As a result, treatment of ZA-M blocked de novo TG biosynthesis and subsequently mitigated intracellular neutral lipid accumulation in HepG2 cells. ZA-M also inhibited OA-induced production of reactive oxygen species (ROS and TNF-α, suggesting that ZA-M possess the anti-inflammatory feature in fatty acid over accumulated condition. Taken together, these results suggest that ZA-M attenuates OA-induced lipid accumulation and inflammation through the activation of LKB1/AMPK signaling pathway in HepG2 cells.

  20. Relaxin attenuates aristolochic acid induced human tubular epithelial cell apoptosis in vitro by activation of the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Xie, Xiang-Cheng; Zhao, Ning; Xu, Qun-Hong; Yang, Xiu; Xia, Wen-Kai; Chen, Qi; Wang, Ming; Fei, Xiao

    2017-06-01

    Aristolochic acid nephropathy remains a leading cause of chronic kidney disease (CKD), however few treatment strategies exist. Emerging evidence has shown that H2 relaxin (RLX) possesses powerful antifibrosis and anti-apoptotic properties, therefore we aimed to investigate whether H2 relaxin can be employed to reduce AA-induced cell apoptosis. Human proximal tubular epithelial (HK-2) cells exposed to AA-I were treated with or without administration of H2 RLX. Cell viability was examined using the WST-8 assay. Apoptotic morphologic alterations were observed using the Hoechst 33342 staining method. Apoptosis was detected using flow cytometry. The expression of caspase 3, caspase 8, caspase 9, ERK1/2, Bax, Bcl-2, and Akt proteins was determined by Western blot. Co-treatment with RLX reversed the increased apoptosis observed in the AA-I only treated group. RLX restored expression of phosphorylated Akt which found to be decreased in the AA-I only treated cells. RLX co-treatment led to a decrease in the Bax/Bcl-2 ratio as well as the cleaved form of caspase-3 compared to the AA-I only treated cells. This anti-apoptotic effect of RLX was attenuated by co-administration of the Akt inhibitor LY294002. The present study demonstrated H2 RLX can decrease AA-I induced apoptosis through activation of the PI3K/Akt signaling pathway.

  1. Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

    Directory of Open Access Journals (Sweden)

    C.M. Queiroz

    2008-05-01

    Full Text Available Intrahippocampal administration of kainic acid (KA induces synaptic release of neurotrophins, mainly brain-derived neurotrophic factor, which contributes to the acute neuronal excitation produced by the toxin. Two protein tyrosine kinase inhibitors, herbimycin A and K252a, were administered intracerebroventricularly, in a single dose, to attenuate neurotrophin signaling during the acute effects of KA, and their role in epileptogenesis was evaluated in adult, male Wistar rats weighing 250-300 g. The latency for the first Racine stage V seizure was 90 ± 8 min in saline controls (N = 4 which increased to 369 ± 71 and 322 ± 63 min in animals receiving herbimycin A (1.74 nmol, N = 4 and K252a (10 pmol, N = 4, respectively. Behavioral alterations were accompanied by diminished duration of EEG paroxysms in herbimycin A- and K252a-treated animals. Notwithstanding the reduction in seizure severity, cell death (60-90% of cell loss in KA-treated animals in limbic regions was unchanged by herbimycin A and K252a. However, aberrant mossy fiber sprouting was significantly reduced in the ipsilateral dorsal hippocampus of K252a-treated animals. In this model of temporal lobe epilepsy, both protein kinase inhibitors diminished the acute epileptic activity triggered by KA and the ensuing morphological alterations in the dentate gyrus without diminishing cell loss. Our current data indicating that K252a, but not herbimycin, has an influence over KA-induced mossy fiber sprouting further suggest that protein tyrosine kinase receptors are not the only factors which control this plasticity. Further experiments are necessary to elucidate the exact signaling systems associated with this K252a effect.

  2. Participation of nuclear factor (erythroid 2-related), factor 2 in ameliorating lithocholic acid-induced cholestatic liver injury in mice.

    Science.gov (United States)

    Tan, K P; Wood, G A; Yang, M; Ito, S

    2010-11-01

    Lithocholic acid (LCA), the most toxic bile acid, induces cholestatic liver injury in rodents. We previously showed that LCA activates the oxidative stress-responsive nuclear factor (erythroid-2 like), factor 2 (Nrf2) in cultured liver cells, triggering adaptive responses that reduce cell injury. In this study, we determined whether Nrf2 protects the liver against LCA-induced toxicity in vivo. Nrf2 disrupted (Nrf2(-/-) ) and wild-type mice were treated with LCA (125 mg·kg(-1) body weight) to induce liver injury. Levels of mRNA, protein and function of important Nrf2 target genes coupled with liver histology and injury biomarkers of mice were examined. In 4 day LCA treatments, we observed a significantly higher hepatic induction of Nrf2 target, cytoprotective genes including thioredoxin reductase 1, glutamate cysteine ligase subunits, glutathione S-transferases, haeme oxygenase-1 and multidrug resistance-associated proteins 3 and 4 in the wild type as compared with the Nrf2(-/-) mice. Moreover, basal and LCA-induced hepatic glutathione and activities of glutathione S-transferases and thioredoxin reductases were higher in wild-type than in Nrf2(-/-) mice. This reduced production of cytoprotective genes against LCA toxicity rendered Nrf2(-/-) mice more susceptible to severe liver damage with the presence of multifocal liver necrosis, inflamed bile ducts and elevation of lipid peroxidation and liver injury biomarkers, such as alanine aminotransferase and alkaline phosphatase. Nrf2 plays a crucial cytoprotective role against LCA-induced liver injury by orchestrating adaptive responses. The pharmacological potential of targeting liver Nrf2 in the management of cholestatic liver diseases is proposed. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

  3. Bile acids and intestinal microbiota in autoimmune cholestatic liver diseases.

    Science.gov (United States)

    Li, You; Tang, Ruqi; Leung, Patrick S C; Gershwin, M Eric; Ma, Xiong

    2017-09-01

    Autoimmune cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are manifested as an impairment of normal bile flow and excessive accumulation of potentially toxic bile acids. Endogenous bile acids are involved in the pathogenesis and progression of cholestasis. Consequently, chronic cholestasis affects the expression of bile acid transporters and nuclear receptors, and results in liver injury. Several lines of evidence suggest that intestinal microbiota plays an important role in the etiopathogenesis of cholestatic liver diseases by regulating metabolism and immune responses. However, progression of the disease may also affect the composition of gut microbiota, which in turn exacerbates the progression of cholestasis. In addition, the interaction between intestinal microbiota and bile acids is not unidirectional. Bile acids can shape the gut microbiota community, and in turn, intestinal microbes are able to alter bile acid pool. In general, gut microbiota actively communicates with bile acids, and together play an important role in the pathogenesis of PBC and PSC. Targeting the link between bile acids and intestinal microbiota offers exciting new perspectives for the treatment of those cholestatic liver diseases. This review highlights current understanding of the interactions between bile acids and intestinal microbiota and their roles in autoimmune cholestatic liver diseases. Further, we postulate a bile acids-intestinal microbiota-cholestasis triangle in the pathogenesis of autoimmune cholestatic liver diseases and potential therapeutic strategies by targeting this triangle. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Effect of bile acids on digestion

    Directory of Open Access Journals (Sweden)

    O. O. Stremoukhov

    2013-12-01

    stable for about 1 minute was observed. Studying of the impact of GPC on bile motor activity of the gastrointestinal tract. The method is based on determining the length of the path traversed by contrast weighing intestine that characterizes asset -ness motility of the gastrointestinal tract. Studying the impact of HPC on bile motor activity of the gastrointestinal tract was performed on white mice weighing 20,0-23,0 for 20 hours exposed to starvation diet without restriction of water intake. Animals were divided into two groups of in 6 each. The first group of animals, which were an hour before the mass introduction of contrast injected bile GPC 25 mg/kg, the second group - the control animals, which an hour before the administration of contrast were injected mass equivalent amount of water. 10% slurry of activated charcoal in 1% starch paste was used as a contrast. After 60 minutes after the injection the animals were administered 0,3 ml of contrast mass. After 40 minutes the animals were taken out of the experiment dislocation of the cervical vertebrae. Measurement of the absolute length of the intestine and the path traversed by contrasting mass through the intestines, carried out on graph paper. Conclusions. It was established that GPC bile promotes the absorption of fats, activates lipase during digestion and stimulates intestinal peristalsis in experimental animals and can be recommended as a preventive measure to improve digestion.

  5. Effects of oral calcium supplementation on intestinal bile-acids and cytolytic activity of fecal water in patients with adenomatous polyps of the colon

    NARCIS (Netherlands)

    Welberg, J. W. M.; Kleibeuker, J. H.; van der Meer, R.; Kuipers, F.; Cats, A.; van Rijsbergen, H.; Termont, D. S. M. L.; Boersma-van Ek, W.; Vonk, R. J.; Mulder, N. H.; de Vries, E. G. E.

    Calcium has been proposed to prevent colon cancer in subjects at risk for this tumour. This effect is supposed to be due at least in part to binding the bile acids to calcium, making them insoluble and harmless. To evaluate the effects of oral calcium supplementation on intestinal bile acids, 19

  6. Interactions between bile salts, gut microbiota, and hepatic innate immunity.

    Science.gov (United States)

    Schubert, Kristin; Olde Damink, Steven W M; von Bergen, Martin; Schaap, Frank G

    2017-09-01

    Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Clinical value of bile acids radioimmunoassay

    International Nuclear Information System (INIS)

    Breckwoldt, R.U.

    1981-01-01

    In 50 blood donors, 87 patients with various liver and bile disorders, 50 hemodialyse patients and 50 patients prior to and immediately after cardiac swigery, cholyl glycine (CG) and sulfolithocholyl glycine (SLCG) were determined. Long-term observations were carried out on a further 10 patients with non-A/non-B hepatitis and 10 patients without hepatitis. Correlations were found between the values of alkaline phosphatase, GPT, GOT and bilirubin. Consequently the determination of bile acid, here above all SLCG, constitutes a suitable means to detect subclinical functional liver disorders. The examination of the post-operative functional liver disorders following cardiac swigery showed that there is a distinct time shift between the mostly transitory increase in enzyme activity and the SLCG levels. Surprisingly, the long-term observations showed that increased bile acid levels are already measured during the hepatitis incubation period at normal enzyme activities. It was not possible, however to identify hepatitic patients already during incubation by assay of the bile acid level. Whereas the determination of standard laboratory parameters remains predominant in the description of liver cell damage, the importance of serum bile acid determination is seen in the description of functional liver disorders which are not characterized by increased enzyme activities. (orig.) [de

  8. Ascorbic Acid Induces Necrosis in Human Laryngeal Squamous Cell Carcinoma via ROS, PKC, and Calcium Signaling.

    Science.gov (United States)

    Baek, Min-Woo; Cho, Heui-Seung; Kim, Sun-Hun; Kim, Won-Jae; Jung, Ji-Yeon

    2017-02-01

    Ascorbic acid induces apoptosis, autophagy, and necrotic cell death in cancer cells. We investigated the mechanisms by which ascorbic acid induces death in laryngeal squamous cell carcinoma Hep2 cells. Ascorbic acid markedly reduced cell viability and induced death without caspase activation and an increase in cytochrome c. Hep2 cells exposed to ascorbic acid exhibited membrane rupture and swelling, the morphological characteristics of necrotic cell death. The generation of reactive oxygen species (ROS) was increased in Hep2 cells treated with ascorbic acid, and pretreatment with N-acetylcysteine blocked ascorbic acid-induced cell death. Ascorbic acid also stimulated protein kinase C (PKC) signaling, especially PKC α/β activation, and subsequently increased cytosolic calcium levels. However, ascorbic acid-induced necrotic cell death was inhibited by Ro-31-8425 (PKC inhibitor) and BAPTA-AM (cytosolic calcium-selective chelator). ROS scavenger NAC inhibited PKC activation induced by ascorbic acid and Ro-31-8425 suppressed the level of cytosolic calcium increased by ascorbic acid, indicating that ROS is represented as an upstream signal of PKC pathway and PKC activation leads to the release of calcium into the cytosol, which ultimately regulates the induction of necrosis in ascorbic acid-treated Hep2 cells. These data demonstrate that ascorbic acid induces necrotic cell death through ROS generation, PKC activation, and cytosolic calcium signaling in Hep2 cells. J. Cell. Physiol. 232: 417-425, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  9. Bile acids for viral hepatitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Liu, J; Gluud, C

    2007-01-01

    Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness.......Trials have assessed bile acids for patients with viral hepatitis, but no consensus has been reached regarding their usefulness....

  10. Impact of Gut Microbiota-Mediated Bile Acid Metabolism on the Solubilization Capacity of Bile Salt Micelles and Drug Solubility.

    Science.gov (United States)

    Enright, Elaine F; Joyce, Susan A; Gahan, Cormac G M; Griffin, Brendan T

    2017-04-03

    In recent years, the gut microbiome has gained increasing appreciation as a determinant of the health status of the human host. Bile salts that are secreted into the intestine may be biotransformed by enzymes produced by the gut bacteria. To date, bile acid research at the host-microbe interface has primarily been directed toward effects on host metabolism. The aim of this work was to investigate the effect of changes in gut microbial bile acid metabolism on the solubilization capacity of bile salt micelles and consequently intraluminal drug solubility. First, the impact of bile acid metabolism, mediated in vivo by the microbial enzymes bile salt hydrolase (BSH) and 7α-dehydroxylase, on drug solubility was assessed by comparing the solubilization capacity of (a) conjugated vs deconjugated and (b) primary vs secondary bile salts. A series of poorly water-soluble drugs (PWSDs) were selected as model solutes on the basis of an increased tendency to associate with bile micelles. Subsequently, PWSD solubility and dissolution was evaluated in conventional biorelevant simulated intestinal fluid containing host-derived bile acids, as well as in media modified to contain microbial bile acid metabolites. The findings suggest that deconjugation of the bile acid steroidal core, as dictated by BSH activity, influences micellar solubilization capacity for some PWSDs; however, these differences appear to be relatively minor. In contrast, the extent of bile acid hydroxylation, regulated by microbial 7α-dehydroxylase, was found to significantly affect the solubilization capacity of bile salt micelles for all nine drugs studied (p solubility and dissolution. Observed differences in biorelevant media appeared to be both drug- and amphiphile (bile salt/lecithin) concentration-dependent. Our studies herein indicate that bile acid modifications occurring at the host-microbe interface could lead to alterations in the capacity of intestinal bile salt micelles to solubilize drugs

  11. The bile acid composition of crane gallbladder bile

    Science.gov (United States)

    Serafin, J.A.

    1983-01-01

    1. The biliary bile acids of the whooping crane (Grus americana) and the Florida sandhill crane (G. canadensis pratensis) have been examined.2. Cholic acid (CA), chenodeoxycholic acid (CDOCA) and lithocholic acid were found in bile from both species of these North American cranes.3. CDOCA and CA were the primary bile acids in both species, together constituting 70% or more of the bile acids by weight.4. The primary bile acids of cranes appear to be the same as those that have been identified in other avian species.

  12. Resistance to ursodeoxycholic acid-induced growth arrest can also result in resistance to deoxycholic acid-induced apoptosis and increased tumorgenicity

    International Nuclear Information System (INIS)

    Powell, Ashley A; Akare, Sandeep; Qi, Wenqing; Herzer, Pascal; Jean-Louis, Samira; Feldman, Rebecca A; Martinez, Jesse D

    2006-01-01

    There is a large body of evidence which suggests that bile acids increase the risk of colon cancer and act as tumor promoters, however, the mechanism(s) of bile acids mediated tumorigenesis is not clear. Previously we showed that deoxycholic acid (DCA), a tumorogenic bile acid, and ursodeoxycholic acid (UDCA), a putative chemopreventive agent, exhibited distinct biological effects, yet appeared to act on some of the same signaling molecules. The present study was carried out to determine whether there is overlap in signaling pathways activated by tumorogenic bile acid DCA and chemopreventive bile acid UDCA. To determine whether there was an overlap in activation of signaling pathways by DCA and UDCA, we mutagenized HCT116 cells and then isolated cell lines resistant to UDCA induced growth arrest. These lines were then tested for their response to DCA induced apoptosis. We found that a majority of the cell lines resistant to UDCA-induced growth arrest were also resistant to DCA-induced apoptosis, implying an overlap in DCA and UDCA mediated signaling. Moreover, the cell lines which were the most resistant to DCA-induced apoptosis also exhibited a greater capacity for anchorage independent growth. We conclude that UDCA and DCA have overlapping signaling activities and that disregulation of these pathways can lead to a more advanced neoplastic phenotype

  13. Bile Duct Exploration

    Science.gov (United States)

    ... 223.2273 Request an Appointment Contact Us Share Facebook Twitter Linkedin Email Bile Duct Exploration Menu Print Full Article Overview Test Details Results and Follow-Up Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We ...

  14. Bile acids alter male fertility through G-protein-coupled bile acid receptor 1 signaling pathways in mice

    NARCIS (Netherlands)

    Baptissart, Marine; Vega, Aurélie; Martinot, Emmanuelle; Pommier, Aurélien J.; Houten, Sander M.; Marceau, Geoffroy; de Haze, Angélique; Baron, Silvère; Schoonjans, Kristina; Lobaccaro, Jean-Marc A.; Volle, David H.

    2014-01-01

    Bile acids (BAs) are signaling molecules that are involved in many physiological functions, such as glucose and energy metabolism. These effects are mediated through activation of the nuclear and membrane receptors, farnesoid X receptor (FXR-α) and TGR5 (G-protein-coupled bile acid receptor 1;

  15. Regulation of Bile Acid and Cholesterol Metabolism by PPARs

    Directory of Open Access Journals (Sweden)

    Tiangang Li

    2009-01-01

    Full Text Available Bile acids are amphipathic molecules synthesized from cholesterol in the liver. Bile acid synthesis is a major pathway for hepatic cholesterol catabolism. Bile acid synthesis generates bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that bile acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ regulate lipoprotein metabolism, fatty acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARα alters bile acid synthesis, conjugation, and transport, and also cholesterol synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in bile acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

  16. Endoplasmic Reticulum Stress Regulates Hepatic Bile Acid Metabolism in MiceSummary

    Directory of Open Access Journals (Sweden)

    Anne S. Henkel

    2017-03-01

    Full Text Available Background & Aims: Cholestasis promotes endoplasmic reticulum (ER stress in the liver, however, the effect of ER stress on hepatic bile acid metabolism is unknown. We aim to determine the effect of ER stress on hepatic bile acid synthesis and transport in mice. Methods: ER stress was induced pharmacologically in C57BL/6J mice and human hepatoma (HepG2 cells. The hepatic expression of genes controlling bile acid synthesis and transport was determined. To measure the activity of the primary bile acid synthetic pathway, the concentration of 7α-hydroxy-4-cholesten-3-1 was measured in plasma. Results: Induction of ER stress in mice and HepG2 cells rapidly suppressed the hepatic expression of the primary bile acid synthetic enzyme, cholesterol 7α-hydroxylase. Plasma levels of 7α-hydroxy-4-cholesten-3-1 were reduced in mice subjected to ER stress, indicating impaired bile acid synthesis. Induction of ER stress in mice and HepG2 cells increased expression of the bile salt export pump (adenosine triphosphate binding cassette [Abc]b11 and a bile salt efflux pump (Abcc3. The observed regulation of Cyp7a1, Abcb11, and Abcc3 occurred in the absence of hepatic inflammatory cytokine activation and was not dependent on activation of hepatic small heterodimer partner or intestinal fibroblast growth factor 15. Consistent with suppressed bile acid synthesis and enhanced bile acid export from hepatocytes, prolonged ER stress decreased the hepatic bile acid content in mice. Conclusions: Induction of ER stress in mice suppresses bile acid synthesis and enhances bile acid removal from hepatocytes independently of established bile acid regulatory pathways. These data show a novel function of the ER stress response in regulating bile acid metabolism. Keywords: Unfolded Protein Response, Cyp7a1, 7α-Hydroxy-4-Cholesten-3-1, Bile Acid Synthesis

  17. A new life for bile acids

    NARCIS (Netherlands)

    Jansen, Peter L. M.

    2010-01-01

    TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show

  18. Bile-Salt-Hydrolases from the Probiotic Strain Lactobacillus johnsonii La1 Mediate Anti-giardial Activity in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Thibault Allain

    2018-01-01

    Full Text Available Giardia duodenalis (syn. G. lamblia, G. intestinalis is the protozoan parasite responsible for giardiasis, the most common and widely spread intestinal parasitic disease worldwide, affecting both humans and animals. After cysts ingestion (through either contaminated food or water, Giardia excysts in the upper intestinal tract to release replicating trophozoites that are responsible for the production of symptoms. In the gut, Giardia cohabits with the host's microbiota, and several studies have revealed the importance of this gut ecosystem and/or some probiotic bacteria in providing protection against G. duodenalis infection through mechanisms that remain incompletely understood. Recent findings suggest that Bile-Salt-Hydrolase (BSH-like activities from the probiotic strain of Lactobacillus johnsonii La1 may contribute to the anti-giardial activity displayed by this strain. Here, we cloned and expressed each of the three bsh genes present in the L. johnsonii La1 genome to study their enzymatic and biological properties. While BSH47 and BSH56 were expressed as recombinant active enzymes, no significant enzymatic activity was detected with BSH12. In vitro assays allowed determining the substrate specificities of both BSH47 and BSH56, which were different. Modeling of these BSHs indicated a strong conservation of their 3-D structures despite low conservation of their primary structures. Both recombinant enzymes were able to mediate anti-giardial biological activity against Giardia trophozoites in vitro. Moreover, BSH47 exerted significant anti-giardial effects when tested in a murine model of giardiasis. These results shed new light on the mechanism, whereby active BSH derived from the probiotic strain Lactobacillus johnsonii La1 may yield anti-giardial effects in vitro and in vivo. These findings pave the way toward novel approaches for the treatment of this widely spread but neglected infectious disease, both in human and in veterinary medicine.

  19. Bile Acids Trigger GLP-1 Release Predominantly by Accessing Basolaterally Located G Protein-Coupled Bile Acid Receptors

    DEFF Research Database (Denmark)

    Brighton, Cheryl A.; Rievaj, Juraj; Kuhre, Rune E.

    2015-01-01

    Bile acids are well-recognized stimuli of glucagon-like peptide-1 (GLP-1) secretion. This action has been attributed to activation of the G protein-coupled bile acid receptor GPBAR1 (TGR5), although other potential bile acid sensors include the nuclear farnesoid receptor and the apical sodium......-coupled bile acid transporter ASBT. The aim of this study was to identify pathways important for GLP-1 release and to determine whether bile acids target their receptors on GLP-1-secreting L-cells from the apical or basolateral compartment. Using transgenic mice expressing fluorescent sensors specifically in L...... chambers optimized for measuring GLP-1 secretion, we found that both a GPBAR1 agonist and TDCA stimulated GLP-1 release better when applied from the basolateral than from the luminal direction and that luminal TDCA was ineffective when intestinal tissue was pretreated with an ASBT inhibitor. ASBT...

  20. Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea

    International Nuclear Information System (INIS)

    Schiller, L.R.; Bilhartz, L.E.; Santa Ana, C.A.

    1990-01-01

    Fecal recovery of radioactivity after ingestion of a bolus of radiolabeled bile acid is abnormally high in most patients with idiopathic chronic diarrhea. To evaluate the significance of this malabsorption, concurrent fecal excretion of both exogenous radiolabeled bile acid and endogenous (unlabeled) bile acid were measured in patients with idiopathic chronic diarrhea. Subjects received a 2.5-microCi oral dose of taurocholic acid labeled with 14C in the 24th position of the steroid moiety. Endogenous bile acid excretion was measured by a hydroxysteroid dehydrogenase assay on a concurrent 72-h stool collection. Both radiolabeled and endogenous bile acid excretion were abnormally high in most patients with chronic diarrhea compared with normal subjects, even when equivoluminous diarrhea was induced in normal subjects by ingestion of osmotically active solutions. The correlation between radiolabeled and endogenous bile acid excretion was good. However, neither radiolabeled nor endogenous bile acid excretion was as abnormal as is typically seen in patients with ileal resection, and none of these diarrhea patients responded to treatment with cholestyramine with stool weights less than 200 g. These results suggest (a) that this radiolabeled bile acid excretion test accurately reflects excess endogenous bile acid excretion; (b) that excess endogenous bile acid excretion is not caused by diarrhea per se; (c) that spontaneously occurring idiopathic chronic diarrhea is often associated with increased endogenous bile acid excretion; and (d) that bile acid malabsorption is not likely to be the primary cause of diarrhea in most of these patients

  1. Inhibitory Activity of Lactid Acid Bacteria Isolated from Tape Waterlily Seed to Enteric Pathogenic Bacteria (Vibrio cholera, Salmonella typhi, Shigella disentri, and E.coli and Its’ Susceptibility to Antibiotic, Bile Salt and Acidic Condition

    Directory of Open Access Journals (Sweden)

    Iin Khusnul Khotimah

    2012-03-01

    Full Text Available The aim of this research was to observe inhibitory activity of LAB isolated from tape waterlily seed to enteric pathogenic bacteria (Vibrio cholera, Salmonella typhi, Shigella disentri, E.coli ATCC 25922 and it’s susceptibility to antibiotic, in bile salt and under acidic condition. Microbia in the tape ( a fermented product of waterlily seed to showed were Streptococcus thermophilus (IKH-1, Pediococcus pentosaceus (IKH-2 and Leuconostoc mesentroides (IKH-8. Streptococcus thermophillus showed inhibition against the growth of Shigella disentri with inhibition zones 16,28 mm, but did not against the growth of V. Cholera, S. typhi, E.coli. Pediococcus pentosaceus inhibit Vibrio cholera, dan Salmonella thypi with inhibition zones 18,59 mm dan 7,91 mm. So that, Leuconostoc mesenteroides inhibit Salmonella thypi with zones inhibits average 8,25 mm. Chloramfenicol at 0.05 mg concentrations did not show inhibition against the growth of isolated Streptococcus thermophillus, Pediococcus pentosaceus and Leuconostoc mesentroides. These isolates could survive too in bile salt (2% and acidified media (pH 3.   Keyword : The tape of  waterlily seed, LAB, probiotic and enteric pathogenic   KEMAMPUAN PENGHAMBATAN BAKTERI ASAM LAKTAT DARI TAPE BIJI TERATAI TERHADAP PATOGENIK ENTERIK (VIBRIO CHOLERA, SALMONELLA THYPI, SHIGELLA DISENTRI, E. COLI, ANTIBIOTIK, KETAHANANNYA TERHADAP BILE SALT DAN ASAM   ABSTRAK   Penelitian ini bertujuan untuk menguji kemampuan penghambatan bakteri asam laktat yang diisolasi dari tape biji teratai terhadap patogenik enterik (Vibrio cholera, Salmonella thypi, Shigella disentri, E. Coli ATCC 25922, antibiotik, bile salt dan asam. Jenis bakteri yang diketahui tumbuh selama fermentasi tape biji teratai adalah Streptococcus thermopilus (IKH-1, Pediococcus pentosaceus(IKH-2, dan Leuconostoc mesentroides (IKH-8. Pengamatan terhadap uji penghambatan patogenik enterik (Vibrio cholera, Salmonella thypi, Shigella disentri, dan E. Coli ATCC

  2. Fatty liver diseases, bile acids, and FXR

    Directory of Open Access Journals (Sweden)

    Yan Zhu

    2016-09-01

    Full Text Available The prevalence of nonalcoholic fatty liver disease (NAFLD worldwide has increased at an alarming rate, which will likely result in enormous medical and economic burden. NAFLD presents as a spectrum of liver diseases ranging from simple steatosis, nonalcoholic steatohepatitis (NASH, fibrosis, cirrhosis, and even to hepatocellular carcinoma (HCC. A comprehensive understanding of the mechanism(s of NAFLD-to-NASH transition remains elusive with various genetic and environmental susceptibility factors possibly involved. An understanding of the mechanism may provide novel strategies in the prevention and treatment to NASH. Abnormal regulation of bile acid homeostasis emerges as an important mechanism to liver injury. The bile acid homeostasis is critically regulated by the farnesoid X receptor (FXR that is activated by bile acids. FXR has been known to exert tissue-specific effects in regulating bile acid synthesis and transport. Current investigations demonstrate FXR also plays a principle role in regulating lipid metabolism and suppressing inflammation in the liver. Therefore, the future determination of the molecular mechanism by which FXR protects the liver from developing NAFLD may shed light to the prevention and treatment of NAFLD.

  3. In vivo imaging of farnesoid X receptor activity reveals the ileum as the primary bile acid signaling tissue

    NARCIS (Netherlands)

    Houten, Sander M.; Volle, David H.; Cummins, Carolyn L.; Mangelsdorf, David J.; Auwerx, Johan

    2007-01-01

    We generated and characterized a firefly luciferase reporter mouse for the nuclear receptor farnesoid X receptor (FXR). This FXR reporter mouse has basal luciferase expression in the terminal ileum, an organ with well-characterized FXRalpha signaling. In vivo luciferase activity reflected the

  4. Bile acids for viral hepatitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Liu, J; Gluud, C

    2003-01-01

    The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness.......The viral hepatitides are common causes of liver diseases globally. Trials have assessed bile acids for patients with viral hepatitis, but no consensus was reached regarding their usefulness....

  5. Intrahepatic transposition of bile ducts.

    Science.gov (United States)

    Delić, Jasmin; Savković, Admedina; Isaković, Eldar; Marković, Sergije; Bajtarevic, Alma; Denjalić, Amir

    2012-01-01

    Objective. To describe the intrahepatic bile duct transposition (anatomical variation occurring in intrahepatic ducts) and to determine the frequency of this variation. Material and Methods. The researches were performed randomly on 100 livers of adults, both sexes. Main research methods were anatomical macrodissection. As a criterion for determination of variations in some parts of bile tree, we used the classification of Segmentatio hepatis according to Couinaud (1957) according to Terminologia Anatomica, Thieme Stuugart: Federative Committee on Anatomical Terminology, 1988. Results. Intrahepatic transposition of bile ducts was found in two cases (2%), out of total examined cases (100): right-left transposition (right segmental bile duct, originating from the segment VIII, joins the left liver duct-ductus hepaticus sinister) and left-right intrahepatic transposition (left segmental bile duct originating from the segment IV ends in right liver duct-ductus hepaticus dexter). Conclusion. Safety and success in liver transplantation to great extent depends on knowledge of anatomy and some common embryological anomalies in bile tree. Variations in bile tree were found in 24-43% of cases, out of which 1-22% are the variations of intrahepatic bile ducts. Therefore, good knowledge on ductal anatomy enables good planning, safe performance of therapeutic and operative procedures, and decreases the risk of intraoperative and postoperative complications.

  6. Endocrine functions of bile acids

    NARCIS (Netherlands)

    Houten, Sander M.; Watanabe, Mitsuhiro; Auwerx, Johan

    2006-01-01

    Bile acids (BAs), a group of structurally diverse molecules that are primarily synthesized in the liver from cholesterol, are the chief components of bile. Besides their well-established roles in dietary lipid absorption and cholesterol homeostasis, it has recently emerged that BAs are also

  7. Protective effect of carvacrol on acetic acid-induced colitis.

    Science.gov (United States)

    de Santana Souza, Marilia Trindade; Teixeira, Daiane Franco; de Oliveira, Janaíne Prata; Oliveira, Alan Santos; Quintans-Júnior, Lucindo José; Correa, Cristiane Bani; Camargo, Enilton Aparecido

    2017-12-01

    The pharmacological therapy for inflammatory bowel diseases continues to be problematic, and requires new alternative options. In this study, we tested the hypothesis that carvacrol (CAR), a phenolic monoterpene with anti-inflammatory and antioxidant activities, can treat experimental colitis in mice. C57BL/6 mice (n=8/group) were subjected to intrarectal administration of acetic acid (5%) to induce colitis. Mice were pretreated with CAR (25, 50 or 100mg/kg, p.o.) every 12h for three days prior to the induction. Abdominal hyperalgesia, macroscopic and microscopic colon damage, myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels, oxidative stress markers, and antioxidant enzyme activities were evaluated. Pretreatment with all doses of CAR significantly decreased abdominal hyperalgesia and colon MPO activity and TNF-α and IL-1β levels. A reduction in macroscopic and microscopic damage (p<0.05) was observed at doses of 50 and 100mg/kg CAR. Pretreatment with CAR significantly reduced lipid peroxidation (for all doses) and increased sulfhydryl groups (at 100mg/kg). This effect was accompanied by a significant increase in catalase, superoxide dismutase, and glutathione peroxidase activities. These findings indicate that CAR protected mice from acetic acid-induced colitis by reducing inflammatory, nociceptive, and oxidative damages. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  8. Human bile sorption by cancrinite-type zeolites

    Energy Technology Data Exchange (ETDEWEB)

    Linares, Carlos F. [Laboratorio de Catalisis y Metales de Transicion, Facultad de Ciencias y Tecnologia, Departamento de Quimica, Universidad de Carabobo, Valencia. Edo. Carabobo, Apartado Postal 3336 (Venezuela, Bolivarian Republic of)], E-mail: clinares@uc.edu.ve; Colmenares, Maryi; Ocanto, Freddy [Laboratorio de Catalisis y Metales de Transicion, Facultad de Ciencias y Tecnologia, Departamento de Quimica, Universidad de Carabobo, Valencia. Edo. Carabobo, Apartado Postal 3336 (Venezuela, Bolivarian Republic of); Valbuena, Oscar [Facultad de Ciencias y Tecnologia, Departamento de Biologia, Universidad de Carabobo, Valencia. Edo. Carabobo, Apartado Postal 3336 (Venezuela, Bolivarian Republic of)], E-mail: ovalbuena@uc.edu.ve

    2009-01-01

    A nitrated cancrinite-type zeolite was synthesized from zeolite X, NaOH and NaNO{sub 3} solutions under autogeneous pressure at 80 deg. C for 48 h. This zeolite was characterized by X-ray diffraction (XRD), FT-IR-spectroscopy, scanning electron microscopy (SEM) and BET surface area. XRD, SEM and FT-IR confirmed the presence of nitrated cancrinite-type zeolite without other collateral phases as sodalite. Then, this sodium zeolite was exchanged with potassium and calcium cations and finally, these modified zeolites were reacted with biliar solutions from human gallbladder. Several factors such as: mass of used cancrinite, nature of the exchanged cation and reaction time of the cancrinite-bile solution interactions were studied. The composition of bile solutions (bile acids, phospholipids and bilirubin) was analyzed before and after the cancrinite-bile solution reaction. Results showed that the components of the bile were notably reduced after the contact with solids. Ca-cancrinite, 120 min of reaction time and 500 mg of solids were the best conditions determined for the bile acid reduction in human bile. When the modified zeolites were compared with the commercial cholestyramine, it was found that zeolites were more active than the latter. These zeolites may be an alternative choice to diminish cholesterol levels in hypercholesterolemic patients.

  9. Intestinal bile acid receptors are key regulators of glucose homeostasis.

    Science.gov (United States)

    Trabelsi, Mohamed-Sami; Lestavel, Sophie; Staels, Bart; Collet, Xavier

    2017-08-01

    In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.

  10. The Effect of Oxygen on Bile Resistance in Listeria monocytogenes

    Science.gov (United States)

    Wright, Morgan L; Pendarvis, Ken; Nanduri, Bindu; Edelmann, Mariola J; Jenkins, Haley N; Reddy, Joseph S; Wilson, Jessica G; Ding, Xuan; Broadway, Paul R; Ammari, Mais G; Paul, Oindrila; Roberts, Brandy; Donaldson, Janet R

    2016-01-01

    Listeria monocytogenes is a Gram-positive facultative anaerobe that is the causative agent of the disease listeriosis. The infectious ability of this bacterium is dependent upon resistance to stressors encountered within the gastrointestinal tract, including bile. Previous studies have indicated bile salt hydrolase activity increases under anaerobic conditions, suggesting anaerobic conditions influence stress responses. Therefore, the goal of this study was to determine if reduced oxygen availability increased bile resistance of L. monocytogenes. Four strains representing three serovars were evaluated for changes in viability and proteome expression following exposure to bile in aerobic or anaerobic conditions. Viability for F2365 (serovar 4b), EGD-e (serovar 1/2a), and 10403S (serovar 1/2a) increased following exposure to 10% porcine bile under anaerobic conditions (P 0.05) in bile resistance between aerobic and anaerobic conditions, indicating that oxygen availability does not influence resistance in this strain. The proteomic analysis indicated F2365 and EGD-e had an increased expression of proteins associated with cell envelope and membrane bioenergetics under anaerobic conditions, including thioredoxin-disulfide reductase and cell division proteins. Interestingly, HCC23 had an increase in several dehydrogenases following exposure to bile under aerobic conditions, suggesting that the NADH:NAD+ is altered and may impact bile resistance. Variations were observed in the expression of the cell shape proteins between strains, which corresponded to morphological differences observed by scanning electron microscopy. These data indicate that oxygen availability influences bile resistance. Further research is needed to decipher how these changes in metabolism impact pathogenicity in vivo and also the impact that this has on susceptibility of a host to listeriosis. PMID:27274623

  11. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    International Nuclear Information System (INIS)

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-01-01

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  12. Bile Duct Obstruction Secondary to Chronic Pancreatitis in Seven Dogs

    OpenAIRE

    Cribb, Alastair E.; Burgener, David C.; Reimann, Keith A.

    1988-01-01

    Seven icteric dogs were determined to have bile duct obstruction secondary to chronic pancreatitis. All dogs had histories of intermittent vomiting and diarrhea. Alkaline phosphatase and alanine aminotransferase activities and total bilirubin concentrations were markedly elevated. Diagnosis was based on exploratory laparotomy and histological examination. Each dog had a 3 to 10 cm mass in the body of the pancreas and obstruction of the common bile duct. Three dogs treated with pancreatectomy,...

  13. Impact of bile acids on the growth of human cholangiocarcinoma via FXR

    Directory of Open Access Journals (Sweden)

    Zhang Yinxin

    2011-10-01

    Full Text Available Abstract Background The objective of the study was to investigate the effect of different types of bile acids on proliferation of cholangiocarcinoma and the potential molecular mechanisms. Methods PCR assay and Western blot were performed to detect the expression of farnesoid × receptor (FXR in mRNA and protein level. Immunohistochemical analysis was carried out to monitor the expression of FXR in cholangiocarcinoma tissues from 26 patients and 10 normal controls. The effects on in vivo tumor growth were also studied in nude mouse model. Results Free bile acids induced an increased expression of FXR; on the contrary, the conjugated bile acids decreased the expression of FXR. The FXR effect has been illustrated with the use of the FXR agonist GW4064 and the FXR antagonist GS. More specifically, when the use of free bile acids combined with FXR agonist GW4064, the tumor cell inhibitory effect was even more pronounced. But adding FXR antagonist GS into the treatment attenuated the tumor inhibitory effect caused by free bile acids. Combined treatment of GS and CDCA could reverse the regulating effect of CDCA on the expression of FXR. Administration of CDCA and GW 4064 resulted in a significant inhibition of tumor growth. The inhibitory effect in combination group (CDCA plus GW 4064 was even more pronounced. Again, the conjugated bile acid-GDCA promoted the growth of tumor. We also found that FXR agonist GW4064 effectively blocked the stimulatory effect of GDCA on tumor growth. And the characteristic and difference of FXR expressions were in agreement with previous experimental results in mouse cholangiocarcinoma tissues. There was also significant difference in FXR expression between normal and tumor tissues from patients with cholangiocarcinoma. Conclusions The imbalance of ratio of free and conjugated bile acids may play an important role in tumorigenesis of cholangiocarcinoma. FXR, a member of the nuclear receptor superfamily, may mediate the

  14. Corosolic Acid Induces Non-Apoptotic Cell Death through Generation of Lipid Reactive Oxygen Species Production in Human Renal Carcinoma Caki Cells

    Directory of Open Access Journals (Sweden)

    Seon Min Woo

    2018-04-01

    Full Text Available Corosolic acid is one of the pentacyclic triterpenoids isolated from Lagerstroemia speciose and has been reported to exhibit anti-cancer and anti-proliferative activities in various cancer cells. In the present study, we investigated the molecular mechanisms of corosolic acid in cancer cell death. Corosolic acid induces a decrease of cell viability and an increase of cell cytotoxicity in human renal carcinoma Caki cells. Corosolic acid-induced cell death is not inhibited by apoptosis inhibitor (z-VAD-fmk, a pan-caspase inhibitor, necroptosis inhibitor (necrostatin-1, or ferroptosis inhibitors (ferrostatin-1 and deferoxamine (DFO. Furthermore, corosolic acid significantly induces reactive oxygen species (ROS levels, but antioxidants (N-acetyl-l-cysteine (NAC and trolox do not inhibit corosolic acid-induced cell death. Interestingly, corosolic acid induces lipid oxidation, and α-tocopherol markedly prevents corosolic acid-induced lipid peroxidation and cell death. Anti-chemotherapeutic effects of α-tocopherol are dependent on inhibition of lipid oxidation rather than inhibition of ROS production. In addition, corosolic acid induces non-apoptotic cell death in other renal cancer (ACHN and A498, breast cancer (MDA-MB231, and hepatocellular carcinoma (SK-Hep1 and Huh7 cells, and α-tocopherol markedly inhibits corosolic acid-induced cell death. Therefore, our results suggest that corosolic acid induces non-apoptotic cell death in cancer cells through the increase of lipid peroxidation.

  15. Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts

    Science.gov (United States)

    Urdaneta, Verónica; Casadesús, Josep

    2017-01-01

    Bile salts and bacteria have intricate relationships. The composition of the intestinal pool of bile salts is shaped by bacterial metabolism. In turn, bile salts play a role in intestinal homeostasis by controlling the size and the composition of the intestinal microbiota. As a consequence, alteration of the microbiome–bile salt homeostasis can play a role in hepatic and gastrointestinal pathological conditions. Intestinal bacteria use bile salts as environmental signals and in certain cases as nutrients and electron acceptors. However, bile salts are antibacterial compounds that disrupt bacterial membranes, denature proteins, chelate iron and calcium, cause oxidative damage to DNA, and control the expression of eukaryotic genes involved in host defense and immunity. Bacterial species adapted to the mammalian gut are able to endure the antibacterial activities of bile salts by multiple physiological adjustments that include remodeling of the cell envelope and activation of efflux systems and stress responses. Resistance to bile salts permits that certain bile-resistant pathogens can colonize the hepatobiliary tract, and an outstanding example is the chronic infection of the gall bladder by Salmonella enterica. A better understanding of the interactions between bacteria and bile salts may inspire novel therapeutic strategies for gastrointestinal and hepatobiliary diseases that involve microbiome alteration, as well as novel schemes against bacterial infections. PMID:29043249

  16. Interactions between Bacteria and Bile Salts in the Gastrointestinal and Hepatobiliary Tracts

    Directory of Open Access Journals (Sweden)

    Verónica Urdaneta

    2017-10-01

    Full Text Available Bile salts and bacteria have intricate relationships. The composition of the intestinal pool of bile salts is shaped by bacterial metabolism. In turn, bile salts play a role in intestinal homeostasis by controlling the size and the composition of the intestinal microbiota. As a consequence, alteration of the microbiome–bile salt homeostasis can play a role in hepatic and gastrointestinal pathological conditions. Intestinal bacteria use bile salts as environmental signals and in certain cases as nutrients and electron acceptors. However, bile salts are antibacterial compounds that disrupt bacterial membranes, denature proteins, chelate iron and calcium, cause oxidative damage to DNA, and control the expression of eukaryotic genes involved in host defense and immunity. Bacterial species adapted to the mammalian gut are able to endure the antibacterial activities of bile salts by multiple physiological adjustments that include remodeling of the cell envelope and activation of efflux systems and stress responses. Resistance to bile salts permits that certain bile-resistant pathogens can colonize the hepatobiliary tract, and an outstanding example is the chronic infection of the gall bladder by Salmonella enterica. A better understanding of the interactions between bacteria and bile salts may inspire novel therapeutic strategies for gastrointestinal and hepatobiliary diseases that involve microbiome alteration, as well as novel schemes against bacterial infections.

  17. Bile acid sequestrants for cholesterol

    Science.gov (United States)

    ... ency/patientinstructions/000787.htm Bile acid sequestrants for cholesterol To use the sharing features on this page, ... are medicines that help lower your LDL (bad) cholesterol . Too much cholesterol in your blood can stick ...

  18. Molecular Mechanisms of Bile Duct Development

    OpenAIRE

    Zong, Yiwei; Stanger, Ben Z.

    2010-01-01

    The mammalian biliary system, consisting of the intrahepatic and extrahepatic bile ducts, is responsible for transporting bile from the liver to the intestine. Bile duct dysfunction, as is seen in some congenital biliary diseases such as Alagille syndrome and biliary atresia, can lead to the accumulation of bile in the liver, preventing the excretion of detoxification products and ultimately leading to liver damage. Bile duct formation requires coordinated cell-cell interactions, resulting in...

  19. Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids

    Directory of Open Access Journals (Sweden)

    Courtney B. Ferrebee

    2015-03-01

    Full Text Available The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size, and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor (FXR and the G-protein-coupled bile acid receptor (TGR5.

  20. The role of bile acids in the pathogenesis of bowel diseases

    Directory of Open Access Journals (Sweden)

    Magdalena Panek-Jeziorna

    2017-08-01

    Full Text Available Bile acids not only play a cardinal role in the digestion and absorption of fat and fat-soluble vitamins, but also significantly affect gastrointestinal motor, sensory and secretory functions, intestinal barrier permeability and the regulation of the inflammatory response. The results of recent studies have revealed complex interactions between bile acids and the gut microbiota. In addition, bile acids also play a role of signaling molecules regulating the activity of lipid and glucose metabolic pathways, as well as a role of ligands for transcription factors. Genetic factors associated with the regulation of bile acid synthesis, transport and action may significantly influence gastrointestinal function and predispose to diarrhea resulting from bile acid malabsorption. Methods used in the diagnosis of bile acid malabsorption include 75selenium-homotaurocholic acid test, serum C4 and fibroblast growth factor 19 (FGF19, as well as fecal bile acid levels. The paper presents the latest data on the role of bile acid in the pathogenesis of irritable bowel syndrome, inflammatory bowel diseases and colorectal cancer. Advances in the treatment of disturbances in bile acids absorption and synthesis are also presented. A better understanding of molecular mechanisms regulating bile acid action may have implication for colorectal cancer prevention.

  1. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection.

    Science.gov (United States)

    Weingarden, Alexa R; Chen, Chi; Bobr, Aleh; Yao, Dan; Lu, Yuwei; Nelson, Valerie M; Sadowsky, Michael J; Khoruts, Alexander

    2014-02-15

    Fecal microbiota transplantation (FMT) has emerged as a highly effective therapy for refractory, recurrent Clostridium difficile infection (CDI), which develops following antibiotic treatments. Intestinal microbiota play a critical role in the metabolism of bile acids in the colon, which in turn have major effects on the lifecycle of C. difficile bacteria. We hypothesized that fecal bile acid composition is altered in patients with recurrent CDI and that FMT results in its normalization. General metabolomics and targeted bile acid analyses were performed on fecal extracts from patients with recurrent CDI treated with FMT and their donors. In addition, 16S rRNA gene sequencing was used to determine the bacterial composition of pre- and post-FMT fecal samples. Taxonomic bacterial composition of fecal samples from FMT recipients showed rapid change and became similar to the donor after the procedure. Pre-FMT fecal samples contained high concentrations of primary bile acids and bile salts, while secondary bile acids were nearly undetectable. In contrast, post-FMT fecal samples contained mostly secondary bile acids, as did non-CDI donor samples. Therefore, our analysis showed that FMT resulted in normalization of fecal bacterial community structure and metabolic composition. Importantly, metabolism of bile salts and primary bile acids to secondary bile acids is disrupted in patients with recurrent CDI, and FMT corrects this abnormality. Since individual bile salts and bile acids have pro-germinant and inhibitory activities, the changes suggest that correction of bile acid metabolism is likely a major mechanism by which FMT results in a cure and prevents recurrence of CDI.

  2. Coexpression of bile salt hydrolase gene and catalase gene remarkably improves oxidative stress and bile salt resistance in Lactobacillus casei.

    Science.gov (United States)

    Wang, Guohong; Yin, Sheng; An, Haoran; Chen, Shangwu; Hao, Yanling

    2011-08-01

    Lactic acid bacteria (LAB) encounter various types of stress during industrial processes and gastrointestinal transit. Catalase (CAT) and bile salt hydrolase (BSH) can protect bacteria from oxidative stress or damage caused by bile salts by decomposing hydrogen peroxide (H(2)O(2)) or deconjugating the bile salts, respectively. Lactobacillus casei is a valuable probiotic strain and is often deficient in both CAT and BSH. In order to improve the resistance of L. casei to both oxidative and bile salts stress, the catalase gene katA from L. sakei and the bile salt hydrolase gene bsh1 from L. plantarum were coexpressed in L. casei HX01. The enzyme activities of CAT and BSH were 2.41 μmol H(2)O(2)/min/10(8) colony-forming units (CFU) and 2.11 μmol glycine/min/ml in the recombinant L. casei CB, respectively. After incubation with 8 mM H(2)O(2), survival ratio of L. casei CB was 40-fold higher than that of L. casei CK. Treatment of L. casei CB with various concentrations of sodium glycodeoxycholate (GDCA) showed that ~10(5) CFU/ml cells survived after incubation with 0.5% GDCA, whereas almost all the L. casei CK cells were killed when treaded with 0.4% GDCA. These results indicate that the coexpression of CAT and BSH confers high-level resistance to both oxidative and bile salts stress conditions in L. casei HX01.

  3. Ethoxyresorufin-O-deethylase activity and fixed wavelength fluorescence detection of PAHs metabolites in bile in turbot (Scophthalmus maximus L.) exposed to a dispersed topped crude oil in a continuous flow system

    International Nuclear Information System (INIS)

    Camus, L.; Aas, E.; Borseth, J.F.

    1998-01-01

    Long term effects of sublethal concentrations of oil on the marine environment have become of general concern. Cytochrome P4501A activity (EROD) in liver and fixed wavelength fluorescence detection of PAHs metabolites (FF) have in this study been used as biomarkers for dispersed oil exposure on a long term period of juvenile turbot (Scophthalmus maximus L.). A Continuous Flow System was used to carry out the study. The fish were continuously exposed to 0.125, 0.5 or 2.0 mg litre -1 dispersed topped crude oil for 6, 15, 24h 4 and 21 days followed by a 9 day recovery period in clean seawater. No induction of the cytochrome P4501A was measured. A maximum level in bile metabolites (4- to 5-fold) was recorded after 24h of exposure revealing thereby a detoxification process, but a decline occurred from day 4 to day 21. This study demonstrated that FF detection of PAHs metabolites in bile could be a more sensitive biomarker than EROD activity in a long term exposure to sublethal concentration of oil. (author)

  4. Acetic acid induces a programmed cell death process in the food spoilage yeast Zygosaccharomyces bailii.

    Science.gov (United States)

    Ludovico, Paula; Sansonetty, Filipe; Silva, Manuel T; Côrte-Real, Manuela

    2003-03-01

    Here we show that 320-800 mM acetic acid induces in Zygosaccharomyces bailii a programmed cell death (PCD) process that is inhibited by cycloheximide, is accompanied by structural and biochemical alterations typical of apoptosis, and occurs in cells with preserved mitochondrial and plasma membrane integrity (as revealed by rhodamine 123 (Rh123) and propidium iodide (PI) staining, respectively). Mitochondrial ultrastructural changes, namely decrease of the cristae number, formation of myelinic bodies and swelling were also seen. Exposure to acetic acid above 800 mM resulted in killing by necrosis. The occurrence of an acetic acid-induced active cell death process in Z. bailii reinforces the concept of a physiological role of the PCD in the normal yeast life cycle.

  5. Specific Osmolyte Transporters Mediate Bile Tolerance in Listeria monocytogenes▿

    Science.gov (United States)

    Watson, Debbie; Sleator, Roy D.; Casey, Pat G.; Hill, Colin; Gahan, Cormac G. M.

    2009-01-01

    The food-borne pathogenic bacterium Listeria monocytogenes has the potential to adapt to an array of suboptimal growth environments encountered within the host. The pathogen is relatively bile tolerant and has the capacity to survive and grow within both the small intestine and the gallbladder in murine models of oral infection. We have previously demonstrated a role for the principal carnitine transport system of L. monocytogenes (OpuC) in gastrointestinal survival of the pathogen (R. Sleator, J. Wouters, C. G. M. Gahan, T. Abee, and C. Hill, Appl. Environ. Microbiol. 67:2692-2698, 2001). However, the mechanisms by which OpuC, or indeed carnitine, protects the pathogen in this environment are unclear. In the current study, systematic analysis of strains with mutations in osmolyte transporters revealed a role for OpuC in resisting the acute toxicity of bile, with a minor role also played by BetL, a secondary betaine uptake system which also exhibits a low affinity for carnitine. In addition, the toxic effects of bile on wild-type L. monocytogenes cells were ameliorated when carnitine (but not betaine) was added to the medium. lux-promoter fusions to the promoters of the genes encoding the principal osmolyte uptake systems Gbu, BetL, and OpuC and the known bile tolerance system BilE were constructed. Promoter activity for all systems was significantly induced in the presence of bile, with the opuC and bilE promoters exhibiting the highest levels of bile-dependent expression in vitro and the betL and bilE promoters showing the highest expression levels in the intestines of orally inoculated mice. A direct comparison of all osmolyte transporter mutants in a murine oral infection model confirmed a major role for OpuC in intestinal persistence and systemic invasion and a minor role for the BetL transporter in fecal carriage. This study therefore demonstrates a previously unrecognized function for osmolyte uptake systems in bile tolerance in L. monocytogenes. PMID

  6. Bile acids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Chen, Weikeng; Gluud, C

    2003-01-01

    Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear.......Bile acids have been used for treating primary sclerosing cholangitis, but their beneficial and harmful effects remain unclear....

  7. [Analysis on replacement of traditional Chinese medicine bear bile with bile acids based on drug properties].

    Science.gov (United States)

    Yuan, Bin; Ren, Ying-Long; Ma, Li; Gu, Hao; Wang, Yun; Qiao, Yan-Jiang

    2014-02-01

    To discuss the rationality of the clinical replacement of traditional Chinese medicine (TCM) bear bile with bile acid constituents, and analyze the difference between these constituents and bear bile in drug properties. Summarizing the drug properties of bear bile by reference to medical literatures for drug properties of TCM bear bile and Science of Traditional Chinese Medicine (China Press of Traditional Chinese Medicine, 2007). Analyzing and summarizing the pharmacological effects of main bile acid constituents according to relevant literatures for studies on pharmacological effects of main bile acid constituents in CNKI database. Predicating the drug properties of these bile acid constituents by using the drug property predication model established by the study group according the pharmacological effects of main bile acid constituents in the paper, and compare the prediction results with the drug properties of bear bile. Bile acid constituents in bear bile were mostly cold in property, bitter in taste, and the combination of their drug properties could reflect the combined drug properties of bear bile. All of these bile acid constituents in bear bile could show part of effects of bear bile. Attention shall be given to regulate the medication scheme in clinical application according to actual conditions.

  8. Modulation of the cannabinoid receptors by andrographolide attenuates hepatic apoptosis following bile duct ligation in rats with fibrosis.

    Science.gov (United States)

    Lee, Tzung-Yan; Lee, Ko-Chen; Chang, Hen-Hong

    2010-08-01

    Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The aim of this study was to test whether the andrographolide limits the evolution of apoptosis in a murine model of bile duct ligation (BDL)-induced hepatic fibrosis. Male Sprague-Dawley rats were divided into four groups and hepatic apoptosis was induced by BDL for 2 weeks. The BDL animals were also treated with andrographolide (50, 100, and 200 mg/kg, i.p.) during the same time period. BDL-induced liver injury was associated with apoptosis and fibrosis, and the latter was significantly reduced in animals receiving andrographolide. The increase in serum alanine aminotransferase, asparate aminotransferase, tumor necrosis factor-alpha and IL-1beta levels caused by BDL were also significantly reduced by treatment with andrographolide. Andrographolide decreased the intrahepatic protein levels of cannabinoid receptor 1 (CB1), Bax, and cytochrome c, along with of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor-beta (TGF-beta), two markers of fibrogenesis. This effect was mediated by the inactivation of the c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2) phosphorylation cascade, but it did not affect the p38 mitogen-activated protein kinase pathway. Additionally, andrographolide reduced the generation of hepatic lipid peroxidation and enhance senescence marker protein-30 levels to resist the hepatic oxidative stress in the presence of BDL. In conclusion, this study has identified AP as a potent protector against cholestasis-induced apoptosis in vivo. Its anti-apoptotic action largely relies on the inhibition of the oxidative stress pathway.

  9. A proteomic analysis of human bile

    DEFF Research Database (Denmark)

    Kristiansen, Troels Zakarias; Bunkenborg, Jakob; Gronborg, Mads

    2004-01-01

    We have carried out a comprehensive characterization of human bile to define the bile proteome. Our approach involved fractionation of bile by one-dimensional gel electrophoresis and lectin affinity chromatography followed by liquid chromatography tandem mass spectrometry. Overall, we identified 87...... of cancer biomarkers from any body fluid. Udgivelsesdato: 2004-Jul...

  10. Rho Kinase ROCK2 Mediates Acid-Induced NADPH Oxidase NOX5-S Expression in Human Esophageal Adenocarcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Jie Hong

    Full Text Available Mechanisms of the progression from Barrett's esophagus (BE to esophageal adenocarcinoma (EA are not fully understood. We have shown that NOX5-S may be involved in this progression. However, how acid upregulates NOX5-S is not well known. We found that acid-induced increase in NOX5-S expression was significantly decreased by the Rho kinase (ROCK inhibitor Y27632 in BE mucosal biopsies and FLO-1 EA cells. In addition, acid treatment significantly increased the Rho kinase activity in FLO-1 cells. The acid-induced increase in NOX5-S expression and H2O2 production was significantly decreased by knockdown of Rho kinase ROCK2, but not by knockdown of ROCK1. Conversely, the overexpression of the constitutively active ROCK2, but not the constitutively active ROCK1, significantly enhanced the NOX5-S expression and H2O2 production. Moreover, the acid-induced increase in Rho kinase activity and in NOX5-S mRNA expression was blocked by the removal of calcium in both FLO-1 and OE33 cells. The calcium ionophore A23187 significantly increased the Rho kinase activity and NOX5-S mRNA expression. We conclude that acid-induced increase in NOX5-S expression and H2O2 production may depend on the activation of ROCK2, but not ROCK1, in EA cells. The acid-induced activation of Rho kinase may be mediated by the intracellular calcium increase. It is possible that persistent acid reflux present in BE patients may increase the intracellular calcium, activate ROCK2 and thereby upregulate NOX5-S. High levels of reactive oxygen species derived from NOX5-S may cause DNA damage and thereby contribute to the progression from BE to EA.

  11. Bile Duct Obstruction Secondary to Chronic Pancreatitis in Seven Dogs

    Science.gov (United States)

    Cribb, Alastair E.; Burgener, David C.; Reimann, Keith A.

    1988-01-01

    Seven icteric dogs were determined to have bile duct obstruction secondary to chronic pancreatitis. All dogs had histories of intermittent vomiting and diarrhea. Alkaline phosphatase and alanine aminotransferase activities and total bilirubin concentrations were markedly elevated. Diagnosis was based on exploratory laparotomy and histological examination. Each dog had a 3 to 10 cm mass in the body of the pancreas and obstruction of the common bile duct. Three dogs treated with pancreatectomy, gastrojejunostomy, and cholecystojejunostomy died within five weeks. Three dogs treated with conservative surgical procedures were alive at 8, 16, and 26 months postoperatively. One dog was euthanized because of suspected neoplasia. Hepatic enzyme activity and bilirubin levels decreased markedly in the surviving dogs. Histological examination of the pancreatic masses indicated chronic pancreatitis. Hepatic biopsies revealed evidence of cholestasis. Chronic pancreatitis should be included in the differential diagnoses of icterus, bile duct obstruction, and masses in the pancreas. PMID:17423102

  12. Metabolic Effects of Bile Acids in the Gut in Health and Disease

    NARCIS (Netherlands)

    Boesjes, Marije; Brufau Dones, Gemma

    2014-01-01

    In the last decade, it became clear that bile acids, in addition to their role in intestinal absorption of lipids and fat-soluble vitamins, are major regulators of metabolism. They activate signal transduction pathways through binding to the specific bile acid receptors TGR5 and FXR. Indirectly,

  13. Identification of estrogenic compounds in fish bile using bioassay-directed fractionation

    NARCIS (Netherlands)

    Houtman, C.J.; van Oostveen, A.M.; Brouwer, A.; Lamoree, M.H.; Legler, J.

    2004-01-01

    Conjugates of estrogenic chemicals, endogenous as well as xenobiotic, are mainly excreted via bile into the intestine. Therefore, measurement of estrogenic activity in bile yields useful information about an organism's internal exposure to (xeno-)estrogens. Although previous studies in The

  14. The microbe-secreted isopeptide poly-γ-glutamic acid induces stress tolerance in Brassica napus L. seedlings by activating crosstalk between H2O2 and Ca2+

    Science.gov (United States)

    Lei, Peng; Pang, Xiao; Feng, Xiaohai; Li, Sha; Chi, Bo; Wang, Rui; Xu, Zongqi; Xu, Hong

    2017-01-01

    Poly-γ-glutamic acid (γ-PGA) is a microbe-secreted isopeptide that has been shown to promote growth and enhance stress tolerance in crops. However, its site of action and downstream signaling pathways are still unknown. In this study, we investigated γ-PGA-induced tolerance to salt and cold stresses in Brassica napus L. seedlings. Fluorescent labeling of γ-PGA was used to locate the site of its activity in root protoplasts. The relationship between γ-PGA-induced stress tolerance and two signal molecules, H2O2 and Ca2+, as well as the γ-PGA-elicited signaling pathway at the whole plant level, were explored. Fluorescent labeling showed that γ-PGA did not enter the cytoplasm but instead attached to the surface of root protoplasm. Here, it triggered a burst of H2O2 in roots by enhancing the transcription of RbohD and RbohF, and the elicited H2O2 further activated an influx of Ca2+ into root cells. Ca2+ signaling was transmitted via the stem from roots to leaves, where it elicited a fresh burst of H2O2, thus promoting plant growth and enhancing stress tolerance. On the basis of these observation, we propose that γ-PGA mediates stress tolerance in Brassica napus seedlings by activating an H2O2 burst and subsequent crosstalk between H2O2 and Ca2+ signaling. PMID:28198821

  15. Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice

    NARCIS (Netherlands)

    Hulzebos, CV; Voshol, PJ; Wolters, H; Kruit, JK; Ottenhof, R; Groen, AK; Stellaard, F; Verkade, HJ; Kuipers, F

    Baekground/Aims: Bile flow consists of bile salt-dependent bile flow (BSDF), generated by canalicular secretion of bile salts, and bile salt-independent flow (BSIF), probably of combined canalicular and ductular origin. Bile salt transport proteins have been identified in cholangiocytes suggesting a

  16. Lipoteichoic acid induces surfactant protein-A biosynthesis in human alveolar type II epithelial cells through activating the MEK1/2-ERK1/2-NF-κB pathway

    Directory of Open Access Journals (Sweden)

    Liu Feng-Lin

    2012-10-01

    Full Text Available Abstract Background Lipoteichoic acid (LTA, a gram-positive bacterial outer membrane component, can cause septic shock. Our previous studies showed that the gram-negative endotoxin, lipopolysaccharide (LPS, could induce surfactant protein-A (SP-A production in human alveolar epithelial (A549 cells. Objectives In this study, we further evaluated the effect of LTA on SP-A biosynthesis and its possible signal-transducing mechanisms. Methods A549 cells were exposed to LTA. Levels of SP-A, nuclear factor (NF-κB, extracellular signal-regulated kinase 1/2 (ERK1/2, and mitogen-activated/extracellular signal-regulated kinase kinase (MEK1 were determined. Results Exposure of A549 cells to 10, 30, and 50 μg/ml LTA for 24 h did not affect cell viability. Meanwhile, when exposed to 30 μg/ml LTA for 1, 6, and 24 h, the biosynthesis of SP-A mRNA and protein in A549 cells significantly increased. As to the mechanism, LTA enhanced cytosolic and nuclear NF-κB levels in time-dependent manners. Pretreatment with BAY 11–7082, an inhibitor of NF-κB activation, significantly inhibited LTA-induced SP-A mRNA expression. Sequentially, LTA time-dependently augmented phosphorylation of ERK1/2. In addition, levels of phosphorylated MEK1 were augmented following treatment with LTA. Conclusions Therefore, this study showed that LTA can increase SP-A synthesis in human alveolar type II epithelial cells through sequentially activating the MEK1-ERK1/2-NF-κB-dependent pathway.

  17. Heat shock protein 70-dependent protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells.

    Science.gov (United States)

    Qin, Ying; Naito, Yuji; Handa, Osamu; Hayashi, Natsuko; Kuki, Aiko; Mizushima, Katsura; Omatsu, Tatsushi; Tanimura, Yuko; Morita, Mayuko; Adachi, Satoko; Fukui, Akifumi; Hirata, Ikuhiro; Kishimoto, Etsuko; Nishikawa, Taichiro; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Takagi, Tomohisa; Yagi, Nobuaki; Kokura, Satoshi; Yoshikawa, Toshikazu

    2011-11-01

    Protection of the small intestine from mucosal injury induced by nonsteroidal anti-inflammatory drugs including acetylsalicylic acid is a critical issue in the field of gastroenterology. Polaprezinc an anti-ulcer drug, consisting of zinc and L-carnosine, provides gastric mucosal protection against various irritants. In this study, we investigated the protective effect of polaprezinc on acetylsalicylic acid-induced apoptosis of the RIE1 rat intestinal epithelial cell line. Confluent rat intestinal epithelial cells were incubated with 70 µM polaprezinc for 24 h, and then stimulated with or without 15 mM acetylsalicylic acid for a further 15 h. Subsequent cellular viability was quantified by fluorometric assay based on cell lysis and staining. Acetylsalicylic acid-induced cell death was also qualified by fluorescent microscopy of Hoechst33342 and propidium iodide. Heat shock proteins 70 protein expression after adding polaprezinc or acetylsalicylic acid was assessed by western blotting. To investigate the role of Heat shock protein 70, Heat shock protein 70-specific small interfering RNA was applied. Cell viability was quantified by fluorometric assay based on cell lysis and staining and apoptosis was analyzed by fluorescence-activated cell sorting. We found that acetylsalicylic acid significantly induced apoptosis of rat intestinal epithelial cells in a dose- and time-dependent manner. Polaprezinc significantly suppressed acetylsalicylic acid-induced apoptosis of rat intestinal epithelial cells at its late phase. At the same time, polaprezinc increased Heat shock protein 70 expressions of rat intestinal epithelial cells in a time-dependent manner. However, in Heat shock protein 70-silenced rat intestinal epithelial cells, polaprezinc could not suppress acetylsalicylic acid -induced apoptosis at its late phase. We conclude that polaprezinc-increased Heat shock protein 70 expression might be an important mechanism by which polaprezinc suppresses acetylsalicylic

  18. Spermine oxidase promotes bile canalicular lumen formation through acrolein production.

    Science.gov (United States)

    Uemura, Takeshi; Takasaka, Tomokazu; Igarashi, Kazuei; Ikegaya, Hiroshi

    2017-11-01

    Spermine oxidase (SMOX) catalyzes oxidation of spermine to generate spermidine, hydrogen peroxide (H 2 O 2 ) and 3-aminopropanal, which is spontaneously converted to acrolein. SMOX is induced by a variety of stimuli including bacterial infection, polyamine analogues and acetaldehyde exposure. However, the physiological functions of SMOX are not yet fully understood. We investigated the physiological role of SMOX in liver cells using human hepatocellular carcinoma cell line HepG2. SMOX localized to the bile canalicular lumen, as determined by F-actin staining. Knockdown of SMOX reduced the formation of bile canalicular lumen. We also found that phospho-Akt (phosphorylated protein kinase B) was localized to canalicular lumen. Treatment with Akt inhibitor significantly reduced the formation of bile canalicular lumen. Acrolein scavenger also inhibited the formation of bile canalicular lumen. PTEN, phosphatase and tensin homolog and an inhibitor of Akt, was alkylated in a SMOX-dependent manner. Our results suggest that SMOX plays a central role in the formation of bile canalicular lumen in liver cells by activating Akt pathway through acrolein production.

  19. [Advances in studies on bear bile powder].

    Science.gov (United States)

    Zhou, Chao-fan; Gao, Guo-jian; Liu, Ying

    2015-04-01

    In this paper, a detailed analysis was made on relevant literatures about bear bile powder in terms of chemical component, pharmacological effect and clinical efficacy, indicating bear bile powder's significant pharmacological effects and clinical application in treating various diseases. Due to the complex composition, bear bile powder is relatively toxic. Therefore, efforts shall be made to study bear bile powder's pharmacological effects, clinical application, chemical composition and toxic side-effects, with the aim to provide a scientific basis for widespread reasonable clinical application of bear bile powder.

  20. Bile acids in regulation of intestinal physiology.

    LENUS (Irish Health Repository)

    Keating, Niamh

    2009-10-01

    In addition to their roles in facilitating lipid digestion and absorption, bile acids are recognized as important regulators of intestinal function. Exposure to bile acids can dramatically influence intestinal transport and barrier properties; in recent years, they have also become appreciated as important factors in regulating cell growth and survival. Indeed, few cells reside within the intestinal mucosa that are not altered to some degree by exposure to bile acids. The past decade saw great advances in the knowledge of how bile acids exert their actions at the cellular and molecular levels. In this review, we summarize the current understanding of the role of bile acids in regulation of intestinal physiology.

  1. Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs

    DEFF Research Database (Denmark)

    Ipharraguerre, Ignacio R; Tedó, Gemma; Menoyo, David

    2013-01-01

    intestinal adaptation in weanling pigs. During the first 6 d after weaning, piglets were intragastrically infused once daily with either deionized water (control), chenodeoxycholic acid (CDC; 60 mg/kg body weight), or β-sitoesterol (BSE; 100 mg/kg body weight). Infusing CDC increased plasma GLP-2 (P

  2. Calcium-dependent nitric oxide production is involved in the cytoprotective properties of n-acetylcysteine in glycochenodeoxycholic acid-induced cell death in hepatocytes

    International Nuclear Information System (INIS)

    Gonzalez-Rubio, Sandra; Linares, Clara I.; Bello, Rosario I.; Gonzalez, Raul; Ferrin, Gustavo; Hidalgo, Ana B.; Munoz-Gomariz, Elisa; Rodriguez, Blanca A.; Barrera, Pilar; Ranchal, Isidora; Duran-Prado, Mario; Aguilar-Melero, Patricia; De la Mata, Manuel; Muntane, Jordi

    2010-01-01

    The intracellular oxidative stress has been involved in bile acid-induced cell death in hepatocytes. Nitric oxide (NO) exerts cytoprotective properties in glycochenodeoxycholic acid (GCDCA)-treated hepatocytes. The study evaluated the involvement of Ca 2+ on the regulation of NO synthase (NOS)-3 expression during N-acetylcysteine (NAC) cytoprotection against GCDCA-induced cell death in hepatocytes. The regulation of Ca 2+ pools (EGTA or BAPTA-AM) and NO (L-NAME or NO donor) production was assessed during NAC cytoprotection in GCDCA-treated HepG2 cells. The stimulation of Ca 2+ entrance was induced by A23187 in HepG2. Cell death, Ca 2+ mobilization, NOS-1, -2 and -3 expression, AP-1 activation, and NO production were evaluated. GCDCA reduced intracellular Ca 2+ concentration and NOS-3 expression, and enhanced cell death in HepG2. NO donor prevented, and L-NAME enhanced, GCDCA-induced cell death. The reduction of Ca 2+ entry by EGTA, but not its release from intracellular stores by BAPTA-AM, enhanced cell death in GCDCA-treated cells. The stimulation of Ca 2+ entrance by A23187 reduced cell death and enhanced NOS-3 expression in GCDCA-treated HepG2 cells. The cytoprotective properties of NAC were related to the recovery of intracellular Ca 2+ concentration, NOS-3 expression and NO production induced by GCDCA-treated HepG2 cells. The increase of NO production by Ca 2+ -dependent NOS-3 expression during NAC administration reduces cell death in GCDCA-treated hepatocytes.

  3. Induction of avian musculoaponeurotic fibrosarcoma proteins by toxic bile acid inhibits expression of glutathione synthetic enzymes and contributes to cholestatic liver injury in mice.

    Science.gov (United States)

    Yang, Heping; Ko, Kwangsuk; Xia, Meng; Li, Tony W H; Oh, Pilsoo; Li, Jiaping; Lu, Shelly C

    2010-04-01

    We previously showed that hepatic expression of glutathione (GSH) synthetic enzymes and GSH levels fell 2 weeks after bile duct ligation (BDL) in mice. This correlated with a switch in nuclear anti-oxidant response element (ARE) binding activity from nuclear factor erythroid 2-related factor 2 (Nrf2) to c-avian musculoaponeurotic fibrosarcoma (c-Maf)/V-maf musculoaponeurotic fibrosarcoma oncogene homolog G (MafG). Our current aims were to examine whether the switch in ARE binding activity from Nrf2 to Mafs is responsible for decreased expression of GSH synthetic enzymes and the outcome of blocking this switch. Huh7 cells treated with lithocholic acid (LCA) exhibited a similar pattern of change in GSH synthetic enzyme expression as BDL mice. Nuclear protein levels of Nrf2 fell at 20 hours after LCA treatment, whereas c-Maf and MafG remained persistently induced. These changes translated to ARE nuclear binding activity. Knockdown of c-Maf or MafG individually blunted the LCA-induced decrease in Nrf2 ARE binding and increased ARE-dependent promoter activity, whereas combined knockdown was more effective. Knockdown of c-Maf or MafG individually increased the expression of GSH synthetic enzymes and raised GSH levels, and combined knockdown exerted an additive effect. Ursodeoxycholic acid (UDCA) or S-adenosylmethionine (SAMe) prevented the LCA-induced decrease in expression of GSH synthetic enzymes and promoter activity and prevented the increase in MafG and c-Maf levels. In vivo knockdown of the Maf genes protected against the decrease in GSH enzyme expression, GSH level, and liver injury after BDL. Toxic bile acid induces a switch from Nrf2 to c-Maf/MafG ARE nuclear binding, which leads to decreased expression of GSH synthetic enzymes and GSH levels and contributes to liver injury during BDL. UDCA and SAMe treatment targets this switch.

  4. Induction of Maf Proteins by Toxic Bile Acid Inhibits Expression of GSH Synthetic Enzymes and Contributes to Cholestatic Liver Injury in Mice

    Science.gov (United States)

    Yang, Heping; Ko, Kwangsuk; Xia, Meng; Li, Tony W.H.; Oh, Pilsoo; Li, Jiaping; Lu, Shelly C.

    2010-01-01

    Background and rationale We previously showed that hepatic expression of GSH synthetic enzymes and GSH levels fell two weeks after bile duct ligation (BDL) in mice. This correlated with a switch in nuclear anti-oxidant response element (ARE) binding activity from nuclear factor-erythroid 2 related factor 2 (Nrf2) to c-Maf/MafG. Our current aims were to examine whether the switch in ARE binding activity from Nrf2 to Mafs is responsible for decreased expression of GSH synthetic enzymes and the outcome of blocking this switch. Results HuH-7 cells treated with lithocholic acid (LCA) exhibited a similar pattern of change in GSH synthetic enzyme expression as BDL mice. Nuclear protein levels of Nrf2 fell at 20 hours following LCA treatment while c-Maf and MafG remained persistently induced. These changes translated to ARE nuclear binding activity. Knockdown of c-Maf or MafG individually blunted the LCA-induced fall in Nrf2 ARE binding and increased ARE-dependent promoter activity while combined knockdown was more effective. Knockdown of c-Maf or MafG individually increased the expression of GSH synthetic enzymes and raised GSH levels and combined knockdown exerted additive effect. Ursodeoxycholic acid (UDCA) or S-adenosylmethionine (SAMe) prevented the LCA-induced fall in expression of GSH synthetic enzymes and promoter activity and prevented the increase in MafG and c-Maf levels. In vivo knockdown of the Maf genes protected against fall in GSH enzymes expression, GSH level and liver injury following BDL. Conclusions Toxic bile acid induces a switch from Nrf2 to c-Maf/MafG ARE nuclear binding, which leads to decreased expression of GSH synthetic enzymes and GSH levels and contributes to liver injury during BDL. UDCA and SAMe treatment targets this switch. PMID:20146260

  5. Sensitivity and Specificity of Plasma ALT, ALP, and Bile Acids for Hepatitis in Labrador Retrievers

    NARCIS (Netherlands)

    Dirksen, K|info:eu-repo/dai/nl/412424428; Burgener, I A; Rothuizen, J|info:eu-repo/dai/nl/071276033; van den Ingh, T S G A M; Penning, L C|info:eu-repo/dai/nl/110369181; Spee, B|info:eu-repo/dai/nl/304830925; Fieten, H|info:eu-repo/dai/nl/314112596

    2017-01-01

    BACKGROUND: Biochemical indicators for diagnosing liver disease are plasma alanine aminotransferase activity (ALT), alkaline phosphatase activity (ALP), and bile acid concentration (BA). OBJECTIVES: To determine the sensitivity and specificity of ALT, ALP, and BA for detecting primary hepatitis (PH)

  6. Organochloride pesticides modulated gut microbiota and influenced bile acid metabolism in mice.

    Science.gov (United States)

    Liu, Qian; Shao, Wentao; Zhang, Chunlan; Xu, Cheng; Wang, Qihan; Liu, Hui; Sun, Haidong; Jiang, Zhaoyan; Gu, Aihua

    2017-07-01

    Organochlorine pesticides (OCPs) can persistently accumulate in body and threaten human health. Bile acids and intestinal microbial metabolism have emerged as important signaling molecules in the host. However, knowledge on which intestinal microbiota and bile acids are modified by OCPs remains unclear. In this study, adult male C57BL/6 mice were exposed to p, p'-dichlorodiphenyldichloroethylene (p, p'-DDE) and β-hexachlorocyclohexane (β-HCH) for 8 weeks. The relative abundance and composition of various bacterial species were analyzed by 16S rRNA gene sequencing. Bile acid composition was analyzed by metabolomic analysis using UPLC-MS. The expression of genes involved in hepatic and enteric bile acids metabolism was measured by real-time PCR. Expression of genes in bile acids synthesis and transportation were measured in HepG2 cells incubated with p, p'-DDE and β-HCH. Our findings showed OCPs changed relative abundance and composition of intestinal microbiota, especially in enhanced Lactobacillus with bile salt hydrolase (BSH) activity. OCPs affected bile acid composition, enhanced hydrophobicity, decreased expression of genes on bile acid reabsorption in the terminal ileum and compensatory increased expression of genes on synthesis of bile acids in the liver. We demonstrated that chronic exposure of OCPs could impair intestinal microbiota; as a result, hepatic and enteric bile acid profiles and metabolism were influenced. The findings in this study draw our attention to the hazards of chronic OCPs exposure in modulating bile acid metabolism that might cause metabolic disorders and their potential to cause related diseases in human. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Acid resistance, bile tolerance and antimicrobial properties of ...

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... antimicrobial activity against a broad spectrum of bacteria, including food spoilage and pathogenic organisms such ... Key words: Baobab seeds, maari, fermentation, lactic acid bacteria, acid resistance, bile tolerance, antimicrobial .... cells was estimated by microscope using a counting chamber. (Neubauer ...

  8. Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context

    NARCIS (Netherlands)

    Vega, Aurélie; Martinot, Emmanuelle; Baptissart, Marine; de Haze, Angélique; Vaz, Frederic; Kulik, Wim; Damon-Soubeyrand, Christelle; Baron, Silvère; Caira, Françoise; Volle, David H.

    2015-01-01

    Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα) and the G-protein coupled receptor

  9. Amino acid infusions induce reversible, dose-related decreases in bile flow in the isolated rat liver.

    Science.gov (United States)

    Shattuck, K E; Grinnell, C D; Rassin, D K

    1993-01-01

    Parenteral infusion of amino acid solutions is known to produce cholestasis in experimental animal models and in the isolated perfused rat liver. To characterize the dose responsiveness and reversibility of amino acid-induced cholestasis, isolated rat livers were perfused with solutions containing 1.5, 3.0, or 6.0 g of amino acids for 1 hour and allowed to recover for 30 minutes. Perfusion of livers resulted in a rapid, dose-related decrease in bile flow (p < .0001 at doses of 3.0 and 6.0 g). When the amino acid solution was discontinued, bile flow recovered to near control rates. Infusion of taurocholate reduced the magnitude of the decrease in bile flow associated with amino acid infusion but did not prevent it. Infusion of amino acid solutions was associated with the following changes in bile: (1) dose-related increases in total free amino acid concentrations; (2) increased osmolarity; (3) increased glucose concentrations; (4) increased potassium concentrations; (5) decreased chloride concentrations; (6) increased oxygen uptake in livers not perfused with added taurocholate; and (7) increased total bile acid concentrations in livers perfused with added taurocholate. Additional investigations are needed to determine whether these associations are attributable to individual amino acids or the total metabolic load of the amino acids.

  10. Intestinal Crosstalk between Bile Acids and Microbiota and Its Impact on Host Metabolism

    DEFF Research Database (Denmark)

    Wahlström, Annika; Sayin, Sama I; Marschall, Hanns-Ulrich

    2016-01-01

    , is produced in the liver from cholesterol and metabolized in the intestine by the gut microbiota. These bioconversions modulate the signaling properties of bile acids via the nuclear farnesoid X receptor and the G protein-coupled membrane receptor 5, which regulate numerous metabolic pathways in the host......The gut microbiota is considered a metabolic "organ" that not only facilitates harvesting of nutrients and energy from the ingested food but also produces numerous metabolites that signal through their cognate receptors to regulate host metabolism. One such class of metabolites, bile acids....... Conversely, bile acids can modulate gut microbial composition both directly and indirectly through activation of innate immune genes in the small intestine. Thus, host metabolism can be affected through microbial modifications of bile acids, which lead to altered signaling via bile acid receptors, but also...

  11. Lithocholic acid feeding induces segmental bile duct obstruction and destructive cholangitis in mice.

    Science.gov (United States)

    Fickert, Peter; Fuchsbichler, Andrea; Marschall, Hanns-Ulrich; Wagner, Martin; Zollner, Gernot; Krause, Robert; Zatloukal, Kurt; Jaeschke, Hartmut; Denk, Helmut; Trauner, Michael

    2006-02-01

    We determined the mechanisms of hepatobiliary injury in the lithocholic acid (LCA)-fed mouse, an increasingly used model of cholestatic liver injury. Swiss albino mice received control diet or 1% (w/w) LCA diet (for 1, 2, and 4 days), followed by assessment of liver morphology and ultrastructure, tight junctions, markers of fibrosis and key proteins of hepatobiliary function, and bile flow and composition. As expected LCA feeding led to bile infarcts, which were followed by a destructive cholangitis with activation and proliferation of periductal myofibroblasts. At the ultrastructural level, small bile ducts were frequently obstructed by crystals. Biliary-excreted fluorescence-labeled ursodeoxycholic acid accumulated in bile infarcts, whereas most infarcts did not stain with India ink injected into the common bile duct; both findings are indicative of partial biliary obstruction. Expression of the main basolateral bile acid uptake proteins (sodium-taurocholate cotransporter and organic anion-transporting polypeptide 1) was reduced, the canalicular transporters bile salt export pump and multidrug-related protein 2 were preserved, and the basolateral transporter multidrug-related protein 3 and the detoxifying enzyme sulfotransferase 2a1 were induced. Thus, we demonstrate that LCA feeding in mice leads to segmental bile duct obstruction, destructive cholangitis, periductal fibrosis, and an adaptive transporter and metabolic enzyme response.

  12. Activation of the bile acid receptor GPBAR1 protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs and aspirin in mice.

    Science.gov (United States)

    Cipriani, Sabrina; Mencarelli, Andrea; Bruno, Angela; Renga, Barbara; Distrutti, Eleonora; Santucci, Luca; Baldelli, Franco; Fiorucci, Stefano

    2013-01-01

    Low doses of aspirin (acetylsalicylic acid; ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal bleeding. GPBAR1 is a bile acid receptor expressed in the gastrointestinal tract. Here, we have investigated whether GPBAR1 was required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs. EXPERIMENTAL APPROCH: GPBAR1(+/+) and GPBAR1(-/-) mice were given ASA (10-50 mg.kg(-1)) or naproxen. Gastric and intestinal mucosal damage was assessed by measuring lesion scores. Expression of GPBAR1, mRNA and protein, was detected in mouse stomach. Mice lacking GPBAR1 were more sensitive to gastric and intestinal injury caused by ASA and NSAIDs and exhibited a markedly reduced expression of cystathionine-γ-liase (CSE), cystathionine-β-synthase (CBS) and endothelial NOS enzymes required for generation of H(2)S and NO, in the stomach. Treating GPBAR1(+/+) mice with two GPBAR1 agonists, ciprofloxacin and betulinic acid, rescued mice from gastric injury caused by ASA and NSAIDs. The protective effect of these agents was lost in GPBAR1(-/-) mice. Inhibition of CSE by DL-propargylglycine completely reversed protection afforded by ciprofloxacin in wild type mice, whereas treating mice with an H(2)S donor restored the protective effects of ciprofloxacin in GPBAR1(-/-) mice. Deletion of GPBAR1 altered the morphology of the small intestine and increased sensitivity to injury caused by naproxen. GPBAR1 is essential to maintain gastric and intestinal mucosal integrity. GPBAR1 agonists protect against gastrointestinal injury caused by ASA and NSAIDs by a COX-independent mechanism. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  13. Heart and bile acids - Clinical consequences of altered bile acid metabolism.

    Science.gov (United States)

    Vasavan, Tharni; Ferraro, Elisa; Ibrahim, Effendi; Dixon, Peter; Gorelik, Julia; Williamson, Catherine

    2018-04-01

    Cardiac dysfunction has an increased prevalence in diseases complicated by liver cirrhosis such as primary biliary cholangitis and primary sclerosing cholangitis. This observation has led to research into the association between abnormalities in bile acid metabolism and cardiac pathology. Approximately 50% of liver cirrhosis cases develop cirrhotic cardiomyopathy. Bile acids are directly implicated in this, causing QT interval prolongation, cardiac hypertrophy, cardiomyocyte apoptosis and abnormal haemodynamics of the heart. Elevated maternal serum bile acids in intrahepatic cholestasis of pregnancy, a disorder which causes an impaired feto-maternal bile acid gradient, have been associated with fatal fetal arrhythmias. The hydrophobicity of individual bile acids in the serum bile acid pool is of relevance, with relatively lipophilic bile acids having a more harmful effect on the heart. Ursodeoxycholic acid can reverse or protect against these detrimental cardiac effects of elevated bile acids. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. Beneficial role of dietary folic acid on cholesterol and bile acid metabolism in ethanol-fed rats.

    Science.gov (United States)

    Delgado-Villa, Maria Jesus; Ojeda, Maria Luisa; Rubio, Jose Maria; Murillo, Maria Luisa; Sánchez, Olimpia Carreras

    2009-07-01

    Cholesterol metabolism is altered by chronic ethanol consumption. In previous articles, we demonstrated the anti-oxidant capacity of folic acid, which may be useful in the prevention of damage provoked by ethanol. We want to determine the effects of ethanol on cholesterol and bile metabolism and whether a folic acid-supplemented diet could change alterations provoked by a chronic ethanol intake in rats. We used four experimental groups: (1) control, (2) alcohol, (3) alcohol supplemented with folic acid, and (4) control supplemented with folic acid. In all the experimental groups, we measured hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and cholesterol and bile acids in serum, liver, bile, and feces. We have found that the alcohol-fed groups showed high hepatic HMG-CoA reductase activity, total hepatic and serum cholesterol concentration, bile cholesterol secretion concentration, and cholesterol enterohepatic circulation. Total serum and hepatic cholesterol levels decreased when alcohol-fed rats were supplemented with folic acid. The hepatic bile acid concentration increased in both chronic ethanol groups. Folic acid supplementation significantly increased bile cholesterol secretion, the bile acids in bile, and fecal bile acid excretion in ethanol-exposed rats. The independent bile acid fraction showed no significant differences between both ethanol groups with respect to Na+, K+, and Cl- concentrations. Folic acid increases bile flow, bile acid synthesis from cholesterol, and bile acid excretion via feces, thus provoking a decrease in serum and hepatic cholesterol. However none of these actions were observed in supplemented control rats. This, therefore, could be yet another beneficial effect of folic acid on alcoholic patients.

  15. Bile canalicular dynamics in hepatocyte sandwich cultures.

    Science.gov (United States)

    Reif, Raymond; Karlsson, Johan; Günther, Georgia; Beattie, Lynette; Wrangborg, David; Hammad, Seddik; Begher-Tibbe, Brigitte; Vartak, Amruta; Melega, Simone; Kaye, Paul M; Hengstler, Jan G; Jirstrand, Mats

    2015-10-01

    Many substances are hepatotoxic due to their ability to cause intrahepatic cholestasis. Therefore, there is a high demand for in vitro systems for the identification of cholestatic properties of new compounds. Primary hepatocytes cultivated in collagen sandwich cultures are known to establish bile canaliculi which enclose secreted biliary components. Cholestatic compounds are mainly known to inhibit bile excretion dynamics, but may also alter canalicular volume, or hepatocellular morphology. So far, techniques to assess time-resolved morphological changes of bile canaliculi in sandwich cultures are not available. In this study, we developed an automated system that quantifies dynamics of bile canaliculi recorded in conventional time-lapse image sequences. We validated the hepatocyte sandwich culture system as an appropriate model to study bile canaliculi in vitro by showing structural similarity measured as bile canaliculi length per hepatocyte to that observed in vivo. Moreover, bile canalicular excretion kinetics of CMFDA (5-chloromethylfluorescein diacetate) in sandwich cultures resembled closely the kinetics observed in vivo. The developed quantification technique enabled the quantification of dynamic changes in individual bile canaliculi. With this technique, we were able to clearly distinguish between sandwich cultures supplemented with dexamethasone and insulin from control cultures. In conclusion, the automated quantification system offers the possibility to systematically study the causal relationship between disturbed bile canalicular dynamics and cholestasis.

  16. Crystal Structure of the Substrate-Binding Domain from Listeria monocytogenes Bile-Resistance Determinant BilE

    NARCIS (Netherlands)

    Ruiz, Stephanie J.; Schuurman-Wolters, Gea K.; Poolman, Bert

    2016-01-01

    BilE has been reported as a bile resistance determinant that plays an important role in colonization of the gastrointestinal tract by Listeria monocytogenes, the causative agent of listeriosis. The mechanism(s) by which BilE mediates bile resistance are unknown. BilE shares significant sequence

  17. Serum gamma glutamyl transferase as a specific indicator of bile duct lesions in the rat liver.

    Science.gov (United States)

    Leonard, T B; Neptun, D A; Popp, J A

    1984-08-01

    Serum gamma-glutamyl transferase (GGT), a marker of hepatic injury used extensively in humans, has been used rarely in rats because its specificity has not been previously defined. Studies were designed for investigation of the specificity of serum GGT activity with the use of cell type specific hepatotoxicants in Fischer 344 rats. Single necrogenic doses of CCl4, allyl alcohol (AA), and alpha-naphthylisothiocyanate (ANIT) were used to produce cell specific injury in centrilobular hepatocytes, periportal hepatocytes, and bile duct cells, respectively. Administration of CCl4 markedly increased serum activities of alanine aminotransferase (ALT), alkaline phosphatase (AP), and serum bile acid concentrations within 24 hours but had no effect on serum GGT activity. ANIT treatment increased serum GGT and AP activities and bile acid concentration 24 hours following administration. Allyl alcohol administration increased serum ALT activity but had no effect on GGT activity. Administration of ANIT in the diet at 0.01%, 0.022%, 0.047%, and 0.1% for 2, 4, and 6 weeks produced dose- and time-dependent increases in serum GGT activity which strongly correlated with quantitative increases in hepatic bile duct volume, which was determined morphometrically. These observations support the use of serum GGT activity in the rat as diagnostic of bile duct cell necrosis when increases are detected shortly after the insult and as an indicator of possible bile duct hyperplasia.

  18. Molecular interactions between bile salts, phospholipids and cholesterol : relevance to bile formation, cholesterol crystallization and bile salt toxicity

    NARCIS (Netherlands)

    Moschetta, Antonio

    2001-01-01

    Cholesterol is a nonpolar lipid dietary constituent, absorbed from the small intestine, transported in blood and taken up by the liver. In bile, the sterol is solubilized in mixed micelles by bile salts and phospholipids. In case of supersaturation, cholesterol is kept in vesicles with phospholipid

  19. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

    OpenAIRE

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-01-01

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes ...

  20. Laparoscopic common bile duct exploration.

    Science.gov (United States)

    Shuchleib, S; Chousleb, A; Mondragon, A; Torices, E; Licona, A; Cervantes, J

    1999-07-01

    Since the introduction of laparoscopic cholecystectomy, the management of common bile duct (CBD) stones has undergone significant change. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy is now routinely done in cases where the diagnosis of choledocholithiasis is suspected preoperatively, with clearance of the bile ducts before laparoscopic cholecystectomy. Intraoperative discovery of CBD stones by cholangiography represents a challenge to the surgeon, who must make a decision about when to perform laparoscopic CBD exploration, convert to open surgery, or send the patient for ERCP during the postoperative period. Because ERCP has a definite failure rate, laparoscopic CBD exploration can be a treatment option. Among 2500 laparoscopic cholecystectomies done by our group from January 1991 to June 1997, 50 patients (2%) underwent laparoscopic CBD exploration, 13 by the transcystic technique and 37 by choledocotomy, with a conversion rate of 8% and a hospital stay of 4.3 days. One patient died from complicated pancreatitis following ERCP and unsuccessful extraction of a CBD stone. We obtained our goal of a CBD free of stones in 92% of the cases. We conclude that laparoscopic CBD exploration is an effective method for treating choledocolithiasis that allows management of this pathology in one stage, although it requires advanced laparoscopic skills and adequate equipment.

  1. Bile salts in control of lipid metabolism

    NARCIS (Netherlands)

    Schonewille, Marleen; de Boer, Jan Freark; Groen, Albert K.

    2016-01-01

    The view on bile salts has evolved over the years from being regarded as simple detergents that aid intestinal absorption of fat-soluble nutrients to being important hormone-like integrators of metabolism. This review provides an update on the rapidly developing field of interactions between bile

  2. Endoscopic management of bile leaks after laparoscopic ...

    African Journals Online (AJOL)

    2013-11-04

    Nov 4, 2013 ... 1 required mesh repair of a large incisional hernia. Discussion. In this study, three-quarters of postoperative bile leaks were suitable for endoscopic management and were treated with combinations of ES and bile duct ... is more rapid in dogs with stents compared with sphincterotomy alone.[8,10,18,19] The.

  3. Bile acid biosynthesis and its regulation

    Directory of Open Access Journals (Sweden)

    Areta Hebanowska

    2010-10-01

    Full Text Available Bile acid biosynthesis is the main pathway of cholesterol catabolism. Bile acids are more soluble than cholesterol so are easier to excrete. As amphipathic molecules they participate in lipid digestion and absorption in the intestine and they help to excrete free cholesterol with bile. They are also ligands for nuclear receptors regulating the expression of genes involved in cholesterol metabolism. Interconversion of cholesterol into bile acids is an important point of its homeostasis. Seventeen enzymes are engaged in this process and many of them are cytochromes P450. Bile acid synthesis initiation may proceed with the “classical” pathway (starting with cholesterol hydroxylation at the C7α position or the “alternative” pathway (starting with cholesterol hydroxylation at the C27 position. Two additional pathways are possible, though their quantitative significance is small (initiated with cholesterol hydroxylations of C24 and C25 positions. Oxysterols produced are not only intermediates of bile acid biosynthesis but also important regulators of metabolism. Bile acid biosynthesis takes place in the liver, but some enzymes are also present in other organs, where they participate in regulation of cholesterol metabolism. Those enzymes are potential targets for new drugs against cholesterol metabolism disturbances. This article is a brief description of the bile acid biosynthesis pathway and participating enzymes.

  4. Successful Endoscopic Therapy of Traumatic Bile Leaks

    Directory of Open Access Journals (Sweden)

    Matthew P. Spinn

    2013-02-01

    Full Text Available Traumatic bile leaks often result in high morbidity and prolonged hospital stay that requires multimodality management. Data on endoscopic management of traumatic bile leaks are scarce. Our study objective was to evaluate the efficacy of the endoscopic management of a traumatic bile leak. We performed a retrospective case review of patients who were referred for endoscopic retrograde cholangiopancreatography (ERCP after traumatic bile duct injury secondary to blunt (motor vehicle accident or penetrating (gunshot trauma for management of bile leaks at our tertiary academic referral center. Fourteen patients underwent ERCP for the management of a traumatic bile leak over a 5-year period. The etiology included blunt trauma from motor vehicle accident in 8 patients, motorcycle accident in 3 patients and penetrating injury from a gunshot wound in 3 patients. Liver injuries were grade III in 1 patient, grade IV in 10 patients, and grade V in 3 patients. All patients were treated by biliary stent placement, and the outcome was successful in 14 of 14 cases (100%. The mean duration of follow-up was 85.6 days (range 54-175 days. There were no ERCP-related complications. In our case review, endoscopic management with endobiliary stent placement was found to be successful and resulted in resolution of the bile leak in all 14 patients. Based on our study results, ERCP should be considered as first-line therapy in the management of traumatic bile leaks.

  5. Bile acid sequestrants : more than simple resins

    NARCIS (Netherlands)

    Out, Carolien; Groen, Albert K.; Brufau, Gemma

    Purpose of review Bile acid sequestrants (BAS) have been used for more than 50 years in the treatment of hypercholesterolemia. The last decade, bile acids are emerging as integrated regulators of metabolism via induction of various signal transduction pathways. Consequently, BAS treatment may exert

  6. Bile acids for liver-transplanted patients

    DEFF Research Database (Denmark)

    Poropat, Goran; Giljaca, Vanja; Stimac, Davor

    2010-01-01

    Liver transplantation has become a widely accepted form of treatment for numerous end-stage liver diseases. Bile acids may decrease allograft rejection after liver transplantation by changing the expression of major histocompatibility complex class molecules in bile duct epithelium and central vein...

  7. Simone Biles: defying the laws of physics?

    OpenAIRE

    Mcinerney, Ciaran; Kelley, John

    2016-01-01

    Simone Biles is a gymnast in a league of her own. In the 2016 Olympics in Rio she stunned audiences with a move some thought defies the laws of physics: the Biles, which incorporates a double somersault, a twist in mid-air, and a blind landing (see the video below). How does she do it?

  8. Acute bile nephropathy secondary to anabolic steroids.

    Science.gov (United States)

    Alkhunaizi, Ahmed M; ElTigani, Mohamed A; Rabah, Rola S; Nasr, Samih H

    2016-02-01

    Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis.

  9. Bile acids in radiation-induced diarrhea

    International Nuclear Information System (INIS)

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-01-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style

  10. Nucleic acid-induced antiviral immunity in invertebrates: an evolutionary perspective.

    Science.gov (United States)

    Wang, Pei-Hui; Weng, Shao-Ping; He, Jian-Guo

    2015-02-01

    Nucleic acids derived from viral pathogens are typical pathogen associated molecular patterns (PAMPs). In mammals, the recognition of viral nucleic acids by pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), induces the release of inflammatory cytokines and type I interferons (IFNs) through the activation of nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) 3/7 pathways, triggering the host antiviral state. However, whether nucleic acids can induce similar antiviral immunity in invertebrates remains ambiguous. Several studies have reported that nucleic acid mimics, especially dsRNA mimic poly(I:C), can strongly induce non-specific antiviral immune responses in insects, shrimp, and oyster. This behavior shows multiple similarities to the hallmarks of mammalian IFN responses. In this review, we highlight the current understanding of nucleic acid-induced antiviral immunity in invertebrates. We also discuss the potential recognition and regulatory mechanisms that confer non-specific antiviral immunity on invertebrate hosts. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Stimulation of apical sodium-dependent bile acid transporter expands the bile acid pool and generates bile acids with positive feedback properties.

    Science.gov (United States)

    Rudling, Mats; Bonde, Ylva

    2015-01-01

    Bile acid synthesis has been considered a prototype for how a physiological process is controlled by end product feedback inhibition. By this feedback inhibition, bile acid concentrations are kept within safe ranges. However, careful examination of published rodent data strongly suggests that bile acid synthesis is also under potent positive feedback control by hydrophilic bile acids. Current concepts on the regulation of bile acid synthesis are derived from mouse models. Recent data have shown that mice have farnesoid X receptor (FXR) antagonistic bile acids capable of quenching responses elicited by FXR agonistic bile acids. This is important to recognize to understand the regulation of bile acid synthesis in the mouse, and in particular to clarify if mouse model findings are valid also in the human situation. In addition to classic end product feedback inhibition, regulation of bile acid synthesis in the mouse largely appears also to be driven by changes in hepatic levels of murine bile acids such as α- and β-muricholic acids. This has not been previously recognized. Stimulated bile acid synthesis or induction of the apical sodium-dependent bile acid transporter in the intestine, increase the availability of chenodeoxycholic acid in the liver, thereby promoting hepatic conversion of this bile acid into muricholic acids. Recognition of these mechanisms is essential for understanding the regulation of bile acid synthesis in the mouse, and for our awareness of important species differences in the regulation of bile acid synthesis in mice and humans. 2015 S. Karger AG, Basel.

  12. The synthesis of taurine-conjugated bile acids and bile acid sulfates labeled with 14C or 3H in the taurine moiety

    International Nuclear Information System (INIS)

    Jie Zhang; Griffiths, W.J.; Sjoevall, Jan

    1997-01-01

    Studies of bile acid transport systems require radio-labeled taurine-conjugated bile acids with high specific activity. An established procedure was optimized to provide mild, fast, and effective conjugation of radio-labeled taurine with different types of bile acids, including those with labile 7α-hydroxy-3-oxo-Δ 4 or 3β, 7α-dihydroxy-Δ 5 structures. Taurine labeled with 14 C or 3 H was reacted with excess bile acid anhydride formed from the tributylamine salt and ethylchloroformate (2/1 M/M) in aqueous dioxane for 15 min at room temperature. The yields were higher than 95% and less than 2% side products were formed. Bile acid sulfates were conjugated with 14 C- or 3 H-labeled taurine by using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as the coupling reagent. The products were effectively purified by chromatography of the sodium salts on Sephadex LH-20. The yields of taurine-conjugated bile acid sulfates were 65-70%. (author)

  13. Increased isoprostane levels in oleic acid-induced lung injury

    Energy Technology Data Exchange (ETDEWEB)

    Ono, Koichi [Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto (Japan); Koizumi, Tomonobu, E-mail: tomonobu@shinshu-u.ac.jp [First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan); Tsushima, Kenji; Yoshikawa, Sumiko; Yokoyama, Toshiki [First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto (Japan); Nakagawa, Rikimaru [Department of Anesthesiology and Resuscitation, Shinshu University School of Medicine, Matsumoto (Japan); Obata, Toru [Department of Molecular Cell Biology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo (Japan)

    2009-10-16

    The present study was performed to examine a role of oxidative stress in oleic acid-induced lung injury model. Fifteen anesthetized sheep were ventilated and instrumented with a lung lymph fistula and vascular catheters for blood gas analysis and measurement of isoprostanes (8-epi prostaglandin F2{alpha}). Following stable baseline measurements, oleic acid (0.08 ml/kg) was administered and observed 4 h. Isoprostane was measured by gas chromatography mass spectrometry with the isotope dilution method. Isoprostane levels in plasma and lung lymph were significantly increased 2 h after oleic acid administration and then decreased at 4 h. The percent increases in isoprostane levels in plasma and lung lymph at 2 h were significantly correlated with deteriorated oxygenation at the same time point, respectively. These findings suggest that oxidative stress is involved in the pathogenesis of the pulmonary fat embolism-induced acute lung injury model in sheep and that the increase relates with the deteriorated oxygenation.

  14. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

    Science.gov (United States)

    Gomez-Ospina, Natalia; Potter, Carol J.; Xiao, Rui; Manickam, Kandamurugu; Kim, Mi-Sun; Kim, Kang Ho; Shneider, Benjamin L.; Picarsic, Jennifer L.; Jacobson, Theodora A.; Zhang, Jing; He, Weimin; Liu, Pengfei; Knisely, A. S.; Finegold, Milton J.; Muzny, Donna M.; Boerwinkle, Eric; Lupski, James R.; Plon, Sharon E.; Gibbs, Richard A.; Eng, Christine M.; Yang, Yaping; Washington, Gabriel C.; Porteus, Matthew H.; Berquist, William E.; Kambham, Neeraja; Singh, Ravinder J.; Xia, Fan; Enns, Gregory M.; Moore, David D.

    2016-01-01

    Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection. PMID:26888176

  15. Protection of dried probiotic bacteria from bile using bile adsorbent resins.

    Science.gov (United States)

    Mahbubani, Krishnaa T; Slater, Nigel K H; Edwards, Alexander D

    2014-01-25

    Enteric coated oral tablets or capsules can deliver dried live cells directly into the intestine. Previously, we found that a live attenuated bacterial vaccine acquired sensitivity to intestinal bile when dried, raising the possibility that although gastric acid can be bypassed, significant loss of viability might occur on release from an enteric coated oral formulations. Here we demonstrate that some food-grade lyophilised preparations of Lactobacillus casei and Lactobacillus salivarius also show temporary bile sensitivity that can be rapidly reversed by rehydration. To protect dried bacterial cells from temporary bile sensitivity, we propose using bile acid adsorbing resins, such as cholestyramine, which are bile acid binding agents, historically used to lower cholesterol levels. Vcaps™ HPMC capsules alone provided up to 830-fold protection from bile. The inclusion of 50% w/w cholestyramine in Vcaps™ HPMC capsules resulted in release of up to 1700-fold more live Lactobacillus casei into simulated intestinal fluid containing 1% bile, when compared to dried cells added directly to bile. We conclude that delivery of dried live probiotic organisms to the intestine may be improved by providing protection from bile by addition of bile adsorbing resins and the use of HPMC capsules. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Structure of plant bile pigments

    Energy Technology Data Exchange (ETDEWEB)

    Schoenleber, R.W.

    1983-12-01

    Selective peptide cleavage has provided a general procedure for the study of the structure, including stereochemistry, of plant bile pigments. The information derived from the synthesis and spectral analysis of a series of 2,3-dihydrodioxobilins allows the determination of the trans relative stereochemistry for ring A of the ..beta../sub 1/-phycocyanobilin from C-phycocyanin as well as for ring A of phytochrome. A complete structure proof of the five phycoerythrobilins attached to the ..cap alpha.. and ..beta.. subunits of B-phycoerythrin is described. One of these tetrapyrroles is doubly-peptide linked to a single peptide chain through two thioethers at the C-3' and C-18' positions. The four remaining phycoerythrobilins are singly-linked to the protein through thioethers at the C-3' position and all possess the probable stereochemistry C-2(R), C-3(R), C-3'(R), and C-16(R).

  17. Bile Duct Adenoma with Oncocytic Features

    Directory of Open Access Journals (Sweden)

    E. J. Johannesen

    2014-01-01

    Full Text Available Bile duct adenomas are benign bile duct proliferations usually encountered as an incidental finding. Oncocytic bile duct neoplasms are rare and the majority are malignant. A 61-year-old male with a diagnosis of colorectal adenocarcinoma was undergoing surgery when a small white nodule was discovered on the surface of the right lobe of his liver. This lesion was composed of cytologically bland cells arranged in tightly packed glands. These cells were immunopositive for cytokeratin 7, negative for Hep Par 1, contained mucin, and had a Ki67 proliferation index of 8%. The morphology, immunophenotype, presence of mucin, and normal appearing bile ducts, as well as the increased Ki67 proliferation rate, were consistent with a bile duct adenoma with oxyphilic (oncocytic change. Oncocytic tumors in the liver are rare; the first described in 1992. Only two bile duct adenomas with oncocytic change have been reported and neither of them had reported mucin production or the presence of normal appearing bile ducts within the lesion.

  18. Ameliorative effects of polyunsaturated fatty acids against palmitic acid-induced insulin resistance in L6 skeletal muscle cells

    Directory of Open Access Journals (Sweden)

    Sawada Keisuke

    2012-03-01

    Full Text Available Abstract Background Fatty acid-induced insulin resistance and impaired glucose uptake activity in muscle cells are fundamental events in the development of type 2 diabetes and hyperglycemia. There is an increasing demand for compounds including drugs and functional foods that can prevent myocellular insulin resistance. Methods In this study, we established a high-throughput assay to screen for compounds that can improve myocellular insulin resistance, which was based on a previously reported non-radioisotope 2-deoxyglucose (2DG uptake assay. Insulin-resistant muscle cells were prepared by treating rat L6 skeletal muscle cells with 750 μM palmitic acid for 14 h. Using the established assay, the impacts of several fatty acids on myocellular insulin resistance were determined. Results In normal L6 cells, treatment with saturated palmitic or stearic acid alone decreased 2DG uptake, whereas unsaturated fatty acids did not. Moreover, co-treatment with oleic acid canceled the palmitic acid-induced decrease in 2DG uptake activity. Using the developed assay with palmitic acid-induced insulin-resistant L6 cells, we determined the effects of other unsaturated fatty acids. We found that arachidonic, eicosapentaenoic and docosahexaenoic acids improved palmitic acid-decreased 2DG uptake at lower concentrations than the other unsaturated fatty acids, including oleic acid, as 10 μM arachidonic acid showed similar effects to 750 μM oleic acid. Conclusions We have found that polyunsaturated fatty acids, in particular arachidonic and eicosapentaenoic acids prevent palmitic acid-induced myocellular insulin resistance.

  19. Bile acids in health and disease

    DEFF Research Database (Denmark)

    Krag, E; Thaysen, E H

    1996-01-01

    , fat malabsorption, and other intestinal disorders were studied. The 'idiopathic ileopathy' as a cause for bile acid malabsorption causing diarrhoea was established as a new disorder. Thus, in the time period concerned, substantial Danish contributions emerged on major and minor topics of the bile acid...... improved. Important physiological research on the mechanisms of hepatic bile flow was conducted. An intestinal perfusion model served as a tool providing information on absorption kinetics and on transmucosal water and electrolyte movements. The gallstone disease, liver diseases, inflammatory bowel disease...

  20. The influence of bile acids homeostasis by cryptotanshinone ...

    African Journals Online (AJOL)

    The homeostasis of bile acids can be tightly regulated through feed-back and feed-forward regula- tion pathways. Bile acids exert their toxicity towards cells at high concentrations, and the accumulation of bile acids can induce the severe damage towards liver cells 2. Bile acids have been reported to induce cell injury.

  1. History of Hepatic Bile Formation: Old Problems, New Approaches

    Science.gov (United States)

    Javitt, Norman B.

    2014-01-01

    Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The…

  2. Taurine ameliorates cholesterol metabolism by stimulating bile acid production in high-cholesterol-fed rats.

    Science.gov (United States)

    Murakami, Shigeru; Fujita, Michiko; Nakamura, Masakazu; Sakono, Masanobu; Nishizono, Shoko; Sato, Masao; Imaizumi, Katsumi; Mori, Mari; Fukuda, Nobuhiro

    2016-03-01

    This study was designed to investigate the effects of dietary taurine on cholesterol metabolism in high-cholesterol-fed rats. Male Sprague-Dawley rats were randomly divided into two dietary groups (n = 6 in each group): a high-cholesterol diet containing 0.5% cholesterol and 0.15% sodium cholate, and a high-cholesterol diet with 5% (w/w) taurine. The experimental diets were given for 2 weeks. Taurine supplementation reduced the serum and hepatic cholesterol levels by 37% and 32%, respectively. Faecal excretion of bile acids was significantly increased in taurine-treated rats, compared with untreated rats. Biliary bile acid concentrations were also increased by taurine. Taurine supplementation increased taurine-conjugated bile acids by 61% and decreased glycine-conjugated bile acids by 53%, resulting in a significant decrease in the glycine/taurine (G/T) ratio. Among the taurine-conjugated bile acids, cholic acid and deoxycholic acid were significantly increased. In the liver, taurine supplementation increased the mRNA expression and enzymatic activity of hepatic cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme for bile acid synthesis, by three- and two-fold, respectively. Taurine also decreased the enzymatic activity of acyl-CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP). These observations suggest that taurine supplementation increases the synthesis and excretion of taurine-conjugated bile acids and stimulates the catabolism of cholesterol to bile acid by elevating the expression and activity of CYP7A1. This may reduce cholesterol esterification and lipoprotein assembly for very low density lipoprotein (VLDL) secretion, leading to reductions in the serum and hepatic cholesterol levels. © 2016 John Wiley & Sons Australia, Ltd.

  3. Postprandial Plasma Concentrations of Individual Bile Acids and FGF-19 in Patients With Type 2 Diabetes

    DEFF Research Database (Denmark)

    Sonne, David P; van Nierop, F Samuel; Kulik, Willem

    2016-01-01

    controls, but differences were not statistically significant due to considerable variation. CONCLUSION: Postprandial plasma patterns of bile acids with FXR agonistic properties (CDCA, DCA, and CA) and FXR antagonistic properties (UDCA) in T2D patients support the notion of a "T2D-bile acid-FGF-19......CONTEXT: Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may...... be implicated in postprandial glucose metabolism. OBJECTIVE: To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. DESIGN AND SETTING: Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital...

  4. Bile salts and their importance for drug absorption

    DEFF Research Database (Denmark)

    Holm, René; Müllertz, Anette; Mu, Huiling

    2013-01-01

    Bile salts are present in the intestines of humans as well as the animals used during the development of pharmaceutical products. This review provides a short introduction into the physical chemical properties of bile salts, a description of the bile concentration and composition of bile in diffe......Bile salts are present in the intestines of humans as well as the animals used during the development of pharmaceutical products. This review provides a short introduction into the physical chemical properties of bile salts, a description of the bile concentration and composition of bile...... in different animal species and an overview of the literature investigating the influence of bile salts on the in vivo performance of different compounds and drug formulations. Generally, there is a positive effect on bioavailability when bile is present in the gastro-intestinal tract, independent...

  5. Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha).

    Science.gov (United States)

    Chen, Wenling; Chiang, John Y L

    2003-08-14

    Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyses sterol side-chain oxidation of bile acid synthesis from cholesterol, and the first reaction of the acidic bile acid biosynthetic pathway. Hydrophobic bile acids suppress human CYP27A1 gene reporter activity when assayed in human hepatocellular blastoma HepG2 cells. Bile acids also inhibit CYP27A1 reporter activity in human embryonic kidney 293 cells. A putative bile acid response element (BARE) was mapped to a region downstream of nt -147 of the human CYP27A1 gene, within which a binding site for a liver-specific nuclear receptor, HNF4alpha, is identified. HNF4alpha strongly stimulates CYP27A1 gene transcription and mutation of its binding site markedly reduced promoter activity. Results suggest that human CYP27A1 gene transcription is suppressed by bile acids and HNF4alpha plays a pivotal role in transcriptional regulation of this gene.

  6. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.

    Science.gov (United States)

    Zhang, Donglu; Frost, Charles E; He, Kan; Rodrigues, A David; Wang, Xiaoli; Wang, Lifei; Goosen, Theunis C; Humphreys, W Griffith

    2013-04-01

    The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

  7. Acid-Induced Rearrangement of Epoxygermacranolides: Synthesis of Furanoheliangolides and Cadinanes from Nobilin

    Directory of Open Access Journals (Sweden)

    Maria De Mieri

    2017-12-01

    Full Text Available The acid-induced rearrangement of three epoxyderivatives of nobilin 1, the most abundant sesquiterpene lactone in Anthemis nobilis flowers, was investigated. From the 1,10-epoxyderivative 2, furanoheliangolide 5 was obtained, while the 4,5-epoxy group of 3 did not react. Conversely, when the 3-hydroxy function of nobilin was acetylated (12, the 4,5-epoxy derivative did cyclize into cadinanes (15 and 16 under Lewis acid catalysis. The reactivity of the 4,5- and 1,10-epoxy derivatives of nobilin (2 and 3 was compared with that of parthenolide, and rationalized on the basis of quantum chemical calculations. All isolated reaction products were fully characterized by spectroscopic and computational methods, and their in vitro anti-protozoal activity was evaluated. The paper could provide new insights into the biosynthesis of this class of natural products.

  8. Cholangiographic evaluation of bile duct carcinoma

    International Nuclear Information System (INIS)

    Nichols, D.A.; MacCarty, R.L.; Gaffey, T.A.

    1983-01-01

    Cholangiograms and clinical histories of 82 patients with biopsy-proved bile duct carcinoma were reviewed. The carcinomas were classified according to morphologic findings and clinical outcome. Ulcerative colitis and antecedent inflammatory disease of the biliary tree, particularly primary sclerosing cholangitis, seem to predispose to the development of bile duct carcinoma. Focal stenotic lesions were the most common morphologic type (62/82). Polypoid carcinomas and diffuse sclerosing carcinomas were less common and of about equal frequency. Prognosis was best for patients with polypoid carcinomas and worst for those with diffuse sclerosing carcinomas. In 69 cases (84%), the tumors involved the intrahepatic or proximal extrahepatic ducts, makin curative resection difficult or impossible. Patients with carcinomas limited to the more distal extrahepatic bile ducts had a longer average survival and a higher probability of surgical cure. Proper management of patients with bile duct carcinoma requires a complete and accurate cholangiographic evaluation of the morphology, location, and extent of the disease

  9. Primary hepatocellular carcinoma in extrahepatic bile duct

    International Nuclear Information System (INIS)

    Jeong, Seok Tae; Ham, Soo Youn; Park, Cheol Min; Kim, Jung Hyuk; Cha, In Ho; Chung, Kyoo Byung; Suh, Woon Hyuck; Lee, Chang Hong

    1991-01-01

    Obstructive jaundice due to hepatocellular carcinoma in an extrahepatic bile duct, without a mass lesion in the liver parenchyma, is extremely rare. We experienced two cases of primary hepatocellular carcinoma arising from an extrahepatic bile duct: one in a 53-year-old man whose α -fetoprotein value was 800 ng/ml, and another in a 39-year-old woman, in whom the mass lesion was found to be attached to an extrahepatic bile duct. These tumors had a well-marginated sausage-like shape on CT and US, and the contrast media passed freely along their margins on both PTC and ERCP. Recurrences of these tumors were observed in the extrahepatic bile duct 6 and 2 months after surgery, respectively

  10. Bile salt deconjugation and cholesterol removal from media by Lactobacillus strains used as probiotics in chickens.

    Science.gov (United States)

    Ramasamy, Kalavathy; Abdullah, Norhani; Wong, Michael Cvl; Karuthan, Chinna; Ho, Yin Wan

    2010-01-15

    Bile salt deconjugation by Lactobacillus strains is often closely linked to bile tolerance and survival of the strains in the gut and lowering of cholesterol in the host. The present study investigated the deconjugation of bile salts and removal of cholesterol by 12 Lactobacillus strains in vitro. The 12 strains were previously isolated from the gastrointestinal tract of chickens. The 12 Lactobacillus strains could deconjugate sodium glycocholate (GCA, 16.87-100%) and sodium taurocholate (TCA, 1.69-57.43%) bile salts to varying degrees, with all strains except L. salivarius I 24 having a higher affinity for GCA. The 12 Lactobacillus strains also showed significant (P strains (C1, C10 and C16) and between cholesterol removal and deconjugation of TCA (r = 0.38) and GCA (r = 0.70) among the L. brevis strains (I 12, I 23, I 25, I 211 and I 218). In contrast, although L. gallinarum I 16 and I 26 and L. panis C 17 showed high deconjugating activity, there was no correlation between cholesterol removal and deconjugation of bile salts in these strains. The results showed that the 12 Lactobacillus strains were able to deconjugate bile salts and remove cholesterol in vitro, but not all strains with high deconjugating activity removed cholesterol effectively. Copyright (c) 2009 Society of Chemical Industry.

  11. Structure and rheological properties of acid-induced egg white protein gels

    NARCIS (Netherlands)

    Weijers, M.; Velde, F. van de; Stijnman, A.; Pijpekamp, A. van de; Visschers, R.W.

    2006-01-01

    This study compares the rheological properties of acid-induced gels prepared of industrial spray-dried egg white proteins (EWP) with the acid-induced gels prepared of ovalbumin (OA) and whey protein isolate (WPI). Also we aimed to form transparent gels of EWP by means of the cold-gelation process.

  12. Bile acids and cardiovascular function in cirrhosis

    DEFF Research Database (Denmark)

    Voiosu, Andrei; Wiese, Signe; Voiosu, Theodor

    2017-01-01

    Cirrhotic cardiomyopathy and the hyperdynamic syndrome are clinically important complications of cirrhosis but their exact pathogenesis is still partly unknown. Experimental models have proven the cardiotoxic effects of bile acidsand recent studies of their varied receptor-mediated functions offer...... cardiovascular disturbances. This review summarizes the evidence regarding the role of bile acids and their receptors in the generation of cardiovascular dysfunction in cirrhosis. This article is protected by copyright. All rights reserved....

  13. Bile acid: a potential inducer of colon cancer stem cells.

    Science.gov (United States)

    Farhana, Lulu; Nangia-Makker, Pratima; Arbit, Evan; Shango, Kathren; Sarkar, Sarah; Mahmud, Hamidah; Hadden, Timothy; Yu, Yingjie; Majumdar, Adhip P N

    2016-12-01

    Although the unconjugated secondary bile acids, specifically deoxycholic acid (DCA) and lithocholic acid (LCA), are considered to be risk factors for colorectal cancer, the precise mechanism(s) by which they regulate carcinogenesis is poorly understood. We hypothesize that the cytotoxic bile acids may promote stemness in colonic epithelial cells leading to generation of cancer stem cells (CSCs) that play a role in the development and progression of colon cancer. Normal human colonic epithelial cells (HCoEpiC) were used to study bile acid DCA/LCA-mediated induction of CSCs. The expression of CSC markers was measured by real-time qPCR. Flow cytometry was used to isolate CSCs. T-cell factor/lymphoid-enhancing factor (TCF/LEF) luciferase assay was employed to examine the transcriptional activity of β-catenin. Downregulation of muscarinic 3 receptor (M3R) was achieved through transfection of corresponding siRNA. We found DCA/LCA to induce CSCs in normal human colonic epithelial cells, as evidenced by the increased proportion of CSCs, elevated levels of several CSC markers, as well as a number of epithelial-mesenchymal transition markers together with increased colonosphere formation, drug exclusion, ABCB1 and ABCG2 expression, and induction of M3R, p-EGFR, matrix metallopeptidases, and c-Myc. Inhibition of M3R signaling greatly suppressed DCA/LCA induction of the CSC marker ALDHA1 and also c-Myc mRNA expression as well as transcriptional activation of TCF/LEF. Our results suggest that bile acids, specifically DCA and LCA, induce cancer stemness in colonic epithelial cells by modulating M3R and Wnt/β-catenin signaling and thus could be considered promoters of colon cancer.

  14. Bile leak detection by radionuclide scintigraphy.

    Science.gov (United States)

    Gupta, V

    2006-01-01

    Bile leak after liver injury has been reported to be a complication associated with significant mortality. Tc99m-IDA (Tc: Technetium) nuclear scan allows rapid and noninvasive diagnosis of bile leak. An accidental case was referred for the detection of suspicious bile leak. The ultrasound could not detect any abnormality. Dynamic Hepatobiliary Scintigraphy (DHBS) using radiolabeled tracer was performed. DHBS promptly detected the site of leak. This technique should be opted because it has been found to be quite sensitive, specific and accurate for detecting the bile leak, whereas, Ultrasound and CT imaging are less sensitive and nonspecific. Though, they are initially helpful in determining the presence of abdominal fluid collections, they are unable to differentiate between a seroma, lymphocele, hematoma or bile leak. Hepatobiliary scintigraphy is more accurate because it can demonstrate continuity of these fluid collections with the biliary tree. Further, hepatobiliary scintigraphy can provide real-time assessment of hepatocytes function and bile progression from the liver to the intestine.

  15. Altered glycine and taurine conjugation of bile acids following aluminum administration to rats.

    Science.gov (United States)

    Klein, G L; Lee, T C; Heyman, M B; Rassin, D K

    1989-10-01

    Aluminum contaminates components of intravenous nutrient solutions and accumulates in the liver with parenteral feeding. Abnormalities in hepatic function associated with aluminum accumulation include increased serum bile acid concentration and glucuronyl transferase activity and reduced mixed function oxidase levels and bile flow. Whether there are other biochemical responses of the liver to aluminum is unclear. We report the effects of aluminum administration on bile acid conjugation in rats given aluminum intravenously as follows: group I, 1 mg/kg/day for 14 days; group II, 5 mg/kg/day for 14 days; and group III, 5 mg/kg/day for 7 days. Taurine-conjugated bile acids were reduced and glycine/taurine elevated in all groups compared with pair-fed controls. Glycine/taurine was greater in group II versus III and varied directly with serum bile acid concentration. These findings suggest that aluminum administration is associated with decreased taurine conjugation of bile acids, a phenomenon that may be associated with cholestasis.

  16. Wnt/β-catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid-induced epilepsy.

    Science.gov (United States)

    Qu, Zhengyi; Su, Fang; Qi, Xueting; Sun, Jianbo; Wang, Hongcai; Qiao, Zhenkui; Zhao, Hong; Zhu, Yulan

    2017-10-01

    Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis with massive neuronal loss and severe gliosis. Aberrant neurogenesis has been shown in the epileptogenesis process of temporal lobe epilepsy. However, the molecular mechanisms underlying aberrant neurogenesis remain unclear. The roles of Wnt signalling cascade have been well established in neurogenesis during multiple aspects. Here, we used kainic acid-induced rat epilepsy model to investigate whether Wnt/β-catenin signalling pathway is involved in the aberrant neurogenesis in temporal lobe epilepsy. Immunostaining and western blotting results showed that the expression levels of β-catenin, Wnt3a, and cyclin D1, the key regulators in Wnt signalling pathway, were up-regulated during acute epilepsy induced by the injection of kainic acids, indicating that Wnt signalling pathway was activated in kainic acid-induced temporal lobe epilepsy. Moreover, BrdU labelling results showed that blockade of the Wnt signalling by knocking down β-catenin attenuated aberrant neurogenesis induced by kainic acids injection. Altogether, Wnt/β-catenin signalling pathway mediated hippocampal neurogenesis during epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Temporal lobe epilepsy is a chronic disorder of nerve system, mainly characterized by hippocampal sclerosis. Aberrant neurogenesis has been shown to involve in the epileptogenesis process of temporal lobe epilepsy. In the present study, we discovered that Wnt3a/β-catenin signalling pathway serves as a link between aberrant neurogenesis and underlying remodelling in the hippocampus, leading to temporal lobe epilepsy, which might provide new strategies for clinical treatment of temporal lobe epilepsy. Copyright © 2017 John Wiley & Sons, Ltd.

  17. Bile Acid Signaling in Liver Metabolism and Diseases

    Directory of Open Access Journals (Sweden)

    Tiangang Li

    2012-01-01

    Full Text Available Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders.

  18. Bile salt tolerance of Lactococcus lactis is enhanced by expression of bile salt hydrolase thereby producing less bile acid in the cells.

    Science.gov (United States)

    Bi, Jie; Liu, Song; Du, Guocheng; Chen, Jian

    2016-04-01

    Changes of bile salt tolerance, morphology and amount of bile acid within cells were studied to evaluate the exact effects of bile salt hydrolase (BSH) on bile salt tolerance of microorganism. The effect of BSHs on the bile salt tolerance of Lactococcus lactis was examined by expressing two BSHs (BSH1 and BSH2). Growth of L. lactis expressing BSH1 or BSH2 was better under bile salt stress compared to wild-type L. lactis. As indicated by transmission electron microscopy, bile acids released by the action of BSH induced the formation of micelles around the membrane surface of cells subject to conjugated bile salt stress. A similar micelle containing bile acid was observed in the cytoplasm by liquid chromatography-mass spectrometry. BSH1 produced fewer bile acid micelles in the cytoplasm and achieved better cell growth of L. lactis compared to BSH2. Expression of BSH improved bile salt tolerance of L. lactis but excessive production by BSH of bile acid micelles in the cytoplasm inhibited cell growth.

  19. Importance of uncharged polar residues and proline in the proximal two-thirds (Pro107–Ser128 of the highly conserved region of mouse ileal Na+-dependent bile acid transporter, Slc10a2, in transport activity and cellular expression

    Directory of Open Access Journals (Sweden)

    Saeki Tohru

    2013-02-01

    Full Text Available Abstract Background SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act not only as detergents but also as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. SLC10A family members and the homologous genes of various species share a highly conserved region corresponding to Gly104–Pro142 of SLC10A2. The functional importance of this region has not been fully elucidated. Results To elucidate the functional importance of this region, we previously performed mutational analysis of the uncharged polar residues and proline in the distal one-third (Thr130–Pro142 of the highly conserved region in mouse Slc10a2. In this study, proline and uncharged polar residues in the remaining two-thirds of this region in mouse Slc10a2 were subjected to mutational analysis, and taurocholic acid uptake and cell surface localization were examined. Cell surface localization of Slc10a2 is necessary for bile acid absorption. Mutants in which Asp or Leu were substituted for Pro107 (P107N or P107L were abundantly expressed, but their cell surface localization was impaired. The S126A mutant was completely impaired in cellular expression. The T110A and S128A mutants exhibited remarkably enhanced membrane expression. The S112A mutant was properly expressed at the cell surface but transport activity was completely lost. Replacement of Tyr117 with various amino acids resulted in reduced transport activity. The degree of reduction roughly depended on the van der Waals volume of the side chains. Conclusions The functional importance of proline and uncharged polar residues in the highly conserved region of mouse Slc10a2 was determined. This information will contribute to the design of bile acid-conjugated prodrugs for efficient drug delivery or SLC10A2 inhibitors for

  20. Mechanism of acid-induced folding of proteins.

    Science.gov (United States)

    Goto, Y; Takahashi, N; Fink, A L

    1990-04-10

    We have previously shown [Goto, Y., Calciano, L. J., & Fink, A. L. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 573-577] that beta-lactamase, cytochrome c, and apomyoglobin are maximally unfolded at pH 2 under conditions of low ionic strength, but a further decrease in pH, by increasing the concentration of HCl, refolds the proteins to the A state with properties similar to those of a molten globule state. To understand the mechanism of acid-induced refolding of protein structure, we studied the effects of various strong acids and their neutral salts on the acid-unfolded states of ferricytochrome c and apomyoglobin. The conformational transition of cytochrome c was monitored at 20 degrees C by using changes in the far-UV CD and in the Soret absorption at 394 nm, and that of apomyoglobin was monitored by changes in the far-UV CD. Various strong acids (i.e., sulfuric acid, perchloric acid, nitric acid, trichloroacetic acid, and trifluoroacetic acid) refolded the acid-unfolded cytochrome c and apomyoglobin to the A states as was the case with HCl. For both proteins neutral salts of these acids caused similar conformational transitions, confirming that the anions are responsible for bringing about the transition. The order of effectiveness of anions was shown to be ferricyanide greater than ferrocyanide greater than sulfate greater than thiocyanate greater than perchlorate greater than iodide greater than nitrate greater than trifluoroacetate greater than bromide greater than chloride.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Hepatic bile acids and bile acid-related gene expression in pregnant and lactating rats

    Directory of Open Access Journals (Sweden)

    Qiong N. Zhu

    2013-08-01

    Full Text Available Background. Significant physiological changes occur during pregnancy and lactation. Intrahepatic cholestasis of pregnancy (ICP is a liver disease closely related to disruption of bile acid homeostasis. The objective of this study was to examine the regulation of bile acid synthesis and transport in normal pregnant and lactating rats.Materials and Methods. Livers from timed pregnant SD rats were collected on gestational days (GD 10, 14 and 19, and postnatal days (PND 1, 7, 14 and 21. Total bile acids were determined by the enzymatic method, total RNA was isolated and subjected to real time RT-PCR analysis. Liver protein was extracted for western-blot analysis.Results. Under physiological conditions hepatic bile acids were not elevated during pregnancy but increased during lactation in rats. Bile acid synthesis rate-limiting enzyme Cyp7a1 was unchanged on gestational days, but increased on PND14 and 21 at mRNA and protein levels. Expression of Cyp8b1, Cyp27a1 and Cyp7b1 was also higher during lactation. The mRNA levels of small heterodimer partner (SHP and protein levels of farnesoid X receptor (FXR were increased during pregnancy and lactation. Bile acid transporters Ntcp, Bsep, Mrp3 and Mrp4 were lower at gestation, but increased during lactation. Hepatic Oatp transporters were decreased during pregnancy and lactation.Conclusion. Hepatic bile acid homeostasis is maintained during normal pregnancy in rats, probably through the FXR-SHP regulation. The expression of bile acid synthesis genes and liver bile acid accumulation were increased during lactation, together with increased expression of bile acid efflux transporter Bsep, Mrp3 and Mrp4.

  2. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD.

    Science.gov (United States)

    Jiao, Na; Baker, Susan S; Chapa-Rodriguez, Adrian; Liu, Wensheng; Nugent, Colleen A; Tsompana, Maria; Mastrandrea, Lucy; Buck, Michael J; Baker, Robert D; Genco, Robert J; Zhu, Ruixin; Zhu, Lixin

    2017-08-03

    Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD. Serum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls. Serum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na + -taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats. The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome. © Article

  3. Vibrio cholerae leuO Transcription Is Positively Regulated by ToxR and Contributes to Bile Resistance.

    Science.gov (United States)

    Ante, Vanessa M; Bina, X Renee; Howard, Mondraya F; Sayeed, Sameera; Taylor, Dawn L; Bina, James E

    2015-11-01

    Vibrio cholerae is an aquatic organism and facultative human pathogen that colonizes the small intestine. In the small intestine, V. cholerae is exposed to a variety of antimicrobial compounds, including bile. V. cholerae resistance to bile is multifactorial and includes alterations in the membrane permeability barrier that are mediated by ToxR, a membrane-associated transcription factor. ToxR has also been shown to be required for activation of the LysR family transcription factor leuO in response to cyclic dipeptides. LeuO has been implicated in the regulation of multiple V. cholerae phenotypes, including biofilm production and virulence. In this study, we investigated the effects of bile on leuO expression. We show that leuO transcription increased in response to bile and bile salts but not in response to other detergents. The bile-dependent increase in leuO expression was dependent on ToxR, which was found to bind directly to the leuO promoter. The periplasmic domain of ToxR was required for basal leuO expression and for the bile-dependent induction of both leuO and ompU transcription. V. cholerae mutants that did not express leuO exhibited increased bile susceptibility, suggesting that LeuO contributes to bile resistance. Our collective results demonstrate that ToxR activates leuO expression in response to bile and that LeuO is a component of the ToxR-dependent responses that contribute to bile resistance. The success of Vibrio cholerae as a human pathogen is dependent upon its ability to rapidly adapt to changes in its growth environment. Growth in the human gastrointestinal tract requires the expression of genes that provide resistance to host antimicrobial compounds, including bile. In this work, we show for the first time that the LysR family regulator LeuO mediates responses in V. cholerae that contribute to bile resistance. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  4. Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice.

    Science.gov (United States)

    Stedman, Catherine; Robertson, Graham; Coulter, Sally; Liddle, Christopher

    2004-03-19

    Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5' regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6beta-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration.

  5. Percutaneous electrohydraulic lithotripsy of bile duct stones

    International Nuclear Information System (INIS)

    Juliani, E.; Righi, D.; Cesarani, F.; Regge, D.; Gandini, G.

    1988-01-01

    The results are reported of percutaneous transhepatic tratment with an electrohydraulic stone disintegrator in 4 cases of bile duct lithiasis. An electri discharge, generated by a bipolar electrode, gives origin to high-amplitude and low-frequency shoc waves in the fluid medium-which cause the stone to fragment. Complete resolution of lithiasis was obtained in 2 patients with intrahepatic calculosis. In the other 2 cases of massive lithiasis of intra and extrahepatic bile ducts the treatment, however incomplete, proved to be useful, as the biliary flux was reabilitated and clinical symptoms disappeared. No relevant immediate side-effects were observed, except for well-tolerated pain during the discharges, and transitory hemobilia which solved spontaneously. No complications were observed in this series of patients. Electrohydraulic lithotripsy proves thus to be useful for supporting standard interventional radiology techniques in very complex cases of intra and extrahepatic bile duct stones

  6. Comparative proteomic analysis of Lactobacillus plantarum for the identification of key proteins in bile tolerance

    Directory of Open Access Journals (Sweden)

    Marchioni Eric

    2011-03-01

    synthase which participate in the active removal of bile-related stress factors. Conclusions These results showed that comparative proteomic analysis can help understand the differential bacterial properties of lactobacilli. In the field of probiotic studies, characteristic proteomic profiles can be identified for individual properties that may serve as bacterial biomarkers for the preliminary selection of strains with the best probiotic potential.

  7. Selenium- or tellurium- containing bile acids and derivatives thereof

    International Nuclear Information System (INIS)

    Monks, R.; Riley, A.L.M.

    1981-01-01

    This invention relates to the preparation of selenium and tellurium derivatives, particularly γ-emitting radioactive derivatives of bile acids and bile salts. Such compounds are valuable in the examination of body function, especially small bowel function. (author)

  8. Transcriptional Elongation Factor Elongin A Regulates Retinoic Acid-Induced Gene Expression during Neuronal Differentiation

    Directory of Open Access Journals (Sweden)

    Takashi Yasukawa

    2012-11-01

    Full Text Available Elongin A increases the rate of RNA polymerase II (pol II transcript elongation by suppressing transient pausing by the enzyme. Elongin A also acts as a component of a cullin-RING ligase that can target stalled pol II for ubiquitylation and proteasome-dependent degradation. It is not known whether these activities of Elongin A are functionally interdependent in vivo. Here, we demonstrate that Elongin A-deficient (Elongin A−/− embryos exhibit abnormalities in the formation of both cranial and spinal nerves and that Elongin A−/− embryonic stem cells (ESCs show a markedly decreased capacity to differentiate into neurons. Moreover, we identify Elongin A mutations that selectively inactivate one or the other of the aforementioned activities and show that mutants that retain the elongation stimulatory, but not pol II ubiquitylation, activity of Elongin A rescue neuronal differentiation and support retinoic acid-induced upregulation of a subset of neurogenesis-related genes in Elongin A−/− ESCs.

  9. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

    Science.gov (United States)

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-08-14

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.

  10. Solitary intrahepatic bile-duct cyst presenting with Jaundice

    International Nuclear Information System (INIS)

    Park, Jeong Mi; Chun, Ki Sung; Ha, Hyun Kwon; Shinn, Kyung Sub; Bahk, Yong Whee; Kim, Jun Gi

    1989-01-01

    Caroli's disease is an uncommon condition, and characterized by congenital segmental saccular dilatation of intrahepatic bile ducts. A case of Caroli's disease, manifested by only a large communicating cystic dilatation of left intrahepatic bile duct and causing extrinsic pressure over the extrahepatic bile duct, is presented. The patient was 43-year-old housewife, hospitalized because of abdominal distension and severe jaundice. To relieve jaundice and alleviate surgical intervention, percutaneous drainage of the bile-duct cyst preceded surgery

  11. Mechanisms of Lower Bile Duct Stricture in Autoimmune Pancreatitis

    OpenAIRE

    Watanabe, Takayuki; Maruyama, Masahiro; Ito, Tetsuya; Maruyama, Masafumi; Muraki, Takashi; Hamano, Hideaki; Arakura, Norikazu; Hasebe, Osamu; Kawa, Shigeyuki

    2014-01-01

    Objectives We attempted to clarify the mechanism underlying lower bile duct stricture in autoimmune pancreatitis. Methods Imaging and histologic finding of the bile duct were assessed for 73 patients with autoimmune pancreatitis to clarify whether IgG4-related biliary inflammation or pancreatic head swelling is associated with lower bile duct stricture. Results Lower bile duct stricture was found in 59 (81%) patients. Pancreatic head swelling was significantly more frequent among patients wit...

  12. Apoptosis-inducing factor (Aif1) mediates anacardic acid-induced apoptosis in Saccharomyces cerevisiae.

    Science.gov (United States)

    Muzaffar, Suhail; Chattoo, Bharat B

    2017-03-01

    Anacardic acid is a medicinal phytochemical that inhibits proliferation of fungal as well as several types of cancer cells. It induces apoptotic cell death in various cell types, but very little is known about the mechanism involved in the process. Here, we used budding yeast Saccharomyces cerevisiae as a model to study the involvement of some key elements of apoptosis in the anacardic acid-induced cell death. Plasma membrane constriction, chromatin condensation, DNA degradation, and externalization of phosphatidylserine (PS) indicated that anacardic acid induces apoptotic cell death in S. cerevisiae. However, the exogenous addition of broad-spectrum caspase inhibitor Z-VAD-FMK or deletion of the yeast caspase Yca1 showed that the anacardic acid-induced cell death is caspase independent. Apoptosis-inducing factor (AIF1) deletion mutant was resistant to the anacardic acid-induced cell death, suggesting a key role of Aif1. Overexpression of Aif1 made cells highly susceptible to anacardic acid, further confirming that Aif1 mediates anacardic acid-induced apoptosis. Interestingly, instead of the increase in the intracellular reactive oxygen species (ROS) normally observed during apoptosis, anacardic acid caused a decrease in the intracellular ROS levels. Quantitative real-time PCR analysis showed downregulation of the BIR1 survivin mRNA expression during the anacardic acid-induced apoptosis.

  13. Investigation of antibacterial, acid and bile tolerance properties of lactobacilli isolated from Koozeh cheese

    Directory of Open Access Journals (Sweden)

    Hassan Hassanzadazar

    2012-09-01

    Full Text Available Lactobacillus strains are a major part of the probiotics, microflora of the intestine and of fermented dairy products, and are found in a variety of environments. The aim of this study was to find out the ability of bile and acid tolerance and antibacterial properties of the twenty eight isolates of three group lactobacilli namely Lactobacillus plantarum, Lactobacillus casei and Lactobacillus delbruki. For this purpose Twenty eight different Lactobacillus strains that isolated from Koozeh cheese as a traditional cheese were screened. The acid tolerance test was studied under pH 2.0 and 3.0 with 7.5 as control. The cell count for the acid tolerance test was obtained at an interval of 0, 1, 2 and 3 hours respectively and was pour plated on Man, Rogosa, and Sharpe (MRS agar to be incubated at 37 °C for 24 hours. All cells were selected for bile tolerance test in MRS broth containing bile concentrations of 0% as control and 0.3% as test. Then cell counts were enumerated after 24 hours of incubation on MRS agar. Results showed twenty seven isolates did not have ability to tolerate acid and bile salts and antimicrobial activity against four indicator bacteria included Eshirichia coli, Listeria monocytogenesis, bacillus cereus, Salmonella entritidis. Only one Isolate namely Lactobacillus casei could tolerate acid and bile salt and had antibacterial activity against of L. monocytogenesis. Therefore we can consider this strain as a native probiotic but extra examinations was required.

  14. Effects of bile salt deconjugation by probiotic strains on the survival of antibiotic-resistant foodborne pathogens under simulated gastric conditions.

    Science.gov (United States)

    He, Xinlong; Zou, Yunyun; Cho, Youngjae; Ahn, Juhee

    2012-06-01

    This study was designed to evaluate the effects of bile acid deconjugation by probiotic strains on the antibiotic susceptibility of antibiotic-sensitive and multiple antibiotic-resistant Salmonella Typhimurium and Staphylococcus aureus. Eight probiotic strains, Bifidobacterium longum B6, Lactobacillus acidophilus ADH, Lactobacillus brevis KACC 10553, Lactobacillus casei KACC 12413, Lactobacillus paracasei ATCC 25598, Lactobacillus rhamnosus GG, Leuconostoc mesenteroides KACC 12312, and Pediococcus acidilactici KACC 12307, were used to examine bile acid tolerance. The ability to deconjugate bile acids was evaluated using both thin-layer chromatography and high-performance liquid chromatography. The antibiotic susceptibility testing was carried out to determine the synergistic inhibitory activity of deconjugated bile acids. L. acidophilus, L. brevis, and P. acidilactici showed the most tolerance to the conjugated bile acids. P. acidilactici deconjugated glycocholic acid and glycodeoxycholate from 3.18 and 3.09 mM to the detection limits, respectively. The antibiotic susceptibility of selected foodborne pathogens was increased by increasing the concentration of deconjugated bile acids. The study results are useful for understanding the relationship between bile acid deconjugation by probiotic strains and antibiotic susceptibility in the presence of deconjugated bile acids, and they may be useful for designing new probiotic-antibiotic combination therapy based on bile acid deconjugation.

  15. A comparative study on the hepatoprotective action of bear bile and Coptidis Rhizoma aqueous extract on experimental liver fibrosis in rats.

    Science.gov (United States)

    Wang, Ning; Feng, Yibin; Cheung, Fan; Chow, Oi-Yee; Wang, Xuanbin; Su, Weiwei; Tong, Yao

    2012-11-29

    Bear bile and Coptidis Rhizoma have been used in Chinese medicine with a long tradition in treating heat-diseases. Both bear bile and Coptidis Rhizoma are used to treat liver diseases in clinical practice of Chinese Medicine. Since bears are currently endangered, it raises the question whether the use of bear bile is ethical. To look for substitute for bear bile, the aim of this study is to compare the anti-fibrotic effects of Coptidis Rhizoma and its major component berberine with the actions of bear bile and its major compound tauroursodeoxycholic acid on experimental liver fibrosis in rats. Quality assessment was conducted with high performance liquid chromatography. The experimental liver fibrosis in rats was induced by carbon tetrachloride, alcohol, and bile duct ligation respectively. The biochemical criteria in the blood and tissue samples were measured to evaluate the anti-fibrotic properties and underlying mechanisms of the drugs. Coptidis Rhizoma Aqueous Extract (CRAE), berberine, and bear bile exerted anti-fibrotic properties on various liver fibrosis models in rats. CRAE and berberine significantly reduced the peroxidative stress in liver through increasing the superoxide dismutase enzyme activity. CRAE and berberine were able to excrete bilirubin products from the liver and protect hepatocytes from cholestatic damage. The effect of CRAE and berberine are comparable to that of bear bile. Instead of using bear bile, CRAE and berberine can be potential substitutes in treating liver fibrosis.

  16. A case of fascioliasis in common bile duct

    International Nuclear Information System (INIS)

    Ham, Soo Youn; Park, Cheol Min; Chung, Kyu Byung; Lee, Chang Hong; Park, Seung Chul; Choi, Sang Yong; Lim, Han Jong

    1989-01-01

    A case of Fascioliasis of common bile duct is confirmed by visualization of adult fluke. Fascioliasis caused by Fasciola hepatica, is common parasitic disease in cattle and sheep. Human is an accidental host. ERCP demonstrated irregular linear conglomerated filling defects in common bile duct. Through surgical intervention, we found adult flukes of F. hepatica and adenomatous hyperplasia of common bile duct

  17. A case of fascioliasis in common bile duct

    Energy Technology Data Exchange (ETDEWEB)

    Ham, Soo Youn; Park, Cheol Min; Chung, Kyu Byung; Lee, Chang Hong; Park, Seung Chul; Choi, Sang Yong; Lim, Han Jong [Korea University College of Medicine, Seoul (Korea, Republic of)

    1989-10-15

    A case of Fascioliasis of common bile duct is confirmed by visualization of adult fluke. Fascioliasis caused by Fasciola hepatica, is common parasitic disease in cattle and sheep. Human is an accidental host. ERCP demonstrated irregular linear conglomerated filling defects in common bile duct. Through surgical intervention, we found adult flukes of F. hepatica and adenomatous hyperplasia of common bile duct.

  18. TRPM5 is critical for linoleic acid-induced CCK secretion from the enteroendocrine cell line, STC-1.

    Science.gov (United States)

    Shah, Bhavik P; Liu, Pin; Yu, Tian; Hansen, Dane R; Gilbertson, Timothy A

    2012-01-01

    Fatty acid-induced stimulation of enteroendocrine cells leads to release of the hormones such as cholecystokinin (CCK) that contribute to satiety. Recently, the fatty acid activated G protein-coupled receptor GPR120 has been shown to mediate long-chain unsaturated free fatty acid-induced CCK release from the enteroendocrine cell line, STC-1, yet the downstream signaling pathway remains unclear. Here we show that linoleic acid (LA) elicits membrane depolarization and an intracellular calcium rise in STC-1 cells and that these responses are significantly reduced when activity of G proteins or phospholipase C is blocked. LA leads to activation of monovalent cation-specific transient receptor potential channel type M5 (TRPM5) in STC-1 cells. LA-induced TRPM5 currents are significantly reduced when expression of TRPM5 or GPR120 is reduced using RNA interference. Furthermore, the LA-induced rise in intracellular calcium and CCK secretion is greatly diminished when expression of TRPM5 channels is reduced using RNA interference, consistent with a role of TRPM5 in LA-induced CCK secretion in STC-1 cells.

  19. Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase

    NARCIS (Netherlands)

    Duan, R. D.; Verkade, H. J.; Cheng, Y.; Havinga, R.; Nilsson, A.

    Alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase (N-CDase) in the intestinal microvillar membrane are responsible for dietary sphingomyelin digestion. The activities of the enzymes require the presence of bile salt, and the enzymes can be released into the gut lumen in active forms by

  20. Acid-induced equilibrium folding intermediate of human platelet profilin.

    Science.gov (United States)

    McLachlan, Glendon D; Cahill, Sean M; Girvin, Mark E; Almo, Steven C

    2007-06-12

    The acid-induced unfolding of human platelet profilin (HPP) can be minimally modeled as a three-state process. Equilibrium unfolding studies have been performed on human platelet profilin1 (HPP) and monitored by far-UV circular dichroism, tryptophan fluorescence, ANS binding, and NMR spectroscopy. Far-UV CD measurements obtained by acid titration demonstrate that HPP unfolds via a three-state mechanism (N --> I --> U), with a highly populated intermediate between pH 4 and 5. Approximately 80% of native helical secondary structural content remains at pH 4, as indicated by monitoring the CD signal at 222 nm. The stability (DeltaGH2O) of the native conformation at pH 7.0 (obtained by monitoring the change in tryptophan signal as a function of urea concentration) is 5.56 +/- 0.51 kcal mol-1; however, the DeltaGH2O for the intermediate species at pH 4 is 2.01 +/- 0.47 kcal mol-1. The calculated m-values for the pH 7.0 and pH 4.0 species were 1.64 +/- 0.15 and 1.34 +/- 0.17 kcal mol-1 M-1, respectively, which is an indication that the native and intermediate species are similarly compact. Additionally, translational diffusion measurements obtained by NMR spectroscopy and ANS binding studies are consistent with a globular and compact conformation at both pH 7.0 and 4.0. The pKa values for the two histidine (His) residues located on helix 4 of HPP were determined to be 5.6 and 5.7 pH units. These pKa values coincide with the midpoint of the far-UV CD acid titration curve and suggest that the protonation of one or both His residues may play a role in the formation of the unfolding intermediate. Stable intermediate species populate the 2D 1H-15N HSQC NMR spectra between pH 4 and 5. A number of backbone and side-chain resonances show significant perturbations relative to the native spectrum; however, considerable nativelike tertiary contacts remain. Interestingly, the residues on HPP that are significantly altered at low pH coincide with segments of the G-actin binding

  1. The human gallbladder secretes fibroblast growth factor 19 into bile: Towards defining the role of fibroblast growth factor 19 in the enterobiliary tract

    NARCIS (Netherlands)

    Zweers, Serge J. L. B.; Booij, Klaske A. C.; Komuta, Mina; Roskams, Tania; Gouma, Dirk J.; Jansen, Peter L. M.; Schaap, Frank G.

    2012-01-01

    Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of bile salt synthesis. In the postprandial state, activation of ileal farnesoid X receptor (FXR) by bile salts results in transcriptional induction of FGF19 and elevation of circulating FGF19 levels. An

  2. Plasma bile acids show a positive correlation with body mass index and are negatively associated with cognitive restraint of eating in obese patients

    Directory of Open Access Journals (Sweden)

    Philip ePrinz

    2015-06-01

    Full Text Available Bile acids may be involved in the regulation of food intake and energy metabolism. The aim of the study was to investigate the association of plasma bile acids with body mass index (BMI and the possible involvement of circulating bile acids in the modulation of physical activity and eating behavior. Blood was obtained in a group of hospitalized patients with normal weight (BMI 18.5-25 kg/m2, underweight (anorexia nervosa, BMI 50 kg/m2, n=14-15/group and plasma bile acid concentrations assessed. Physical activity and plasma bile acids were measured in a group of patients with anorexia nervosa (BMI 14.6±0.3 kg/m2, n=43. Lastly, in a population of obese patients (BMI 48.5±0.9 kg/m2, n=85, psychometric parameters related to disordered eating and plasma bile acids were assessed. Plasma bile acids showed a positive correlation with BMI (r=0.26, p=0.03 in the population of patients with broad range of BMI (9-85 kg/m2, n=74. No associations were observed between plasma bile acids and different parameters of physical activity in anorexic patients (p>0.05. Plasma bile acids were negatively correlated with cognitive restraint of eating (r=-0.30, p=0.008, while no associations were observed with other psychometric eating behavior-related parameters (p>0.05 in obese patients. In conclusion, these data may point towards a role of bile acids in the regulation of body weight. Since plasma bile acids are negatively correlated with the cognitive restraint of eating in obese patients, this may represent a compensatory adaptation to prevent further overeating.

  3. Clinical pathology of primary bile reflux gastritis

    Directory of Open Access Journals (Sweden)

    Ping YAO

    2011-05-01

    Full Text Available Objective To analyze the clinical and pathological features of primary bile reflux gastritis(BRG.Methods Endoscopy,Helicobacter pylori(H.pylori detection,and histopathologic examination were performed in 218 patients with primary BRG(observed group and 236 patients with simple chronic gastritis(SCG,control group as identified by gastroscope in order to analyze the endoscopic abnormalities,the frequency of H.pylori infection,pathological features and scores of inflammation.Results The frequency of H.pylori infection was 39.0%(85/218 in the observed group,which was significantly lower than that in the control group [52.1%(123/236].The topographic abnormalities of the antral mucosa as detected by gastroscopy,i.e.,congestion,hemorrhagic spots,erosion were not significantly different between BRG and SCG patients(P > 0.05.The scores of chronic and active inflammation were higher in patients when H.pylori infection was present than in patients without H.pylori infection in both groups(P < 0.05.The scores of inflammation,the detection rates of the antral intestinal metaplasia,antral atrophy and atypical hyperplasia were all higher in observed group than in control group(P < 0.05.The incidence of lengthening of gastric pits,telangiectasis or interstitial edema in BRG patients was also significantly higher than those in SCG patients(P < 0.05.Conclusions Primary BRG shows features of chemical gastritis with a higher tendency toward mucosal atrophy,intestinal metaplasia and atypical hyperplasia.Gastropic examination and biopsy should be emphasized.

  4. The "flying" bile duct: avulsion of the common bile duct in a plane crash survivor.

    LENUS (Irish Health Repository)

    Mohan, H

    2012-02-01

    Blunt trauma is an unusual cause of extrahepatic bile duct injury. This is a case of a 51-year-old gentleman who sustained a significant seatbelt injury in a plane crash. Laparotomy, performed due to persistent abdominal pain, revealed that the common bile duct (CBD) was completely avulsed from the duodenum. Following insertion of drains and transfer to a hepatobiliary centre, the devascularised CBD was excised and replaced with a roux-en-y hepaticojejunostomy. Necrotic tissue was debrided from the pancreatic head. A persistent bile leak developed from the sub-hepatic drain. Repeat laparotomy revealed a bile leak from small ducts on the liver surface. Ligation of the ducts and bioglue sealing of the area were successfully performed. Subsequent to this a pancreatic fistula developed from the main pancreatic duct, which has since resolved. This unusual case illustrates the need for prompt recognition and early repair to optimise outcomes in traumatic CBD injury.

  5. Rotavirus nonstructural protein 1 antagonizes innate immune response by interacting with retinoic acid inducible gene I

    Directory of Open Access Journals (Sweden)

    Qin Lan

    2011-12-01

    Full Text Available Abstract Background The nonstructural protein 1 (NSP1 of rotavirus has been reported to block interferon (IFN signaling by mediating proteasome-dependent degradation of IFN-regulatory factors (IRFs and (or the β-transducin repeat containing protein (β-TrCP. However, in addition to these targets, NSP1 may subvert innate immune responses via other mechanisms. Results The NSP1 of rotavirus OSU strain as well as the IRF3 binding domain truncated NSP1 of rotavirus SA11 strain are unable to degrade IRFs, but can still inhibit host IFN response, indicating that NSP1 may target alternative host factor(s other than IRFs. Overexpression of NSP1 can block IFN-β promoter activation induced by the retinoic acid inducible gene I (RIG-I, but does not inhibit IFN-β activation induced by the mitochondrial antiviral-signaling protein (MAVS, indicating that NSP1 may target RIG-I. Immunoprecipitation experiments show that NSP1 interacts with RIG-I independent of IRF3 binding domain. In addition, NSP1 induces down-regulation of RIG-I in a proteasome-independent way. Conclusions Our findings demonstrate that inhibition of RIG-I mediated type I IFN responses by NSP1 may contribute to the immune evasion of rotavirus.

  6. Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampus.

    Science.gov (United States)

    Kim, Seung-Tae; Doo, Ah-Reum; Kim, Seung-Nam; Kim, Song-Yi; Kim, Yoon Young; Kim, Jang-Hyun; Lee, Hyejung; Yin, Chang Shik; Park, Hi-Joon

    2012-09-01

    The administration of kainic acid (KA) causes seizures and produces neurodegeneration in hippocampal CA3 pyramidal cells. The present study investigated a possible role of acupuncture in reducing hippocampal cell death and inflammatory events, using a mouse model of kainic acid-induced epilepsy. Male C57BL/6 mice received acupuncture treatments at acupoint HT8 or in the tail area bilaterally once a day for 2 days and again immediately after an intraperitoneal injection of KA (30 mg/kg). HT8 is located on the palmar surface of the forelimbs, between the fourth and fifth metacarpal bones. Twenty-four hours after the KA injection, neuronal cell survival, the activations of microglia and astrocytes, and mRNA expression of two proinflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were measured in the hippocampus. Acupuncture stimulation at HT8, but not in the tail area, significantly reduced the KA-induced seizure, neuron death, microglial and astrocyte activations, and IL-1β mRNA expression in the hippocampus. The acupuncture stimulation also decreased the mRNA expression of TNF-α, but it was not significant. These results indicate that acupuncture at HT8 can inhibit hippocampal cell death and suppress KA-induced inflammatory events, suggesting a possible role for acupuncture in the treatment of epilepsy.

  7. Bile salts in control of lipid metabolism

    NARCIS (Netherlands)

    Schonewille, Marleen; de Boer, Jan Freark; Groen, Albert K.

    Purpose of review The view on bile salts has evolved over the years from being regarded as simple detergents that aid intestinal absorption of fat-soluble nutrients to being important hormone-like integrators of metabolism. This review provides an update on the rapidly developing field of

  8. Bile acids for primary sclerosing cholangitis

    DEFF Research Database (Denmark)

    Poropat, Goran; Giljaca, Vanja; Stimac, Davor

    2011-01-01

    Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients...

  9. Endoscopic management of bile leaks after laparoscopic ...

    African Journals Online (AJOL)

    Of 84 patients managed endoscopically, 44 had a cystic duct (CD) leak, 26 a CD leak and common bile duct (CBD) stones, and 14 a CBD injury amenable to endoscopic stenting. Of the 70 patients with CD leaks (group A), 24 underwent sphincterotomy only (including 8 stone extractions), 43 had a sphincterotomy with stent ...

  10. Attenuation of proinflammatory cytokines and apoptotic process by verapamil and diltiazem against quinolinic acid induced Huntington like alterations in rats.

    Science.gov (United States)

    Kalonia, Harikesh; Kumar, Puneet; Kumar, Anil

    2011-02-04

    Huntington disease is a neurodegenerative disease with complex pathophysiology. Recently, role of neuroinflammation and interplay between various other cellular cascades have been suggested to be involved in pathophysiology of Huntington disease. Involvement of calcium overload mediated oxidative damage and excitotoxicity have been suggested to play a central role in quinolinic acid induced Huntington like symptoms. The present study has been carried out to investigate the neuroprotective effect of calcium channel blockers (verapamil and diltiazem) against quinolinic acid induced dysfunction in motor, biochemical and neuroinflammatory signaling in rats. Intrastriatal quinolinic acid administration leads to significant motor [locomotor (72% reduction), rotarod (55% reduction), balance beam walk performance] dysfunction coupled with the marked oxidative damage and increased neuroinflammatory markers [TNF-α (140%), IL-6 (115%), caspase-3(75%)] levels in striatum as compared to the sham treatment. Verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) drug treatment for 21days resulted in a significant improvement in the motor function (improvement in locomotor activity, rotarod and balance beam walk performance). Further, verapamil (10 and 20mg/kg), diltiazem (10 and 20mg/kg) treatment significantly attenuated oxidative damage, level of proinflammatory mediators (TNF-α IL-6 and caspase-3) in quinolinic acid treated animals. Results of the present study demonstrate that protective effect of these calcium channel blockers (verapamil, diltiazem) might be due to their inhibitory action on different neuroinflammatory pathways against quinolinic acid induced Huntington disease like symptoms in rats. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Hepatoprotective bile acid 'ursodeoxycholic acid (UDCA)' Property and difference as bile acids.

    Science.gov (United States)

    Ishizaki, Kaoru; Imada, Teruaki; Tsurufuji, Makoto

    2005-10-01

    Ursodeoxycholic acid (UDCA) is a bile acid, which is present in human bile at a low concentration of only 3% of total bile acids. It is a 7beta-hydroxy epimer of the primary bile acid chenodeoxycholic acid (CDCA). UDCA is isolated from the Chinese drug 'Yutan' a powder preparation derived from the dried bile of adult bears. For centuries, Yutan has been used in the treatment of hepatobiliary disorders. In Japan, it has also been in widespread use as a folk medicine from the mid-Edo period. In Japan, not only basic studies such as isolation, crystallization, definition of the chemical structure and establishment of the synthesis of UDCA have been conducted but clinical studies have been conducted. First reports on the effects of UDCA in patients with liver diseases came from Japan as early as 1961. In the 1970s, the first prospective study of patients with gallbladder stones treated with UDCA demonstrating gallstone dissolution was reported. In late 1980s, a number of controlled trials on the use of UDCA in primary biliary cirrhosis (PBC) were reported. Since then, a variety of clinical studies have shown the beneficial effect of UDCA in liver disease worldwide. To date, UDCA is utilized for the treatment of PBC for which it is the only drug approved by the U.S. Food and Drug Administration (FDA). In recent years, with the advent of molecular tools, the mechanisms of action of bile acids and UDCA have been investigated, and various bioactivities and pharmacological effects have been revealed. Based on the results of these studies, the bioactive substances in bile acids that are involved in digestive absorption may play important roles in signal transduction pathways. Furthermore, the mechanisms of action of UDCA is evidently involved. We reveal the physicochemical properties of UDCA as bile acid and overview the established pharmacological effects of UDCA from its metabolism. Furthermore, we overview the current investigations into the mechanism of action of UDCA in

  12. Bile Acid Derivatives: From Old Molecules to a New Potent Therapeutical Use: an Overview.

    Science.gov (United States)

    Blanchet, Marine; Brunel, Jean Michel

    2018-03-08

    Bile acids or bile salts, belong to a large family of biological steroid derivatives found predominantly in the bile of mammals and other vertebrates. These amphipathic molecules possess numerous functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites, emulsifying fat-soluble vitamins to enable their absorption, aiding in motility and in reducing the bacteria flora found in the small intestine and biliary tract. In this review, we investigate progress towards synthetic bile acid derivatives, with special emphasis on how they might be used for various biological applications and the challenges that remain in developing these compounds as potent drugs of the future especially in the field of microbiology (antimicrobial activities) and cancer (anticancer agents). We will emphasize the fact that even few researches are devoted around these peculiar structures al the researches pointed out the important potential of such derivatives for the design of new classes of drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. Simultaneous bile duct and portal vein ligation induces faster atrophy/hypertrophy complex than portal vein ligation: role of bile acids.

    Science.gov (United States)

    Ren, Weizheng; Chen, Geng; Wang, Xiaofeng; Zhang, Aiqun; Li, Chonghui; Lv, Wenping; Pan, Ke; Dong, Jia-Hong

    2015-02-13

    Portal vein ligation (PVL) induces atrophy/hypertrophy complex (AHC). We hypothesised that simultaneous bile duct and portal vein ligation (BPL) might induce proper bile acid (BA) retention to enhance AHC by activating BA-mediated FXR signalling in the intact liver and promoting apoptosis in the ligated liver. We established rat models of 90% BPL and 90% PVL and found that BPL was well-tolerated and significantly accelerated AHC. The enhanced BA retention in the intact liver promoted hepatocyte proliferation by promoting the activation of FXR signalling, while that in the ligated liver intensified caspase3-mediated apoptosis. Decreasing the BA pools in the rats that underwent BPL could compromise these effects, whereas increasing the bile acid pools of rats that underwent PVL could induce similar effects. Second-stage resection of posterior-caudate-lobe-spearing hepatectomy was performed 5 days after BPL (B-Hx), PVL (V-Hx) or sham (S-SHx), as well as whole-caudate-lobe-spearing hepatectomy 5 days after sham (S-Hx). The B-Hx group had the most favourable survival rate (93.3%, the S-SHx group 0%, the S-Hx group 26.7%, the V-Hx group 56.7%, P < 0.01) and the most sustained regeneration. We conclude that BPL is a safe and effective method, and the acceleration of AHC was bile acid-dependent.

  14. Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice.

    Science.gov (United States)

    Slijepcevic, Davor; Roscam Abbing, Reinout L P; Katafuchi, Takeshi; Blank, Antje; Donkers, Joanne M; van Hoppe, Stéphanie; de Waart, Dirk R; Tolenaars, Dagmar; van der Meer, Jonathan H M; Wildenberg, Manon; Beuers, Ulrich; Oude Elferink, Ronald P J; Schinkel, Alfred H; van de Graaf, Stan F J

    2017-11-01

    The Na + -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).

  15. Direct measurement of first-pass ileal clearance of a bile acid in humans

    International Nuclear Information System (INIS)

    Galatola, G.; Jazrawi, R.P.; Bridges, C.; Joseph, A.E.; Northfield, T.C.

    1991-01-01

    The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%)

  16. A study on CT features of intrahepatic bile duct abscess

    International Nuclear Information System (INIS)

    Min Pengqiu; Li Peng; He Zhiyan; Chen Weixia; Liu Yan

    2001-01-01

    Objective: To evaluate CT features of intrahepatic bile duct abscess (IBDA) and its pathologic basis. Methods: The CT imaging data of 31 consecutive cases of intrahepatic bile duct abscess proved by surgery or clinical treatments from October 1989 to February 1999 were retrospectively studied. The causes included acute obstructive suppurative cholangitis and retrograde infection due to different etiologies. For all the cases, the CT manifestations of liver abscess, bile duct abnormalities, and their relationship were observed respectively. Results: Manifestations of liver abscess were revealed in all cases (31/31, 100%). The CT manifestations of bile duct abnormalities included signs of etiologies caused bile duct obstruction and other signs including cholangiectasis (29/31, 93.5%), the dilated bile ducts communicated with (5/31, 16.1%) or abut on (8/31, 25.8%) the abscesses, and gas collection in bile ducts (10/31, 32.2%). The signs showing the relationship between liver abscess and bile duct abnormalities were that the abscesses complied with the obstructive site and the dilated bile ducts (15/31, 48.4%), and the liver abscesses located in different (7/31, 22.6%) or same (4/31, 12.9%) liver lobes or segments with gas collection in the dilated bile ducts. Conclusion: The CT manifestations of IBDA included signs of liver abscess, abnormalities of bile ducts, and signs showing their relationship. CT scanning was helpful in making comprehensive and accurate diagnosis of IBDA

  17. Human sweet taste receptor mediates acid-induced sweetness of miraculin.

    Science.gov (United States)

    Koizumi, Ayako; Tsuchiya, Asami; Nakajima, Ken-ichiro; Ito, Keisuke; Terada, Tohru; Shimizu-Ibuka, Akiko; Briand, Loïc; Asakura, Tomiko; Misaka, Takumi; Abe, Keiko

    2011-10-04

    Miraculin (MCL) is a homodimeric protein isolated from the red berries of Richadella dulcifica. MCL, although flat in taste at neutral pH, has taste-modifying activity to convert sour stimuli to sweetness. Once MCL is held on the tongue, strong sweetness is sensed over 1 h each time we taste a sour solution. Nevertheless, no molecular mechanism underlying the taste-modifying activity has been clarified. In this study, we succeeded in quantitatively evaluating the acid-induced sweetness of MCL using a cell-based assay system and found that MCL activated hT1R2-hT1R3 pH-dependently as the pH decreased from 6.5 to 4.8, and that the receptor activation occurred every time an acid solution was applied. Although MCL per se is sensory-inactive at pH 6.7 or higher, it suppressed the response of hT1R2-hT1R3 to other sweeteners at neutral pH and enhanced the response at weakly acidic pH. Using human/mouse chimeric receptors and molecular modeling, we revealed that the amino-terminal domain of hT1R2 is required for the response to MCL. Our data suggest that MCL binds hT1R2-hT1R3 as an antagonist at neutral pH and functionally changes into an agonist at acidic pH, and we conclude this may cause its taste-modifying activity.

  18. Human sweet taste receptor mediates acid-induced sweetness of miraculin

    Science.gov (United States)

    Koizumi, Ayako; Tsuchiya, Asami; Nakajima, Ken-ichiro; Ito, Keisuke; Terada, Tohru; Shimizu-Ibuka, Akiko; Briand, Loïc; Asakura, Tomiko; Misaka, Takumi; Abe, Keiko

    2011-01-01

    Miraculin (MCL) is a homodimeric protein isolated from the red berries of Richadella dulcifica. MCL, although flat in taste at neutral pH, has taste-modifying activity to convert sour stimuli to sweetness. Once MCL is held on the tongue, strong sweetness is sensed over 1 h each time we taste a sour solution. Nevertheless, no molecular mechanism underlying the taste-modifying activity has been clarified. In this study, we succeeded in quantitatively evaluating the acid-induced sweetness of MCL using a cell-based assay system and found that MCL activated hT1R2-hT1R3 pH-dependently as the pH decreased from 6.5 to 4.8, and that the receptor activation occurred every time an acid solution was applied. Although MCL per se is sensory-inactive at pH 6.7 or higher, it suppressed the response of hT1R2-hT1R3 to other sweeteners at neutral pH and enhanced the response at weakly acidic pH. Using human/mouse chimeric receptors and molecular modeling, we revealed that the amino-terminal domain of hT1R2 is required for the response to MCL. Our data suggest that MCL binds hT1R2-hT1R3 as an antagonist at neutral pH and functionally changes into an agonist at acidic pH, and we conclude this may cause its taste-modifying activity. PMID:21949380

  19. Antinociceptive Effect of Ondansetron in Albino Mice Using Acetic Acid Induced Writhing Model

    Directory of Open Access Journals (Sweden)

    Abhay Purohit

    2016-10-01

    Full Text Available Background: Pain is an unpleasant sensory and emotional experience. Pain is a protective mechanism. Pain occurs whenever any tissues are being damaged, and it causes the individual to react and to remove the pain stimulus. Aim and Objectives: To evaluate the antinociceptive effect of ondansetron in comparison with the standard diclofenac. Material and Methods: The antinociceptive effect was tested by using the acetic acid induced writhing model in Swiss Albino mice. Animals were divided into 4 groups of 6 animals each. Animals were received distilled water (control, diclofenac (standard, ondansetron 0.5mg/kg (test I and ondansetron 1mg/kg (test II. After 30 minutes of drug administration, 0.1 ml of 1% acetic acid was injected. Mice were placed individually into glass beakers and five minutes were allowed to elapse. They were then observed for a period of ten minutes and the numbers of writhes were recorded in each animal. The results were expressed as mean ± SEM. One way ANOVA with post-test was used for statistical calculation. Results: The numbers of writhes were 1.33±0.494 for diclofenac; 6.33±1.872 and 9.33±1.706 for ondansetron 0.5 and 1mg/kg respectively. Conclusion: Ondansetron demonstrated statistical significant antinociceptive activity at both doses (0.5mg/kg and 1mg/kg and statistically similar effect as diclofenac

  20. Recovery of bile secretion following orthotopic liver transplantation.

    Science.gov (United States)

    Shiffman, M L; Carithers, R L; Posner, M P; Moore, E W

    1991-05-01

    Recovery of hepatic function following orthotopic liver transplantation includes the ability to produce 'adequate' bile. What constitutes adequate bile flow, however, has not previously been defined. The present study was undertaken to characterize biliary water and electrolyte secretion following hepatic transplantation. Bile was sampled from nine liver transplant recipients for 15-25 consecutive days during chronic t-tube biliary drainage. Liver biopsies and t-tube cholangiograms were unremarkable in all patients. During the first post-operative day mean bile flow, bile salt concentration, [BS], and bile salt output (BSO) were 60.0 microliters/min, 6.8 mM and 0.41 mumol/min, respectively. [BS] increased over days 1-5 and then plateaued at 12.2 mM over days 6-25 post-transplant. BSO and bile flow increased over days 1-12 before achieving steady-state values of 4.52 mumol/min and 334.7 microliters/min, respectively. In each patient bile flow increased linearly with increasing BSO. Choleretic index (CI), varied from 36.9-77.1 microliters/mumol (mean: 50.7 +/- 8.8). The y-intercept for this relationship ranged from 52.4-156.9 microliters/min (mean: 95.9 +/- 81.8). Only primary bile salts (82% cholate and 17% chenodeoxycholate), were observed in the bile of each patient. Biliary electrolyte concentrations were similar to that observed in plasma. Each was relatively unaffected by changes in bile flow and BSO. Electrolyte outputs increased linearly with respect to both BSO and bile flow. We conclude that recovery of bile secretion following orthotopic liver transplantation occurs gradually over a 10-12 day period and is strongly dependent upon bile salt secretion.

  1. Genetic Cholestasis: Lessons from the Molecular Physiology of Bile Formation

    Directory of Open Access Journals (Sweden)

    Peter LM Jansen

    2000-01-01

    Full Text Available Progressive familial intrahepatic cholestasis (PFIC is a group of severe genetic cholestatic liver diseases of early life. PFIC types 1 and 2 are characterized by cholestasis and a low to normal serum gamma-glutamyltransferase (GGT activity, whereas in PFIC type 3, the serum GGT activity is elevated. PFIC types 1 and 2 occur due to mutations in loci at chromosome 18 and chromosome 2, respectively. The pathophysiology of PFIC type 1 is not well understood. PFIC types 2 and 3 are caused by transport defects in the liver affecting the hepatobiliary secretion of bile acids and phospholipids, respectively. Benign recurrent intrahepatic cholestasis (BRIC is linked to a mutation in the same familial intrahepatic cholestasis 1 locus at chromosome 18. Defects of bile acid synthesis may be difficult to differentiate from these transport defects.Intrahepatic cholestasis of pregnancy (ICP appears to be related to these cholestatic diseases. For example, heterozygosity in families with PFIC type 3 is associated with ICP, but ICP has also been reported in families with BRIC.In Dubin-Johnson syndrome there is no cholestasis; only the hepatobiliary transport of conjugated bilirubin is affected. This, therefore, is a mild disease, and patients have a normal lifespan.

  2. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Patti, Mary-Elizabeth; Houten, Sander M; Bianco, Antonio C

    2009-01-01

    The multifactorial mechanisms promoting weight loss and improved metabolism following Roux-en-Y gastric bypass (GB) surgery remain incompletely understood. Recent rodent studies suggest that bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2...... thyroid hormone deiodinase. Altered gastrointestinal anatomy following GB could affect enterohepatic recirculation of bile acids. We assessed whether circulating bile acid concentrations differ in patients who previously underwent GB, which might then contribute to improved metabolic homeostasis. We...... performed cross-sectional analysis of fasting serum bile acid composition and both fasting and post-meal metabolic variables, in three subject groups: (i) post-GB surgery (n = 9), (ii) without GB matched to preoperative BMI of the index cohort (n = 5), and (iii) without GB matched to current BMI...

  3. Cape Gooseberry [Physalis peruviana L.] Calyces Ameliorate TNBS Acid-induced Colitis in Rats.

    Science.gov (United States)

    Castro, Jenny; Ocampo, Yanet; Franco, Luis

    2015-11-01

    Physalis peruviana [cape gooseberry] is highly appreciated for its commercial value. The Colombian ecotype is in great demand in the international market, particularly for the unique morphological characteristics of the calyx, which has extended use as a traditional herbal remedy in Colombia because of its anti-inflammatory properties. In this work, the anti-inflammatory activity of the total ethereal extract of Physalis peruviana calyces was evaluated in preventive and therapeutic protocols in a TNBS acid-induced colitis rat model. Colitis was induced by intrarectal administration of TNBS. An evaluation of macroscopic and histopathological parameters in colonic tissue was performed, along with the determination of myeloperoxidase enzyme activity, cytokine levels and gene expression. Additionally, effects on nitric oxide release by lipopolysaccharide [LPS]-stimulated RAW264.7 macrophages and the scavenging activity of DPPH and ABTS free radicals were determined. The treatment with the Physalis peruviana extract produced a significant improvement in the colonic tissue at both macroscopic and histological levels. IL-1β and TNF-α production was reduced by the extract in both experimental approaches. The groups treated with Physalis peruviana showed a tendency to MUC2 up-regulation and down-regulation of COX-2, iNOS, NLRP3, IL-1β, IL-6 and IL-10 expression. Nitric oxide release in RAW264.7 macrophages was significantly inhibited. The Physalis peruviana extract showed intestinal anti-inflammatory activity in the TNBS-induced colitis model, placing this species' calyx, a natural derivative, as a promising source of metabolites that could be used in treatment for inflammatory bowel disease. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Irinotecan (CPT-11)-induced elevation of bile acids potentiates suppression of IL-10 expression

    International Nuclear Information System (INIS)

    Fang, Zhong-Ze; Zhang, Dunfang; Cao, Yun-Feng; Xie, Cen; Lu, Dan; Sun, Dong-Xue; Tanaka, Naoki; Jiang, Changtao; Chen, Qianming; Chen, Yu; Wang, Haina; Gonzalez, Frank J.

    2016-01-01

    Irinotecan (CPT-11) is a first-line anti-colon cancer drug, however; CPT-11-induced toxicity remains a key factor limiting its clinical application. To search for clues to the mechanism of CPT-11-induced toxicity, metabolomics was applied using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Intraperitoneal injection of 50 mg/kg of CPT-11 induced loss of body weight, and intestine toxicity. Changes in gallbladder morphology suggested alterations in bile acid metabolism, as revealed at the molecular level by analysis of the liver, bile, and ileum metabolomes between the vehicle-treated control group and the CPT-11-treated group. Analysis of immune cell populations further showed that CPT-11 treatment significantly decreased the IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes, but not in spleen or mesenteric lymph nodes. In vitro cell culture studies showed that the addition of bile acids deoxycholic acid and taurodeoxycholic acid accelerated the CPT-11-induced suppression of IL-10 secretion by activated CD4 + naive T cells isolated from mouse splenocytes. These results showed that CPT-11 treatment caused metabolic changes in the composition of bile acids that altered CPT-11-induced suppression of IL-10 expression. - Highlights: • CPT-11 is an effective anticancer drug, but induced toxicity limits its application in the clinic. • CPT-11 decreased IL-10-producing CD4 T cell frequency in intestinal lamina propria lymphocytes. • CPT-11 altered the composition of bile acid metabolites, notably DCA and TDCA in liver, bile and intestine. • DCA and TDCA potentiated CPT-11-induced suppression of IL-10 secretion by active CD4 + naive T cells.

  5. Oblique bile duct predisposes to the recurrence of bile duct stones.

    Directory of Open Access Journals (Sweden)

    Pavel Strnad

    Full Text Available BACKGROUND AND STUDY AIMS: Bile stones represent a highly prevalent condition and abnormalities of the biliary tree predispose to stone recurrence due to development of biliary stasis. In our study, we assessed the importance of an altered bile duct course for stone formation. PATIENTS AND METHODS: 1,307 patients with choledocholithiasis in the absence of any associated hepatobiliary disease who underwent endoscopic retrograde cholangiopancreatography (ERCP between 2002 and 2009 were analysed. The angle enclosed between the horizontal portion of the common bile duct (CBD and the horizontal plane was measured (angle α. Oblique common bile duct (OCBD was defined as a CBD with angle α < 45°. RESULTS: 103 patients (7.9% were found to harbour OCBD and these were compared to 104 randomly selected control subjects. Compared to controls, OCBD patients were (i significantly older (72 ± 13 vs. 67 ± 13, p<0.00001; (ii more frequently underwent a cholecystectomy (p = 0.02 and biliary surgery (p = 0.003 prior to the diagnosis and (iii more often developed chronic pancreatitis (p = 0.04 as well as biliary fistulae (p = 0.03. Prior to and after ERCP, OCBD subjects displayed significantly elevated cholestatic parameters and angle α negatively correlated with common bile duct diameter (r = -0.29, p = 0.003. OCBD subjects more often required multiple back-to-back ERCP sessions to remove bile stones (p = 0.005 as well as more ERCPs later on due to recurrent stone formation (p<0.05. CONCLUSION: OCBD defines a novel variant of the biliary tree, which is associated with chronic cholestasis, hampers an efficient stone removal and predisposes to recurrence of bile duct stones.

  6. Causes and Prevention of Laparoscopic Bile Duct Injuries

    Science.gov (United States)

    Way, Lawrence W.; Stewart, Lygia; Gantert, Walter; Liu, Kingsway; Lee, Crystine M.; Whang, Karen; Hunter, John G.

    2003-01-01

    Objective To apply human performance concepts in an attempt to understand the causes of and prevent laparoscopic bile duct injury. Summary Background Data Powerful conceptual advances have been made in understanding the nature and limits of human performance. Applying these findings in high-risk activities, such as commercial aviation, has allowed the work environment to be restructured to substantially reduce human error. Methods The authors analyzed 252 laparoscopic bile duct injuries according to the principles of the cognitive science of visual perception, judgment, and human error. The injury distribution was class I, 7%; class II, 22%; class III, 61%; and class IV, 10%. The data included operative radiographs, clinical records, and 22 videotapes of original operations. Results The primary cause of error in 97% of cases was a visual perceptual illusion. Faults in technical skill were present in only 3% of injuries. Knowledge and judgment errors were contributory but not primary. Sixty-four injuries (25%) were recognized at the index operation; the surgeon identified the problem early enough to limit the injury in only 15 (6%). In class III injuries the common duct, erroneously believed to be the cystic duct, was deliberately cut. This stemmed from an illusion of object form due to a specific uncommon configuration of the structures and the heuristic nature (unconscious assumptions) of human visual perception. The videotapes showed the persuasiveness of the illusion, and many operative reports described the operation as routine. Class II injuries resulted from a dissection too close to the common hepatic duct. Fundamentally an illusion, it was contributed to in some instances by working too deep in the triangle of Calot. Conclusions These data show that errors leading to laparoscopic bile duct injuries stem principally from misperception, not errors of skill, knowledge, or judgment. The misperception was so compelling that in most cases the surgeon did not

  7. Molecular cloning, characterization and comparison of bile salt hydrolases from Lactobacillus johnsonii PF01.

    Science.gov (United States)

    Chae, J P; Valeriano, V D; Kim, G-B; Kang, D-K

    2013-01-01

    To clone, characterize and compare the bile salt hydrolase (BSH) genes of Lactobacillus johnsonii PF01. The BSH genes were amplified by polymerase chain reaction (PCR) using specific oligonucleotide primers, and the products were inserted into the pET21b expression vector. Escherichia coli BLR (DE3) cells were transformed with pET21b vectors containing the BSH genes and induced using 0·1 mmol l(-1) isopropylthiolgalactopyranoside. The overexpressed BSH enzymes were purified using a nickel-nitrilotriacetic acid (Ni(2+) -NTA) agarose column and their activities characterized. BSH A hydrolysed tauro-conjugated bile salts optimally at pH 5·0 and 55°C, whereas BSH C hydrolysed glyco-conjugated bile salts optimally at pH 5·0 and 70°C. The enzymes had no preferential activities towards a specific cholyl moiety. BSH enzymes vary in their substrate specificities and characteristics to broaden its activity. Despite the lack of conservation in their putative substrate-binding sites, these remain functional through motif conservation. This is to our knowledge the first report of isolation of BSH enzymes from a single strain, showing hydrolase activity towards either glyco-conjugated or tauro-conjugated bile salts. Future structural homology studies and site-directed mutagenesis of sites associated with substrate specificity may elucidate specificities of BSH enzymes. © 2012 The Society for Applied Microbiology.

  8. Plasma Bile Acids Are Associated with Energy Expenditure and Thyroid Function in Humans

    NARCIS (Netherlands)

    Ockenga, Johann; Valentini, Luzia; Schuetz, Tatjana; Wohlgemuth, Franziska; Glaeser, Silja; Omar, Ajmal; Kasim, Esmatollah; duPlessis, Daniel; Featherstone, Karen; Davis, Julian R.; Tietge, Uwe J. F.; Kroencke, Thomas; Biebermann, Heike; Koehrle, Josef; Brabant, Georg

    Background/Aims: Animal studies implicate a role of bile acids (BA) in thyroid-regulated energy expenditure (EE) via activation of the TGR-5/adenylate cyclase/deiodinase type 2 pathway. Here we investigated these possible associations in humans. Methods: EE, BA, and thyroid hormone status were

  9. CT findings of common bile duct stones

    Energy Technology Data Exchange (ETDEWEB)

    Koh, Byung Hee; Lee, Sang Kil; Kim, Jong Sung; Joo, Kyung Bin; Cho, On Koo; Hahm, Chang Kok; Kim, Yong Il [College of Medicine, Hanyang University, Seoul (Korea, Republic of)

    1992-11-15

    A retrospective study on computed tomographic (CT) findings in 35 surgically confirmed cases of common bile duct stones was performed to analyze the characteristic CT findings. Choledocholithiasis was correctly diagnosed by CT in 33 out of 35 cases (sensitivity, 94.3%) and among these CT demonstrated calculi of high attenuation in 32 and of soft tissue density in one case. The thirty two included 23 totally calcified. 5 rim calcified and 4 laminated stones. The target sign was observed in 30 out of 33 CT positive cases (90.1%). We concluded that CT is an accurate modality in the diagnosis of common bile duct stones with its' reliable display of the calcified or the laminated stone itself and its' characteristic target sign.

  10. CT findings of common bile duct stones

    International Nuclear Information System (INIS)

    Koh, Byung Hee; Lee, Sang Kil; Kim, Jong Sung; Joo, Kyung Bin; Cho, On Koo; Hahm, Chang Kok; Kim, Yong Il

    1992-01-01

    A retrospective study on computed tomographic (CT) findings in 35 surgically confirmed cases of common bile duct stones was performed to analyze the characteristic CT findings. Choledocholithiasis was correctly diagnosed by CT in 33 out of 35 cases (sensitivity, 94.3%) and among these CT demonstrated calculi of high attenuation in 32 and of soft tissue density in one case. The thirty two included 23 totally calcified. 5 rim calcified and 4 laminated stones. The target sign was observed in 30 out of 33 CT positive cases (90.1%). We concluded that CT is an accurate modality in the diagnosis of common bile duct stones with its' reliable display of the calcified or the laminated stone itself and its' characteristic target sign

  11. Praeruptorin D and E attenuate lipopolysaccharide/hydrochloric acid induced acute lung injury in mice.

    Science.gov (United States)

    Yu, Peng-Jiu; Li, Jing-Rong; Zhu, Zheng-Guang; Kong, Huan-Yu; Jin, Hong; Zhang, Jun-Yan; Tian, Yuan-Xin; Li, Zhong-Huang; Wu, Xiao-Yun; Zhang, Jia-Jie; Wu, Shu-Guang

    2013-06-15

    Acute lung injury is a life-threatening syndrome characterized by overwhelming lung inflammation and increased microvascular permeability, which causes a high mortality rate worldwide. The dry root of Peucedanum praeruptorum Dunn has been long used to treat respiratory diseases in China. In the present study, Praeruptorin A, C, D and E (PA, PC, PD and PE), four pyranocoumarins extracted from this herb, have been investigated for the pharmacological effects in experimental lung injury mouse models. In lipopolysaccharide (LPS) challenged mice, PA and PC did not show protective effect against lung injury at the dose of 80 mg/kg. However, PD and PE significantly inhibited the infiltration of activated polymorphonuclear leukocytes (PMNs) and decreased the levels of TNF-α and IL-6 in bronchoalveolar lavage fluid at the same dose. There was no statistically significant difference between PD and PE group. Further study demonstrated that PD and PE suppressed protein extravasations in bronchoalveolar lavage fluid, attenuated myeloperoxidase (MPO) activity and the pathological changes in the lung. Both PD and PE suppressed LPS induced Nuclear Factor-kappa B (NF-κB) pathway activation in the lung by decreasing the cytoplasmic loss of Inhibitor κB-α (IκB-α) protein and inhibiting the translocation of p65 from cytoplasm to nucleus. We also extended our study to acid-induced acute lung injury and found that these two compounds protected mice from hydrochloric acid (HCl)-induced lung injury by inhibiting PMNs influx, IL-6 release and protein exudation. Taken together, these results suggested that PD and PE might be useful in the therapy of lung injury. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Percutaneous treatment of benign bile duct strictures

    Energy Technology Data Exchange (ETDEWEB)

    Koecher, Martin [Department of Radiology, University Hospital, I.P.Pavlova 6, 775 20 Olomouc (Czech Republic)]. E-mail: martin.kocher@seznam.cz; Cerna, Marie [Department of Radiology, University Hospital, I.P.Pavlova 6, 775 20 Olomouc (Czech Republic); Havlik, Roman [Department of Surgery, University Hospital, I.P.Pavlova 6, 775 20 Olomouc (Czech Republic); Kral, Vladimir [Department of Surgery, University Hospital, I.P.Pavlova 6, 775 20 Olomouc (Czech Republic); Gryga, Adolf [Department of Surgery, University Hospital, I.P.Pavlova 6, 775 20 Olomouc (Czech Republic); Duda, Miloslav [Department of Surgery, University Hospital, I.P.Pavlova 6, 775 20 Olomouc (Czech Republic)

    2007-05-15

    Purpose: To evaluate long-term results of treatment of benign bile duct strictures. Materials and methods: From February 1994 to November 2005, 21 patients (9 men, 12 women) with median age of 50.6 years (range 27-77 years) were indicated to percutaneous treatment of benign bile duct stricture. Stricture of hepatic ducts junction resulting from thermic injury during laparoscopic cholecystectomy was indication for treatment in one patient, stricture of hepaticojejunostomy was indication for treatment in all other patients. Clinical symptoms (obstructive jaundice, anicteric cholestasis, cholangitis or biliary cirrhosis) have appeared from 3 months to 12 years after surgery. Results: Initial internal/external biliary drainage was successful in 20 patients out of 21. These 20 patients after successful initial drainage were treated by balloon dilatation and long-term internal/external drainage. Sixteen patients were symptoms free during the follow-up. The relapse of clinical symptoms has appeared in four patients 9, 12, 14 and 24 months after treatment. One year primary clinical success rate of treatment for benign bile duct stricture was 94%. Additional two patients are symptoms free after redilatation (15 and 45 months). One patient is still in treatment, one patient died during secondary treatment period without interrelation with biliary intervention. The secondary clinical success rate is 100%. Conclusion: Benign bile duct strictures of hepatic ducts junction or biliary-enteric anastomosis are difficult to treat surgically and endoscopically inaccessible. Percutaneous treatment by balloon dilatation and long-term internal/external drainage is feasible in the majority of these patients. It is minimally invasive, safe and effective.

  13. Bacteria, bile salts, and intestinal monosaccharide malabsorption

    Science.gov (United States)

    Gracey, Michael; Burke, Valerie; Oshin, Ademola; Barker, Judith; Glasgow, Eric F.

    1971-01-01

    Intestinal monosaccharide transport was studied in a series of rats with a self-filling jejunal blind loop using 3mM arbutin (p-hydroxyphenyl-B-glucoside) or 1mM D-fructose as substrate in vitro and 10 mM arbutin or 5mM D-fructose in vivo. These results were compared with changes in the bacterial flora and state of conjugation of intraluminal bile salts in those animals. Observations were also made of the microscopic and ultrastructural appearances of the small-intestinal epithelium. In the small intestine of blind-loop rats intestinal monosaccharide transport is impaired, and in vitro is most marked in the blind loop, less so in the efferent jejunum, and not significantly altered in the afferent jejunum. A similar pattern of disturbed monosaccharide absorption was demonstrated by perfusions in vivo. The degree of the transport defect correlates closely with the luxuriance of the anaerobic flora, which averaged 108 per millilitre in the blind loop, 107 in the efferent jejunum, and 106 in the afferent jejunum. A similar pattern of abnormality of bile salt conjugation occurred. In the blind loop the ratio of free to conjugated bile salts was grossly abnormal; this disturbance was somewhat less marked in the efferent jejunum and considerably less in the intraluminal contents of the afferent jejunum. An irregularly distributed lesion, consisting of swelling and vacuolation of microvilli and intracellular organelles, was demonstrated in the small-intestinal epithelium of blind-loop animals. Impaired absorption of monosaccharides is a further consequence of bacterial contamination of the upper gut. It is suggested that this defect is caused by the presence of high levels of deconjugated bile salts produced by an abnormal anaerobic bacterial flora in the small intestine. ImagesFig. 3Fig. 4 PMID:4329096

  14. Percutaneous treatment of benign bile duct strictures

    International Nuclear Information System (INIS)

    Koecher, Martin; Cerna, Marie; Havlik, Roman; Kral, Vladimir; Gryga, Adolf; Duda, Miloslav

    2007-01-01

    Purpose: To evaluate long-term results of treatment of benign bile duct strictures. Materials and methods: From February 1994 to November 2005, 21 patients (9 men, 12 women) with median age of 50.6 years (range 27-77 years) were indicated to percutaneous treatment of benign bile duct stricture. Stricture of hepatic ducts junction resulting from thermic injury during laparoscopic cholecystectomy was indication for treatment in one patient, stricture of hepaticojejunostomy was indication for treatment in all other patients. Clinical symptoms (obstructive jaundice, anicteric cholestasis, cholangitis or biliary cirrhosis) have appeared from 3 months to 12 years after surgery. Results: Initial internal/external biliary drainage was successful in 20 patients out of 21. These 20 patients after successful initial drainage were treated by balloon dilatation and long-term internal/external drainage. Sixteen patients were symptoms free during the follow-up. The relapse of clinical symptoms has appeared in four patients 9, 12, 14 and 24 months after treatment. One year primary clinical success rate of treatment for benign bile duct stricture was 94%. Additional two patients are symptoms free after redilatation (15 and 45 months). One patient is still in treatment, one patient died during secondary treatment period without interrelation with biliary intervention. The secondary clinical success rate is 100%. Conclusion: Benign bile duct strictures of hepatic ducts junction or biliary-enteric anastomosis are difficult to treat surgically and endoscopically inaccessible. Percutaneous treatment by balloon dilatation and long-term internal/external drainage is feasible in the majority of these patients. It is minimally invasive, safe and effective

  15. Ocular injury secondary to sheep bile exposure

    Science.gov (United States)

    Okullo, Alfin Taddeo; Low, Tim; Baker, Louise Leslie

    2012-01-01

    A 57-year-old abattoir worker was seen at a general practitioner after sheep bile splashed into his left eye. Flourescein examination revealed extensive ulceration involving at least two-thirds of the corneal surface. Copious irrigation with normal saline, application of chloramphenicol ointment and an eye patch resulted in excellent healing within 2 days with return to normal vision for the patient thereafter. PMID:23208813

  16. A CASE SERIES ON FISH BILE TOXICITY

    Directory of Open Access Journals (Sweden)

    Dwijen

    2015-08-01

    Full Text Available A case series of 3 cases of fish bile poisoning are reported. After ingestion of gall bladder of Labeo rohita for alleged vision improvement, generally presented with gastrointestinal symptoms such as cramping pain abdomen, nausea and vomiting within 12 hours after ingestion. Subsequently rena l and hepatic dysfunctions were found in all the three cases. The patient recovered fully with conservative treatment and supportive haemodialysis.

  17. Iatrogenic injury to the common bile duct.

    Science.gov (United States)

    Buturovic, Sead

    2014-08-01

    The formation of gallstones in the gall bladder is very common. It is now considered that approximately 10% to 15% of the adult population has gallstones. It is more frequent in women than men. age, sex, diet, sudden weight loss, etc. According to the report of the US National Institute of Health, it is estimated that 6.3 million men and 14.2 million women, aged 20-74 years in the United States has calculosis of the gallbladder, due to which every year is performed about 700,000 cholecystectomy. Male patient, aged about 40 years, admitted at the Clinic and laparoscopic surgery was performed in our department for chronic, as multiple, symptomatic gallbladder calculi. Intraoperative findings showed chronically inflamed, curled gall bladder, and wall thickening. After the first postoperative day there is no content in the drain bag and it is taken out, and the patient leaves the hospital without any problems. The seventh post-operative day occurred abdominal pain, weakness and fatigue, with striking yellow skin and visible mucous membranes. Clinical, laboratory and echo determined abdomen full of fluids, so it was suspected lesion of the bile duct. Urgent revision was performed. Intraoperative was found a lesion of the common bile duct in the form of a complete interruption. Created is anastomosis through transhepatic drain according to Pradera. Early and late postoperative flow was entirely normal with normal laboratory and echofindings. Control, contrast imaging through a drain showed the orderly flow of extrahepatic bile ducts, with minimal extravasation of contrast. At the Department of Surgery of General Hospital in Konjic laparoscopic cholecystectomy is performed since 1999. In the beginning it was done by three trocars (European style), and later, in order to prevent complications or injury of the bile duct is performed surgery with four trocars (American style). The number of complicated procedures in our hospital does not differ from similar indicators in

  18. Bear bile: dilemma of traditional medicinal use and animal protection

    Directory of Open Access Journals (Sweden)

    Nagamatsu Tadashi

    2009-01-01

    Full Text Available Abstract Bear bile has been used in Traditional Chinese Medicine (TCM for thousands of years. Modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. However, extensive consumption of bear bile made bears endangered species. In the 1980's, bear farming was established in China to extract bear bile from living bears with "Free-dripping Fistula Technique". Bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. Efforts are now given by non-governmental organizations, mass media and Chinese government to end bear farming ultimately. At the same time, systematic research has to be done to find an alternative for bear bile. In this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in English and Chinese databases. We examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from TCM. We then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future.

  19. Bear bile: dilemma of traditional medicinal use and animal protection

    Science.gov (United States)

    Feng, Yibin; Siu, Kayu; Wang, Ning; Ng, Kwan-Ming; Tsao, Sai-Wah; Nagamatsu, Tadashi; Tong, Yao

    2009-01-01

    Bear bile has been used in Traditional Chinese Medicine (TCM) for thousands of years. Modern investigations showed that it has a wide range of pharmacological actions with little toxicological side effect and the pure compounds have been used for curing hepatic and biliary disorders for decades. However, extensive consumption of bear bile made bears endangered species. In the 1980's, bear farming was established in China to extract bear bile from living bears with "Free-dripping Fistula Technique". Bear farming is extremely inhumane and many bears died of illness such as chronic infections and liver cancer. Efforts are now given by non-governmental organizations, mass media and Chinese government to end bear farming ultimately. At the same time, systematic research has to be done to find an alternative for bear bile. In this review, we focused on the literature, laboratory and clinical results related to bear bile and its substitutes or alternative in English and Chinese databases. We examined the substitutes or alternative of bear bile from three aspects: pure compounds derived from bear bile, biles from other animals and herbs from TCM. We then discussed the strategy for stopping the trading of bear bile and issues of bear bile related to potential alternative candidates, existing problems in alternative research and work to be done in the future. PMID:19138420

  20. Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context.

    Directory of Open Access Journals (Sweden)

    Aurélie Vega

    Full Text Available Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα and the G-protein coupled receptor (TGR5. These recent studies have led to the idea that molecules derived from bile acids (BAs and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes. Thus it might be important to decipher the potential long term impact of such treatment on different physiological functions. Indeed, BAs have recently been demonstrated to alter male fertility. Here we demonstrate that in mice with overweight induced by high fat diet, BA exposure leads to increased rate of male infertility. This is associated with the altered germ cell proliferation, default of testicular endocrine function and abnormalities in cell-cell interaction within the seminiferous epithelium. Even if the identification of the exact molecular mechanisms will need more studies, the present results suggest that both FXRα and TGR5 might be involved. We believed that this work is of particular interest regarding the potential consequences on future approaches for the treatment of metabolic diseases.

  1. Bile Acid Alters Male Mouse Fertility in Metabolic Syndrome Context

    Science.gov (United States)

    Baptissart, Marine; De Haze, Angélique; Vaz, Frederic; Kulik, Wim; Damon-Soubeyrand, Christelle; Baron, Silvère; Caira, Françoise; Volle, David H.

    2015-01-01

    Bile acids have recently been demonstrated as molecules with endocrine activities controlling several physiological functions such as immunity and glucose homeostases. They act mainly through two receptors, the nuclear receptor Farnesol-X-Receptor alpha (FXRα) and the G-protein coupled receptor (TGR5). These recent studies have led to the idea that molecules derived from bile acids (BAs) and targeting their receptors must be good targets for treatment of metabolic diseases such as obesity or diabetes. Thus it might be important to decipher the potential long term impact of such treatment on different physiological functions. Indeed, BAs have recently been demonstrated to alter male fertility. Here we demonstrate that in mice with overweight induced by high fat diet, BA exposure leads to increased rate of male infertility. This is associated with the altered germ cell proliferation, default of testicular endocrine function and abnormalities in cell-cell interaction within the seminiferous epithelium. Even if the identification of the exact molecular mechanisms will need more studies, the present results suggest that both FXRα and TGR5 might be involved. We believed that this work is of particular interest regarding the potential consequences on future approaches for the treatment of metabolic diseases. PMID:26439743

  2. Valproic acid-induced pancreatitis in a 15-year-old boy with juvenile myoclonic epilepsy.

    Science.gov (United States)

    Veri, Kadi; Uibo, Oivi; Talvik, Inga; Talvik, Tiina

    2013-01-01

    Drug-induced acute pancreatitis is a rare condition in childhood, and information about the incidence of valproic acid-induced acute pancreatitis in the pediatric population is scarce. In this clinical case, we report a first documented pediatric case of valproic acid-induced pancreatitis in Estonia. A 15-year-old boy with juvenile myoclonic epilepsy developed acute pancreatitis after 2-month therapy with valproic acid. The symptoms of pancreatitis subsided within 1 week after the discontinuation of treatment with valproic acid. Acute pancreatitis should be suspected in any pediatric patient with gastrointestinal symptoms during valproate treatment.

  3. Experimental Protoporphyria: Effect of Bile Acids on Liver Damage Induced by Griseofulvin

    Directory of Open Access Journals (Sweden)

    María del Carmen Martinez

    2015-01-01

    Full Text Available The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA, dehydrocholic (DHA, chenodeoxycholic, or ursodeoxycholic (URSO. The administration of Gris alone increased the activities of glutathione reductase (GRed, superoxide dismutase (SOD, alkaline phosphatase (AP, gamma glutamyl transpeptidase (GGT, and glutathione-S-transferase (GST, as well as total porphyrins, glutathione (GSH, and cytochrome P450 (CYP levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.

  4. Experimental protoporphyria: effect of bile acids on liver damage induced by griseofulvin.

    Science.gov (United States)

    Martinez, María Del Carmen; Ruspini, Silvina Fernanda; Afonso, Susana Graciela; Meiss, Roberto; Buzaleh, Ana Maria; Batlle, Alcira

    2015-01-01

    The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris) was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA), dehydrocholic (DHA), chenodeoxycholic, or ursodeoxycholic (URSO). The administration of Gris alone increased the activities of glutathione reductase (GRed), superoxide dismutase (SOD), alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), and glutathione-S-transferase (GST), as well as total porphyrins, glutathione (GSH), and cytochrome P450 (CYP) levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.

  5. Serum Bile Acids Are Higher in Humans With Prior Gastric Bypass: Potential Contribution to Improved Glucose and Lipid Metabolism

    Science.gov (United States)

    Patti, Mary-Elizabeth; Houten, Sander M.; Bianco, Antonio C.; Bernier, Raquel; Larsen, P. Reed; Holst, Jens J.; Badman, Michael K.; Maratos-Flier, Eleftheria; Mun, Edward C.; Pihlajamaki, Jussi; Auwerx, Johan; Goldfine, Allison B.

    2015-01-01

    The multifactorial mechanisms promoting weight loss and improved metabolism following Roux-en-Y gastric bypass (GB) surgery remain incompletely understood. Recent rodent studies suggest that bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2 thyroid hormone deiodinase. Altered gastrointestinal anatomy following GB could affect enterohepatic recirculation of bile acids. We assessed whether circulating bile acid concentrations differ in patients who previously underwent GB, which might then contribute to improved metabolic homeostasis. We performed cross-sectional analysis of fasting serum bile acid composition and both fasting and post-meal metabolic variables, in three subject groups: (i) post-GB surgery (n = 9), (ii) without GB matched to preoperative BMI of the index cohort (n = 5), and (iii) without GB matched to current BMI of the index cohort (n = 10). Total serum bile acid concentrations were higher in GB (8.90 ± 4.84 µmol/l) than in both overweight (3.59 ± 1.95, P = 0.005, Ov) and severely obese (3.86 ± 1.51, P = 0.045, MOb). Bile acid subfractions taurochenodeoxycholic, taurodeoxycholic, glycocholic, glycochenodeoxycholic, and glycodeoxycholic acids were all significantly higher in GB compared to Ov (P fasting triglycerides (r = −0.40, P = 0.05), and positively correlated with adiponectin (r = −0.48, P < 0.02) and peak glucagon-like peptide-1 (GLP-1) (r = 0.58, P < 0.003). Total bile acids strongly correlated inversely with thyrotropic hormone (TSH) (r = −0.57, P = 0.004). Together, our data suggest that altered bile acid levels and composition may contribute to improved glucose and lipid metabolism in patients who have had GB. PMID:19360006

  6. Foeniculum vulgare essential oil ameliorates acetic acid-induced colitis in rats through the inhibition of NF-kB pathway.

    Science.gov (United States)

    Rezayat, Seyed Mahdi; Dehpour, Ahmad-Reza; Motamed, Saeed Mohammadi; Yazdanparast, Maryam; Chamanara, Mohsen; Sahebgharani, Mousa; Rashidian, Amir

    2017-10-24

    The aim of the present study is to investigate the protective effects of Foeniculum vulgare essential oil on intestinal inflammation through the inhibition of NF-kB pathway in acetic acid-induced rat colitis. Acute colitis was induced by intra-rectal administration of 2 mL of diluted acetic acid (4%) solution. Two hours after the induction of colitis, 0.2% tween 80 in normal saline, dexamethasone (2 mg/kg) and F. vulgare essential oil (100, 200, 400 mg/kg) were administered to the animals by oral gavage and continued for 5 consecutive days. Assessment of macroscopic and microscopic lesions was done. MPO activity was evaluated by biochemical method. Furthermore, TNF-α activity was detected by immunohistochemistry (IHC) and the expression level of p-NF-kB p65 protein was measured by western blot analysis. Dexamethasone and F. vulgare essential oil (200, 400 mg/kg) reduced the macroscopic and microscopic lesions compared to the acetic acid group (p acetic acid group. Furthermore, they inhibited acetic acid-induced expression of p-NF-kB p65 protein (p acetic acid-induced colitis in rats may involve the inhibition of NF-kB pathway.

  7. Tetramethylpyrazine attenuates oleic acid-induced acute lung injury ...

    African Journals Online (AJOL)

    The protein expression of NF-kB in the lung was measured by immunohistochemistry and Western blotting. The results showed an increase in tumor necrosis factor α and interleukin 1β in the ALI/ARDS rat models. The activation of NF-kB was suppressed by TMP in the ALI/ARDS rats. The suppression of those molecules is ...

  8. Protective effect of gadolinium chloride on early warm ischemia/reperfusion injury in rat bile duct during liver transplantation.

    Directory of Open Access Journals (Sweden)

    Biao Wang

    Full Text Available BACKGROUND: Activation of Kupffer cell (KC is acknowledged as a key event in the initiation and perpetuation of bile duct warm ischemia/reperfusion injury. The inhibitory effect of gadolinium chloride (GdCl(3 on KC activation shows potential as a protective intervention in liver injury, but there is less research with regard to bile duct injury. METHODS: Sixty-five male Sprague-Dawley rats (200-250 g were randomly divided into three experimental groups: a sham group (n = 15, a control group (n = 25, and a GdCl(3 group (n = 25. Specimen was collected at 0.5, 2, 6, 12 and 24 h after operation. Alanine aminotransferase (ALT, alkaline phosphatase (ALP and total bilirubin (TBIL of serum were measured. Tumor necrosis factor-α (TNF-α, Capase-3 activity and soluble Fas (sFas were detected. The pathologic changes of bile duct were observed. Immunochemistry for bile duct Fas was performed. Apoptosis of bile duct cells was evaluated by the terminal UDP nick end labeling assay. RESULTS: GdCl(3 significantly decreased the levels of ALT, ALP and TBIL at 2, 6, 12, and 24 h, and increased serum sFas at 2, 6 and 12 h (P<0.05. TNF-α was lower in the GdCl(3 group than in the control group at 2, 6, 12 and 24 h (P<0.05. Preadministration of GdCl(3 significantly reduced the Caspase-3 activity and bile duct cell apoptosis at 2, 6, 12 and 24 h. After operation for 2, 6 and 12 h, the expression of Fas protein was lower in the GdCl(3 group than in the control group (P<0.05. CONCLUSIONS: GdCl(3 plays an important role in suppressing bile duct cell apoptosis, including decreasing ALT, ALP, TBIL and TNF-α; suppressing Fas-FasL-Caspase signal transduction during transplantation.

  9. Clearance of refractory bile duct stones with extracorporeal shockwave lithotripsy

    OpenAIRE

    Ellis, R; Jenkins, A; Thompson, R; Ede, R

    2000-01-01

    BACKGROUND—Extracorporeal shockwave lithotripsy (ESWL) has been used since the mid-1980s to fragment bile duct stones which cannot be removed endoscopically. Early machines required general anaesthesia and immersion in a waterbath.
AIMS—To investigate the effectiveness of the third generation Storz Modulith SL20 lithotriptor in fragmenting bile duct stones that could not be cleared by mechanical lithotripsy.
METHODS—Eighty three patients with retained bile duct stones were treated. All patien...

  10. Squamous Cell Carcinoma of the Distal Common Bile Duct

    OpenAIRE

    Jain A; Juneja M; Naik S; Sharma S; Kapoor S; Sewkani A; Varshney S

    2005-01-01

    CONTEXT: Squamous cell carcinoma of the biliary tree is rare. Although few cases of squamous cell carcinoma of the intrahepatic bile-duct and gallbladder have been reported, until today, only four cases of squamous cell carcinoma of the extrahepatic bile duct have been reported in the literature. CASE REPORT: We present a case of squamous cell carcinoma of the distal common bile duct presenting with obstructive jaundice in a 60-year-old male which was successfully managed by a Whipple's pancr...

  11. Postnatal development of bile secretory physiology in the dog

    International Nuclear Information System (INIS)

    Tavoloni, N.; Jones, M.J.; Berk, P.D.

    1985-01-01

    To determine whether bile formation in the dog is an immature process at birth, several determinants of bile secretion were studied in anesthetized, bile duct-cannulated puppies of 0-42 days of age and adult dogs. Basal canalicular bile flow rate, estimated by 14 C-erythritol biliary clearance, averaged 0.182 microliter/min/g liver in 0-3 day-old puppies and increased to 0.324 and 0.461 microliter/min/g in puppies 7-21 and 28-42 days of age, respectively. Calculated ductular bile water reabsorption ( 14 C-erythritol biliary clearance-bile flow) was virtually absent in 0-3 day-old puppies, and averaged 0.017 and 0.092 microliter/min/g in puppies of 7-21 and 28-42 days of age, respectively. In adult dogs, ductular bile water reabsorption was 0.132 microliter/min/g. These functional deficiencies of the newborn dog were associated with an increased biliary permeability to 3 H-inulin which could not be accounted for solely by an increased solute diffusion due to the lower rate of canalicular bile flow. Administration of taurocholate up to 2000 nmol/min/kg produced in all animals a similar increase in canalicular bile flow and bile acid excretion, and was not associated with changes in ductular bile water reabsorption rate. These findings are interpreted to indicate that, in the dog, bile secretory function is immature at birth and develops during postnatal life

  12. Docosahexaenoic acid induces apoptosis in primary chronic lymphocytic leukemia cells

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    Romain Guièze

    2015-12-01

    Full Text Available Chronic lymphocytic leukemia is an indolent disorder with an increased infectious risk remaining one of the main causes of death. Development of therapies with higher safety profile is thus a challenging issue. Docosahexaenoic acid (DHA, 22:6 is an omega-3 fatty acid, a natural compound of normal cells, and has been shown to display antitumor potency in cancer. We evaluated the potential in vitro effect of DHA in primary CLL cells. DHA induces high level of in vitro apoptosis compared to oleic acid in a dose-dependent and time-dependent manner. Estimation of IC50 was only of 4.813 μM, which appears lower than those reported in solid cancers. DHA is highly active on CLL cells in vitro. This observation provides a rationale for further studies aiming to understand its mechanisms of action and its potent in vivo activity.

  13. Contents and implications of ammonia human and canine bile.

    Science.gov (United States)

    Alderete, J S; Gaines, E L; Hudson, N L

    1978-08-01

    The quantification and physiological significance of ammonia in human and canine bile has not been clearly documented or analyzed previously. Bile from the gallbladder, common hepatic duct, and from T-tubes obtained from patients undergoing cholecystectomy and choledochotomy. Similar samples were obtained in 6 dogs by cannulation of their hepatic duct and various blood vessels. Simultaneous blood and bile samples were obtained at 15-min intervals before during, and after an exogenous load of ammonia, given intravenously. Ammonia levels were measured in all samples. Ammonia was measurable by conventional methods in human and canine bile. In both species the gallbladder bile contained at least twice as much ammonia as bile from the common hepatic duct. After an exogenous ammonia load, the levels of ammonia in canine bile increased in similar patterns, but in lesser magnitude than the ammonia levels measured at several sites in the circulation. The findings document that the bile contains ammonia in different quantities and suggest that bile could be an additional pathway for the removal of ammonia by the liver, in addition to the urea cycle. The loss of the biliary pathway for ammonia excretion could contribute to the pathophysiology of the signs and symptoms attributed to hyperammoniemia occurring in human beings and dogs with decreased hepatic function.

  14. Heterologous expression of a tannic acid-inducible laccase3 of Cryphonectria parasitica in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Kim Dae-Hyuk

    2010-02-01

    Full Text Available Abstract Background A tannic acid-inducible and mycoviral-regulated laccase3 (lac3 from the chestnut blight fungus Cryphonectria parasitica has recently been identified, but further characterization was hampered because of the precipitation of protein products by tannic acid supplementation. The present study investigated the heterologous expression of the functional laccase3 using a yeast Saccharomyces cerevisiae. Results Laccase activity in the culture broth of transformants measured using a laccase-specific substrate suggested that the lac3 gene was successfully expressed and the corresponding protein product secreted into the culture media. In addition, activity staining and Western blot analysis of a native gel revealed that the enzyme activity co-existed with the protein product specific to anti-laccase3 antibody, confirming that the cloned lac3 gene is responsible for the laccase activity. When transformants were grown on plates containing tannic acid-supplemented media, brown coloration was observed around transformed cells, indicating the oxidation of tannic acid. However, the enzymatic activity was measurable only in the selective ura- media and was negligible in nonselective nutrient-rich culture conditions. This was in part because of the increased plasmid instability in the nonselective media. Moreover, the protein product of lac3 appears to be sensitive to the cultured nonselective nutrient-rich broth, because a rapid decline in enzymatic activity was observed when the cultured broth of ura- media was mixed with that of nonselective nutrient-rich broth. In addition, constitutive expression of the lac3 gene resulted in a reduced cell number of the lac3 transformants compared to that of vector-only transformed control. However, the presence of recombinant vector without lac3 induction did not affect the growth of transformants. Conclusions The results suggest that expression of the lac3 gene has an inhibitory effect on the growth of

  15. Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction.

    Science.gov (United States)

    Perreault, Martin; Białek, Andrzej; Trottier, Jocelyn; Verreault, Mélanie; Caron, Patrick; Milkiewicz, Piotr; Barbier, Olivier

    2013-01-01

    Biliary obstruction, a severe cholestatic condition, results in a huge accumulation of toxic bile acids (BA) in the liver. Glucuronidation, a conjugation reaction, is thought to protect the liver by both reducing hepatic BA toxicity and increasing their urinary elimination. The present study evaluates the contribution of each process in the overall BA detoxification by glucuronidation. Glucuronide (G), glycine, taurine conjugates, and unconjugated BAs were quantified in pre- and post-biliary stenting urine samples from 12 patients with biliary obstruction, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The same LC-MS/MS procedure was used to quantify intra- and extracellular BA-G in Hepatoma HepG2 cells. Bile acid-induced toxicity in HepG2 cells was evaluated using MTS reduction, caspase-3 and flow cytometry assays. When compared to post-treatment samples, pre-stenting urines were enriched in glucuronide-, taurine- and glycine-conjugated BAs. Biliary stenting increased the relative BA-G abundance in the urinary BA pool, and reduced the proportion of taurine- and glycine-conjugates. Lithocholic, deoxycholic and chenodeoxycholic acids were the most cytotoxic and pro-apoptotic/necrotic BAs for HepG2 cells. Other species, such as the cholic, hyocholic and hyodeoxycholic acids were nontoxic. All BA-G assayed were less toxic and displayed lower pro-apoptotic/necrotic effects than their unconjugated precursors, even if they were able to penetrate into HepG2 cells. Under severe cholestatic conditions, urinary excretion favors the elimination of amidated BAs, while glucuronidation allows the conversion of cytotoxic BAs into nontoxic derivatives.

  16. Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction.

    Directory of Open Access Journals (Sweden)

    Martin Perreault

    Full Text Available Biliary obstruction, a severe cholestatic condition, results in a huge accumulation of toxic bile acids (BA in the liver. Glucuronidation, a conjugation reaction, is thought to protect the liver by both reducing hepatic BA toxicity and increasing their urinary elimination. The present study evaluates the contribution of each process in the overall BA detoxification by glucuronidation. Glucuronide (G, glycine, taurine conjugates, and unconjugated BAs were quantified in pre- and post-biliary stenting urine samples from 12 patients with biliary obstruction, using liquid chromatography-tandem mass spectrometry (LC-MS/MS. The same LC-MS/MS procedure was used to quantify intra- and extracellular BA-G in Hepatoma HepG2 cells. Bile acid-induced toxicity in HepG2 cells was evaluated using MTS reduction, caspase-3 and flow cytometry assays. When compared to post-treatment samples, pre-stenting urines were enriched in glucuronide-, taurine- and glycine-conjugated BAs. Biliary stenting increased the relative BA-G abundance in the urinary BA pool, and reduced the proportion of taurine- and glycine-conjugates. Lithocholic, deoxycholic and chenodeoxycholic acids were the most cytotoxic and pro-apoptotic/necrotic BAs for HepG2 cells. Other species, such as the cholic, hyocholic and hyodeoxycholic acids were nontoxic. All BA-G assayed were less toxic and displayed lower pro-apoptotic/necrotic effects than their unconjugated precursors, even if they were able to penetrate into HepG2 cells. Under severe cholestatic conditions, urinary excretion favors the elimination of amidated BAs, while glucuronidation allows the conversion of cytotoxic BAs into nontoxic derivatives.

  17. Beneficial effect of rice bran extract against 3-nitropropionic acid induced experimental Huntington's disease in rats

    Directory of Open Access Journals (Sweden)

    Navneet Kaur

    2015-01-01

    Full Text Available Huntington's disease (HD is a neurodegenerative disorder, characterized by progressive motor and non-motor dysfunction due to degeneration of medium spiny neurons in striatum. 3-Nitropropionic acid is commonly used to induce the animal model of HD. Rice bran is supposed to have beneficial effects on mitochondrial function. The present study has been designed to explore the effect of rice bran extract against 3-Nitropropionic acid induced neurotoxicity in rats. 3-Nitropropionic acid (10 mg/kg, i.p was administered systemically for 21 days. Hexane and ethanol extract of rice bran were prepared using Soxhlation. Hexane (250 mg/kg and ethanol extract (250 mg/kg were administered per os for 21 days in 3-NP treated groups. Behavioral parameters (body weight, grip strength, motor coordination, locomotion were conducted on 7th, 14th and 21st day. Animals were sacrificed on 22nd day for biochemical, mitochondrial dysfunction (Complex II, neuroinflammatory and neurochemical estimation in striatum. This study demonstrates significant alteration in behavioral parameters, oxidative burden (increased lipid peroxidation, nitrite concentration and decreased glutathione, mitochondrial function (decreased Complex II enzyme activity, pro-inflammatory mediators and neurochemical levels in 3-nitropropionic acid treated animals. Administration of hexane and ethanol extract prevented the behavioral, biochemical, neuroinflammatory (increased TNF-α, IL-1β and IL-6 and neurochemical alterations (decreased dopamine, norepinephrine, serotonin, 5-hydroxy indole acetic acid, GABA and increased 3,4-dihydro phenyl acetaldehyde, homovanillic acid and glutamate levels induced by 3-nitropropionic acid. The outcomes of present study suggest that rice bran extract is beneficial and might emerge as an adjuvant or prophylactic therapy for treatment of HD like symptoms.

  18. Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores.

    Science.gov (United States)

    Zutz, Christoph; Bacher, Markus; Parich, Alexandra; Kluger, Bernhard; Gacek-Matthews, Agnieszka; Schuhmacher, Rainer; Wagner, Martin; Rychli, Kathrin; Strauss, Joseph

    2016-01-01

    One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called "cryptic," often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these "cryptic" metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity against antibiotic

  19. Rosmarinic acid potentiates carnosic acid induced apoptosis in lung fibroblasts.

    Directory of Open Access Journals (Sweden)

    Sana Bahri

    Full Text Available Pulmonary fibrosis is characterized by over-population and excessive activation of fibroblasts and myofibroblasts disrupting normal lung structure and functioning. Rosemary extract rich in carnosic acid (CA and rosmarinic acid (RA was reported to cure bleomycin-(BLM-induced pulmonary fibrosis. We demonstrate that CA decreased human lung fibroblast (HLF viability with IC50 value of 17.13±1.06 μM, while RA had no cytotoxic effect. In the presence of 50 μM of RA, dose-response for CA shifted to IC50 value of 11.70±1.46 μM, indicating synergic action. TGFβ-transformed HLF, rat lung fibroblasts and L929 cells presented similar sensitivity to CA and CA+RA (20μM+100μM, respectively treatment. Rat alveolar epithelial cells died only under CA+RA treatment, while A549 cells were not affected. Annexin V staining and DNA quantification suggested that HLF are arrested in G0/G1 cell cycle phase and undergo apoptosis. CA caused sustained activation of phospho-Akt and phospho-p38 expression and inhibition of p21 protein.Addition of RA potentiated these effects, while RA added alone had no action.Only triple combination of inhibitors (MAPK-p38, pan-caspase, PI3K/Akt/autophagy partially attenuated apoptosis; this suggests that cytotoxicity of CA+RA treatment has a complex mechanism involving several parallel signaling pathways. The in vivo antifibrotic effect of CA and RA was compared with that of Vitamine-E in BLM-induced fibrosis model in rats. We found comparable reduction in fibrosis score by CA, RA and CA+RA, attenuation of collagen deposition and normalization of oxidative stress markers. In conclusion, antifibrotic effect of CA+RA is due to synergistic pro-apoptotic action on lung fibroblasts and myofibroblasts.

  20. Tolerance of bile duct to intraoperative irradiation

    International Nuclear Information System (INIS)

    Sindelar, W.F.; Tepper, J.; Travis, E.L.

    1982-01-01

    In order to determine the effects of intraoperative radiation therapy of the bile duct and surrounding tissues, seven adult dogs were subjected to laparotomy and intraoperative irradiation with 11 MeV electrons. Two animals were treated at each dose level of 2000, 3000, and 4500 rads. A single dog which received a laparotomy and sham irradiation served as a control. The irradiation field consisted of a 5 cm diameter circle encompassing the extrahepatic bile duct, portal vein, hepatic artery, and lateral duodenal wall. The animals were followed clinically for mor than 18 months after treatment, and autopsies were performed on dogs that died to assess radiation-induced complications or tissue damage. All dogs developed fibrosis and mural thickening of the common duct, which appeared by 6 weeks following irradiation and which was dose-related, being mild at low doses and more severe at high doses. Hepatic changes were seen as early as 6 weeks after irradiation, consisting of periportal inflammation and fibrosis. The hepatic changes appeared earliest at the highest doses. Frank biliary cirrhosis eventually developed at all dose levels. Duodenal fibrosis appeared in the irradiation portal, being most severe at the highest doses and in some animals resulting in duodenal obstruction. No changes were observed in irradiated portions of portal vein and hepatic artery at any dose level. It was concluded that intraoperative radiation therapy delivered to the region of the common duct leads to ductal fibrosis, partial biliary obstruction with secondary hepatic changes, and duodenal fibrosis if bowel wall is included in the field. Clinical use of intraoperative radiation therapy to the bile duct in humans may require routine use of biliary and duodenal bypass to prevent obstructive complications

  1. NMR-based modelling and binding studies of a ternary complex between chicken liver bile acid binding protein and bile acids

    NARCIS (Netherlands)

    Tomasell, S.; Ragona, L.; Zetta, L.; Assfalg, M.; Ferranti, P.; Longhi, R.; Bonvin, A.M.J.J.; Molinari, H.

    2007-01-01

    Chicken liver bile acid binding protein (cL-BABP) is involved in bile acid transport in the liver cytosol. A detailed study of the mechanism of binding and selectivity of bile acids binding proteins towards the physiological pool of bile salts is a key issue for the complete understanding of the

  2. Sphingomyelin exhibits greatly enhanced protection compared with egg yolk phosphatidylcholine against detergent bile salts

    NARCIS (Netherlands)

    Moschetta, A.; vanBerge-Henegouwen, G. P.; Portincasa, P.; Palasciano, G.; Groen, A. K.; van Erpecum, K. J.

    2000-01-01

    Inclusion of phosphatidylcholine within bile salt micelles protects against bile salt-induced cytotoxicity. In addition to phosphatidylcholine, bile may contain significant amounts of sphingomyelin, particularly under cholestatic conditions. We compared protective effects of egg yolk

  3. Predicting Infected Bile Among Patients Undergoing Percutaneous Cholecystostomy

    International Nuclear Information System (INIS)

    Beardsley, Shannon L.; Shlansky-Goldberg, Richard D.; Patel, Aalpen; Freiman, David B.; Soulen, Michael C.; Stavropoulos, S. William; Clark, Timothy W.I.

    2005-01-01

    Purpose. Patients may not achieve a clinical benefit after percutaneous cholecystostomy due to the inherent difficulty in identifying patients who truly have infected gallbladders. We attempted to identify imaging and biochemical parameters which would help to predict which patients have infected gallbladders. Methods. A retrospective review was performed of 52 patients undergoing percutaneous cholecystostomy for clinical suspicion of acute cholecystitis in whom bile culture results were available. Multiple imaging and biochemical variables were examined alone and in combination as predictors of infected bile, using logistic regression. Results. Of the 52 patients, 25 (48%) had infected bile. Organisms cultured included Enterococcus, Enterobacter, Klebsiella, Pseudomonas, E. coli, Citrobacter and Candida. No biochemical parameters were significantly predictive of infected bile; white blood cell count >15,000 was weakly associated with greater odds of infected bile (odds ratio 2.0, p = NS). The presence of gallstones, sludge, gallbladder wall thickening and pericholecystic fluid by ultrasound or CT were not predictive of infected bile, alone or in combination, although a trend was observed among patients with CT findings of acute cholecystitis toward a higher 30-day mortality. Radionuclide scans were performed in 31% of patients; all were positive and 66% of these patients had infected bile. Since no patient who underwent a radionuclide scan had a negative study, this variable could not be entered into the regression model due to collinearity. Conclusion. No single CT or ultrasound imaging variable was predictive of infected bile, and only a weak association of white blood cell count with infected bile was seen. No other biochemical parameters had any association with infected bile. The ability of radionuclide scanning to predict infected bile was higher than that of ultrasound or CT. This study illustrates the continued challenge to identify bacterial cholecystitis

  4. Betulinic acid induces cell death by necrosis in Trypanosoma cruzi.

    Science.gov (United States)

    Sousa, Paloma Leão; Souza, Racquel Oliveira da Silva; Tessarolo, Louise Donadello; de Menezes, Ramon Róseo Paula Pessoa Bezerra; Sampaio, Tiago Lima; Canuto, Jader Almeida; Martins, Alice Maria Costa

    2017-10-01

    Chagas' disease is a neglected disease caused by the protozoan parasite Trypanosoma cruzi and constitutes a serious health problem worldwide. The treatment is limited, with variable efficacy of benznidazole and nifurtimox. Betulinic Acid (BA), a triterpene, can be found in medicinal herbs and has a wide variety of biological and pharmacological activities. The objective was to evaluate betulinic acid effects on the cell death mechanism in Trypanosoma cruzi strain Y. BA inhibited the growth of epimastigotes in periods of 24h (IC 50 =73.43μM), 48h (IC 50 =119.8μM) and 72h (IC 50 =212.2μM) of incubation; of trypomastigotes (IC 50 =51.88μM) in periods of 24h and intracellular amastigotes (IC 50 =25.94μM) in periods of 24 and 48h of incubation, no toxicity on LLC-MK 2 cells at the concentrations used. Analysis of the possible mechanism of parasite cell death showed alterations in mitochondrial membrane potential, alterations in cell membrane integrity, an increase in the formation of reactive oxygen species and increase swelling of the reservosomes. In conclusion, betulinic acid was be able to inhibition all developmental forms of Trypanosoma cruzi Y strain with necrotic mechanism and involvement of mitochondrial membrane potential alteration and increase in reactive oxygen species. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. The valproic acid-induced rodent model of autism.

    Science.gov (United States)

    Nicolini, Chiara; Fahnestock, Margaret

    2018-01-01

    Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Albumin-associated free fatty acids induce macropinocytosis in podocytes

    Science.gov (United States)

    Chung, Jun-Jae; Huber, Tobias B.; Gödel, Markus; Jarad, George; Hartleben, Björn; Kwoh, Christopher; Keil, Alexander; Karpitskiy, Aleksey; Hu, Jiancheng; Huh, Christine J.; Cella, Marina; Gross, Richard W.; Miner, Jeffrey H.; Shaw, Andrey S.

    2015-01-01

    Podocytes are specialized epithelial cells in the kidney glomerulus that play important structural and functional roles in maintaining the filtration barrier. Nephrotic syndrome results from a breakdown of the kidney filtration barrier and is associated with proteinuria, hyperlipidemia, and edema. Additionally, podocytes undergo changes in morphology and internalize plasma proteins in response to this disorder. Here, we used fluid-phase tracers in murine models and determined that podocytes actively internalize fluid from the plasma and that the rate of internalization is increased when the filtration barrier is disrupted. In cultured podocytes, the presence of free fatty acids (FFAs) associated with serum albumin stimulated macropinocytosis through a pathway that involves FFA receptors, the Gβ/Gγ complex, and RAC1. Moreover, mice with elevated levels of plasma FFAs as the result of a high-fat diet were more susceptible to Adriamycin-induced proteinuria than were animals on standard chow. Together, these results support a model in which podocytes sense the disruption of the filtration barrier via FFAs bound to albumin and respond by enhancing fluid-phase uptake. The response to FFAs may function in the development of nephrotic syndrome by amplifying the effects of proteinuria. PMID:25915582

  7. Transforming growth factor-beta 1 and mannose 6-phosphate/insulin-like growth factor-II receptor expression during intrahepatic bile duct hyperplasia and biliary fibrosis in the rat.

    Science.gov (United States)

    Saperstein, L A; Jirtle, R L; Farouk, M; Thompson, H J; Chung, K S; Meyers, W C

    1994-02-01

    These studies investigate the role of transforming growth factor-beta 1, a potent inhibitor of epithelial cell proliferation and stimulator of extracellular matrix biosynthesis, during intrahepatic bile duct hyperplasia and biliary fibrosis. These pathogenic responses were induced in rats by common bile duct ligation. Bile duct cell replication, measured by the bromodeoxyuridine labeling index, was significantly increased 24 hr after common bile duct ligation. This response diminished to baseline by 1 wk. Liver collagen content, determined by quantification of hydroxyproline, was increased significantly after 1 wk of common bile duct ligation, and by 4 wk was increased by a factor of 4. Immunohistochemistry revealed low levels of TGF-beta 1 in normal intrahepatic bile duct epithelium. In contrast, the bile duct epithelium in bile duct-ligated rats stained strongly positive for transforming growth factor-beta 1 at 1 and 4 wk after ligation. These results suggest that transforming growth factor-beta 1 may play a role in both the termination of the bile duct epithelial cell proliferative response and the induction of fibrogenesis after common bile duct ligation. In addition, the mannose 6-phosphate/insulin-like growth factor II receptor was up-regulated in hyperplastic bile duct epithelium 1 and 4 wk after ligation. Because the mannose 6-phosphate/insulin-like growth factor-II receptor has been shown to facilitate the proteolytic activation of transforming growth factor-beta 1, these results suggest that the bile duct epithelium may also be involved in the activation of transforming growth factor-beta 1.

  8. Biofilm Formation and Detachment in Gram-Negative Pathogens Is Modulated by Select Bile Acids.

    Directory of Open Access Journals (Sweden)

    Laura M Sanchez

    Full Text Available Biofilms are a ubiquitous feature of microbial community structure in both natural and host environments; they enhance transmission and infectivity of pathogens and provide protection from human defense mechanisms and antibiotics. However, few natural products are known that impact biofilm formation or persistence for either environmental or pathogenic bacteria. Using the combination of a novel natural products library from the fish microbiome and an image-based screen for biofilm inhibition, we describe the identification of taurine-conjugated bile acids as inhibitors of biofilm formation against both Vibrio cholerae and Pseudomonas aeruginosa. Taurocholic acid (1 was isolated from the fermentation broth of the fish microbiome-derived strain of Rhodococcus erythropolis and identified using standard NMR and MS methods. Screening of the twelve predominant human steroidal bile acid components revealed that a subset of these compounds can inhibit biofilm formation, induce detachment of preformed biofilms under static conditions, and that these compounds display distinct structure-activity relationships against V. cholerae and P. aeruginosa. Our findings highlight the significance of distinct bile acid components in the regulation of biofilm formation and dispersion in two different clinically relevant bacterial pathogens, and suggest that the bile acids, which are endogenous mammalian metabolites used to solubilize dietary fats, may also play a role in maintaining host health against bacterial infection.

  9. Long-term fate of the bile duct cells proliferated during chronic thioacetamide poisoning.

    Science.gov (United States)

    Malvaldi, G; Pollera, M

    1982-01-01

    The cell composition of the biliary proliferations induced by thioacetamide administration was investigated. At the end of the intoxication period the main cell types identified among the neoformed bile duct cells were as follows: i) poorly differentiated cells (oval cells) usually arranged in clusters or tiny cords, provided with a great amount of free ribosomes; ii) cells arranged in bile ducts of normal appearance; iii) cells arranged in bile ducts and showing intestinal metaplasia. After withdrawal of TAA most of the biliary proliferations disappeared; in the remaining ones, where the incorporation of 3H-thymidine was still appreciable, significant changes in the bile duct cell composition were evident; in fact whereas the oval cells were no longer identifiable, those suggesting an intestinal metaplasia underwent a relative increment as well as those displaying butyrocholinesterase activity; cells devoid of junctional apparatus and filled with free ribosomes were also seen. Some of the reported finding could support the hypothesis that the biological meaning of the different cell types arisen during intoxication is different; some of them could be due to a reactive hyperplasia, while other could be considered as representing a preneoplastic step.

  10. Proteomics and transcriptomics characterization of bile stress response in probiotic Lactobacillus rhamnosus GG.

    Science.gov (United States)

    Koskenniemi, Kerttu; Laakso, Kati; Koponen, Johanna; Kankainen, Matti; Greco, Dario; Auvinen, Petri; Savijoki, Kirsi; Nyman, Tuula A; Surakka, Anu; Salusjärvi, Tuomas; de Vos, Willem M; Tynkkynen, Soile; Kalkkinen, Nisse; Varmanen, Pekka

    2011-02-01

    Lactobacillus rhamnosus GG (GG) is a widely used and intensively studied probiotic bacterium. Although the health benefits of strain GG are well documented, the systematic exploration of mechanisms by which this strain exerts probiotic effects in the host has only recently been initiated. The ability to survive the harsh conditions of the gastrointestinal tract, including gastric juice containing bile salts, is one of the vital characteristics that enables a probiotic bacterium to transiently colonize the host. Here we used gene expression profiling at the transcriptome and proteome levels to investigate the cellular response of strain GG toward bile under defined bioreactor conditions. The analyses revealed that in response to growth of strain GG in the presence of 0.2% ox gall the transcript levels of 316 genes changed significantly (p GG cells of gut entrance. Notably, the surfome analyses demonstrated significant reduction in the abundance of a protein catalyzing the synthesis of exopolysaccharides, whereas a protein dedicated for active removal of bile compounds from the cells was up-regulated. These findings suggest a role for these proteins in facilitating the well founded interaction of strain GG with the host mucus in the presence of sublethal doses of bile. The significance of these findings in terms of the functionality of a probiotic bacterium is discussed.

  11. Inside the adaptation process of Lactobacillus delbrueckii subsp. lactis to bile

    OpenAIRE

    Burns, Patricia; Sánchez García, Borja; Vinderola, Gabriel; Ruas-Madiedo, Patricia; Ruíz García, Lorena; Margolles Barros, Abelardo; Reinheimer, Jorge A.; González de los Reyes-Gavilán, Clara

    2010-01-01

    Progressive adaptation to bile might render some lactobacilli able to withstand physiological bile salt concentrations. In this work, the adaptation to bile was evaluated on previously isolated dairy strains of Lactobacillus delbrueckii subsp. lactis 200 and L. delbrueckii subsp. lactis 200+, a strain derived thereof with stable bile-resistant phenotype. The adaptation to bile was obtained by comparing cytosolic proteomes of both strains grown in the presence or absence of bile. Proteomics we...

  12. Bile Acid-Mediated Sphingosine-1-Phosphate Receptor 2 Signaling Promotes Neuroinflammation during Hepatic Encephalopathy in Mice

    Directory of Open Access Journals (Sweden)

    Matthew McMillin

    2017-07-01

    Full Text Available Hepatic encephalopathy (HE is a neuropsychiatric complication that occurs due to deteriorating hepatic function and this syndrome influences patient quality of life, clinical management strategies and survival. During acute liver failure, circulating bile acids increase due to a disruption of the enterohepatic circulation. We previously identified that bile acid-mediated signaling occurs in the brain during HE and contributes to cognitive impairment. However, the influences of bile acids and their downstream signaling pathways on HE-induced neuroinflammation have not been assessed. Conjugated bile acids, such as taurocholic acid (TCA, can activate sphingosine-1-phosphate receptor 2 (S1PR2, which has been shown to promote immune cell infiltration and inflammation in other models. The current study aimed to assess the role of bile-acid mediated S1PR2 signaling in neuroinflammation and disease progression during azoxymethane (AOM-induced HE in mice. Our findings demonstrate a temporal increase of bile acids in the cortex during AOM-induced HE and identified that cortical bile acids were elevated as an early event in this model. In order to classify the specific bile acids that were elevated during HE, a metabolic screen was performed and this assay identified that TCA was increased in the serum and cortex during AOM-induced HE. To reduce bile acid concentrations in the brain, mice were fed a diet supplemented with cholestyramine, which alleviated neuroinflammation by reducing proinflammatory cytokine expression in the cortex compared to the control diet-fed AOM-treated mice. S1PR2 was expressed primarily in neurons and TCA treatment increased chemokine ligand 2 mRNA expression in these cells. The infusion of JTE-013, a S1PR2 antagonist, into the lateral ventricle prior to AOM injection protected against neurological decline and reduced neuroinflammation compared to DMSO-infused AOM-treated mice. Together, this identifies that reducing bile acid

  13. Bile pigments in pulmonary and vascular disease

    Directory of Open Access Journals (Sweden)

    Stefan W. Ryter

    2012-03-01

    Full Text Available The bile pigments, biliverdin and bilirubin, are endogenously-derived substances generated during enzymatic heme degradation. These compounds have been shown to act as chemical antioxidants in vitro. Bilirubin formed in tissues circulates in the serum, prior to undergoing hepatic conjugation and biliary excretion. The excess production of bilirubin has been associated with neurotoxicity, in particular to the newborn. Nevertheless, clinical evidence suggests that mild states of hyperbilirubinemia may be beneficial in protecting against cardiovascular disease in adults. Pharmacological application of either bilirubin and/or its biological precursor biliverdin, can provide therapeutic benefit in several animal models of cardiovascular and pulmonary disease. Furthermore, biliverdin and bilirubin can confer protection against ischemia/reperfusion injury and graft rejection secondary to organ transplantation in animal models. Several possible mechanisms for these effects have been proposed, including direct antioxidant and scavenging effects, and modulation of signaling pathways regulating inflammation, apoptosis, cell proliferation, and immune responses. The practicality and therapeutic-effectiveness of bile pigment application to humans remains unclear.

  14. Bile secretion in albino rat following chronic honey intake | Alagwu ...

    African Journals Online (AJOL)

    This study was carried out to evaluate the effect of honey intake on bile secretion, bile electrolytes, bilirubin and cholesterol levels including plasma cholesterol in albino rats. 20 male albino rats (200-210g) were used in the study. The rats were assigned randomly into 2 groups (control and honey-fed groups), each group ...

  15. The influence of bile acids homeostasis by cryptotanshinone ...

    African Journals Online (AJOL)

    Background: Herbs might affect the homeostasis of bile acids through influence of multiple metabolic pathways of bile acids. Aim: The present study aims to investigate the inhibition of cryptotanshinone towards the glucuronidation of LCA, trying to indicate the possible influence of cryptotanshinone-containing herbs towards ...

  16. Enhancing Effect of Bile Salts on Gastrointestinal Absorption of Insulin

    African Journals Online (AJOL)

    Purpose: To investigate the effect of co-administration of two absorption enhancing bile salts, sodium glycocholate (NaGc) and ... Keywords: Bile salts, Sodium glycocholate, Sodium salicylate, Insulin, Gastrointestinal administration. Tropical Journal of ..... such as micelle formation, solubilization, alteration of the mucus layer ...

  17. Bile Acids as Building Blocks of Supramolecular Hosts

    Directory of Open Access Journals (Sweden)

    Erkki Kolehmainen

    2001-01-01

    Full Text Available A review of the use of bile acid-based compounds as building blocks for designing novel supramolecular hosts for molecular recognition is presented. Pharmacological applications and the newest spectroscopic and computational studies of bile acid derivatives are also shortly considered.

  18. Biomechanical modelling of bile flow in the biliary system

    Directory of Open Access Journals (Sweden)

    Kuchumov Alex

    2018-01-01

    Full Text Available The biliary system consists of the biliary tree, gallbladder and major duodenal papilla. Soft tissues compliance plays important role in the bio-fluids transport. Particularly, bile flow disturbances due to bile duct wall motor function changes in the extra-hepatic ducts, from medicine point of view are called dyscinesia of biliary tract. Fluid motion in the elastic and compliant ducts can be described by different models (for example, Windkessel model, peristaltic fluid motion, FSI algorithm. Our approach is decomposition of the biliary system into three compartments (extra-hepatic biliary tree, gallbladder, major duodenal papilla. Bile flow in the extra-hepatic ducts is simulated using FSI algorithm. Bile flow in the gallbladder can be described as flow in the reservoir with compliant ducts using Windkessel model. Bile flow in the major duodenal papilla is considered as peristaltic fluid motion, because the wall contraction is really important factor of fluid motion in that segment. The coupling of these compartments is performed by boundary conditions. The biliary system geometry was obtained using MRI patient-specific data. It was confirmed that normal bile can be modeled as Newtonian fluid and lithogenic bile can be modeled as non-Newtonian fluid (Carreau fluid. Bile ducts were modeled as hyperelastic material.

  19. Toxicity of peroxisomal C27-bile acid intermediates

    NARCIS (Netherlands)

    Ferdinandusse, Sacha; Denis, Simone; Dacremont, Georges; Wanders, Ronald J. A.

    2009-01-01

    Peroxisomes play an important role in bile acid biosynthesis because the last steps of the synthesis pathway are performed by the beta-oxidation system located inside peroxisomes. As a consequence, C(27)-bile acid intermediates accumulate in several peroxisomal disorders. It has been suggested that

  20. In vitro evidence of possible influence of scutellarein towards bile ...

    African Journals Online (AJOL)

    In vitro evidence of possible influence of scutellarein towards bile acids' metabolism. Z Shu-Yao, J Hong, L Chao-Xian, Z Zhi-Wei, D Xin, C Lei. Abstract. Background: The glucuronidation process has been regarded as the key elimination process for toxic bile acids. UDPglucuronosyltransferase (UGT) 1A3 is one important ...

  1. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition.

    Directory of Open Access Journals (Sweden)

    Ling Zhang

    Full Text Available Severe acute malnutrition (SAM is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis.An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4 and FGF-19 were quantified.On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01 in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19, a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower.SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

  2. Olodaterol Attenuates Citric Acid-Induced Cough in Naïve and Ovalbumin-Sensitized and Challenged Guinea Pigs

    Science.gov (United States)

    Wex, Eva; Bouyssou, Thierry

    2015-01-01

    Excessive coughing is a common feature of airway diseases. Different G-protein coupled receptors, including β2-adrenergic receptors (β2-AR), have been implicated in the molecular mechanisms underlying the cough reflex. However, the potential antitussive property of β2-AR agonists in patients with respiratory disease is a matter of ongoing debate. The aim of our study was to test the efficacy of the long-acting β2-AR agonist olodaterol with regard to its antitussive property in a pre-clinical model of citric acid-induced cough in guinea pigs and to compare the results to different clinically relevant β2-AR agonists. In our study β2-AR agonists were intratracheally administered, as dry powder, into the lungs of naïve or ovalbumin-sensitized guinea pigs 15 minutes prior to induction of cough by exposure to citric acid. Cough events were counted over 15 minutes during the citric acid exposure. Olodaterol dose-dependently inhibited the number of cough events in naïve and even more potently and with a greater maximal efficacy in ovalbumin-sensitized guinea pigs (p citric acid-induced cough in naïve and ovalbumin-sensitized guinea pigs. This is in agreement with pre-clinical and clinical studies showing antitussive efficacy of β2-AR agonists. Indacaterol increased the number of coughs in this model, which concurs with clinical data where a transient cough has been observed after indacaterol inhalation. While the antitussive properties of β2-AR agonists can be explained by their ability to lead to the cAMP-induced hyperpolarization of the neuron membrane thereby inhibiting sensory nerve activation and the cough reflex, the mechanism underlying the pro-tussive property of indacaterol is not known. PMID:25781609

  3. Displacement of Drugs From Cyclodextrin Complexes by Bile Salts

    DEFF Research Database (Denmark)

    Olesen, Niels Erik; Westh, Peter; Holm, Rene

    2016-01-01

    of drug from the cyclodextrin cavity by bile salts present in the small intestine. As bile salts in the intestine are present at concentrations above the critical micelle concentration, an understanding of the interaction between cyclodextrins and bile salts at such supramicellar concentrations (SMC...... results and earlier data demonstrated that direct interactions between bile salt micelles and cyclodextrin were negligible. From this knowledge, an extended form of the UCD was suggested to describe the concentration of cyclodextrins to achieve full drug solubilization in the intestine where bile salts......The dosing of drugs in an aqueous cyclodextrin formulation requires sufficient amount of cyclodextrins to fully solubilize the drug, as described by Stella's cyclodextrin utility number (UCD). However, this framework does not take biopharmaceutical elements into account, such as the displacement...

  4. Bile acid aspiration in suspected ventilator-associated pneumonia.

    Science.gov (United States)

    Wu, Yu-Chung; Hsu, Po-Kuei; Su, Kang-Cheng; Liu, Lung-Yu; Tsai, Cheng-Chien; Tsai, Shu-Ho; Hsu, Wen-Hu; Lee, Yu-Chin; Perng, Diahn-Warng

    2009-07-01

    The aims of this study were to measure the levels of bile acids in patients with suspected ventilator-associated pneumonia (VAP) and provide a possible pathway for neutrophilic inflammation to explain its proinflammatory effect on the airway. Bile acid levels were measured by spectrophotometric enzymatic assay, and liquid chromatography mass spectrometry was used to quantify the major bile acids. Alveolar cells were grown on modified air-liquid interface culture inserts, and bile acids were then employed to stimulate the cells. Reverse transcriptase polymerase chain reaction and Western blots were used to determine the involved gene expression and protein levels. The mean (+/- SE) concentration of total bile acids in tracheal aspirates was 6.2 +/- 2.1 and 1.1 +/- 0.4 mumol/L/g sputum, respectively, for patients with and without VAP (p VAP group (p aspiration may reduce the intensity of neutrophilic inflammation in intubated and mechanically ventilated patients in the ICU.

  5. Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters.

    Science.gov (United States)

    Iwaki, Tomomichi; Ishizaki, Kaoru; Kinoshita, Shuji; Tanaka, Hideki; Fukunari, Atsushi; Tsurufuji, Makoto; Imada, Teruaki

    2007-10-07

    To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver. Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d. UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment. At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 +/- 77.5 U/L vs 333.6 +/- 50.4 U/L and 254.3 +/- 35.5 U/L, respectively, P LCA, which accumulate and show the cytotoxicity in the liver.

  6. Binding orientation and interaction of bile salt in its ternary complex with pancreatic lipase-colipase system.

    Science.gov (United States)

    Haque, Neshatul; Prakash Prabhu, N

    2018-05-23

    The interfacial activity of pancreatic lipases (PL) depends on the presence of colipase and bile salt. The activity of PL is inhibited by micellar concentrations of bile salt which can be restored by the addition of colipase. Though the formation of 1:1:1 tertiary complex by lipase-colipase-bile salt micelle is well accepted, the residue-level interactions between lipase-colipase and bile salt are yet to be clearly understood. Molecular dynamic simulations of lipase-colipase complex, lipase and colipase were performed in the presence of a model bile salt, sodium taurocholate (NaTC), at its near-CMC and supra-micellar concentrations. From the interactions obtained from the molecular dynamic simulations, the ternary complex was modelled and compared with earlier reports. The analysis suggested that a micelle of NaTC consisting of nine monomers was formed at the concave groove between lipase and colipase chain and it mainly interacted with the fourth finger of colipase. This complex was mainly stabilized by van der Waals interactions. Interestingly, the C-terminal domain of lipase which holds the colipase did not show any significant role in formation or stabilization of NaTC micelle. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Clinical relevance of the bile acid receptor TGR5 in metabolism

    DEFF Research Database (Denmark)

    van Nierop, F Samuel; Scheltema, Matthijs J; Eggink, Hannah M

    2017-01-01

    The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex...... such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus...... on the translation of preclinical studies into clinically applicable findings. Studies in rodents suggest an important role for Tgr5 in Glp-1 secretion, insulin sensitivity, and energy expenditure. However, evidence of effects on these processes from human studies is less convincing. Ultimately, safe and selective...

  8. Extracts of Edible Plants Inhibit Pancreatic Lipase, Cholesterol Esterase and Cholesterol Micellization, and Bind Bile Acids

    Directory of Open Access Journals (Sweden)

    Julnaryn Intrawangso

    2012-01-01

    Full Text Available The application of edible plants with more effective ability to inhibit fat digestion and absorption has recently been explored for possible treatment of hyperlipidaemia. The aim of the present study is to investigate the effect of nine edible plants on the inhibition of pancreatic lipase and pancreatic cholesterol esterase activities, as well as the inhibition of cholesterol micelle formation, and bile acid binding. Our findings have shown strong pancreatic lipase inhibitory activity and the inhibition of cholesterol micellization by mulberry leaf extract. Safflower extract was the most potent inhibitor of pancreatic cholesterol esterase. In addition, cat’s whiskers and safflower extracts had a potent bile acid binding activity. It is suggested that a daily intake of these edible plants may delay postprandial hypertriacylglycerolaemia and hypercholesterolaemia, and therefore may be applied for the prevention and treatment of hyperlipidaemia.

  9. Receptor-mediated uptake of low density lipoprotein stimulates bile acid synthesis by cultured rat hepatocytes

    International Nuclear Information System (INIS)

    Junker, L.H.; Davis, R.A.

    1989-01-01

    The cellular mechanisms responsible for the lipoprotein-mediated stimulation of bile acid synthesis in cultured rat hepatocytes were investigated. Adding 280 micrograms/ml of cholesterol in the form of human or rat low density lipoprotein (LDL) to the culture medium increased bile acid synthesis by 1.8- and 1.6-fold, respectively. As a result of the uptake of LDL, the synthesis of [14C]cholesterol from [2-14C]acetate was decreased and cellular cholesteryl ester mass was increased. Further studies demonstrated that rat apoE-free LDL and apoE-rich high density lipoprotein (HDL) both stimulated bile acid synthesis 1.5-fold, as well as inhibited the formation of [14C]cholesterol from [2-14C]acetate. Reductive methylation of LDL blocked the inhibition of cholesterol synthesis, as well as the stimulation of bile acid synthesis, suggesting that these processes require receptor-mediated uptake. To identify the receptors responsible, competitive binding studies using 125I-labeled apoE-free LDL and 125I-labeled apoE-rich HDL were performed. Both apoE-free LDL and apoE-rich HDL displayed an equal ability to compete for binding of the other, suggesting that a receptor or a group of receptors that recognizes both apolipoproteins is involved. Additional studies show that hepatocytes from cholestyramine-treated rats displayed 2.2- and 3.4-fold increases in the binding of apoE-free LDL and apoE-rich HDL, respectively. These data show for the first time that receptor-mediated uptake of LDL by the liver is intimately linked to processes activating bile acid synthesis

  10. Characterization of bile acid metabolism in man using bile acids labeled with stable isotopes. [/sup 13/C

    Energy Technology Data Exchange (ETDEWEB)

    Hofmann, A.F. Klein, P.D.

    1977-01-01

    Bile acids labeled with stable isotopes in the steroid moiety can be used to characterize bile acid metabolism in man. Isotope dilution studies give information on pool size and input. Biotransformations are easily characterized. Stable isotopically labeled bile acids offer the advantage of freedom from radiation hazard, and also offer the possibility of monitoring all pools simultaneously, since all bile acids are separated by gas chromatography before isotope measurements are made. Further, since the proportion of the pool labeled with stable isotopes is greater than that achieved when radioactive isotopes are used, stable isotopes may permit isotope dilution studies to be done on serum samples in which the absolute concentration of bile acids is very low. A major disadvantage is the complex technology required for stable isotope measurement which often makes remote processing necessary. Bile acid labeled with /sup 13/C in the amino acid moiety, e.g. cholylglycine-1-/sup 13/C can be used for detection of increased bile acid deconjugation by intestinal bacteria, since the glycine-/sup 13/C, when liberated, is rapidly converted to /sup 13/CO/sub 2/, which is expired in breath. Bile acids labeled with stable isotopes may also be used for quantitation by inverse isotope dilution, but the technique is still in the development stage and seems unlikely to compete successfully with radioimmunoassay.

  11. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective

    Directory of Open Access Journals (Sweden)

    Sha Li

    2016-01-01

    Full Text Available Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential substitutes for bear bile have displayed the same therapeutic effects as bear bile. However, stopping the use of bear bile is a challenging task. In this review, we extensively searched PubMed and CNKI for literatures, focusing on comparative studies between bear bile and its substitutes for the treatment of liver diseases. Recent research progress in potential substitutes for bear bile in the last decade is summarized, and a strategy for the use of substitutes for bear bile is discussed carefully.

  12. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective

    Science.gov (United States)

    Li, Sha; Tan, Hor Yue; Wang, Ning; Hong, Ming; Li, Lei; Cheung, Fan; Feng, Yibin

    2016-01-01

    Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential substitutes for bear bile have displayed the same therapeutic effects as bear bile. However, stopping the use of bear bile is a challenging task. In this review, we extensively searched PubMed and CNKI for literatures, focusing on comparative studies between bear bile and its substitutes for the treatment of liver diseases. Recent research progress in potential substitutes for bear bile in the last decade is summarized, and a strategy for the use of substitutes for bear bile is discussed carefully. PMID:27087822

  13. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective.

    Science.gov (United States)

    Li, Sha; Tan, Hor Yue; Wang, Ning; Hong, Ming; Li, Lei; Cheung, Fan; Feng, Yibin

    2016-01-01

    Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential substitutes for bear bile have displayed the same therapeutic effects as bear bile. However, stopping the use of bear bile is a challenging task. In this review, we extensively searched PubMed and CNKI for literatures, focusing on comparative studies between bear bile and its substitutes for the treatment of liver diseases. Recent research progress in potential substitutes for bear bile in the last decade is summarized, and a strategy for the use of substitutes for bear bile is discussed carefully.

  14. The effect of prostanoids on hepatic bile flow in dogs with normal liver and bile duct cell hyperplasia.

    Science.gov (United States)

    Solomon, H; Contis, J; Li, A P; Kaminski, D L

    1996-04-01

    Bile flow rates and composition are subject to a wide variety of neural, endocrine and paracrine influences. The effects of these multiple factors may be different in the diseased liver compared to the response produced in the normal liver. As prostanoids may have a therapeutic role in liver disease it was intended to evaluate the effects of two principal therapeutic prostanoids, prostaglandin E2 and prostacyclin, on bile flow in dogs with a normal liver and in dogs with hepatotoxin-induced liver injury. Initially, in awake animals with chronic biliary and gastric fistulas the bile flow response to prostaglandin E2 and prostacyclin was evaluated and compared to the response produced by bile salt infusion alone and to that produced by the standard choleretic hormones, secretin and glucagon. The animals were then fed alpha-naphthylisothiocyanate (ANIT) and the studies repeated. ANIT is a hepatoxin that produces bile duct cell hyperplasia which was confirmed in dogs by demonstrating that ANIT increased [3H]thymidine incorporation by isolated canine bile duct cells. In normal dogs, the prostanoids, secretin, and glucagon increased hepatic bile flow. 10 days of ANIT feeding produced a hypercholeresis. While secretin was able to stimulate the hyperplastic biliary epithelium and increase bile flow over values produced by the hyperplastic biliary epithelium alone, neither prostaglandin E2, prostacyclin, or glucagon appeared to stimulate the hyperplastic biliary epithelium. As ANIT produced evidence of cholestasis and hepatocellular damage, only secretin would seem to have a potential therapeutic role in increasing bile flow in cholestatic liver disorders associated with bile duct cell hyperplasia.

  15. Effects of bile acid administration on bile acid synthesis and its circadian rhythm in man

    International Nuclear Information System (INIS)

    Pooler, P.A.; Duane, W.C.

    1988-01-01

    In man bile acid synthesis has a distinct circadian rhythm but the relationship of this rhythm to feedback inhibition by bile acid is unknown. We measured bile acid synthesis as release of 14CO2 from [26-14C]cholesterol every 2 hr in three normal volunteers during five separate 24-hr periods. Data were fitted by computer to a cosine curve to estimate amplitude and acrophase of the circadian rhythm. In an additional six volunteers, we measured synthesis every 2 hr from 8:00 a.m. to 4:00 p.m. only. During the control period, amplitude (expressed as percentage of mean synthesis) averaged 52% and acrophase averaged 6:49 a.m. During administration of ursodeoxycholic acid (15 mg per kg per day), synthesis averaged 126% of baseline (p less than 0.1), amplitude averaged 43% and acrophase averaged 6:20 a.m. During administration of chenodeoxycholic acid (15 mg per kg per day), synthesis averaged 43% of baseline (p less than 0.001), amplitude averaged 53% and acrophase averaged 9:04 a.m. Addition of prednisone to this regimen of chenodeoxycholic acid to eliminate release of 14CO2 from corticosteroid hormone synthesis resulted in a mean amplitude of 62% and a mean acrophase of 6:50 a.m., values very similar to those in the baseline period. Administration of prednisone alone also did not significantly alter the baseline amplitude (40%) or acrophase (6:28 a.m.). We conclude that neither chenodeoxycholic acid nor ursodeoxycholic acid significantly alters the circadian rhythm of bile acid synthesis in man

  16. Granular Cell Tumour of the Bile Duct in Association with Intrahepatic Bile Duct Adenomas

    OpenAIRE

    Schweiger, F; Radhi, J; Coop, FW; Murphy, RW

    1994-01-01

    Granular cell tumour of the extrahepatic biliary tract is a rare benign lesion likely of neurogenic origin. Review of the previously reported cases indicates that almost all patients are female, and the majority is Black. Symptoms usually are those of biliary obstruction or cholecystitis. Surgical resection of the tumour is curative. Intrahepatic bile duct adenoma is another rare benign biliary neoplasm that does not manifest clinically but can be confused with metastatic carcinoma, cholangio...

  17. Common bile duct pathologies at nawabshah

    International Nuclear Information System (INIS)

    Talpur, A.A.; Memon, J.M.; Ansari, A.G.

    2007-01-01

    To determine the causes, presentation, management and outcome of Common Bile Duct (CBD) pathologies. All patients who presented with CBD pathologies. Data of all the patients with CBD pathologies was collected and entered on a proforma, including their complaints, positive examination findings, investigations, diagnosis, procedure performed and its outcome. During the study period 45 patients presented with CBD pathology. Amongst them 14 were males and the rest females (31), with a mean age of 36.7 years. Around 67% patients had choledocholithiasis as the commonest cause. Exploration of the CBD with T-tube insertion was the commonest procedure, performed in 69% patients. About 4% patients had retained stones and 20% developed wound infection. Mean hospital stay was 13 days. Most common pathology involving the CBD was secondary stones; 95% patients had associated gall stones also. (author)

  18. Comparative studies of bile salts. Bile salts of the lamprey Petromyzon marinus L

    Science.gov (United States)

    Haslewood, G. A. D.; Tökés, L.

    1969-01-01

    1. Bile salts of Petromyzon marinus L. ammocoetes appeared to consist solely or chiefly of a crystalline substance, whose chromatographic and i.r.-spectral characteristics suggested that it was a monosulphate ester of a bile alcohol having the 3α,7α,12α-trihydroxy pattern of substitution in a 5α-steroid nucleus. 2. This substance on cleavage with dioxan–trichloroacetic acid gave petromyzonol, n.m.r. and mass-spectral examination of which suggested the structure 5α-cholane-3α,7α,12α,24-tetrol. 3. 3α,7α,12α-Trihydroxy-5α-cholanoic acid (allocholic acid) from the lizards Anolis lineatopus lineatopus Gray and Cyclura carinata Harlan (family Iguanidae) was esterified with propan-1-ol and reduced by lithium aluminium hydride to 5α-cholane-3α,7α,12α,24-tetrol, identical with petromyzonol. 4. Chromic acid oxidation of petromyzonol sulphate from lamprey bile, followed by acid hydrolysis, gave 24-hydroxy-5α-cholane-3,7,12-trione; hence the sulphate ester group is at C-24. 5. Petromyzonol sulphate is both primitive and unique: a study of its biogenesis might improve our understanding of evolution at the molecular level. PMID:5810077

  19. Navigation in bile acid chemical space: discovery of novel FXR and GPBAR1 ligands.

    Science.gov (United States)

    Finamore, Claudia; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Carino, Adriana; Masullo, Dario; Biagioli, Michele; Marchianò, Silvia; Capolupo, Angela; Monti, Maria Chiara; Fiorucci, Stefano; Zampella, Angela

    2016-07-06

    Bile acids are signaling molecules interacting with nuclear receptors and membrane G-protein-coupled receptors. Among these receptors, the farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) have gained increasing consideration as druggable receptors and their exogenous dual regulation represents an attractive strategy in the treatment of enterohepatic and metabolic disorders. However, the therapeutic use of dual modulators could be associated to severe side effects and therefore the discovery of selective GPBAR1 and FXR agonists is an essential step in the medicinal chemistry optimization of bile acid scaffold. In this study, a new series of 6-ethylcholane derivatives modified on the tetracyclic core and on the side chain has been designed and synthesized and their in vitro activities on FXR and GPBAR1 were assayed. This speculation resulted in the identification of compound 7 as a potent and selective GPBAR1 agonist and of several derivatives showing potent dual agonistic activity.

  20. Bile lipids in rats under chronic social stress

    Directory of Open Access Journals (Sweden)

    A. M. Liashevych

    2017-08-01

    Full Text Available Our experiments studied changes in lipid compound of bile of non-purebred male rats under the condition of social stress while the preparation “Korvitin” was used against the stress. Using the method of thin-layer chromatography, we determined the concentrations of phospholipids, cholesterol and its esters, free fatty acids and triglycerides in the animals’ bile, which was obtained through vivesection a day and a month after the rats were first subjected to chronic social stress (model of social defeat, and also in the bile of the animals which were treated intragastrically with “Korvitin” against the stress (1 mg/kg, 7 days. In the bile of the male rats which experienced chronic social stress the concentration of free cholesterol decreased and the content of its esters increased both immediately after the initiation of stress and after a month of exposure to stress. The concentration of free fatty acids in the bile decreased after modeling chronic social stress, but increased in liver secretion, taken a month after the animals had first experienced stress. In the bile of male rats immediately after the procedure of exposing the animals to stress, the content of phospholipids decreased. Using “Korvitin” during the modeling of social stress caused decrease in the content of phospholipids in the rats’ bile and caused significant increase in the concentration of free fatty acids, triglycerides and cholesterol esters in the liver secretion. The study found significant changes in the concentration of lipids in the bile and in their distribution in the organism of male rats under the conditions of experimentally induced chronic stress. The effect of stress on the bile of rats requires further study for determining its pathogenic role.

  1. Effect of Azadirachta indica leaves extract on acetic acid-induced colitis in rats:Role of antioxidants, free radicals and myeloperoxidase

    Directory of Open Access Journals (Sweden)

    Ghatule RR

    2012-10-01

    Full Text Available Objective: To evaluate the healing effects of extract of dried leaves of Azadirachta indica (Neem on acetic acid-induced colitis in rats. Neem tree is known as ‘arishtha ’ in Sanskrit, meaning ‘reliever of sicknesses ’. Methods: 50% ethanolic extract of Azadirachta indica leaves was administered orally, once daily for 14 days in rats after the induction of colitis with acetic acid and 500 mg/kg dose of extract was found to have an optimal effect against acetic acid-induced colonic damage score, weight and adhesions (Macroscopic. Effect of Azadirachta indica extract was then further studied on various physical (mucous/blood in stool, food and water intake and body weight changes, colonic mucosal damage and inflammation (microscopic, antibacterial and biochemical parameters viz. i antioxidants (superoxide dismutase, catalase and reduced glutathione and ii free radicals (nitric oxide and lipid peroxidation and myeloperoxidase (acute inflammatory marker activities in acetic acid-induced colitis. Results: Azadirachta indica extract decreased colonic mucosal damage and inflammation (macroscopic and microscopic, mucous/bloody diarrhea, fecal frequency and increased body weight. Azadirachta indica extract showed intestinal antibacterial activity and enhanced the antioxidants but decreased free radicals and myeloperoxidase activities. Acute toxicity study indicated no mortality or other ANS or CNS related adverse effects even with 5.0 g/kg dose (10 times of effective dose indicating its safety. Conclusions: Azadirachta indica seemed to be safe and effective in colitis by its predominant effect on promoting antioxidant status and decreasing intestinal bacterial load, free radicals and myeloperoxidase responsible for tissue damage and delayed healing.

  2. Phenylbutyric acid induces the cellular senescence through an Akt/p21{sup WAF1} signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hag Dong [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of); Jang, Chang-Young [Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul 140-742 (Korea, Republic of); Choe, Jeong Min [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of); Department of Biochemistry, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705 (Korea, Republic of); Sohn, Jeongwon, E-mail: biojs@korea.ac.kr [Department of Biochemistry, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705 (Korea, Republic of); Kim, Joon, E-mail: joonkim@korea.ac.kr [Laboratory of Biochemistry, School of Life Sciences and Biotechnology, and BioInstitute, Korea University, Seoul 136-701 (Korea, Republic of)

    2012-06-01

    Highlights: Black-Right-Pointing-Pointer Phenylbutyric acid induces cellular senescence. Black-Right-Pointing-Pointer Phenylbutyric acid activates Akt kinase. Black-Right-Pointing-Pointer The knockdown of PERK also can induce cellular senescence. Black-Right-Pointing-Pointer Akt/p21{sup WAF1} pathway activates in PERK knockdown induced cellular senescence. -- Abstract: It has been well known that three sentinel proteins - PERK, ATF6 and IRE1 - initiate the unfolded protein response (UPR) in the presence of misfolded or unfolded proteins in the ER. Recent studies have demonstrated that upregulation of UPR in cancer cells is required to survive and proliferate. Here, we showed that long exposure to 4-phenylbutyric acid (PBA), a chemical chaperone that can reduce retention of unfolded and misfolded proteins in ER, induced cellular senescence in cancer cells such as MCF7 and HT1080. In addition, we found that treatment with PBA activates Akt, which results in p21{sup WAF1} induction. Interestingly, the depletion of PERK but not ATF6 and IRE1 also induces cellular senescence, which was rescued by additional depletion of Akt. This suggests that Akt pathway is downstream of PERK in PBA induced cellular senescence. Taken together, these results show that PBA induces cellular senescence via activation of the Akt/p21{sup WAF1} pathway by PERK inhibition.

  3. Integrated chemical and biological analysis to explain estrogenic potency in bile extracts of red mullet (Mullus barbatus)

    Energy Technology Data Exchange (ETDEWEB)

    Martínez-Gómez, Concepción, E-mail: concepcion.martinez@mu.ieo.es [Instituto Español de Oceanografía, Oceanografic Centre of Murcia, Varadero 1, San Pedro del Pinatar, 30740 Murcia (Spain); Lamoree, M.; Hamers, T.; Velzen, M. van; Kamstra, J.H. [VU University Amsterdam, Amsterdam Global Change Institute, Institute for Environmental Studies, De Boelelaan 1085, 1081 HV Amsterdam (Netherlands); Fernández, B.; Benedicto, J.; León, V.M. [Instituto Español de Oceanografía, Oceanografic Centre of Murcia, Varadero 1, San Pedro del Pinatar, 30740 Murcia (Spain); Vethaak, A.D. [VU University Amsterdam, Amsterdam Global Change Institute, Institute for Environmental Studies, De Boelelaan 1085, 1081 HV Amsterdam (Netherlands); Deltares, Marine and Coastal Systems, P.O. Box 177, 2600 MH Delft (Netherlands)

    2013-06-15

    Highlights: •In vitro estrogenic activity was quantified in male bile extracts of feral red mullet. •Major PAH metabolites and alkylphenols were quantified in the same fish bile extracts. •Contribution of these compounds to the estrogenicity measured was found negligible. •PAH and alkylphenol fish exposure was low in most of the studied Mediterranean sites. •High estrogenicity in male fish from Mar Menor lagoon warrants further studies. -- Abstract: A biological screening was performed to establish the total exposure to estrogenic compounds of red mullet (Mullus barbatus) collected at several sites along the Spanish Mediterranean coast by testing male fish bile extracts using the in vitro ER-LUC reporter gene assay. In addition, major metabolites were identified and measurements of OH-PAHs (1-naphthol, 9-phenantrol, 9-fluorenol, 1-pyrenol, 1OH-BaP and 3OH-BaP) and alkylphenols (4-n-nonylphenol (4-n-NP) and 4-tertoctylphenol (4-tert-OP)) in the same fish bile extracts were taken by gas chromatography–mass spectrometry in electron ionization mode (GC–EI-MS). Relative in vitro estrogenic potencies of the chemically quantified compounds were also tested. The highest biliary concentrations of 1-pyrenol, 9-fluorenol and 4-n-NP were found in fish from Barcelona and from the Mar Menor coastal lagoon. However, these concentrations can be considered relatively low compared to values reported in red mullet from other polluted waters in the Mediterranean Sea. The contribution of 1-pyrenol, 4-n-NP and 4-tert-OP to the total estrogenic potency measured in male fish bile was found to be negligible, indicating the presence of other estrogenic compounds in red mullet bile. Estrogenic potency in bile from male fish was markedly elevated in Mar Menor lagoon (234.8 ± 5.7 pg E2EQ/μl), and further research will be necessary to explain whether the presence of natural and synthetic-hormones in the lagoon contributed to this finding. Values of approximately 15–16 E2EQ pg

  4. Administration of phosphatidylcholine-cholesterol liposomes partially reconstitutes fat absorption in chronically bile-diverted rats

    NARCIS (Netherlands)

    Nishioka, T; Havinga, R; Tazuma, S; Stellaard, F; Kuipers, F; Verkade, HJ

    2004-01-01

    Background and aims: Intestinal bile deficiency in cholestatic patients leads to fat malabsorption. We addressed the potency of model bile, bile salts and phosphatidylcholine (PC)-cholesterol (CH) liposomes to reconstitute fat absorption in permanently bile-diverted (BD) rats. Methods: The plasma

  5. Modulation of hepatic biotransformation and biliary excretion of bile acid by age and sinusoidal bile acid load

    International Nuclear Information System (INIS)

    Baumgartner, U.; Miyai, K.; Hardison, W.G.M.

    1987-01-01

    Pericentral hepatocytes excrete bile acids more slowly and biotransform them more than periportal cells. This may reflect adaptation to low pericentral bile acid concentration or may be intrinsic. The authors studied two models in which pericentral bile acid concentrations are high: the 72-h choledocho-caval shunt (CCS) rat and the 3- to 4-wk-old rat. Livers were perfused forward or backward to assess periportal or pericentral hepatocyte function. Taurodeoxycholate (TDC) was infused at 32 nmol x min -1 x g liver -1 , and a bolus of [ 3 H]TDC was given to assess metabolism and excretion of bile acids. In CCS livers perfused backward, pericentral cells resembled periportal cells of controls in that time to excrete 50% of administered [ 3 H]-TDC (t 50 ) was reduced by two-thirds and [ 3 H]TDC biotransformation was reduced by about half. In young livers t 50 was half that of adult livers when perfused backward. Biotransformation, however, was not reduced. Young livers biotransformed more than adult controls for any given residence time of bile acid in the liver. They conclude that the difference between pericentral and perioportal cells as regards bile acid processing is adaptive. Livers from young rats biotransform more bile acid than those from controls under similar conditions

  6. Role of hepatocytes and bile duct cells in preservation-reperfusion injury of liver grafts.

    Science.gov (United States)

    Kukan, M; Haddad, P S

    2001-05-01

    In liver transplantation, it is currently hypothesized that nonparenchymal cell damage and/or activation is the major cause of preservation-related graft injury. Because parenchymal cells (hepatocytes) appear morphologically well preserved even after extended cold preservation, their injury after warm reperfusion is ascribed to the consequences of nonparenchymal cell damage and/or activation. However, accumulating evidence over the past decade indicated that the current hypothesis cannot fully explain preservation-related liver graft injury. We review data obtained in animal and human liver transplantation and isolated perfused animal livers, as well as isolated cell models to highlight growing evidence of the importance of hepatocyte disturbances in the pathogenesis of normal and fatty graft injury. Particular attention is given to preservation time-dependent decreases in high-energy adenine nucleotide levels in liver cells, a circumstance that (1) sensitizes hepatocytes to various stimuli and insults, (2) correlates well with graft function after liver transplantation, and (3) may also underlie the preservation time-dependent increase in endothelial cell damage. We also review damage to bile duct cells, which is increasingly being recognized as important in the long-lasting phase of reperfusion injury. The role of hydrophobic bile salts in that context is particularly assessed. Finally, a number of avenues aimed at preserving hepatocyte and bile duct cell integrity are discussed in the context of liver transplantation therapy as a complement to reducing nonparenchymal cell damage and/or activation.

  7. The mechanism of gentisic acid-induced relaxation of the guinea pig isolated trachea: the role of potassium channels and vasoactive intestinal peptide receptors.

    Science.gov (United States)

    Cunha, J F; Campestrini, F D; Calixto, J B; Scremin, A; Paulino, N

    2001-03-01

    We examined some of the mechanisms by which the aspirin metabolite and the naturally occurring metabolite gentisic acid induced relaxation of the guinea pig trachea in vitro. In preparations with or without epithelium and contracted by histamine, gentisic acid caused concentration-dependent and reproducible relaxation, with mean EC(50) values of 18 microM and E(max) of 100% (N = 10) or 20 microM and E(max) of 92% (N = 10), respectively. The relaxation caused by gentisic acid was of slow onset in comparison to that caused by norepinephrine, theophylline or vasoactive intestinal peptide (VIP). The relative rank order of potency was: salbutamol 7.9 > VIP 7.0 > gentisic acid 4.7 > theophylline 3.7. Gentisic acid-induced relaxation was markedly reduced (24 +/- 7.0, 43 +/- 3.9 and 78 +/- 5.6%) in preparations with elevated potassium concentration in the medium (20, 40 or 80 mM, respectively). Tetraethylammonium (100 microM), a nonselective blocker of the potassium channels, partially inhibited the relaxation response to gentisic acid, while 4-AP (10 microM), a blocker of the voltage potassium channel, inhibited gentisic acid-induced relaxation by 41 +/- 12%. Glibenclamide (1 or 3 microM), at a concentration which markedly inhibited the relaxation induced by the opener of ATP-sensitive K(+) channels, levcromakalim, had no effect on the relaxation induced by gentisic acid. Charybdotoxin (0.1 or 0.3 microM), a selective blocker of the large-conductance Ca(2+)-activated K(+) channels, caused rightward shifts (6- and 7-fold) of the gentisic acid concentration-relaxation curve. L-N(G)-nitroarginine (100 microM), a NO synthase inhibitor, had no effect on the relaxant effect of gentisic acid, and caused a slight displacement to the right in the relaxant effect of the gentisic acid curve at 300 microM, while methylene blue (10 or 30 microM) or ODQ (1 microM), the inhibitors of soluble guanylate cyclase, all failed to affect gentisic acid-induced relaxation. D-(P)-Cl-Phe(6),Leu(17

  8. Effect of piperine on inhibition of FFA induced TLR4 mediated inflammation and amelioration of acetic acid induced ulcerative colitis in mice.

    Science.gov (United States)

    Gupta, Rohit A; Motiwala, Meha N; Dumore, Nitin G; Danao, Kishor R; Ganjare, Anjali B

    2015-04-22

    Piperine, a main component of Piper longum Linn. and Piper nigrum Linn., is a plant alkaloid with a long history of medicinal use. Piperine exhibits antidepressant, hepatoprotective, anti-metastatic, anti-thyroid, immunomodulatory, antitumor and anti-inflammatory activities, However its therapeutic potential in amelioration of ulcerative colitis and the underlying mechanism for anti-inflammatory activity remains unknown.The objective of the present investigation was to unravel the therapeutic potential of piperine on amelioration of IBD using acetic acid induced experimental animal model for ulcerative colitis and to determine the role of TLR4 receptor in signalling pathway of inflammatory gene expression in ulcerative colitis. We induced colitis using acetic acid (150µl of 5% once, intrarectally) in mice and estimated disease activity index (DAI), which took into account weight loss, stool consistency, and occult/gross bleeding. Colon length, spleen weights, ulcer area and ulcer index were measured; histological changes were observed by H&E staining. Effect of piperine on various antioxidant parameter of mice colon such as tissue myeloperoxidase (MPO) accumulation, SOD concentrations, reduced GSH and lipid peroxidation were determined. Pro-inflammatory mediators, namely, nitric oxide (NO), tumour necrosis factor-α (TNF-α) were determined by a TNF-α ELISA kit obtained from Thermo fisher scientific India Pvt. Ltd. Effect of piperine on haematological parameters of mice in acetic acid induced IBD was also determined which involves the estimation of FFA using a commercial free fatty acid fluorometric assay kit. Piperine significantly attenuated acetic acid induced DAI score which implies that it suppresses weight loss, diarrhoea, gross bleeding and infiltration of immune cells. Piperine administration also effectively and dose dependently prevented shortening of colon length and enlargement of spleen size. Histological examination indicated that piperine reduces

  9. Surgical versus endoscopic treatment of bile duct stones

    DEFF Research Database (Denmark)

    Martin, D J; Vernon, D R; Toouli, J

    2006-01-01

    10% to 18% of patients undergoing cholecystectomy for gallstones have common bile duct (CBD) stones. Treatment options for these stones include pre- or post-operative endoscopic retrograde cholangiopancreatography (ERCP) or open or laparoscopic surgery....

  10. Clues to the Etiology of Bile Duct Injury in Biliary Atresia

    Science.gov (United States)

    Mack, Cara L.; Feldman, Amy G.; Sokol, Ronald J.

    2013-01-01

    Biliary atresia (BA) is an infantile obstructive cholangiopathy of unknown etiology with suboptimal therapy, which is responsible for 40 to 50% of all pediatric liver transplants. Although the etiology of bile duct injury in BA in unknown, it is postulated that a pre- or perinatal viral infection initiates cholangiocyte apoptosis and release of antigens that trigger a Th1 immune response that leads to further bile duct injury, inflammation, and obstructive fibrosis. Humoral immunity and activation of the innate immune system may also play key roles in this process. Moreover, recent investigations from the murine BA model and human data suggest that regulatory T cells and genetic susceptibility factors may orchestrate autoimmune mechanisms. What controls the coordination of these events, why the disease only occurs in the first few months of life, and why a minority of infants with perinatal viral infections develop BA are remaining questions to be answered. PMID:23397531

  11. Substitutes for Bear Bile for the Treatment of Liver Diseases: Research Progress and Future Perspective

    OpenAIRE

    Li, Sha; Tan, Hor Yue; Wang, Ning; Hong, Ming; Li, Lei; Cheung, Fan; Feng, Yibin

    2016-01-01

    Bear bile has been a well-known Chinese medicine for thousands of years. Because of the endangered species protection, the concept on substitutes for bear bile was proposed decades ago. Based on their chemical composition and pharmacologic actions, artificial bear bile, bile from other animals, synthetic compounds, and medicinal plants may be the promising candidates to replace bear bile for the similar therapeutic purpose. Accumulating research evidence has indicated that these potential sub...

  12. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism

    NARCIS (Netherlands)

    Patti, Mary-Elizabeth; Houten, Sander M.; Bianco, Antonio C.; Bernier, Raquel; Larsen, P. Reed; Holst, Jens J.; Badman, Michael K.; Maratos-Flier, Eleftheria; Mun, Edward C.; Pihlajamaki, Jussi; Auwerx, Johan; Goldfine, Allison B.

    2009-01-01

    The multifactorial mechanisms promoting weight loss and improved metabolism following Roux-en-Y gastric bypass (GB) surgery remain incompletely understood. Recent rodent studies suggest that bile acids can mediate energy homeostasis by activating the G-protein coupled receptor TGR5 and the type 2

  13. Clinical effect of laparoscopic reoperation combined with choledochoscope in treatment of intra- and extrahepatic bile duct stones: analysis of 35 cases

    Directory of Open Access Journals (Sweden)

    WU Liming

    2013-07-01

    Full Text Available ObjectiveTo investigate the feasibility and safety of laparoscopic reoperation combined with choledochoscope in the treatment of intra- and extrahepatic bile duct stones. MethodsThe 35 patients with intra- and extrahepatic bile duct stones who underwent laparoscopic bile duct reoperation from January 2008 to May 2012 were selected as a laparoscopic treatment group; 50 patients with recurrent intra- and extrahepatic bile duct stones who underwent open surgery in the same period were selected as an open surgery group. The t-test was used to compare the two groups in terms of off-bed activity early after operation, recovery of intestinal function, and length of hospital stay; the chi-square test was used to compare the incision infection rate between the two groups. ResultsAmong the 35 cases of intra- and extrahepatic bile duct stones, 32 completed laparoscopic surgery, 2 had the procedure converted to open surgery due to severe adhesion, and 1 had the procedure converted to open surgery due to subcutaneous emphysema. In the laparoscopic treatment group, the mean operative time of laparoscopic bile duct reoperation was 148 min (range, 105-200 min; there were no bleeding and bile leak in the perioperative period. All patients underwent T-tube drainage; postoperative peritoneal drainage was performed for 2-5 d; the mean length of hospital stay after operation was 5-8 d. No case of incision infection occurred in the laparoscopic treatment group. The laparoscopic treatment group had a significantly better outcome than the open surgery group in terms of time to off-bed activity early after operation, time to recovery of intestinal function, length of hospital stay after operation, and incision infection rate (P<0.05. In the laparoscopic treatment group, 3 cases had retained bile duct stones, and the stones were taken out through the sinus tract using a fiber choledochoscope at 2 months after operation. All cases were followed up for 6-24 months after

  14. A Microfluidic Chip for Detecting Cholangiocarcinoma Cells in Human Bile.

    Science.gov (United States)

    Hung, Lien-Yu; Chiang, Nai-Jung; Tsai, Wei-Chun; Fu, Chien-Yu; Wang, Yu-Chun; Shan, Yan-Shen; Lee, Gwo-Bin

    2017-06-26

    Cholangiocarcinoma (CCA), a biliary tract malignancy, accounts for 20% of all liver cancers. There are several existing methods for diagnosis of CCA, though they are generally expensive, laborious, and suffer from low detection rates. Herein we first developed a means of partially purifying human bile for consequent injection into a microfluidic chip. Then, the novel microfluidic system, which featured 1) a cell capture module, 2) an immunofluorescence (IF) staining module featuring two CCA-specific biomarkers, and 3) an optical detection module for visualization of antibody probes bound to these CCA marker proteins, was used to detect bile duct cancer cells within partially purified bile samples. As a proof of concept, CCA cells were successfully captured and identified from CCA cell cultures, blood samples inoculated with CCA cells, and clinical bile specimens. In 7.5 ml of bile, this system could detect >2, 0, and 1 positive cells in advanced stage patients, healthy patients, and chemotherapy-treated patients, respectively. In conclusion, our microfluidic system could be a promising tool for detection of cancer cells in bile, even at the earliest stages of CCA when cancer cells are at low densities relative to the total population of epithelial cells.

  15. Anti-inflammatory and immunomodulatory effects of Spirulina platensis in comparison to Dunaliella salina in acetic acid-induced rat experimental colitis.

    Science.gov (United States)

    Abdel-Daim, Mohamed M; Farouk, Sameh M; Madkour, Fedekar F; Azab, Samar S

    2015-04-01

    Spirulina platensis (SP) is used as a source of protein and vitamin supplement in humans without any significant side-effects. Dunaliella salina (DS) is also regarded as one of the richest natural producers of carotenoid, thus used as a source of antioxidants to protect cells from oxidative damage. The aim of the present study is to compare the ameliorative effect of Spirulina and Dunaliella in experimental colitis. Spirulina and Dunaliella were investigated at the same dose of 500 mg/kg body weight for their modulatory effect against acetic-acid induced ulcerative colitis (UC) in rats. The colonic lesion was analyzed by examining macroscopic damage, bloody diarrhea scores, colon weight/length and change in body weight of tested rats. Colon lipid peroxidation and oxidative stress markers were examined by evaluating malondialdehyde (MDA), protein carbonyl (PCO), catalase (CAT), reduced glutathione (GSH) and superoxide dismutase (SOD). Colon inflammatory markers; myeloperoxidase (MPO) and prostaglandin (PGE2) as well as proinflammatory cytokines; tumor necrosis factor (TNF-α) and interleukins (IL-1β, IL-6) were also studied. The colonic mucosal injury, biochemical and histopathologic results suggest that both SP and DS exhibit significant modulatory effect on acetic acid-induced colitis in rats, which may be due to a significant increase of antioxidant enzymes activity and significant inhibition of lipid peroxidation and inflammation markers. Results showed that in comparison to Sulfasalazine, SP exhibited better therapeutic and safety profile than DS against acetic acid-induced UC. This study suggests potential benefits of SP and DS in an experimental model of colitis.

  16. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.

    Science.gov (United States)

    Sayin, Sama I; Wahlström, Annika; Felin, Jenny; Jäntti, Sirkku; Marschall, Hanns-Ulrich; Bamberg, Krister; Angelin, Bo; Hyötyläinen, Tuulia; Orešič, Matej; Bäckhed, Fredrik

    2013-02-05

    Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Synergic Interaction of Rifaximin and Mutaflor (Escherichia coli Nissle 1917 in the Treatment of Acetic Acid-Induced Colitis in Rats

    Directory of Open Access Journals (Sweden)

    Artur Dembiński

    2016-01-01

    Full Text Available Background. Inflammatory bowel disease results from the dysregulation of immune response to environmental and microbial agents in genetically susceptible individuals. The aim of the present study was to examine the effect of rifaximin and/or Mutaflor (Escherichia coli Nissle 1917, EcN administration on the healing of acetic acid-induced colitis. Methods. Colitis was induced in male Wistar rats by rectal enema with 3.5% acetic acid solution. Rifaximin (50 mg/kg/dose and/or Mutaflor (109 CFU/dose were given intragastrically once a day. The severity of colitis was assessed at the 8th day after induction of inflammation. Results. Treatment with rifaximin significantly accelerated the healing of colonic damage. This effect was associated with significant reversion of the acetic acid-evoked decrease in mucosal blood flow and DNA synthesis. Moreover, administration of rifaximin significantly reduced concentration of proinflammatory TNF-α and activity of myeloperoxidase in colonic mucosa. Mutaflor given alone was without significant effect on activity of colitis. In contrast, Mutaflor given in combination with rifaximin significantly enhanced therapeutic effect of rifaximin. Moreover, Mutaflor led to settle of the colon by EcN and this effect was augmented by pretreatment with rifaximin. Conclusion. Rifaximin and Mutaflor exhibit synergic anti-inflammatory and therapeutic effect in acetic acid-induced colitis in rats.

  18. Aggregation behaviour of amphiphilic drug and bile salt mixtures at different compositions and temperatures

    International Nuclear Information System (INIS)

    Rub, Malik Abdul; Sheikh, Mohmad Shafi; Asiri, Abdullah M.; Azum, Naved; Khan, Anish; Khan, Aftab Aslam Parwaz; Khan, Sher Bahadar; Kabir-ud-Din

    2013-01-01

    Highlights: • Aggregation behavior of promethazine hydrochloride-bile salt mixtures has been investigated. • The negative β values indicate attractive interactions between the components. • For PMT/PMT-bile salt systems, ΔH m ∘ values change from negative to positive with temperature. • The ΔS m ∘ values are positive, their magnitude being more at T = 298.15 K and above. • The results have applicability in drug delivery. -- Abstract: The micellization and adsorption behaviour of the amphiphilic drug promethazine hydrochloride (PMT – a phenothiazine) and bile salts mixtures were analyzed at different compositions in pure and mixed states in aqueous solutions. By using regular solution theory (RST) and Rosen’s model different physicochemical properties such as critical micellar concentration (cmc), micellar composition, surface excess concentration (Γ max ), minimum area per molecule (A min ), interaction parameters (β m , β σ ), energetic parameters of micellization as well as other micellar and surface properties have been determined. The values of interaction parameters (β) and activity coefficients f 1 and f 2 (for both, in mixed monolayer as well as in mixed micelles) indicate the synergistic behaviour. The thermodynamic parameters propose release of water from the hydrophobic portion of the drug at higher temperatures

  19. Histogenesis of bile duct-like cells proliferating during ethionine hepatocarcinogenesis. Evidence for a biliary epithelial nature of oval cells.

    Science.gov (United States)

    Lenzi, R; Liu, M H; Tarsetti, F; Slott, P A; Alpini, G; Zhai, W R; Paronetto, F; Lenzen, R; Tavoloni, N

    1992-03-01

    The origin of bile duct-like cells (oval cells) proliferating during chemical hepatocarcinogenesis is highly controversial. To illuminate this issue, we induced oval cell proliferation by feeding rats a choline-devoid diet containing 0.1% ethionine (CDE), a hepatocarcinogenic diet, for up to 60 days. At various times we studied 1) oval cell morphology by light and electron microscopy, 2) the immunohistochemical expression of albumin and intermediate filament proteins by the various hepatic cells, 3) hepatic incorporation of [3H]thymidine by histoautoradiography, 4) the fractional area occupied by duct-like structures in liver cross sections, 5) the biliary tree volume in vivo to establish the possible continuity of the proliferated structures to the existing biliary lumina, and 6) spontaneous bile flow rate and the choleretic responsiveness to the hormone secretin, which stimulates ductular secretory activity. The results demonstrated the following: 1) oval cells resemble bile duct cells with respect to their histologic and ultrastructural appearance and their formation of duct-like structures; 2) as normal and hyperplastic bile duct cells induced by bile duct ligation, oval cells are positive for cytokeratins 7 and 19 (markers of glandular epithelia) and 8 and 18 (markers of simple epithelia) and are negative for vimentin and desmin, markers of mesenchymal and muscular differentiation, respectively; 3) in general, oval cells are negative for albumin, which is expressive of hepatocyte lineage, even though a few are positive for this protein, particularly those morphologically resembling small hepatocytes; 4) after initiation of the CDE diet, DNA synthesis begins in biliary epithelial cells; and 5) the degree of oval cell proliferation parallels the increase in biliary tree volume, spontaneous bile flow rate, and responsiveness to secretin choleresis, as in bile duct cell hyperplasia induced by biliary obstruction. Although the involvement of a periductular

  20. Protective Effect of Ocimum basilicum Essential Oil Against Acetic Acid-Induced Colitis in Rats.

    Science.gov (United States)

    Rashidian, Amir; Roohi, Parnia; Mehrzadi, Saeed; Ghannadi, Ali Reza; Minaiyan, Mohsen

    2016-10-01

    Ocimum basilicum L has been traditionally used for the treatment of inflammatory bowel disease in Iran. This study investigates the ameliorative effect of Ocimum basilicum essential oil on an acetic acid-induced colitis model in rats. Ocimum basilicum essential oil with 2 doses (200 and 400 μL/kg) significantly ameliorated wet weight/length ratio of colonic tissue compared to the control group. Higher doses of essential oil (200 and 400 μL/kg) significantly reduced ulcer severity, ulcer area, and ulcer index. On the other hand, histological examination revealed the diminution of total colitis index as a marker for inflammatory cell infiltration in the colonic segments of rats treated with Ocimum basilicum essential oil (200 and 400 μL/kg). The increased level of myeloperoxidase was significantly decreased after the treatment with the essential oil (200 and 400 μL/kg). These results suggest that Ocimum basilicum exhibits protective effect against acetic acid-induced colitis. © The Author(s) 2015.

  1. Protective Effects of Nigella Sativaon Acetylsalicylic Acid-Induced Nephrotoxicity in Albino Rats.

    Science.gov (United States)

    Asif, Sania; Malik, Lubna

    2017-09-01

    To see the effects of Nigella sativaon acetylsalicylic acid-induced nephrotoxicity in albino rats. An experimental study. The Anatomy Department of University of Health Sciences, Lahore, from January 2014 to December 2015. Thirty-two female albino rats were divided into four groups. Group A(control) was given single dose of 10 mg/100 gm body weight of 1% methylcellulose, orally. Group B and C were treated with oral 1000 mg/kg acetylsalicylic acid as a single dose. Group D was given 250 mg/kg ethanolic extract of Nigella sativa(NSE) by oral gavage followed by single dose of 1000 mg/kg acetylsalicylic acid on 1st day of experiment; after that only NSE was continued till 7 days. Animals of groups A, C and D were sacrificed on day 8 and that of group B on day 2 of experiment. Cardiac puncture was performed to draw blood from each animal for renal function tests. Animals were evaluated for gross (Paired kidney weight, body weight, relative tissue body weight index) as well as for biochemical (Serum urea and creatinine) parameters. Gross as well as biochemical parameters were markedly impaired in group B, but statistically significant improvement was noticed in Nigella sativatreated group. There was no self recovery in group C. Ethanolic extract of Nigella sativahas a protective role against acetylsalicylic acid-induced nephrotoxicity in albino rats.

  2. Stability of the acetic acid-induced bladder irritation model in alpha chloralose-anesthetized female cats.

    Directory of Open Access Journals (Sweden)

    F Aura Kullmann

    Full Text Available Time- and vehicle-related variability of bladder and urethral rhabdosphincter (URS activity as well as cardiorespiratory and blood chemistry values were examined in the acetic acid-induced bladder irritation model in α-chloralose-anesthetized female cats. Additionally, bladder and urethra were evaluated histologically using Mason trichrome and toluidine blue staining. Urodynamic, cardiovascular and respiratory parameters were collected during intravesical saline infusion followed by acetic acid (0.5% to irritate the bladder. One hour after starting acetic acid infusion, a protocol consisting of a cystometrogram, continuous infusion-induced rhythmic voiding contractions, and a 5 min "quiet period" (bladder emptied without infusion was precisely repeated every 30 minutes. Administration of vehicle (saline i.v. occurred 15 minutes after starting each of the first 7 cystometrograms and duloxetine (1mg/kg i.v. after the 8(th. Acetic acid infusion into the bladder increased URS-EMG activity, bladder contraction frequency, and decreased contraction amplitude and capacity, compared to saline. Bladder activity and URS activity stabilized within 1 and 2 hours, respectively. Duloxetine administration significantly decreased bladder contraction frequency and increased URS-EMG activity to levels similar to previous reports. Cardiorespiratory parameters and blood gas levels remained consistent throughout the experiment. The epithelium of the bladder and urethra were greatly damaged and edema and infiltration of neutrophils in the lamina propria of urethra were observed. These data provide an ample evaluation of the health of the animals, stability of voiding function and appropriateness of the model for testing drugs designed to evaluate lower urinary tract as well as cardiovascular and respiratory systems function.

  3. Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1) mutations associated with Smith-Magenis Syndrome.

    Science.gov (United States)

    Carmona-Mora, Paulina; Encina, Carolina A; Canales, Cesar P; Cao, Lei; Molina, Jessica; Kairath, Pamela; Young, Juan I; Walz, Katherina

    2010-08-25

    Smith-Magenis Syndrome is a contiguous gene syndrome in which the dosage sensitive gene has been identified: the Retinoic Acid Induced 1 (RAI1). Little is known about the function of human RAI1. We generated the full-length cDNA of the wild type protein and five mutated forms: RAI1-HA 2687delC, RAI1-HA 3103delC, RAI1 R960X, RAI1-HA Q1562R, and RAI1-HA S1808N. Four of them have been previously associated with SMS clinical phenotype. Molecular weight, subcellular localization and transcription factor activity of the wild type and mutant forms were studied by western blot, immunofluorescence and luciferase assays respectively. The wild type protein and the two missense mutations presented a higher molecular weight than expected, localized to the nucleus and activated transcription of a reporter gene. The frameshift mutations generated a truncated polypeptide with transcription factor activity but abnormal subcellular localization, and the same was true for the 1-960aa N-terminal half of RAI1. Two different C-terminal halves of the RAI1 protein (1038aa-end and 1229aa-end) were able to localize into the nucleus but had no transactivation activity. Our results indicate that transcription factor activity and subcellular localization signals reside in two separate domains of the protein and both are essential for the correct functionality of RAI1. The pathogenic outcome of some of the mutated forms can be explained by the dissociation of these two domains.

  4. Functional and cellular characterization of human Retinoic Acid Induced 1 (RAI1 mutations associated with Smith-Magenis Syndrome

    Directory of Open Access Journals (Sweden)

    Carmona-Mora Paulina

    2010-08-01

    Full Text Available Abstract Background Smith-Magenis Syndrome is a contiguous gene syndrome in which the dosage sensitive gene has been identified: the Retinoic Acid Induced 1 (RAI1. Little is known about the function of human RAI1. Results We generated the full-length cDNA of the wild type protein and five mutated forms: RAI1-HA 2687delC, RAI1-HA 3103delC, RAI1 R960X, RAI1-HA Q1562R, and RAI1-HA S1808N. Four of them have been previously associated with SMS clinical phenotype. Molecular weight, subcellular localization and transcription factor activity of the wild type and mutant forms were studied by western blot, immunofluorescence and luciferase assays respectively. The wild type protein and the two missense mutations presented a higher molecular weight than expected, localized to the nucleus and activated transcription of a reporter gene. The frameshift mutations generated a truncated polypeptide with transcription factor activity but abnormal subcellular localization, and the same was true for the 1-960aa N-terminal half of RAI1. Two different C-terminal halves of the RAI1 protein (1038aa-end and 1229aa-end were able to localize into the nucleus but had no transactivation activity. Conclusion Our results indicate that transcription factor activity and subcellular localization signals reside in two separate domains of the protein and both are essential for the correct functionality of RAI1. The pathogenic outcome of some of the mutated forms can be explained by the dissociation of these two domains.

  5. Effect of marine mangrove Avicennia marina (Forssk.) Vierh against acetic acid-induced ulcerative colitis in experimental mice.

    Science.gov (United States)

    Rise, C L Victoria; Prabhu, V Vinod; Guruvayoorappan, Chandrasekharan

    2012-01-01

    Ulcerative colitis and Crohn's disease are two conditions that have many features in common and are referred as inflammatory bowel disease (IBD). Patients with IBD are predisposed to colorectal cancer. This investigation evaluates the effect of marine mangrove Avicennia marina against acetic acid-induced colitis. The treatment of A marina extract significantly decreased the colonic lipid peroxides, glutathione peroxidase, and serum nitric oxide and significantly increased the colonic and erythrocyte superoxide dismutase and glutathione levels compared with colitis control. In addition, A marina extract significantly decreased the lesion score and wet colon weight compared with colitis control. Treatment with A marina extract reflects its therapeutic activity against UC by minimal damage of colonic epithelial cells compared with colitis control during histopathologic examination. These protective role of A marina extract against UC could be attributed to the presence of higher levels of decanoic acid, diethylhydroxylamine (DEHA), pentanoic acid, pyrrolidine, 4-chlorophenyl, thiazolidinones, and arabinopyranoside (flavonoid). These findings suggest that A marina extract could be useful as a potential (natural) therapeutic agent for IBD.

  6. Protective effect of gadolinium chloride on early warm ischemia/reperfusion injury in rat bile duct during liver transplantation.

    Science.gov (United States)

    Wang, Biao; Zhang, Qi; Zhu, Bili; Cui, Zhonglin; Zhou, Jie

    2013-01-01

    Activation of Kupffer cell (KC) is acknowledged as a key event in the initiation and perpetuation of bile duct warm ischemia/reperfusion injury. The inhibitory effect of gadolinium chloride (GdCl(3)) on KC activation shows potential as a protective intervention in liver injury, but there is less research with regard to bile duct injury. Sixty-five male Sprague-Dawley rats (200-250 g) were randomly divided into three experimental groups: a sham group (n = 15), a control group (n = 25), and a GdCl(3) group (n = 25). Specimen was collected at 0.5, 2, 6, 12 and 24 h after operation. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL) of serum were measured. Tumor necrosis factor-α (TNF-α), Capase-3 activity and soluble Fas (sFas) were detected. The pathologic changes of bile duct were observed. Immunochemistry for bile duct Fas was performed. Apoptosis of bile duct cells was evaluated by the terminal UDP nick end labeling assay. GdCl(3) significantly decreased the levels of ALT, ALP and TBIL at 2, 6, 12, and 24 h, and increased serum sFas at 2, 6 and 12 h (Pbile duct cell apoptosis at 2, 6, 12 and 24 h. After operation for 2, 6 and 12 h, the expression of Fas protein was lower in the GdCl(3) group than in the control group (Pbile duct cell apoptosis, including decreasing ALT, ALP, TBIL and TNF-α; suppressing Fas-FasL-Caspase signal transduction during transplantation.

  7. Clearance of refractory bile duct stones with extracorporeal shockwave lithotripsy.

    Science.gov (United States)

    Ellis, R D; Jenkins, A P; Thompson, R P; Ede, R J

    2000-11-01

    Extracorporeal shockwave lithotripsy (ESWL) has been used since the mid-1980s to fragment bile duct stones which cannot be removed endoscopically. Early machines required general anaesthesia and immersion in a waterbath. To investigate the effectiveness of the third generation Storz Modulith SL20 lithotriptor in fragmenting bile duct stones that could not be cleared by mechanical lithotripsy. Eighty three patients with retained bile duct stones were treated. All patients received intravenous benzodiazepine sedation and pethidine analgesia. Stones were targeted by fluoroscopy following injection of contrast via a nasobiliary drain or T tube. Residual fragments were cleared at endoscopic retrograde cholangiopancreatography. Complete stone clearance was achieved in 69 (83%) patients and in 18 of 24 patients (75%) who required more than one ESWL treatment. Stone clearance was achieved in all nine patients (100%) with intrahepatic stones and also in nine patients (100%) referred following surgical exploration of the bile duct. Complications included six cases of cholangitis and one perinephric haematoma which resolved spontaneously. Using the Storz Modulith, 83% of refractory bile duct calculi were cleared with a low rate of complications. These results confirm that ESWL is an excellent alternative to surgery in those patients in whom endoscopic techniques have failed.

  8. Optimizing Human Bile Preparation for Two-Dimensional Gel Electrophoresis

    Directory of Open Access Journals (Sweden)

    Hao-Tsai Cheng

    2016-01-01

    Full Text Available Aims. Bile is an important body fluid which assists in the digestion of fat and excretion of endogenous and exogenous compounds. In the present study, an improved sample preparation for human bile was established. Methods and Material. The method involved acetone precipitation followed by protein extraction using commercially available 2D Clean-Up kit. The effectiveness was evaluated by 2-dimensional electrophoresis (2DE profiling quality, including number of protein spots and spot distribution. Results. The total protein of bile fluid in benign biliary disorders was 0.797 ± 0.465 μg/μL. The sample preparation method using acetone precipitation first followed by 2D Clean-Up kit protein extraction resulted in better quality of 2DE gel images in terms of resolution as compared with other sample preparation methods. Using this protocol, we obtained approximately 558 protein spots on the gel images and with better protein spots presentation of haptoglobin, serum albumin, serotransferrin, and transthyretin. Conclusions. Protein samples of bile prepared using acetone precipitation followed by 2D Clean-Up kit exhibited high protein resolution and significant protein profile. This optimized protein preparation protocol can effectively concentrate bile proteins, remove abundant proteins and debris, and yield clear presentation of nonabundant proteins and its isoforms on 2-dimensional electrophoresis gel images.

  9. Congenital dilatation of the large and segmental intrahepatic bile ducts (Caroli's disease in two Golden retriever littermates : clinical communication

    Directory of Open Access Journals (Sweden)

    R.D. Last

    2006-06-01

    Full Text Available Two, sibling, male Golden retriever puppies, 13 weeks of age, were presented with congenital biliary cysts of the liver involving both hepatic and segmental bile ducts, as well as bilateral polycystic kidney disease. Ultrasonography of the livers of both pups demonstrated segmental cystic lesions that were contiguous with the bile ducts. Histopathology revealed cystic ectatic bile duct hyperplasia and dysplasia with variable portal fibrosis in the liver, while in the kidneys there were radially arranged, cylindrically dilated cysts of the collecting ducts, which extended through the medulla and cortex. This pathology was compatible with that of congenital dilatation of the large and segmental bile ducts (Caroli's disease described in humans, dogs and rats. In humans Caroli's disease has an autosomal recessive inheritance pattern, while in rats activation of the MEK5/ERK cascade initiates the biliary dysgenesis of Caroli's disease in this species. However, the exact mode of inheritance and pathogenesis of Caroli's disease in dogs is as yet unknown. Previous reports on congenital hepatic cystic diseases of the dog have described Caroli's disease like lesions in various breeds, but these are believed to be the 1st reported cases in the Golden retriever breed.

  10. First-time report of metalloproteinases in fish bile and their potential as bioindicators regarding environmental contamination.

    Science.gov (United States)

    Hauser-Davis, R A; Lima, A A; Ziolli, R L; Campos, R C

    2012-04-01

    Gallbladder bile from 2 fish species, mullet (Mugil liza) and tilapias (Tilapia rendalli), contain substantial matrix metalloproteinases (MMPs). Extensive purification studies were conducted in order to obtain workable samples for SDS-PAGE and zymography analysis. Proteinase activities were assayed by gelatin substrate zymography. Several protein bands were observed, corresponding to molecular weights of 200, 136, 43, 36, 34, 29, 23 and 14 kDa in mullet bile and 179, 97, 79, 61, 54, 45, 36, 33 and 21 kDa in tilapia bile. Specific inhibitor studies were conducted, in which MMPS were inhibited by EDTA and 1,10 phenanthroline, but not by serine and cysteine protease inhibitors, such as phenylmethylsulfonyl fluoride (PMSF) and transepoxysuccinyl-l-leucylamido-l-guanidino butane (E-64), confirming the proteinase identities as MMPs. Differences in proteinase expression were observed in fish from a contaminated and reference site. Some studies regarding MMPs in different fish tissues exist, however this is the first study conducted in fish bile, and their involvement in detoxification processes and organism protection against the effects of aquatic contaminants may be a possibility. Copyright © 2011 Elsevier B.V. All rights reserved.

  11. Radiation therapy in extrahepatic bile duct carcinoma

    International Nuclear Information System (INIS)

    Mahe, Marc; Romestaing, Pascale; Talon, Bernard; Ardiet, J.M.; Salerno, Nathalie; Sentenac, Irenee; Gerard, J.P.

    1991-01-01

    Fifty-one patients with carcinoma of the extrahepatic bile ducts (EHBD) received radiation therapy between Jan 1980-Dec 1988. The location of the tumors was: proximal third, 20 patients; middle third, 23; distal third, 3; diffuse, 5 patients. Thirty-six patients underwent surgery with complete gross resection in 14 (10/14 with positive margins), incomplete gross resection in 12 and only biopsy in 10. Fifteen patients had only biliary drainage without laparotomy after cytologic diagnosis of malignancy in 11/15. Radiation therapy was done with curative intent after complete or incomplete resection (n=26) and it was palliative in patients who had no resection or only biliary drainage (n=25). Twenty-five patients received external radiation-therapy (ERT) alone to the tumor and lymph nodes (mean dose 45 Gy/2Gy per fraction for cure, 35 Gy/10 fractions for palliation), 8 patients had only iridium-192 ( 192 Ir) implant (50-60 Gy at a 1 cm radius for cure, 30 Gy for palliation), 17 patients had both ERT + 192 Ir(ERT 42.5 Gy + 192 Ir 10-15 Gy for cure; ERT 20 Gy/5 fractions + 192 Ir 20-30 Gy for palliation) and one intra-operative irradiation + ERT. The overall survival rate for the entire group was 55, 28.5 and 15 percent at 12, 24, 36 months and median survival 12 months. Median survival was 22 months in patients treated with curative intent and only 10 months after palliative treatment (p0.03). Among patients who had curative treatment, median survival was 27.5 months after complete gross resection and 13 months after incomplete gross resection (p0.045). After complete gross resection 5/14 patients were alive without evolutive disease at 11, 19, 20, 23 and 41 months, 2 were alive with metastases at 25 and 27 months and 7/14 died of cancer from 7 to 59 months. The rate of complications was low: 3 cholangitis responsive to antibiotics, 1 hemobilia and 2 gastric ulcers. These results are encouraging especially for patients with complete gross resection but they must be

  12. Gelation of self-assembed bile acid-PEG conjugates

    Science.gov (United States)

    Strandman, Satu; Le Devedec, Frantz; Zhu, X. X.

    2012-02-01

    The aggregation of macromolecules and low-molar-mass compounds into elongated self-assemblies such as wormlike micelles, fibers, or tubules increases the viscosity of the solutions and often leads to gelation due to network formation, even in organic solvents. Such one-dimensional nanostructures are promising candidates for drug delivery vehicles, packing materials for separation, templates for metal nanowires, biocides, and photo- or biocatalysis. An interesting group of compounds capable of this type of self-organization are bile acids, which are endogeneous steroids known to form gels at high concentrations and appropriate pH conditions. Grafting poly(ethylene oxide) on bile acids via anionic polymerization brings along thermoresponsiveness represented by lower critical solution temperature (LCST), while self-assembling occurs below another threshold temperature leading to a gelation at high concentrations, as shown by rheological experiments. The latter transition is assigned to the nanotube formation of pegylated bile acids, visualized by electron microscopy.

  13. Salivary a-amylase protects enamel surface against acid induced softening

    DEFF Research Database (Denmark)

    Lazovic, Maja Bruvo; Moe, Dennis; Kirkeby, Svend

    -TOF mass fingerprinting following trypsin digestion. Each persistent peak in the HPLC chromatograms was related to the protective effect against acid-induced enamel softening obtained by the corresponding saliva sample by multiple regression analysis. Results: One peak identified as a-amylase had......% (psample the second peak was not identified. Conclusion: Protective effects of experimentally developed salivary pellicles can be related to their protein composition, although, not all proteins could be identified in this study......., and one Chinese. After collection, saliva was dialysed and lyophilised and re-dissolved at 0.5% in Type I water. Next, four polished bovine enamel specimens were immersed into each sample under gentle and constant shaking for 12 hours. Last, specimens were exposed to an erosive challenge of pH 2.3 for 4...

  14. Raw data of the effects of Chlorogenic acid in 3-Nitropropionic acid induced toxicity and genotoxicity

    Directory of Open Access Journals (Sweden)

    Alarcón-Herrera Norberto

    2017-10-01

    Full Text Available The raw data showed in this article comes from the published research article entitled “Protective effects of Chlorogenic acid in 3-Nitropropionic acid induced toxicity and genotoxicity” Food Chem Toxicol. 2017 May 3. pii: S0278-6915(1730226-0. DOI:10.1016/j.fct.2017.04.048. [1]. Data illustrates antitoxic and antigenotoxic effects of Chlorogenic acid (CGA on toxicity and genotoxicity produced by the in vivo treatment with mitochondria toxin 3-Nitropropionic acid (3-NP in mice. Toxicity and genotoxicity was evaluated in erythrocytes of peripheral blood through the micronuclei assay. Data was share at the Elsevier repository under the reference number FCT9033.

  15. Unsaturated fatty acids protect trophoblast cells from saturated fatty acid-induced autophagy defects.

    Science.gov (United States)

    Hong, Ye-Ji; Ahn, Hyo-Ju; Shin, Jongdae; Lee, Joon H; Kim, Jin-Hoi; Park, Hwan-Woo; Lee, Sung Ki

    2018-02-01

    Dysregulated serum fatty acids are associated with a lipotoxic placental environment, which contributes to increased pregnancy complications via altered trophoblast invasion. However, the role of saturated and unsaturated fatty acids in trophoblastic autophagy has yet to be explored. Here, we demonstrated that prolonged exposure of saturated fatty acids interferes with the invasiveness of human extravillous trophoblasts. Saturated fatty acids (but not unsaturated fatty acids) inhibited the fusion of autophagosomes and lysosomes, resulting in the formation of intracellular protein aggregates. Furthermore, when the trophoblast cells were exposed to saturated fatty acids, unsaturated fatty acids counteracted the effects of saturated fatty acids by increasing degradation of autophagic vacuoles. Saturated fatty acids reduced the levels of the matrix metalloproteinases (MMP)-2 and MMP-9, while unsaturated fatty acids maintained their levels. In conclusion, saturated fatty acids induced decreased trophoblast invasion, of which autophagy dysfunction plays a major role. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Cell wall dynamics modulate acetic acid-induced apoptotic cell death of Saccharomyces cerevisiae

    Science.gov (United States)

    Rego, António; Duarte, Ana M.; Azevedo, Flávio; Sousa, Maria J.; Côrte-Real, Manuela; Chaves, Susana R.

    2014-01-01

    Acetic acid triggers apoptotic cell death in Saccharomyces cerevisiae, similar to mammalian apoptosis. To uncover novel regulators of this process, we analyzed whether impairing MAPK signaling affected acetic acid-induced apoptosis and found the mating-pheromone response and, especially, the cell wall integrity pathways were the major mediators, especially the latter, which we characterized further. Screening downstream effectors of this pathway, namely targets of the transcription factor Rlm1p, highlighted decreased cell wall remodeling as particularly important for acetic acid resistance. Modulation of cell surface dynamics therefore emerges as a powerful strategy to increase acetic acid resistance, with potential application in industrial fermentations using yeast, and in biomedicine to exploit the higher sensitivity of colorectal carcinoma cells to apoptosis induced by acetate produced by intestinal propionibacteria. PMID:28357256

  17. Determination of the pK for the acid-induced denaturation of ferrocytochrome c.

    Science.gov (United States)

    Varhac, Rastislav; Antalík, Marián

    2004-03-30

    Optical absorption spectroscopy was used to characterize the acid-induced conformational transition of horse heart ferrocytochrome c in the presence of urea. By using linear extrapolation to zero denaturant concentration, an apparent pK value for denaturation was found to be 0.86 +/- 0.07 at 25 degrees C. Visible absorption spectra in the presence of high urea concentration indicate that the dominant population is a high-spin, five-coordinate form under acidic conditions. Ferricytochrome c, used as a model reference system, shows a linear dependence of pK values versus urea concentration in the range from 0 to 4.1 M. Our data also indicate that even at a pH below 2 the iron-sulfur bond in ferrocytochrome c is present.

  18. Proteomic investigation into betulinic acid-induced apoptosis of human cervical cancer HeLa cells.

    Science.gov (United States)

    Xu, Tao; Pang, Qiuying; Zhou, Dong; Zhang, Aiqin; Luo, Shaman; Wang, Yang; Yan, Xiufeng

    2014-01-01

    Betulinic acid is a pentacyclic triterpenoid that exhibits anticancer functions in human cancer cells. This study provides evidence that betulinic acid is highly effective against the human cervical cancer cell line HeLa by inducing dose- and time-dependent apoptosis. The apoptotic process was further investigated using a proteomics approach to reveal protein expression changes in HeLa cells following betulinic acid treatment. Proteomic analysis revealed that there were six up- and thirty down-regulated proteins in betulinic acid-induced HeLa cells, and these proteins were then subjected to functional pathway analysis using multiple analysis software. UDP-glucose 6-dehydrogenase, 6-phosphogluconate dehydrogenase decarboxylating, chain A Horf6-a novel human peroxidase enzyme that involved in redox process, was found to be down-regulated during the apoptosis process of the oxidative stress response pathway. Consistent with our results at the protein level, an increase in intracellular reactive oxygen species was observed in betulinic acid-treated cells. The proteins glucose-regulated protein and cargo-selection protein TIP47, which are involved in the endoplasmic reticulum pathway, were up-regulated by betulinic acid treatment. Meanwhile, 14-3-3 family proteins, including 14-3-3β and 14-3-3ε, were down-regulated in response to betulinic acid treatment, which is consistent with the decrease in expression of the target genes 14-3-3β and 14-3-3ε. Furthermore, it was found that the antiapoptotic bcl-2 gene was down-regulated while the proapoptotic bax gene was up-regulated after betulinic acid treatment in HeLa cells. These results suggest that betulinic acid induces apoptosis of HeLa cells by triggering both the endoplasmic reticulum pathway and the ROS-mediated mitochondrial pathway.

  19. CD36 Mediated Fatty Acid-Induced Podocyte Apoptosis via Oxidative Stress.

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    Wei Hua

    Full Text Available Hyperlipidemia-induced apoptosis mediated by fatty acid translocase CD36 is associated with increased uptake of ox-LDL or fatty acid in macrophages, hepatocytes and proximal tubular epithelial cells, leading to atherosclerosis, liver damage and fibrosis in obese patients, and diabetic nephropathy (DN, respectively. However, the specific role of CD36 in podocyte apoptosis in DN with hyperlipidemia remains poorly investigated.The expression of CD36 was measured in paraffin-embedded kidney tissue samples (Ctr = 18, DN = 20 by immunohistochemistry and immunofluorescence staining. We cultured conditionally immortalized mouse podocytes (MPC5 and treated cells with palmitic acid, and measured CD36 expression by real-time PCR, Western blot analysis and immunofluorescence; lipid uptake by Oil red O staining and BODIPY staining; apoptosis by flow cytometry assay, TUNEL assay and Western blot analysis; and ROS production by DCFH-DA fluorescence staining. All statistical analyses were performed using SPSS 21.0 statistical software.CD36 expression was increased in kidney tissue from DN patients with hyperlipidemia. Palmitic acid upregulated CD36 expression and promoted its translocation from cytoplasm to plasma membrane in podocytes. Furthermore, palmitic acid increased lipid uptake, ROS production and apoptosis in podocytes, Sulfo-N-succinimidyloleate (SSO, the specific inhibitor of the fatty acid binding site on CD36, decreased palmitic acid-induced fatty acid accumulation, ROS production, and apoptosis in podocytes. Antioxidant 4-hydroxy-2,2,6,6- tetramethylpiperidine -1-oxyl (tempol inhibited the overproduction of ROS and apoptosis in podocytes induced by palmitic acid.CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress might participate in the process of DN.

  20. Hypertonic saline reduces inflammation and enhances the resolution of oleic acid induced acute lung injury

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    Costello Joseph F

    2008-07-01

    Full Text Available Abstract Background Hypertonic saline (HTS reduces the severity of lung injury in ischemia-reperfusion, endotoxin-induced and ventilation-induced lung injury. However, the potential for HTS to modulate the resolution of lung injury is not known. We investigated the potential for hypertonic saline to modulate the evolution and resolution of oleic acid induced lung injury. Methods Adult male Sprague Dawley rats were used in all experiments. Series 1 examined the potential for HTS to reduce the severity of evolving oleic acid (OA induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 12 or hypertonic saline (HTS, n = 12, and the extent of lung injury assessed after 6 hours. Series 2 examined the potential for HTS to enhance the resolution of oleic acid (OA induced acute lung injury. Following intravenous OA administration, animals were randomized to receive isotonic (Control, n = 6 or hypertonic saline (HTS, n = 6, and the extent of lung injury assessed after 6 hours. Results In Series I, HTS significantly reduced bronchoalveolar lavage (BAL neutrophil count compared to Control [61.5 ± 9.08 versus 102.6 ± 11.89 × 103 cells.ml-1]. However, there were no between group differences with regard to: A-a O2 gradient [11.9 ± 0.5 vs. 12.0 ± 0.5 KPa]; arterial PO2; static lung compliance, or histologic injury. In contrast, in Series 2, hypertonic saline significantly reduced histologic injury and reduced BAL neutrophil count [24.5 ± 5.9 versus 46.8 ± 4.4 × 103 cells.ml-1], and interleukin-6 levels [681.9 ± 190.4 versus 1365.7 ± 246.8 pg.ml-1]. Conclusion These findings demonstrate, for the first time, the potential for HTS to reduce pulmonary inflammation and enhance the resolution of oleic acid induced lung injury.

  1. Microdroplet fusion mass spectrometry: accelerated kinetics of acid-induced chlorophyll demetallation.

    Science.gov (United States)

    Lee, Jae Kyoo; Nam, Hong Gil; Zare, Richard N

    2017-01-01

    Kinetics of acid-induced chlorophyll demetallation was recorded in microdroplets by fusing a stream of microdroplets containing 40 µM chlorophyll a or b dissolved in methanol with a stream of aqueous microdroplets containing 35 mM hydrochloric acid (pH = 1·46). The kinetics of the demetallation of chlorophyll in the fused microdroplets (14 ± 6 µm diameter; 84 ± 18 m s-1 velocity) was recorded by controlling the traveling distance of the fused microdroplets between the fusion region and the inlet of a mass spectrometer. The rate of acid-induced chlorophyll demetallation was about 960 ± 120 times faster in the charged microdroplets compared with that reported in bulk solution. If no voltage was applied to the sprayed microdroplets, then the acceleration factor was about 580 ± 90, suggesting that the applied voltage is not a major factor determining the acceleration. Chlorophyll a was more rapidly demetallated than chlorophyll b by a factor of ~26 in bulk solution and ~5 in charged microdroplets. The demetallation kinetics was second order in the H+ concentration, but the acceleration factor of microdroplets compared with bulk solution appeared to be unchanged in going from pH = 1·3 to 7·0. The water:methanol ratio of the fused microdroplets was varied from 7:3 to 3:7 causing an increase in the reaction rate of chlorophyll a demetallation by 20%. This observation demonstrates that the solvent composition, which has different evaporation rates, does not significantly affect the acceleration. We believe that a major portion of the acceleration can be attributed to confinement effects involving surface reactions rather than either to evaporation of solvents or to the introduction of charges to the microdroplets.

  2. Evaluation of the effects of a new series of SMTPs in the acetic acid-induced embolic cerebral infarct mouse model.

    Science.gov (United States)

    Shibata, Keita; Hashimoto, Terumasa; Hasumi, Keiji; Honda, Kazuo; Nobe, Koji

    2018-01-05

    We reported previously that Stachybotrys microspora triprenyl phenol-7 (SMTP-7) showed potential thrombolytic, anti-inflammatory and anti-oxidant effects that account for its excellent pharmacological activity such as having a wider therapeutic time window than tissue plasminogen activator (t-PA) and a significant protection against hemorrhage. The aim of the present study was to evaluate and compare the effect of a new series of SMTPs in the acetic acid-induced embolic cerebral infarct mouse model. Thrombotic occlusion was produced in mice by inducing the transfer of acetic acid-induced thrombi from the right common carotid artery into the brain. SMTPs were evaluated by their effect on reducing infarct area, neurological score and edema. Furthermore, plasmin formation, anti-inflammatory and anti-oxidant activities were assessed by fibrin zymography, measuring pro-inflammatory gene expression, and thiobarbituric acid reactive substances (TBARS) assay, respectively. Treatment with either SMTP-22 or SMTP-43 (10mg/kg), which have similar plasmin formation, anti-inflammatory and anti-oxidant activities to SMTP-7, resulted in reduced infarct area, neurological score and edema. Coexistence of all these three activities appears to be important for the treatment of embolic infarction because SMTP-6, SMTP-25, and SMTP-44D (10mg/kg), which are each missing at least one of the three functions, were not as effective. Therefore, these results indicate that SMTP-22 and SMTP-43 have potential as medicinal compounds for the treatment of embolic cerebral infarction. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Bile acid malabsorption in chronic diarrhea: pathophysiology and treatment.

    Science.gov (United States)

    Barkun, Alan N; Love, Jonathan; Gould, Michael; Pluta, Henryk; Steinhart, Hillary

    2013-11-01

    Bile acid malabsorption (BAM) is a common but frequently under-recognized cause of chronic diarrhea, with an estimated prevalence of 4% to 5%. The published literature for the period 1965 to 2012 was examined for articles regarding the pathophysiology and treatment of BAM to provide an overview of the management of BAM in gastroenterology practice. BAM is classified as type 1 (secondary to ileal dysfunction), type 2 (idiopathic) or type 3 (secondary to gastrointestinal disorders not associated with ileal dysfunction). The estimated prevalence of BAM is >90% in patients with resected Crohn disease (CD) and 11% to 52% of unresected CD patients (type 1); 33% in diarrhea-predominant irritable bowel syndrome (type 2); and is a frequent finding postcholecystectomy or postvagotomy (type 3). Investigations include BAM fecal bile acid assay, 23-seleno-25-homo-tauro-cholic acid (SeHCAT) testing and high-performance liquid chromatography of serum 7-α-OH-4-cholesten-3-one (C4), to determine the level of bile acid synthesis. A less time-consuming and expensive alternative in practice is an empirical trial of the bile acid sequestering agent cholestyramine. An estimated 70% to 96% of chronic diarrhea patients with BAM respond to short-course cholestyramine. Adverse effects include constipation, nausea, borborygmi, flatulence, bloating and abdominal pain. Other bile acid sequestering agents, such as colestipol and colesevelam, are currently being investigated for the treatment of BAM-associated diarrhea. BAM is a common cause of chronic diarrhea presenting in gastroenterology practice. In accordance with current guidelines, an empirical trial of a bile acid sequestering agent is warranted as part of the clinical workup to rule out BAM.

  4. Bile loss in the acute intestinal radiation syndrome in rats

    International Nuclear Information System (INIS)

    Geraci, J.P.; Dunston, S.G.; Jackson, K.L.; Mariano, M.S.; Holeski, C.; Eaton, D.L.

    1987-01-01

    The effects of bile duct ligation (BDL), choledochostomy, bile acid sequestering within the intestinal lumen by cholestyramine, and fluid and electrolyte replacement on survival time and development of diarrhea after whole-body exposure to doses of ionizing radiation that result in death from acute intestinal injury were studied. BDL significantly prolonged survival and delayed the onset of diarrhea after exposure to 137 Cs gamma rays, fission neutrons, or cyclotron-produced neutrons in the range of doses that produce intestinal death or death from a combination of intestinal and hematopoietic injuries. Cannulation of the bile duct with exteriorized bile flow (choledochostomy) to protect the irradiated intestine from the mucolytic action of bile salts did not duplicate the effect of BDL in increasing survival time. Choledochostomy without fluid replacement eliminated the occurrence of diarrhea in 15.4 Gy irradiated rats. Diarrhea did occur in irradiated animals with choledochostomy if they received duodenal injections of fluid and electrolytes to replace the fluid lost as a result of bile drainage. Duodenal injection of fluid and electrolytes had no significant effect on survival time in irradiated rats. Injection of fluid and electrolytes into the peritoneal cavity of irradiated rats resulted in an increase in survival time that was comparable to that observed after BDL. Addition of antibiotics to the peritoneally injected fluid and electrolytes further increased survival time (up to 9 days). This survival time approached that seen in animals receiving the same radiation dose but which had the intestine exteriorized and shielded to minimize radiation injury to the intestine. Postmortem histological examinations of the irradiated small intestine showed mucosal regeneration in these long-term survivors receiving fluid and antibiotic therapy

  5. El Salterio bilingüe prealfonsí

    OpenAIRE

    Cátedra, Pedro M.

    2005-01-01

    En este artículo, adelanto de un libro en prensa sobre la materia, se da a conocer una primitiva versión del Salterio que se ha conservado en forma bilingüe latina/romace castellano. Es el primer caso en la Europa meridional de un salterio bilingüe del siglo XIII, que pone en relación la cultura y los usos del Salterio en la España Medieval con los propios de las tradiciones anglo-normandas.

  6. Common bile duct stones: analysis of the videolaparoscopic surgical treatment

    Directory of Open Access Journals (Sweden)

    Marco Aurelio Santo

    2012-03-01

    Full Text Available CONTEXT: About 9% of the Brazilian population has gallstones and the incidence increases significantly with aging. The choledocholithiasis is found around 15% of these patients, and a third to half of these cases presented as asymptomatic. Once the lithiasis in the common bile duct is characterized through intraoperative cholangiography, the laparoscopic surgical exploration can be done through the transcystic way or directly through choledochotomy. OBJECTIVE: To evaluate the results and outcomes of the laparoscopic treatment of common bile duct lithiasis. METHODS: Seventy consecutive patients were evaluated. They prospectively underwent the treatment of the lithiasis in the common bile duct and the exploration ways were compared according to the following parameters: criteria on their indication, success in the clearance, surgical complications. It was verified that about ½ of the choledocholithiasis carriers did not show any expression of predictive factors (clinical antecedents of jaundice and/or acute pancreatitis, compatible sonographic data and the pertaining lab tests. The laparoscopic exploration through the transcystic way is favored when there are no criteria for the practice of primary choledochotomy, which are: lithiasis in the proximal bile duct, large (over 8 mm or numerous calculi (multiple calculosis. RESULTS: The transcystic way was employed in about 50% of the casuistic and the choledochotomy in about 30%. A high success rate (around 80% was achieved in the clearance of the common bile duct stones through laparoscopic exploration. The transcystic way, performed without fluoroscopy or choledochoscopy, attained a low rate of success (around 45%, being 10% of those by transpapilar pushing of calculi less than 3 mm. The exploration through choledochotomy, either primary or secondary, if the latter was performed after the transcystic route failure, showed high success rate (around 95%. When the indication to choledochotomy was

  7. Congenital double bile duct presenting as recurrent cholangitis in a child

    Directory of Open Access Journals (Sweden)

    K.D. Chakravarty

    2015-12-01

    Full Text Available Double common bile duct (DCBD is a rare congenital anomaly. Most of these bile duct anomalies are associated with bile duct stones, anomalous pancreaticobiliary junction (APBJ, pancreatitis and bile duct or gastric cancers. Early detection and treatment is important to avoid long term complications. Surgical resection of the anomalous bile duct and reconstruction of the biliary enteric anastomosis is the treatment of choice. We report a rare case of DCBD anomaly in a girl, who presented with recurrent cholangitis. She had type Va DCBD anomaly. She underwent successful resection of the bile duct and reconstruction of the biliary enteric anastomosis. Preoperative imaging and diagnosis of the congenital biliary anomaly is very important to avoid intraoperative bile duct injury. Review of the literature shows very few cases of type Va DCBD, presenting with either bile duct stones or APBJ.

  8. The protective role of yeast cathepsin D in acetic acid-induced apoptosis depends on ANT (Aac2p) but not on the voltage-dependent channel (Por1p).

    Science.gov (United States)

    Pereira, Helena; Azevedo, Flávio; Rego, António; Sousa, Maria João; Chaves, Susana R; Côrte-Real, Manuela

    2013-01-16

    We have previously shown that the yeast Cathepsin D (CatD) Pep4p translocates from the vacuole to the cytosol during acetic acid-induced apoptosis and is required for efficient mitochondrial degradation, though its specific role in this process is still elusive. Here, we show that the protective role of Pep4p in acetic acid-induced apoptosis depends on its catalytic activity and is independent of the yeast voltage-dependent anion channel Por1p (which has no role on mitochondrial degradation) but dependent on AAC proteins, the yeast adenine nucleotide translocator. Our results demonstrate a differential interplay between yeast vacuolar CatD and mitochondrial proteins involved in apoptosis regulation. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  9. Anti-inflammatory effect of Moringa oleifera Lam. seeds on acetic acid-induced acute colitis in rats

    Directory of Open Access Journals (Sweden)

    Mohsen Minaiyan

    2014-02-01

    Full Text Available Objective: Anti-inflammatory, immuno-modulatory, and antioxidant properties of Moringa oleifera Lam. suggest that it might have beneficial effects on colitis. The present study was performed to investigate the anticolitis effect of Moringa oleifera seeds hydro-alcoholic extract (MSHE and its chloroform fraction (MCF on acetic acid-induced colitis in rats. Materials and Methods: Both MSHE and MCF with three increasing doses (50, 100, and 200 mg/kg were administered orally to separate groups of male Wistar rats, 2 h before ulcer induction (using acetic acid 4% and continued for 5 days. Prednisolone (4 mg/kg and normal saline (1 ml/kg were used in reference and control groups, respectively. All rats were sacrificed 24 h after the last dose (at day 6 and tissue injuries were assessed macroscopically and pathologically. Results: Extracts with three doses mentioned before were effective to reduce weight of distal colon (8 cm as a marker for inflammation and tissue edema. Three doses of MSHE and two greater doses of MCF (100 and 200 mg/kg were effective to reduce ulcer severity, area, and index as well as mucosal inflammation severity and extent, crypt damage, invasion involvement, total colitis index, and MPO activity compared with controls. MCF (50 mg/kg was not significantly effective in reducing evaluated parameters of colitis compared with controls. Conclusion: It is concluded that MSHE and MCF were both effective to treat experimental colitis and this might be attributed to their similar major components, biophenols and flavonoids. Since the efficacy was evident even in low doses of MSHE, presence of active constituents with high potency in seeds is persuasive.

  10. Classical bile acids in animals, beta-phocaecholic acid in ducks.

    Science.gov (United States)

    Jirsa, M; Klinot, J; Klinotová, E; Ubik, K; Kucera, K

    1989-01-01

    1. Bile samples of different animals were analysed and the percentage content of classical bile acids was determined. 2. Herbivorous birds mostly excreted a large proportion of chenodeoxycholic acid. 3. The anteater (Myrmecophaga tridactyla) excreted deoxycholic acid most probably as a primary bile acid. 4. In the bile of ducks (Anas platyrhynchos) a large amount of (23R)3 alpha, 7 alpha, 23-trihydroxy-5 beta-cholan-24-oic acid (beta-phocaecholic acid) was found.

  11. Association between cholesterol-phospholipid vesicles and cholesterol crystals in human gallbladder bile

    OpenAIRE

    Schriever, Carolin Erika; Jüngst, Dieter

    1989-01-01

    Rapid aggregation of cholesterol-phospholipid vesicles in gallbladder bile seems to be the first event in the production of cholesterol crystals, a prerequisite for cholesterol gallstone formation. We examined the amount of these vesicles in 33 human gallbladder biles in relation to biliary lipid composition and to the presence of cholesterol crystals. Biliary microscopy detected cholesterol crystals in all 19 biles from patients with cholesterol gallstones but in none of 14 biles from patien...

  12. In Vitro Binding Capacity of Bile Acids by Defatted Corn Protein Hydrolysate

    Directory of Open Access Journals (Sweden)

    Pierre Claver Irakoze

    2011-02-01

    Full Text Available Defatted corn protein was digested using five different proteases, Alcalase, Trypsin, Neutrase, Protamex and Flavourzyme, in order to produce bile acid binding peptides. Bile acid binding capacity was analyzed in vitro using peptides from different proteases of defatted corn hydrolysate. Some crystalline bile acids like sodium glycocholate, sodium cholate and sodium deoxycholate were individually tested using HPLC to see which enzymes can release more peptides with high bile acid binding capacity. Peptides from Flavourzyme defatted corn hydrolysate exhibited significantly (p

  13. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism

    Science.gov (United States)

    di Leva, Francesco Saverio; Festa, Carmen; Renga, Barbara; Sepe, Valentina; Novellino, Ettore; Fiorucci, Stefano; Zampella, Angela; Limongelli, Vittorio

    2015-11-01

    Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

  14. Response to Bile Salts in Clinical Strains of Acinetobacter baumannii Lacking the AdeABC Efflux Pump: Virulence Associated with Quorum Sensing

    Science.gov (United States)

    López, Maria; Blasco, Lucia; Gato, Eva; Perez, Astrid; Fernández-Garcia, Laura; Martínez-Martinez, Luis; Fernández-Cuenca, Felipe; Rodríguez-Baño, Jesús; Pascual, Alvaro; Bou, German; Tomás, Maria

    2017-01-01

    Introduction: Acinetobacter baumannii is an opportunistic nosocomial pathogen associated with multiple infections. This pathogen usually colonizes (first stage of microbial infection) host tissues that are in contact with the external environment. As one of the sites of entry in human hosts is the gastrointestinal tract, the pathogen must be capable of tolerating bile salts. However, studies analyzing the molecular characteristics involved in the response to bile salts in clinical strains of A. baumannii are scarce. Material and Methods: Microbiological and transcriptional studies (arrays and RT-PCR) in the response to bile salts were carried out in isogenic (A. baumanni ΔadeB ATCC 17978 and A. baumannii ΔadeL ATCC 17978) and clinical strains from clone ST79/PFGE-HUI-1 which is characterized by lacking the AdeABC efflux pump and by overexpression the AdeFGH efflux pump. Results and Discussion: In presence of bile salts, in addition to the glutamate/aspartate transporter were found overexpressed in A. baumannii ΔadeB ATCC 17978, the virulence factors (surface motility, biofilm, and Type VI Secretion System) which are associated with activation of the Quorum Sensing system. Overexpression of these factors was confirmed in clinical strains of clone ST79/PFGE-HUI-1. Conclusions: This the first study about the adaptive response to bile salts investigating the molecular and microbiological characteristics in response to bile salts of an isogenic model of A. baumannii ATCC 17978 and clinical isolates of A. baumannii (clinical strains of ST79/PFGE-HUI-1) lacking the main RND efflux pump (AdeABC). Clinical isolates of A. baumannii lacking the AdeABC efflux pump (clone ST79/PFGE-HUI-1) displayed a new clinical profile (increased invasiveness) possibly associated with the response to stress conditions (such as the presence of bile salts). PMID:28536672

  15. Taurine zinc solid dispersions enhance bile-incubated L02 cell viability and improve liver function by inhibiting ERK2 and JNK phosphorylation during cholestasis

    International Nuclear Information System (INIS)

    Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lai, Xiaofang; Xu, Donghui

    2016-01-01

    Highlights: • Taurine zinc SDs could prevent the bile-induced reduction in L02 cell viability. • Taurine zinc SDs can prevent cholestatic liver injury. • Taurine zinc SDs can inhibit BDL-induced hepatocyte apoptosis. • Taurine zinc SDs shows the cholesterol-lowering effects on cholestasis. • Taurine zinc SDs may suppress inflammation via dampening JNK phosphorylation. - Abstract: Dietary intakes of taurine and zinc are associated with decreased risk of liver disease. In this study, solid dispersions (SDs) of a taurine zinc complex on hepatic injury were examined in vitro using the immortalized human hepatocyte cell line L02 and in a rat model of bile duct ligation. Sham-operated and bile duct ligated Sprague-Dawley rats were treated with the vehicle alone or taurine zinc (40, 80, 160 mg/kg) for 17 days. Bile duct ligation significantly increased blood lipid levels, and promoted hepatocyte apoptosis, inflammation and compensatory biliary proliferation. In vitro, incubation with bile significantly reduced L02 cell viability; this effect was significantly attenuated by pretreatment with SP600125 (a JNK inhibitor) and enhanced when co-incubated with taurine zinc SDs. In vivo, administration of taurine zinc SDs decreased serum alanine aminotransferase and aspartate aminotransferase activities in a dose-dependent manner and attenuated the increases in serum total bilirubin, total cholesterol and low density lipoprotein cholesterol levels after bile duct ligation. Additionally, taurine zinc SDs downregulated the expression of interleukin-1β and inhibited the phosphorylation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase2 (ERK2) in the liver after bile duct ligation. Moreover, taurine zinc SDs had more potent blood lipid regulatory and anti-apoptotic effects than the physical mixture of taurine and zinc acetate. Therefore, we speculate that taurine zinc SDs protect liver function at least in part via a mechanism linked to reduce

  16. Response to Bile Salts in Clinical Strains of Acinetobacter baumannii Lacking the AdeABC Efflux Pump: Virulence Associated with Quorum Sensing.

    Science.gov (United States)

    López, Maria; Blasco, Lucia; Gato, Eva; Perez, Astrid; Fernández-Garcia, Laura; Martínez-Martinez, Luis; Fernández-Cuenca, Felipe; Rodríguez-Baño, Jesús; Pascual, Alvaro; Bou, German; Tomás, Maria

    2017-01-01

    Introduction: Acinetobacter baumannii is an opportunistic nosocomial pathogen associated with multiple infections. This pathogen usually colonizes (first stage of microbial infection) host tissues that are in contact with the external environment. As one of the sites of entry in human hosts is the gastrointestinal tract, the pathogen must be capable of tolerating bile salts. However, studies analyzing the molecular characteristics involved in the response to bile salts in clinical strains of A. baumannii are scarce. Material and Methods: Microbiological and transcriptional studies (arrays and RT-PCR) in the response to bile salts were carried out in isogenic ( A. baumanni Δ adeB ATCC 17978 and A. baumannii Δ adeL ATCC 17978) and clinical strains from clone ST79/PFGE-HUI-1 which is characterized by lacking the AdeABC efflux pump and by overexpression the AdeFGH efflux pump. Results and Discussion: In presence of bile salts, in addition to the glutamate/aspartate transporter were found overexpressed in A. baumannii Δ adeB ATCC 17978, the virulence factors (surface motility, biofilm, and Type VI Secretion System) which are associated with activation of the Quorum Sensing system. Overexpression of these factors was confirmed in clinical strains of clone ST79/PFGE-HUI-1. Conclusions: This the first study about the adaptive response to bile salts investigating the molecular and microbiological characteristics in response to bile salts of an isogenic model of A. baumannii ATCC 17978 and clinical isolates of A. baumannii (clinical strains of ST79/PFGE-HUI-1) lacking the main RND efflux pump (AdeABC). Clinical isolates of A. baumannii lacking the AdeABC efflux pump (clone ST79/PFGE-HUI-1) displayed a new clinical profile (increased invasiveness) possibly associated with the response to stress conditions (such as the presence of bile salts).

  17. Aspectos ultra-sonográficos dos hamartomas dos ductos biliares (complexo de von Meyenburg: resultado de uma busca ativa de oito anos Ultrasonography findings in patients with bile duct hamartomas (von Meyenburg complex: result of an active search of eight years

    Directory of Open Access Journals (Sweden)

    Márcio Martins Machado

    2003-06-01

    Full Text Available A correta identificação de tumores hepáticos benignos é importante, pois a maioria não necessita de conduta intervencionista. Os autores relatam os aspectos ultra-sonográficos dos hamartomas de ductos biliares (complexo de von Meyenburg em 16 pacientes estudados prospectivamente, resultados de uma busca ativa de oito anos. Em 14 pacientes foram identificadas múltiplas lesões menores ou iguais a 0,8 cm, e em dois, apenas duas lesões em cada (medindo de 0,4 cm a 1,3 cm. O aspecto ultra-sonográfico que predominou foi o de múltiplas pequenas imagens hiperecogênicas com ou sem reverberação sonora posterior e margens irregulares (14 pacientes. Menos comumente, foi encontrado o aspecto "em alvo", com centro com maior ecogenicidade que a periferia (dois pacientes com duas lesões cada e margens bem definidas.The recognition and identification of benign liver tumors is important since most of these tumors do not require any intervention. The authors report the ultrasonography findings in 16 patients with bile duct hamartomas (von Meyenburg complex that were evaluated prospectively by an active search of eight years. Multiple lesions with size equal or less than 0.8 cm were identified in 14 patients. Two other patients had only two lesions measuring 0.4 cm to 1.3 cm. The most common ultrasonographic pattern was that of multiple small hyperechogenic lesions (with or without posterior acoustic reverberation with irregular margins (14 patients. A less common finding (two patients with two lesions each was the "target" pattern with echogenic center and well defined limits.

  18. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Xue, Ruyi [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Ji, Lingling [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shen, Xizhong [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Chen, She, E-mail: shechen@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhang, Si, E-mail: zhangsi@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2014-05-23

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

  19. Kinetics for the synthetic bile acid 75-selenohomocholic acid-taurine in humans: comparison with [14C]taurocholate

    International Nuclear Information System (INIS)

    Jazrawi, R.P.; Ferraris, R.; Bridges, C.; Northfield, T.C.

    1988-01-01

    The apparent fractional turnover rate of the gamma-labeled bile acid analogue 75-selenohomocholic acid-taurine (75-SeHCAT) was assessed from decline in radioactivity over the gallbladder area on 4 successive days using a gamma-camera, and was compared in the same subjects with the fractional turnover rate of the corresponding natural bile acid, cholic acid-taurine, labeled with 14C ([14C]CAT) using the classical Lindstedt technique. Very similar results were obtained in 5 healthy individuals (coefficient of variation 4.8%, medians 0.35 and 0.34, respectively). By contrast, the fractional deconjugation rate assessed from zonal scanning of glycine- and taurine-conjugated bile acids on thin-layer chromatography was much less for 75-SeHCAT than for [14C]CAT (0.02 and 0.13, respectively; p less than 0.05). The fractional rate for deconjugation plus dehydroxylation was also determined by zonal scanning, and gave lower values for 75-SeHCAT than for [14C]CAT (0.02 and 0.12, respectively; p less than 0.05). There was a striking similarity between the fractional rate for deconjugation alone and that for deconjugation plus dehydroxylation for both bile acids in individual samples (r = 0.999, p less than 0.001), suggesting that these two processes might occur simultaneously and probably involve the same bacteria. We conclude that our scintiscanning technique provides an accurate, noninvasive method of measuring fractional turnover rate of a bile acid in humans, and that the finding that 75SeHCAT remains conjugated with taurine during enterohepatic recycling means that absorption should be specific for the ileal active transport site, thus rendering it an ideal substance for assessing ileal function

  20. Structure based classification for bile salt export pump (BSEP) inhibitors using comparative structural modeling of human BSEP

    Science.gov (United States)

    Jain, Sankalp; Grandits, Melanie; Richter, Lars; Ecker, Gerhard F.

    2017-06-01

    The bile salt export pump (BSEP) actively transports conjugated monovalent bile acids from the hepatocytes into the bile. This facilitates the formation of micelles and promotes digestion and absorption of dietary fat. Inhibition of BSEP leads to decreased bile flow and accumulation of cytotoxic bile salts in the liver. A number of compounds have been identified to interact with BSEP, which results in drug-induced cholestasis or liver injury. Therefore, in silico approaches for flagging compounds as potential BSEP inhibitors would be of high value in the early stage of the drug discovery pipeline. Up to now, due to the lack of a high-resolution X-ray structure of BSEP, in silico based identification of BSEP inhibitors focused on ligand-based approaches. In this study, we provide a homology model for BSEP, developed using the corrected mouse P-glycoprotein structure (PDB ID: 4M1M). Subsequently, the model was used for docking-based classification of a set of 1212 compounds (405 BSEP inhibitors, 807 non-inhibitors). Using the scoring function ChemScore, a prediction accuracy of 81% on the training set and 73% on two external test sets could be obtained. In addition, the applicability domain of the models was assessed based on Euclidean distance. Further, analysis of the protein-ligand interaction fingerprints revealed certain functional group-amino acid residue interactions that could play a key role for ligand binding. Though ligand-based models, due to their high speed and accuracy, remain the method of choice for classification of BSEP inhibitors, structure-assisted docking models demonstrate reasonably good prediction accuracies while additionally providing information about putative protein-ligand interactions.

  1. Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

    International Nuclear Information System (INIS)

    Wu, Weibin; Liu, Xijun; Peng, Xiaomin; Xue, Ruyi; Ji, Lingling; Shen, Xizhong; Chen, She; Gu, Jianxin; Zhang, Si

    2014-01-01

    Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR −/− ) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR −/− mice fed MCD diet (FXR −/− /MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR −/− /MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR −/− /MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR −/− /MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection

  2. Mechanism of prevention of aspirin-induced gastric lesions by bile duct legation in the rat.

    Science.gov (United States)

    Guth, P H; Paulsen, G; Lynn, D; Aures, D

    1976-11-01

    Gastric reflux of bile has been reported to be essential for the production of acute gastric mucosal lesions by intragastric aspirin in the rat. The purpose of the present study was to determine whether bile duct legation of pylorus ligation in the rat inhibits asprin-induced gastric lesions, and, if so, what the protective mechanisms are. Operations were performed under ether anesthesia. Asprin, 200 mg per kg, was instilled into the stomach 1/2 hr postsurgery (bile duct ligation or pylorus ligation). Four hours later the rats were killed, the stomachs were examined, and mucosal lesions were scored. Bile duct ligation, but not pylorus ligation, significantly protected against aspirin-induced gastric-lesions. Bile duct ligation, in pylorus-ligated rats, inhibited gastric acid output by 78%. Instilling HCl + aspirin in bile duct-ligated rats restored lesion formation. Shunting bile to the colon (to prevent bile reflux) did not prevent aspirin lesions. Salicylate determination, to ascertain whether bile duct ligation altered asprin absorption, revealed no significant differences between bile duct ligation and aspirin, shunt + aspirin, and sham shunt + aspirin in plasma and gastric tissue salicylate concentrations. (1) Bile duct legation protects against aspirin-induced gastric mucosal lesions by inhibiting gastric HCl secretion. As a corollary, a certain amount of acid in the stomach is necessary for aspirin-induced gastric lesions to form. (2) Bile reflux is not necessary for aspirn-induced gastric lesions in the rat.

  3. Mucin secretion by the human colon cell line LS174T is regulated by bile salts

    NARCIS (Netherlands)

    Klinkspoor, J. H.; Mok, K. S.; van Klinken, B. J.; Tytgat, G. N.; Lee, S. P.; Groen, A. K.

    1999-01-01

    We recently reported that bile salts play a role in the regulation of mucin secretion by cultured dog gallbladder epithelial cells. In this study we have examined whether bile salts also influence mucin secretion by the human epithelial colon cell line LS174T. Solutions of bile salts were applied to

  4. Outcome of 49 repairs of bile duct injuries after laparoscopic cholecystectomy

    NARCIS (Netherlands)

    Schol, F. P.; Go, P. M.; Gouma, D. J.

    1995-01-01

    Treatment of bile duct injuries after laparoscopic cholecystectomy is still under discussion. The aim of this study was to evaluate the results of end-to-end or biliodigestive anastomosis for various types of bile duct injury. Patient charts of 49 (0.81%) classified bile duct injuries from a

  5. Improved annotation of conjugated bile acid hydrolase superfamily members in Gram-positive bacteria.

    NARCIS (Netherlands)

    Lambert, J.M.; Siezen, R.J.; Vos, W.M. de; Kleerebezem, M.

    2008-01-01

    Most Gram-positive bacteria inhabiting the gastrointestinal tract are capable of hydrolysing bile salts. Bile salt hydrolysis is thought to play an important role in various biological processes in the host. Therefore, correct annotation of bacterial bile salt hydrolases (Bsh) in public databases

  6. Synthesis and evaluation of bile acid amides of [Formula: see text]-cyanostilbenes as anticancer agents.

    Science.gov (United States)

    Agarwal, Devesh S; Singh, Rajnish Prakash; Lohitesh, K; Jha, Prabhat N; Chowdhury, Rajdeep; Sakhuja, Rajeev

    2017-12-13

    A series of amino-substituted [Formula: see text]-cyanostilbene derivatives and their bile acid (cholic and deoxycholic acid) amides were designed and synthesized. A comparative study on the anticancer and antibacterial activity evaluation on the synthesized analogs was carried against the human osteosarcoma (HOS) cancer cell line, and two gram -ve (E. coli and S. typhi) and two gram [Formula: see text]ve (B. subtilis and S. aureus) bacterial strains. All the cholic acid [Formula: see text]-cyanostilbene amides showed an [Formula: see text] in the range 2-13 [Formula: see text] against human osteosarcoma cells (HOS) with the most active analog (6g) possessing an [Formula: see text] of [Formula: see text]. One of the amino-substituted [Formula: see text]-cyanostilbene, 4e, was found to possess an [Formula: see text] of [Formula: see text]. An increase in the number of cells at the sub-[Formula: see text] phase of the cell was observed in the in vitro cell cycle analysis of two most active compounds in the series (4e, 6g) suggesting a clear indication toward induction of apoptotic cascade. With respect to antibacterial screening, amino-substituted [Formula: see text]-cyanostilbenes were found to be more active than their corresponding bile acid amides. The synthesized compounds were also subjected to in silico study to predict their physiochemical properties and drug-likeness score.

  7. Bile salt-stimulated lipase: an animal model for human lactation

    International Nuclear Information System (INIS)

    Hamosh, M.; Freed, L.M.; York, C.M.; Sturman, J.A.; Hamosh, P.

    1986-01-01

    To date, bile salt-stimulated lipase (BSSL), an important digestive enzyme for the newborn, has only been described in the milk of primates - human and gorilla. The authors report the presence of BSSL in milks of dog and cat. Serial collections from two dogs (day 1-49) and cats (day 5-57) were analyzed for BSSL activity using a 3 H-triolein emulsion as substrate. Comparable analyses of pooled, term human milk were made for comparison. BSSL activity in individual dog milks (x = 32.0; range: 4.8-107.4 U/ml) was similar, while that in cat milk (x = 6.6; range: 2.2-16.9 U/ml) was lower than in human milk (x = 37.0; range: 10-80 U/ml; n = 35). Longitudinal patterns for BSSL differed depending upon the enzyme source. Dog, cat and human milk BSSL all showed a neutral to alkaline pH optimum (pH 7.0-8.4), stability at low pH, and 95-100% inhibition (at concentrations of 0.6 mM) by NaCl and eserine. BSSL activity from all sources had an obligate requirement for primary bile salts. These data are the first to show BSSL activity in milk from mammals other than human and gorilla. Presence of BSSL in nonprimate milk will permit the careful study of BSSL biology in the mammary gland as well as its role in neonatal fat digestion

  8. Ventajas y desventajas del bilingüismo

    Directory of Open Access Journals (Sweden)

    Alfredo Ardila

    2012-01-01

    Full Text Available Las personas bilingües tienen que coordinar dos sistemas lingüísticos. Esto implica algunas ganancias, pero también un costo. Las ganancias del bilingüismo incluyen: un incremento de la flexibilidad mental; una superioridad en el desarrollo de aquellas funciones cognitivas relacionadas con la atención y la inhibición; el uso de una cantidad mayor de estrategias cognoscitivas en la solución de problemas; un aumento de la llamada conciencia metalingüística; y una habilidad mayor de comunicación. Entre los costos del bilingüismo se menciona: cierto retraso aparente en la adquisición del lenguaje; una interferencia entre ambos sistemas fonológicos, léxicos y gramaticales; y un posible decremento en el vocabulario en las dos lenguas. Se concluye que existe una gran variabilidad de experiencias lingüísticas en las personas bilingües y un gran número de variables afecta su ejecución en diferentes tareas intelectuales.

  9. Acid resistance, bile tolerance and antimicrobial properties of ...

    African Journals Online (AJOL)

    Maari is a fermented food condiment obtained by spontaneous fermentation of seeds from the baobab tree (Adansonia digitata). Nine dominant lactic acid bacteria (LAB) strains, isolated from traditional maari fermentation were examined for their resistance to pH 2.5, their tolerance to 0.3% bile and their antimicrobial ...

  10. Percutaneous management of bile duct injury after laparoscopic cholecystectomy

    International Nuclear Information System (INIS)

    Islim, F.; Ors, S.; Salik, A.; Guven, K.; Yanar, F.; Alis, H.

    2012-01-01

    Full text: Introduction: The risk of bile duct injury after laparoscopic cholecystectomy is higher than open cholecystectomy. Objective: To discuss the importance of minimally invasive treatment options in the management of bile duct injuries after laparoscopic cholecystectomy and to present our approach in the management. Materials and methods: Management of 25 patients with symptomatic bile duct injury after laparoscopic cholecystectomy was retrospectively evaluated. Percutaneous collection drainage, endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) and percutaneous biliary drainage were performed for the management of the patients. Results: Mean age of the patients (15 women, 10 men) was 55. Either ultrasonography or computed tomography guided percutaneous drainage was performed in 13 patients. 9 of them completely recovered only with percutaneous drainage. In 4 of them ERCP was performed because of high drainage volume. In 9 of the patients with jaundice and high bilirubin levels ERCP was performed as the first option. And 3 patients were reoperated because of acute abdomen signs. ERCP, MRCP and PTC revealed type A in 7, type E2 in 3, type E3 in 3 and type E4 in 1 of the patients according to Strasberg classification. Conclusion: Presenting symptoms of the patients with symptomatic bile duct injury are useful in the determination of the treatment option.

  11. Spontaneous bile duct perforation in an infant, managed with simple ...

    African Journals Online (AJOL)

    Spontaneous bile duct perforation is a very rare but important cause of surgical jaundice in pediatric patients and one of the most common causes of surgical jaundice during infancy after biliary atresia. Preoperative diagnosis may not be possible in most of the cases. The exact cause of the perforation remains unclear.

  12. Abnormalities of intrahepatic bile ducts in extrahepatic biliary atresia.

    Science.gov (United States)

    Raweily, E A; Gibson, A A; Burt, A D

    1990-12-01

    The infantile cholangiopathies are a group of conditions associated with neonatal jaundice, which include extrahepatic biliary atresia, paucity of intra-hepatic bile ducts and disorders associated with persistence of fetal biliary structures, the so-called ductal plate malformations. Although previously regarded as distinct entities, it has recently been suggested that they may represent parts of a disease spectrum in which the principal process is one of bile duct destruction, the morphological manifestations in individual cases being influenced by the stage of intra-uterine development at which such injury occurs and by the site within the biliary system at which there is maximum damage. To further examine this concept, we have studied liver biopsy specimens from 37 neonates with extrahepatic biliary atresia, with particular reference to abnormalities of the intrahepatic bile ducts. Paucity of intrahepatic ducts, defined as a bile duct: portal tract ratio of less than 0.9, was identified in six cases (16.2%). In eight cases (21.6%) we found concentric tubular ductal structures similar to those observed in ductal plate malformations. In one case, both abnormalities could be demonstrated. Our findings support the concept that there is overlap between the various types of infantile cholangiopathy.

  13. Iatrogenic injury of an aberrant right posterior sectoral bile duct

    African Journals Online (AJOL)

    (Figs 1 and 2). A week later, an endoscopic retrograde cholangiopancreatography. (ERCP) examination was performed. This showed no filling of the right posterior sectoral ducts but normal opacification of the other ducts. (Figs 3a and b). These findings led to the diagnosis of an aberrant right posterior sectoral bile duct that ...

  14. Determinants of postprandial plasma bile acid kinetics in human volunteers

    NARCIS (Netherlands)

    Fiamoncini, J.; Yiorkas, A.M.; Gedrich, K.; Rundle, M.; Alsters, S.I.; Roeselers, G.; Broek, T.J. van den; Clavel, T.; Lagkouvardos, I.; Wopereis, S.; Frost, G.; Ommen, B. van; Blakemore, A.I.; Daniel, H.

    2017-01-01

    Bile acids (BA) are signaling molecules with a wide range of biological effects, also identified among the most responsive plasma metabolites in the postprandial state. We here describe this response to different dietary challenges and report on key determinants linked to its interindividual

  15. Gallbladder duplication masquerading as a dilated common bile ...

    African Journals Online (AJOL)

    A duplicate gall bladder was diagnosed at laparoscopy, having been erroneously diagnosed on ultrasonography as a dilated common bile duct with choledocholithiasis. Gallbladder duplication is a congenital abnormality with a rare incidence, occuring in approximately 1 in 4 000 births and 0.020% in al large autopsy ...

  16. T-tube vs Primary Common Bile Duct Closure

    Directory of Open Access Journals (Sweden)

    M R Joshi

    2010-09-01

    Full Text Available INTRODUCTION: Closure of the common bile duct over T-tube after exploration is a widely practiced traditional method. However, its use may give rise to many complications. We do primary closure of common bile duct after exploration. Aim of the study is to see the efficacy and safety of the primary closure. METHODS: Study was carried out to compare the results of both the techniques from 2006 to 2009 in the cases proven to have common bile duct stone with or without the features of obstructive jaundice. Post operative hospital stay and morbidities related to both the groups were recorded and analyzed. RESULTS: There were total 71 cases included in the study. Thirty one in T-tube group and 40 in primary closure group. T-tube was removed in most of the cases after three weeks where as average time of drain removal in primary closure group is 5.79 +/-1.79 days. Incidence of retained stone was equal in each group. Major complication in T-tube group is biliary peritonitis in four patients at the time of T-tube removal whereas none of the patient from primary closure group suffered from such major complication. CONCLUSIONS: Primary closure after the common bile duct exploration is safe and it helps to avoid the morbidities related to T-tube. Keywords: Choledocholithiasis, Primary closure, retained stone, T-tube, Ureterorenoscope.

  17. Ultrafast fluorescence resonance energy transfer in a bile salt ...

    Indian Academy of Sciences (India)

    Fluorescence resonance energy transfer (FRET) from Coumarin 153 (C153) to Rhodamine 6G (R6G) in a secondary aggregate of a bile salt (sodium deoxycholate, NaDC) is studied by femtosecond up-conversion. The emission spectrum of C153 in NaDC is analysed in terms of two spectra-one with emission maximum at ...

  18. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition

    NARCIS (Netherlands)

    Zhang, Ling; Voskuijl, Wieger; Mouzaki, Marialena; Groen, Albert K.; Alexander, Jennifer; Bourdon, Celine; Wang, Alice; Versloot, Christian J.; Di Giovanni, Valeria; Wanders, Ronald J. A.; Bandsma, Robert

    2016-01-01

    Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to

  19. Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition

    NARCIS (Netherlands)

    Zhang, Ling; Voskuijl, Wieger; Mouzaki, Marialena; Groen, Albert K.; Alexander, Jennifer; Bourdon, Celine; Wang, Alice; Versloot, Christian J.; Di Giovanni, Valeria; Wanders, Ronald J. A.; Bandsma, Robert

    2016-01-01

    Objective Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work

  20. Percutaneous lithotripsy for removing difficult bile duct stones using endoscopy

    International Nuclear Information System (INIS)

    Kim, See Hyung; Sohn, Chul Ho; Kim, Young Hwan

    2008-01-01

    To describe efficacy of percutaneous lithotripsy for removing difficult bile duct stones using endoscopy. A total of 88 patients with difficulties for the removal of bile duct stones using endoscopy (an impacted stone, stone size > 15 mm, intrahepatic duct (IHD) stone, stone size to bile duct diameter ratio > 1.0), were enrolled in this study. A 12 Fr sheath was inserted through the percutaneous transhepatic biliary drainage (PTBD) tract, and then nitrol stone baskets and a 0.035' snare wire were used to capture, fragment and remove the stones. The technical and clinical success rates were analyzed, together with an analysis of any complications. The overall technical success rate of stone removal was achieved in 79 of 88 patients (89.8%). In five of nine patients with failed stone removal, small residual IHD stones were noted on a cholangiogram. Even if stone removal failed in these cases, cholangitic symptoms were improved and the drainage catheter was successfully removed. Therefore, clinical success was achieved in 84 of 88 patients (95.5%). There were no significant procedure-related complications, except for sepsis in one case. Billiary stone removal using the stone basket and guide-wire snare technique through the PTBD tract is a safe and effective procedure that can be used as a primary method in patients with difficulties for the removal of bile duct stones using endoscopy

  1. Function and regulation of the human bile salt export pump

    NARCIS (Netherlands)

    Plass, Jacqueline Regina Maria

    2005-01-01

    During the past decade, important progress has been made in our understanding of the pathophysiology of cholestasis. Inherited disorders have been explained at the molecular level and were shown to be the result of mutations in enzymes involved in bile salt biosynthesis or transmembrane transporters

  2. Incidence and management of bile leakage after partial liver resection

    NARCIS (Netherlands)

    Erdogan, D.; Busch, O. R. C.; van Delden, O. M.; Rauws, E. A. J.; Gouma, D. J.; van Gulik, T. M.

    2008-01-01

    Background/Aims: Bile leakage after partial liver resection still is a common complication and is associated with substantial morbidity and even mortality. Methods: A total of 234 consecutive liver resections without biliary reconstruction, performed between January 1992 and December 2004, were

  3. Incidence and management of postoperative bile leaks: A ...

    African Journals Online (AJOL)

    Incidence and management of postoperative bile leaks: A prospective cohort analysis of 467 liver resections. A.J. Dell, J.E.J. Krige, E. Jonas, S.R. Thomson, S.J. Beningfield, U.K. Kotze, S.A. Tromp, S. Burmeister, M.M. Bernon, P.C. Bornman ...

  4. A pilot study of bendamustine in advanced bile duct cancer.

    Science.gov (United States)

    Schoppmeyer, Konrad; Kreth, Florian; Wiedmann, Marcus; Mössner, Joachim; Preiss, Rainer; Caca, Karel

    2007-07-01

    We performed a pilot study to evaluate the safety and tolerability of bendamustine in patients with advanced hilar bile duct cancer and impaired liver function. Six patients with histologically proven, unresectable adenocarcinoma of the hilar bile duct were treated with bendamustine 140 mg/m intravenously on day 1 of the first cycle and with bendamustine 100 mg/m on days 1 and 2 of the second to fourth cycle. Treatment cycles were repeated every 21 days. Primary endpoint was the safety and tolerability of the treatment; secondary endpoints were response rate, time to progression and overall survival. Transient lymphopenia grade 3 occurred in all six patients. No other grade 3 or 4 toxicities were present. The most common nonhematologic toxicity was mouth dryness grade 2 in six patients. Three patients had stable disease. No partial or complete responses were observed. Median time to progression was 3.3 months; median overall survival was 6 months. Our study demonstrates that bendamustine can be safely administered in patients with hilar bile duct cancer and impaired liver function. A potential role of bendamustine in combination therapies for bile duct cancer will be a subject of further trials.

  5. Microbiology of bile in symptomatic uncomplicated gallstone disease

    International Nuclear Information System (INIS)

    Ahmad, M.; Akhtar, M.R.; Akhtar, M.R.

    2015-01-01

    To determine the microbiology of the bile culture and antimicrobial susceptibility in patients with symptomatic gallstone disease in our setup. Study Design: A descriptive study. Place and Duration of Study: Surgical Department Combined Military Hospital (CMH) Kharian from Oct, 2010 to Jun, 2011. Patients and Methods: A total of 106 patients underwent cholecystectomy due to symptomatic gallstones and their bile was cultured for aerobic and anaerobic bacteria and culture sensitivity was performed. Data was analysed by using statistical package for social sciences (SPSS) version 13. Results: Bile culture was negative in 81 patients (76.4%) and was positive in only 25 patients (23.6%). Escheria Coli was the most common cultured organism in 10 (40%) patients, Klebsiella in 5 (20%) patients, Pseudomonas in 5 (20%) patients, Proteus in 2 (8%) patients, Staphlococcus aureus in 2 (8%) patients and mixed organisms were cultured in 1 patient (4%). Cefoperazone with sulbactum and Amikacin were the most effective prophylactic antibiotics. Conclusion: Bile in majority of patients with symtomatic uncomplicated gallstone disease is sterile. E. coli is the most commonly cultured organism and cefoperazone with sulbactum and amikacin are the most appropriate antibiotics in our setup. (author)

  6. Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation.

    Science.gov (United States)

    Afonso, Milessa Silva; Lavrador, Maria Silvia Ferrari; Koike, Marcia Kiyomi; Cintra, Dennys Esper; Ferreira, Fabiana Dias; Nunes, Valeria Sutti; Castilho, Gabriela; Gioielli, Luiz Antonio; Paula Bombo, Renata; Catanozi, Sergio; Caldini, Elia Garcia; Damaceno-Rodrigues, Nilsa Regina; Passarelli, Marisa; Nakandakare, Edna Regina; Lottenberg, Ana Maria

    2016-06-01

    Interesterified fats are currently being used to replace trans fatty acids. However, their impact on biological pathways involved in the atherosclerosis development was not investigated. Weaning male LDLr-KO mice were fed for 16weeks on a high-fat diet (40% energy as fat) containing polyunsaturated (PUFA), TRANS, palmitic (PALM), palmitic interesterified (PALM INTER), stearic (STEAR) or stearic interesterified (STEAR INTER). Plasma lipids, lipoprotein profile, arterial lesion area, macrophage infiltration, collagen content and inflammatory response modulation were determined. Macrophage cholesterol efflux and the arterial expression of cholesterol uptake and efflux receptors were also performed. The interesterification process did not alter plasma lipid concentrations. Although PALM INTER did not increase plasma cholesterol concentration as much as TRANS, the cholesterol enrichment in the LDL particle was similar in both groups. Moreover, PALM INTER induced the highest IL-1β, MCP-1 and IL-6 secretion from peritoneal macrophages as compared to others. This inflammatory response elicited by PALM INTER was confirmed in arterial wall, as compared to PALM. These deleterious effects of PALM INTER culminate in higher atherosclerotic lesion, macrophage infiltration and collagen content than PALM, STEAR, STEAR INTER and PUFA. These events can partially be attributed to a macrophage cholesterol accumulation, promoted by apoAI and HDL2-mediated cholesterol efflux impairment and increased Olr-1 and decreased Abca1 and Nr1h3 expressions in the arterial wall. Interesterified fats containing palmitic acid induce atherosclerosis development by promoting cholesterol accumulation in LDL particles and macrophagic cells, activating the inflammatory process in LDLr-KO mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The Healing Effect of Hydroalcoholic Extract of Hypericum Perforatum on Acetic Acid-Induced Ulcerative Colitis in Male Rats

    Directory of Open Access Journals (Sweden)

    Nader Tanideh

    2017-02-01

    Full Text Available Background & Objective: Anti-inflammatory effect of Hypericum have long been considered. Ulcerative Colitis (UC is a form of Inflammatory Bowel Disease (IBD. In this study, the effects of Hypericum perforatum on histopathological changes and tissue malondialdehyde (MDA level of colonic tissue in rats with induced UC were evaluated. Materials & Methods: 70 rats were divided into seven equal groups. Colitis was induced by acetic acid.. Groups I and II received 1 mL of 600 and 300 mg/kg H. perforatum extract orally per day respectively; groups III and IV received 1 mL of 20% and 10% intra-colonic gel form of H. perforatum extract daily respectively; group V, as positive control, received 1 mL of intra-colonic Asacol; group VI received 1 mL of normal saline as negative control; group VII received just intra-colonic gel base. All the animals were evaluated for histological changes and tissue MDA level of colon seven days after the treatment. Results: H. perforatum extract in the two forms of trans-rectal and oral administration could result in a more healing effect on acetic acid-induced damaged colonic tissue with a reduction in the MDA activity. In trans-rectal administration, the 20% gel had a better healing response than the 10% gel. In oral administration, the 600 mg/kg dosage had a better healing response than the 300 mg/kg. Conclusions: Therefor, H. perforatum can be considered as a treatment of choice for UC especially in trans-rectal gel form.

  8. Matrix metalloproteinase-14 mediates formation of bile ducts and hepatic maturation of fetal hepatic progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Otani, Satoshi [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Kakinuma, Sei, E-mail: skakinuma.gast@tmd.ac.jp [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Kamiya, Akihide [Institute of Innovative Science and Technology, Tokai University, Isehara (Japan); Goto, Fumio; Kaneko, Shun; Miyoshi, Masato; Tsunoda, Tomoyuki; Asano, Yu; Kawai-Kitahata, Fukiko; Nitta, Sayuri; Nakata, Toru; Okamoto, Ryuichi; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Asahina, Yasuhiro [Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo (Japan); Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo (Japan); Yamaguchi, Tomoyuki [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Koshikawa, Naohiko [Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); Seiki, Motoharu [Medical School, Kanazawa University, Kanazawa (Japan); Nakauchi, Hiromitsu [Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo (Japan); and others

    2016-01-22

    Fetal hepatic stem/progenitor cells, called hepatoblasts, play central roles in liver development; however, the molecular mechanisms regulating the phenotype of these cells have not been completely elucidated. Matrix metalloproteinase (MMP)-14 is a type I transmembrane proteinase regulating pericellular proteolysis of the extracellular matrix and is essential for the activation of several MMPs and cytokines. However, the physiological functions of MMP-14 in liver development are unknown. Here we describe a functional role for MMP-14 in hepatic and biliary differentiation of mouse hepatoblasts. MMP-14 was upregulated in cells around the portal vein in perinatal stage liver. Formation of bile duct-like structures in MMP-14–deficient livers was significantly delayed compared with wild-type livers in vivo. In vitro biliary differentiation assays showed that formation of cholangiocytic cysts derived from MMP-14–deficient hepatoblasts was completely impaired, and that overexpression of MMP-14 in hepatoblasts promoted the formation of bile duct-like cysts. In contrast, the expression of molecules associated with metabolic functions in hepatocytes, including hepatic nuclear factor 4α and tryptophan 2,3-dioxygenase, were significantly increased in MMP-14–deficient livers. Expression of the epidermal growth factor receptor and phosphorylation of mitogen-activated protein kinases were significantly upregulated in MMP-14–deficient livers. We demonstrate that MMP-14–mediated signaling in fetal hepatic progenitor cells promotes biliary luminal formation around the portal vein and negatively controls the maturation of hepatocytes. - Highlights: • Loss of MMP-14 delayed formation of bile duct-like structures in perinatal liver. • Overexpression of MMP-14 in hepatobalsts promoted the biliary formation in vitro. • Loss of MMP-14 promoted hepatocyte maturation of hepatoblasts in vivo. • MMP-14–mediated signaling regulates terminal differentiation of

  9. Bile acids and their oxo derivatives: Potential inhibitors of carbonic anhydrase I and II, androgen receptor antagonists and CYP3A4 substrates.

    Science.gov (United States)

    Trifunović, Jovana; Borčić, Vladan; Mikov, Momir

    2017-05-01

    Some biological properties of bile acids and their oxo derivatives have not been sufficiently investigated, although the interest in bile acids as signaling molecules is rising. The aim of this work was to evaluate physico-chemical parametar b (slope) that represents the lipophilicity of the examined molecules and to investigate interactions of bile acids with carbonic anhydrase I, II, androgen receptor and CYP450s. Thirteen candidates were investigated using normal-phase thin-layer chromatography in two solvent systems. Retention parameters were used in further quantitative structure-activity relationship analysis and docking studies to predict interactions and binding affinities of examined molecules with enzymes and receptors. Prediction of activity on androgen receptor showed that compounds 3α-hydroxy-12-oxo-5β-cholanoic and 3α-hydroxy-7-oxo-5β-cholanoic acid have stronger antiandrogen activity than natural bile acids. The inhibitory potential for carbonic anhydrase I and II was tested and it was concluded that molecules 3α-hydroxy-12-oxo-5β-cholanoic, 3α-hydroxy-7-oxo-5β-cholanoic, 3,7,12-trioxo-5β-cholanoic acid and hyodeoxycholic acid show the best results. Substrate behavior for CYP3A4 was confirmed for all investigated compounds. Oxo derivatives of bile acids show stronger interactions with enzymes and receptors as classical bile acids and lower membranolytic activity compared with them. These significant observations could be valuable in consideration of oxo derivatives as building blocks in medicinal chemistry. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Bile Salt and Acid Tolerant of Lactic Acid Bacteria Isolated from Proventriculus of Broiler Chicken

    Directory of Open Access Journals (Sweden)

    E. Damayanti

    2014-08-01

    Full Text Available The aim of this research was to obtain the lactic acid bacteria (LAB as probiotic candidates which have resistance to bile salt and acid condition. LAB was obtained using isolation method from proventriculus of broiler chicken. Selective MRS media with 0.2% CaCO3 addition were used for LAB isolation using pour plate sampling method under anaerobic condition. The result showed that four selected isolates had morphological and biochemical characteristics as LAB. The selected LAB was characterized as follow: antibacterial activities, antibiotic sensitivity, resistance on bile salt, gastric juice and acid condition, and biochemical identification. Antibacterial activities assay of cell free supernatant was confirmed using disc paper diffusion method which was arranged on factorial design and each treatment consisted of three replications. The cell free supernatant of LAB isolates had antibacterial activities against Escherichia coli, Pseudomonas aerugenosa, and Salmonella pullorum. Molecular identification procedure using 16S rRNA sequence analysis showed that R01 and R02 as Pediococcus acidilactici. The viability of the two isolates were tested by acid pH (pH 1, 2, and 3, gastric juice pH 2, and bile salt condition for digestives tract simulation. The result showed that R01 and R02 had a high viability percentages at pH 1, 2, and 3 (95.45%, 99.49%, 104.01%, and 67.17%, 120.74%, 103.4%, respectively and at bile salt simulation for 1-2 hours (100.35%-102.71% and 100.02%-102.65%, respectively, but at gastric juice simulation for 1-2 hours, the P. acidilactici R01 had higher viability than P. acidilactici R02 (59.69%-76.53% versus 43.57%-40.69%, respectively. In the antibiotic sensitivity test for three antibiotics (i.e. erythromicin 15 µg, penicillin G 10 µg, and streptomycin 10 µg, the P. acidilactici R02 showed resistance to Streptomycin and Penicillin. It is concluded that P. acidilactici R01 and P. acidilactici R02 isolated from proventriculus

  11. Does the bile duct angulation affect recurrence of choledocholithiasis?

    Science.gov (United States)

    Seo, Dong Beom; Bang, Byoung Wook; Jeong, Seok; Lee, Don Haeng; Park, Shin Goo; Jeon, Yong Sun; Lee, Jung Il; Lee, Jin-Woo

    2011-01-01

    AIM: To investigate whether bile duct angulation and T-tube choledochostomy influence the recurrence of choledocholithiasis. METHODS: We conducted a retrospective study inclu-ding 259 patients who underwent endoscopic sphincterotomy and cholecystectomy for choledocholithiasis between 2000 and 2007. The imaginary line was drawn along the center of the bile duct and each internal angle was measured at the two angulation sites of the bile duct respectively. The values of both angles were added together. We then tested our hypothesis by examining whether T-tube choledochostomy was performed and stone recurrence occurred by reviewing each subject’s medical records. RESULTS: The overall recurrence rate was 9.3% (24 of 259 patients). The mean value of sums of angles in the recurrence group was 268.3° ± 29.6°, while that in the non-recurrence group was 314.8° ± 19.9° (P < 0.05). Recurrence rate of the T-tube group was 15.9% (17 of 107), while that of the non T-tube group was 4.6% (7 of 152) (P < 0.05). Mean value of sums of angles after T-tube drainage was 262.5° ± 24.6° and that before T-tube drainage was 298.0° ± 23.9° in 22 patients (P < 0.05). CONCLUSION: The bile duct angulation and T-tube choledochostomy may be risk factors of recurrence of bile duct stones. PMID:22039327

  12. [Common bile duct stones: the surgical treatment is always valid].

    Science.gov (United States)

    Nardi, F; Gavelli, A; Dapri, G; Huguet, C

    2004-02-01

    The treatment of common bile duct stones has changed with the new therapeutic techniques, that have replaced the conventional therapy, represented by surgery. Anyway, they could cause some problems, that must be regarded. Therefore, we wish to confirm the importance of the conventional surgery in the management of patients with common bile duct stones. A total of 147 patients were operated for common bile duct stones (73 in emergency and 74 in election). The intraoperative cholangiography was carried out in 141 patients and a choledocoscopy in 130 patients. A drain of Kehr was positioned in 120 patients, a bilio-digestive anastomosis in 26 cases and in 1 case there was a direct suture of the common bile duct without drain. All patients were treated with a short-term antibioticotherapy, protracted to 5 days in the emergency cases. In the patients with the drain of Kehr there was a control cholangiography after 7 days from operation and it was removed after 25 days. The analysis of the results was done dividing the patients according to the age: old and >75 years old. Nobody died during the operation. Complications were 17.4% in the patients >75 years old and 2,6% in the patients old. There were 2 death, in the postoperative period, for the group >75 years old. Cases operated in emergency were 68.1% of "old" patients and 37.2% of "young" patients. The postoperative period was 14.9+/-9.2 days for the "old" group and 10.9+/-5.2 days for the "young" group. The treatment of common bile duct stones is still a surgical treatment, particularly for "old" patients.

  13. Protective effects of yangonin from an edible botanical Kava against lithocholic acid-induced cholestasis and hepatotoxicity.

    Science.gov (United States)

    Kong, Yulong; Gao, Xiaoguang; Wang, Changyuan; Ning, Chenqing; Liu, Kexin; Liu, Zhihao; Sun, Huijun; Ma, Xiaodong; Sun, Pengyuan; Meng, Qiang

    2018-04-05

    Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin, a product isolated from an edible botanical Kava against lithocholic acid (LCA)-induced cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by intraperitoneal injections of LCA in C57BL/6 mice. Serum biomarkers and H&E staining were used to identify the amelioration of cholestasis after yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying yangonin hepatoprotection. The results indicated that yangonin promoted bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep, Mrp2 expression and an inhibition in Ntcp, all of which are responsible for bile acid transport. Furthermore, yangonin reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in bile acid synthesis and metabolism. In addition, yangonin suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α and IL-1β. In vitro evidences showed that the changes in transporters and enzymes induced by yangonin were abrogated when FXR was silenced. In conclusions, yangonin produces protective effect against LCA-induced hepatotoxity and cholestasis due to FXR-mediated regulation. Yangonin may be an effective approach for the prevention against cholestatic liver diseases. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. CT evaluation of the bile ducts in patients with fatty liver

    International Nuclear Information System (INIS)

    Quint, L.E.; Glazer, G.M.

    1984-01-01

    Computed tomographic (CT) evaluation of the bile ducts in the fatty liver can be difficult, since hepatic attenuation decreases with increased triglyceride content, and liver parenchyma may become isodense with bile. Forty-seven patients with fatty infiltration of the liver were retrospectively identified. In 7 of these patients, attenuation of liver and bile differed by less than 10 HU. In 2 patients, dilated intrahepatic ducts were invisible using CT, because bile was isodense with fatty liver parenchyma. Thus, the fatty liver presents a potential pitfall in CT evaluation of the bile ducts. For maximal accuracy scans should be obtained both before and after administration of intravenous urographic contrast material

  15. Effect of Bile Salt Hydrolase Inhibitors on a Bile Salt Hydrolase from Lactobacillus acidophilus

    Directory of Open Access Journals (Sweden)

    Jun Lin

    2014-12-01

    Full Text Available Bile salt hydrolase (BSH, a widely distributed function of the gut microbiota, has a profound impact on host lipid metabolism and energy harvest. Recent studies suggest that BSH inhibitors are promising alternatives to antibiotic growth promoters (AGP for enhanced animal growth performance and food safety. Using a high-purity BSH from Lactobacillus salivarius strain, we have identified a panel of BSH inhibitors. However, it is still unknown if these inhibitors also effectively inhibit the function of the BSH enzymes from other bacterial species with different sequence and substrate spectrum. In this study, we performed bioinformatics analysis and determined the inhibitory effect of identified BSH inhibitors on a BSH from L. acidophilus. Although the L. acidophilus BSH is phylogenetically distant from the L. salivarius BSH, sequence analysis and structure modeling indicated the two BSH enzymes contain conserved, catalytically important amino residues and domain. His-tagged recombinant BSH from L. acidophilus was further purified and used to determine inhibitory effect of specific compounds. Previously identified BSH inhibitors also exhibited potent inhibitory effects on the L. acidophilus BSH. In conclusion, this study demonstrated that the BSH from L. salivarius is an ideal candidate for screening BSH inhibitors, the promising alternatives to AGP for enhanced feed efficiency, growth performance and profitability of food animals.

  16. Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning

    NARCIS (Netherlands)

    Falix, Farah A.; Weeda, Víola B.; Labruyere, Wilhelmina T.; Poncy, Alexis; de Waart, Dirk R.; Hakvoort, Theodorus B. M.; Lemaigre, Frédéric; Gaemers, Ingrid C.; Aronson, Daniël C.; Lamers, Wouter H.

    2014-01-01

    Notch signaling plays an acknowledged role in bile-duct development, but its involvement in cholangiocyte-fate determination remains incompletely understood. We investigated the effects of early Notch2 deletion in Notch2(fl/fl)/Alfp-Cre(tg/-) ("Notch2-cKO") and Notch2(fl/fl)/Alfp-Cre(-/-)

  17. Analgesic and Anti-Inflammatory Properties of Gelsolin in Acetic Acid Induced Writhing, Tail Immersion and Carrageenan Induced Paw Edema in Mice.

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    Ashok Kumar Gupta

    Full Text Available Plasma gelsolin levels significantly decline in several disease conditions, since gelsolin gets scavenged when it depolymerizes and caps filamentous actin released in the circulation following tissue injury. It is well established that our body require/implement inflammatory and analgesic responses to protect against cell damage and injury to the tissue. This study was envisaged to examine analgesic and anti-inflammatory activity of exogenous gelsolin (8 mg/mouse in mice models of pain and acute inflammation. Administration of gelsolin in acetic acid-induced writhing and tail immersion tests not only demonstrated a significant reduction in the number of acetic acid-induced writhing effects, but also exhibited an analgesic activity in tail immersion test in mice as compared to placebo treated mice. Additionally, anti-inflammatory function of gelsolin (8 mg/mouse compared with anti-inflammatory drug diclofenac sodium (10 mg/kg] was confirmed in the carrageenan injection induced paw edema where latter was measured by vernier caliper and fluorescent tomography imaging. Interestingly, results showed that plasma gelsolin was capable of reducing severity of inflammation in mice comparable to diclofenac sodium. Analysis of cytokines and histopathological examinations of tissue revealed administration of gelsolin and diclofenac sodium significantly reduced production of pro-inflammatory cytokines, TNF-α and IL-6. Additionally, carrageenan groups pretreated with diclofenac sodium or gelsolin showed a marked decrease in edema and infiltration of inflammatory cells in paw tissue. Our study provides evidence that administration of gelsolin can effectively reduce the pain and inflammation in mice model.

  18. Recurrence of choledocholithiasis following endoscopic bile duct clearance: Long term results and factors associated with recurrent bile duct stones

    Science.gov (United States)

    Konstantakis, Christos; Triantos, Christos; Theopistos, Vasileios; Theocharis, Georgios; Maroulis, Ioannis; Diamantopoulou, Georgia; Thomopoulos, Konstantinos

    2017-01-01

    AIM To evaluate the rate of recurrence of symptomatic choledocholithiasis and identify factors associated with the recurrence of bile duct stones in patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic sphincterotomy (EST) for bile duct stone disease. METHODS All patients who underwent ERCP and EST for bile duct stone disease and had their bile duct cleared from 1/1/2005 until 31/12/2008 was enrolled. All symptomatic recurrences during the study period (until 31/12/2015) were recorded. Clinical and laboratory data potentially associated with common bile duct (CBD) stone recurrence were retrospectively retrieved from patients’ files. RESULTS A total of 495 patients were included. Sixty seven (67) out of 495 patients (13.5%) presented with recurrent symptomatic choledocholithiasis after 35.28 ± 16.9 mo while twenty two (22) of these patients (32.8%) experienced a second recurrence after 35.19 ± 23.2 mo. Factors associated with recurrence were size (diameter) of the largest CBD stone found at first presentation (10.2 ± 6.9 mm vs 7.2 ± 4.1 mm, P = 0.024), diameter of the CBD at the first examination (15.5 ± 6.3 mm vs 12.0 ± 4.6 mm, P = 0.005), use of mechanical lithotripsy (ML) (P = 0.04) and presence of difficult lithiasis (P = 0.04). Periampullary diverticula showed a trend towards significance (P = 0.066). On the contrary, number of stones, angulation of the CBD, number of ERCP sessions required to clear the CBD at first presentation, more than one ERCP session needed to clear the bile duct initially and a gallbladder in situ did not influence recurrence. CONCLUSION Bile duct stone recurrence is a possible late complication following endoscopic stone extraction and CBD clearance. It appears to be associated with anatomical parameters (CBD diameter) and stone characteristics (stone size, use of ML, difficult lithiasis) at first presentation. PMID:28101305

  19. The mechanism of gentisic acid-induced relaxation of the guinea pig isolated trachea: the role of potassium channels and vasoactive intestinal peptide receptors

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    J.F. Cunha

    2001-03-01

    Full Text Available We examined some of the mechanisms by which the aspirin metabolite and the naturally occurring metabolite gentisic acid induced relaxation of the guinea pig trachea in vitro. In preparations with or without epithelium and contracted by histamine, gentisic acid caused concentration-dependent and reproducible relaxation, with mean EC50 values of 18 µM and Emax of 100% (N = 10 or 20 µM and Emax of 92% (N = 10, respectively. The relaxation caused by gentisic acid was of slow onset in comparison to that caused by norepinephrine, theophylline or vasoactive intestinal peptide (VIP. The relative rank order of potency was: salbutamol 7.9 > VIP 7.0 > gentisic acid 4.7 > theophylline 3.7. Gentisic acid-induced relaxation was markedly reduced (24 ± 7.0, 43 ± 3.9 and 78 ± 5.6% in preparations with elevated potassium concentration in the medium (20, 40 or 80 mM, respectively. Tetraethylammonium (100 µM, a nonselective blocker of the potassium channels, partially inhibited the relaxation response to gentisic acid, while 4-AP (10 µM, a blocker of the voltage potassium channel, inhibited gentisic acid-induced relaxation by 41 ± 12%. Glibenclamide (1 or 3 µM, at a concentration which markedly inhibited the relaxation induced by the opener of ATP-sensitive K+ channels, levcromakalim, had no effect on the relaxation induced by gentisic acid. Charybdotoxin (0.1 or 0.3 µM, a selective blocker of the large-conductance Ca2+-activated K+ channels, caused rightward shifts (6- and 7-fold of the gentisic acid concentration-relaxation curve. L-N G-nitroarginine (100 µM, a NO synthase inhibitor, had no effect on the relaxant effect of gentisic acid, and caused a slight displacement to the right in the relaxant effect of the gentisic acid curve at 300 µM, while methylene blue (10 or 30 µM or ODQ (1 µM, the inhibitors of soluble guanylate cyclase, all failed to affect gentisic acid-induced relaxation. D-P-Cl-Phe6,Leu17[VIP] (0.1 µM, a VIP receptor antagonist

  20. Extracts from the Mongolian traditional medicinal plants Dianthus versicolorFisch. and Lilium pumilum Delile stimulate bile flow in an isolated perfused rat liver model.

    Science.gov (United States)

    Obmann, Astrid; Tsendayush, Damba; Thalhammer, Theresia; Zehl, Martin; Vo, Thanh Phuong Nha; Purevsuren, Sodnomtseren; Natsagdorj, Damdinsuren; Narantuya, Samdan; Kletter, Christa; Glasl, Sabine

    2010-10-05

    Dianthus versicolor (Caryophyllaceae) and Lilium pumilum (Liliaceae) are two medicinal plants used in traditional Mongolian medicine to treat hepatic and gastrointestinal disorders. In this study aqueous (AE) and methanolic (ME) extracts of Dianthus versicolor and Lilium pumilum were investigated for their influence on the bile flow. The aqueous extracts of both plants were tested in absence and presence of 10 μM taurocholic acid at three different concentrations (100, 250, and 500 mg/L). The aqueous extract of Dianthus versicolor was further purified in order to locate the active principles. Two resulting fractions, one enriched in flavonoids and the other in sugars, were investigated for their influence on the bile flow in absence of taurocholic acid at 10, 20, and 40 mg/L. The aqueous extracts of both plants were analysed qualitatively by LC-MS(n) and quantitatively by UV-spectrophotometry. The bile flow experiments were performed in the isolated perfused rat liver. The compounds were identified by LC-DAD-MS(n) and TLC using references. The UV-spectrophotometric analysis was based on the monograph "Passiflorae herba" of the European Pharmacopoeia, and the total flavonoid contents were calculated and expressed as vitexin. AE and ME of both plants increased the bile flow dose-dependently (between 9% and 30%), and no hepatotoxic effect was seen even during longer perfusions. Stimulation of bile secretion was comparable in the presence and in the absence of taurocholic acid. The flavonoid fraction of Dianthus versicolor increased the bile flow by 18% (pLilium pumilum (total flavonoid content 1.04%) the flavonoids rutoside, kaempferol-3-O-rutinoside, and isorhamnetin-3-O-rutinoside were detected. The results show that choleresis under extract application is due to a stimulation of the bile-salt-independent bile flow which might be caused by the osmotic power of the extracts (hydrocholeresis). The flavonoids seem to contribute to the bile-flow-stimulating effect of

  1. Effect of galactose on acid induced molten globule state of Soybean Agglutinin: Biophysical approach

    Science.gov (United States)

    Alam, Parvez; Naseem, Farha; Abdelhameed, Ali Saber; Khan, Rizwan Hasan

    2015-11-01

    In the present study the formation of molten globule-like unfolding intermediate Soybean Agglutinin (SBA) in acidic pH range has been established with the help of acrylamide quenching, intrinsic fluorescence, ANS fluorescence measurement, far UV CD and dynamic light scattering measurement. A marked increase in ANS fluorescence was observed at pH 2.2. Ksv of acrylamide quenching was found to be higher at pH 2.2 than that of native SBA at pH 7. Far UV CD spectra of pH induced state suggest that SBA shows significant retention of secondary structure closure to native. Hydrodynamic radius of SBA at pH 2.2 was found be more as compared to native state and also in other pH induced states. Further we checked the effect of galactose on the molten globule state of SBA. This study suggests that SBA exist as molten globule at pH 2.2 and this study will help in acid induced molten globule state of other proteins.

  2. Hexanoic acid-induced resistance against Botrytis cinerea in tomato plants.

    Science.gov (United States)

    Vicedo, Begonya; Flors, Víctor; de la O Leyva, María; Finiti, Ivan; Kravchuk, Zhana; Real, María Dolores; García-Agustín, Pilar; González-Bosch, Carmen

    2009-11-01

    We have demonstrated that root treatment with hexanoic acid protects tomato plants against Botrytis cinerea. Hexanoic acid-induced resistance (Hx-IR) was blocked in the jasmonic acid (JA)-insensitive mutant jai1 (a coi1 homolog) and in the abscisic acid (ABA)-deficient mutant flacca (flc). Upon infection, the LoxD gene as well as the oxylipin 12-oxo-phytodienoic acid and the bioactive molecule JA-Ile were clearly induced in treated plants. However, the basal ABA levels were not altered. Hexanoic acid primed callose deposition against B. cinerea in a cultivar-dependent manner. Treated plants from Ailsa Craig, Moneymaker, and Rheinlands Ruhm showed increased callose deposition but not from Castlemart. Hexanoic acid did not prime callose accumulation in flc plants upon B. cinerea infection; therefore, ABA could act as a positive regulator of Hx-IR by enhancing callose deposition. Furthermore, although hexanoic acid protected the JA-deficient mutant defensless1 (def1), the priming for callose was higher than in the wild type. This suggests a link between JA and callose deposition in tomato. Hence, the obtained results support the idea that callose, oxylipins, and the JA-signaling pathway are involved in Hx-IR against B. cinerea. Moreover our data support the relevance of JA-signaling for basal defense against this necrotroph in tomato. Hexanoic acid also protected against Pseudomonas syringae, indicating a broad-spectrum effect for this new inducer.

  3. PDIA3 Knockdown Exacerbates Free Fatty Acid-Induced Hepatocyte Steatosis and Apoptosis.

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    Xue-qun Zhang

    Full Text Available Nonalcoholic fatty liver disease (NAFLD has emerged as one of the most common chronic liver disease over the past decades. Endoplasmic reticulum stress (ERS plays a pivotal role during the development of NAFLD. This study aims to analyze the potential role of protein disulfide isomerase A3 precursor (PDIA3, one of the ER chaperones, in free fatty acid-induced cell model of NAFLD. Human liver L02 cell line was treated with sodium palmitate for 24 hours, which developed severe intracellular lipid accumulation. The increased protein level of PDIA3 was detected via immunoblotting analysis in the fat loaded cell models of NAFLD. siRNA-mediated knockdown of PDIA3 in L02 cells not only increased the cellular lipid accumulation, but also exacerbated hepatocytes apoptosis induced by sodium palmitate. Further investigation revealed that knockdown of PDIA3 up-regulated protein expression of fatty acid synthase (FAS, a key enzyme involved in fatty acid synthesis. PDIA3 knockdown also up-regulated key molecules of ERS pathway, including glucose-regulated protein 78 (GRP78, phospho-PKR-like ER kinase (p-PERK, and C/EBP homologous protein (CHOP. Our results suggested that ER chaperone PDIA3 plays a pivotal role in FFA-induced hepatocyte steatosis and apoptosis.

  4. Periodic variation in bile acids controls circadian changes in uric acid via regulation of xanthine oxidase by the orphan nuclear receptor PPARα.

    Science.gov (United States)

    Kanemitsu, Takumi; Tsurudome, Yuya; Kusunose, Naoki; Oda, Masayuki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro

    2017-12-29

    Xanthine oxidase (XOD), also known as xanthine dehydrogenase, is a rate-limiting enzyme in purine nucleotide degradation, which produces uric acid. Uric acid concentrations in the blood and liver exhibit circadian oscillations in both humans and rodents; however, the underlying mechanisms remain unclear. Here, we demonstrate that XOD expression and enzymatic activity exhibit circadian oscillations in the mouse liver. We found that the orphan nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) transcriptionally activated the mouse XOD gene and that bile acids suppressed XOD transactivation. The synthesis of bile acids is known to be under the control of the circadian clock, and we observed that the time-dependent accumulation of bile acids in hepatic cells interfered with the recruitment of the co-transcriptional activator p300 to PPARα, thereby repressing XOD expression. This time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the hepatic expression of XOD, which, in turn, led to circadian alterations in uric acid production. Finally, we also demonstrated that the anti-hyperuricemic effect of the XOD inhibitor febuxostat was enhanced by administering it at the time of day before hepatic XOD activity increased. These results suggest an underlying mechanism for the circadian alterations in uric acid production and also underscore the importance of selecting an appropriate time of day for administering XOD inhibitors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Early effects of dietary orotic acid upon liver lipid synthesis and bile cholesterol secretion in rats

    International Nuclear Information System (INIS)

    Tokmakjian, S.D.; Haines, D.S.

    1985-01-01

    Dietary orotic acid is known to cause impaired fatty acid synthesis and increased cholesterol synthesis in rats. The authors found that the impaired fatty acid synthesis occurs during the first day of orotic acid feeding and, in studies with albumin-bound [1- 14 C]palmitic acid, an associated decrease in the rate of esterification of this fatty acid into triacylglycerol, phospholipid, and cholesteryl ester was observed. These changes may result from the known decreases in liver levels of adenine nucleotides or, as reported here, from decreased liver CoASH levels in orotic acid-fed rats. The increase in hepatic cholesterol synthesis occurred during the second day of orotic acid feeding. It was detected by increased incorporation of [1,2- 14 C]acetate into cholesterol by liver slices and by a 7-fold increase in HMG-CoA reductase activity. At the same time the biliary output of cholesterol was increased 2-fold and studies using 3 H 2 O revealed that the output of newly synthesized cholesterol in bile was increased 5-fold. The content of cholesteryl ester in hepatic microsomes decreased during orotic acid feeding but free cholesterol was unchanged. The findings are interpreted to suggest that the increased bile cholesterol secretion caused by orotic acid is a result of impaired hepatic cholesterol esterification and that the increase in HMG-CoA reductase activity is a result of diminished negative feedback due to the depleted content of cholesteryl ester in the hepatic microsomes

  6. Effect of Vitamin B5 on Liver Enzyme Levels in Bile Duct Ligation Cholestatic Rat Model

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    Fatemeh Sadat Emami

    2017-01-01

    Full Text Available Background and Objectives: Accumulation of toxic bile salts in a bile duct ligation (BDL animal model plays a pivotal role in the induction of liver fibrosis. Vitamin B5 is an essential nutrient, which acts as a cofactor in many detoxification system enzymes. In the present research, the antifibrotic effect of vitamin B5 was investigated on liver cholestasis induced by BDL in rats. Methods: In this experimental study, 72 male Wistar rats were divided into 9 groups: Control, sham-operated, vitamin B5 (5, 50, and 100mg/kg bw, BDL, and BDL+vitamin B5 (5, 50, and 100mg/kg bw. After BDL, rats were given vitamin B5 via intragastric gavage for 28 consecutive days. At the end of the experiment, blood was collected from heart and activity of aspartate aminotransferase (AST, alanine aminotransferase (ALT, and alkaline phosphatase (ALP enzymes, were measured. The data were analyzed using one-way ANOVA test. Results: In the BDL animals, the serum activities of AST, ALT, and ALP significantly increased (p<0.001. Treatment of BDL rats with vitamin B5 significantly attenuated these changes. Conclusion: The results of this study indicated that vitamin B5 has hepatoprotective and antifibrotic effects in the cholestatic liver, which is likely due to the antioxidative and free radical scavenging effects of this vitamin.

  7. Meconium Impairs Pulmonary Surfactant by a Combined Action of Cholesterol and Bile Acids

    Science.gov (United States)

    Lopez-Rodriguez, Elena; Echaide, Mercedes; Cruz, Antonio; Taeusch, H. William; Perez-Gil, Jesus

    2011-01-01

    Mechanisms for meconium-induced inactivation of pulmonary surfactant as part of the meconium aspiration syndrome in newborn infants, to our knowledge, are not clearly understood. Here we have studied the biophysical mechanisms of how meconium affects surface activity of pulmonary surfactant and whether the membrane-perturbing effects of meconium can be mimicked by exposure of surfactant to a mixture of bile acids and cholesterol. Surface activity of pulmonary surfactant complexes purified from animal lungs was analyzed in the absence and in the presence of meconium in standard surface balances and in a captive bubble surfactometer. We have also evaluated accumulation of surfactant at the air-liquid interface by what we believe to be a novel microtiter plate fluorescent assay, and the effect of meconium components on surfactant membrane fluidity using Laurdan fluorescence thermotropic profiles and differential scanning calorimetry thermograms. Rapid interfacial adsorption, low surface tension upon film compression, efficient film replenishment upon expansion, and thermotropic properties of surfactant complexes are all adversely affected by meconium, and, in a similar manner, they are affected by cholesterol/taurocholate mixtures but not by taurocholate alone. We conclude that inhibition of surfactant by meconium can be mimicked by a bile salt-promoted incorporation of excess cholesterol into surfactant complexes. These results highlight the potential pathogenic role of cholesterol-mobilizing agents as a crucial factor resulting in cholesterol induced alterations of structure and dynamics of surfactant membranes and films. PMID:21281579

  8. Caveolin-1 Is Necessary for Hepatic Oxidative Lipid Metabolism: Evidence for Crosstalk between Caveolin-1 and Bile Acid Signaling

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    Manuel A. Fernández-Rojo

    2013-07-01

    Full Text Available Caveolae and caveolin-1 (CAV1 have been linked to several cellular functions. However, a model explaining their roles in mammalian tissues in vivo is lacking. Unbiased expression profiling in several tissues and cell types identified lipid metabolism as the main target affected by CAV1 deficiency. CAV1−/− mice exhibited impaired hepatic peroxisome proliferator-activated receptor α (PPARα-dependent oxidative fatty acid metabolism and ketogenesis. Similar results were recapitulated in CAV1-deficient AML12 hepatocytes, suggesting at least a partial cell-autonomous role of hepatocyte CAV1 in metabolic adaptation to fasting. Finally, our experiments suggest that the hepatic phenotypes observed in CAV1−/− mice involve impaired PPARα ligand signaling and attenuated bile acid and FXRα signaling. These results demonstrate the significance of CAV1 in (1 hepatic lipid homeostasis and (2 nuclear hormone receptor (PPARα, FXRα, and SHP and bile acid signaling.

  9. Dietary and biliary cholesterol absorption in rats. Effect of dietary cholesterol level and cholesterol saturation of bile

    International Nuclear Information System (INIS)

    Wilson, M.D.

    1985-01-01

    The principal objective of this research was to determine if cholesterol introduced into the duodenum of rats in a micellar form as occurs with bile, is absorbed more efficiently than cholesterol presented in a nonmicellar form, as occurs with dietary cholesterol. Cholesterol absorption was measured during the constant intraduodenal infusion of liquid diets ([ 14 C] cholesterol) and artificial biles ([ 3 H] cholesterol) in thoracic lymph duct cannulated rats. Percentage absorption was calculated by dividing the rate of appearance of radiolabeled cholesterol in lymph by its rate of infusion when lymph cholesterol specific activity was constant. Results provide strong evidence that under certain conditions biliary cholesterol is more efficiently absorbed than is dietary cholesterol, and that this differential must be considered when evaluating the influence of diet or drug therapy on cholesterol absorption

  10. Kainic Acid-Induced Post-Status Epilepticus Models of Temporal Lobe Epilepsy with Diverging Seizure Phenotype and Neuropathology

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    Daniele Bertoglio

    2017-11-01

    Full Text Available The aim of epilepsy models is to investigate disease ontogenesis and therapeutic interventions in a consistent and prospective manner. The kainic acid-induced status epilepticus (KASE rat model is a widely used, well-validated model for temporal lobe epilepsy (TLE. As we noted significant variability within the model between labs potentially related to the rat strain used, we aimed to describe two variants of this model with diverging seizure phenotype and neuropathology. In addition, we evaluated two different protocols to induce status epilepticus (SE. Wistar Han (Charles River, France and Sprague-Dawley (Harlan, The Netherlands rats were subjected to KASE using the Hellier kainic acid (KA and a modified injection scheme. Duration of SE and latent phase were characterized by video-electroencephalography (vEEG in a subgroup of animals, while animals were sacrificed 1 week (subacute phase and 12 weeks (chronic phase post-SE. In the 12 weeks post-SE groups, seizures were monitored with vEEG. Neuronal loss (neuronal nuclei, microglial activation (OX-42 and translocator protein, and neurodegeneration (Fluorojade C were assessed. First, the Hellier protocol caused very high mortality in WH/CR rats compared to SD/H animals. The modified protocol resulted in a similar SE severity for WH/CR and SD/H rats, but effectively improved survival rates. The latent phase was significantly shorter (p < 0.0001 in SD/H (median 8.3 days animals compared to WH/CR (median 15.4 days. During the chronic phase, SD/H rats had more seizures/day compared to WH/CR animals (p < 0.01. However, neuronal degeneration and cell loss were overall more extensive in WH/CR than in SD/H rats; microglia activation was similar between the two strains 1 week post-SE, but higher in WH/CR rats 12 weeks post-SE. These neuropathological differences may be more related to the distinct neurotoxic effects of KA in the two rat strains than being the outcome of seizure

  11. Eosinophilic cholecystitis with common bile duct stricture: a rare disease.

    Science.gov (United States)

    Mehanna, Daniel; Naseem, Zainab; Mustaev, Muslim

    2016-05-24

    Although the most common cause of cholecystitis is gallstones, other conditions may present as acute cholecystitis. We describe a case of eosinophilic cholecystitis with common bile duct stricture. A 36-year-old woman initially had generalised abdominal pain and peripheral eosinophilia. Diagnostic laparoscopy showed eosinophilic ascites and necrotic nodules on the posterior abdominal wall. She was treated with anthelminthics on presumption of toxacara infection based on borderline positivity of serological tests. She later presented with acute cholecystitis and had a cholecystectomy and choledocotomy. Day 9 T-tube cholangiogram showed irregular narrowing of the distal common bile duct. The patient's symptoms were improved with steroids and the T-tube was subsequently removed. 2016 BMJ Publishing Group Ltd.

  12. Transhepatic cholangiography in patients with nondilated bile ducts

    International Nuclear Information System (INIS)

    Teplick, S.K.; Flick, P.; Brandon, J.C.; Haskin, P.H.; Goldstein, R.C.; Brennan, C.

    1988-01-01

    Transhepatic cholangiography was performed in 90 patients with suspected biliary tract disease and nondilated ducts. A21- or 22-gauge needle was used, and the number of passes were not limited. The bile ducts were visualized in 62 of 90 patients, and the study was diagnostic in 58 of 90. In 13 patients, the ducts were not adequately opacified, and in one, a left hepatic duct stone was missed. Seventeen of 62 cholangiograms were abnormal (eight strictures, six calculi three cases of poor emptying); eight of the 17 patients underwent percutaneous transhepatic biliary drainage. Twenty-one of 90 patients had complications. Two deaths resulted from sepsis and hemorrhage. Sixteen of 90 patients had significant abdominal pain lasting several hours to several days. One patient had bile peritonitis, and one each developed increasing pancreatitis and transient bacteremia. The authors conclude that transhepatic cholangiography should not be the initial invasive procedure of choice in patients with nondilated ducts

  13. Primary sclerosing cholangitis – The arteriosclerosis of the bile duct?

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    Trauner Michael

    2007-01-01

    Full Text Available Abstract Primary sclerosing cholangitis (PSC is a chronic inflammatory disease of unknown aetiology affecting the large bile ducts and characterized by periductal fibrosis and stricture formation, which ultimately result in biliary cirrhosis and liver failure. Arteriosclerosis involves the accumulation of altered lipids and lipoproteins in large arteries; this drives inflammation and fibrosis and ultimately leads to narrowing of the arteries and hypoperfusion of dependent organs and tissues. Knowledge of the causative factors is crucial to the understanding of disease mechanisms and the development of specific treatment. Based on pathogenetic similarities between PSC and arteriosclerosis, we hypothesize that PSC represents "arteriosclerosis of the bile duct" initiated by toxic biliary lipids. This hypothesis is based on common molecular, cellular, and morphological features providing the conceptual framework for a deeper understanding of their pathogenesis. This hypothesis should stimulate translational research to facilitate the search for novel treatment strategies for both diseases.

  14. Human and rat bile acid-CoA : Amino acid N-acyltransferase are liver-specific peroxisomal enzymes: Implications for intracellular bile salt transport

    NARCIS (Netherlands)

    Pellicoro, Antonella; van den Heuvel, Fiona A. J.; Geuken, Mariska; Moshage, Han; Jansen, Peter L. M.; Faber, Klaas Nico

    Bile acid-coenzyme A:amino acid N-acyltransferase (BAAT) is the sole enzyme responsible for conjugation of primary and secondary bile acids to taurine and glycine. Previous studies indicate a peroxisomal location of BAAT in peroxisomes with variable amounts up to 95% detected in cytosolic fractions.

  15. Human and rat bile acid-CoA : Amino acid N-acyltransferase are liver-specific peroxisomal enzymes: Implications for intracellular bile salt transport

    NARCIS (Netherlands)

    Pellicoro, Antonella; van den Heuvel, Fiona A. J.; Geuken, Mariska; Moshage, Han; Jansen, Peter L. M.; Faber, Klaas Nico

    2007-01-01

    Bile acid-coenzyme A:amino acid N-acyltransferase (BAAT) is the sole enzyme responsible for conjugation of primary and secondary bile acids to taurine and glycine. Previous studies indicate a peroxisomal location of BAAT in peroxisomes with variable amounts up to 95% detected in cytosolic fractions.

  16. Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures

    DEFF Research Database (Denmark)

    Penkowa, M; Molinero, A; Carrasco, J

    2001-01-01

    and were killed six days later. Morphological damage to the hippocampal field CA1-CA3 was seen after kainic acid treatment. Reactive astrogliosis and microgliosis were prominent in kainic acid-injected normal mice hippocampus, and clear signs of increased oxidative stress were evident. Thus......The role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid glutamate analogue inducing epileptic seizures, has been studied by means of interleukin-6 null mice. At 35mg/kg, kainic acid induced convulsions in both control (75%) and interleukin-6 null (100%) mice......, and caused a significant mortality (62%) only in the latter mice, indicating that interleukin-6 deficiency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75mg/kg kainic acid...

  17. Diameter of common bile duct: what are the predicting factors?

    OpenAIRE

    Atoosa Adibi; Behrooz Givechian

    2007-01-01

    BACKGROUND: This was a study to determine the correlation between the common bile duct (CBD) diameter and demographic data, fasting, and the history of opium addiction.
    METHODS: This was a cross-sectional study on 375 patients (>16 years old) including 219 females and 156 males. They had no evident hepatobiliary or pancreatic disease and underwent abdominopelvic ultrasonography for measurement of their CBD di...

  18. Laparoscopic Transcystic Common Bile Duct Exploration: Advantages over Laparoscopic Choledochotomy.

    Directory of Open Access Journals (Sweden)

    Qian Feng

    Full Text Available The ideal treatment for choledocholithiasis should be simple, readily available, reliable, minimally invasive and cost-effective for patients. We performed this study to compare the benefits and drawbacks of different laparoscopic approaches (transcystic and choledochotomy for removal of common bile duct stones.A systematic search was implemented for relevant literature using Cochrane, PubMed, Ovid Medline, EMBASE and Wanfang databases. Both the fixed-effects and random-effects models were used to calculate the odds ratio (OR or the mean difference (MD with 95% confidence interval (CI for this study.The meta-analysis included 18 trials involving 2,782 patients. There were no statistically significant differences between laparoscopic choledochotomy for common bile duct exploration (LCCBDE (n = 1,222 and laparoscopic transcystic common bile duct exploration (LTCBDE (n = 1,560 regarding stone clearance (OR 0.73, 95% CI 0.50-1.07; P = 0.11, conversion to other procedures (OR 0.62, 95% CI 0.21-1.79; P = 0.38, total morbidity (OR 1.65, 95% CI 0.92-2.96; P = 0.09, operative time (MD 12.34, 95% CI -0.10-24.78; P = 0.05, and blood loss (MD 1.95, 95% CI -9.56-13.46; P = 0.74. However, the LTCBDE group showed significantly better results for biliary morbidity (OR 4.25, 95% CI 2.30-7.85; P<0.001, hospital stay (MD 2.52, 95% CI 1.29-3.75; P<0.001, and hospital expenses (MD 0.30, 95% CI 0.23-0.37; P<0.001 than the LCCBDE group.LTCBDE is safer than LCCBDE, and is the ideal treatment for common bile duct stones.

  19. Bile acids cycle disruption in patients with nasopharyngeal ...

    African Journals Online (AJOL)

    2014-12-31

    Dec 31, 2014 ... Cite as: Wang C-S, Liu S-H, Peng J, Tang C, Zhu W-G. Bile acids cycle disruption in patients .... stein-Barr virus in the development of nasopharyngeal carcinoma. Chin. J. Cancer 2014; 33(11): 556 PubMed. -568. 2. Mrizak D, Martin N, Barjon C, Jimenez-Pailhes AS,. Mustapha R, Niki T, Guigay J, Pancre V, ...

  20. Laparoscopic common bile duct exploration. Lessons learned after 200 cases.

    Science.gov (United States)

    Abellán Morcillo, Israel; Qurashi, Kamran; Abrisqueta Carrión, Jesús; Martinez Isla, Alberto

    2014-05-01

    Laparoscopic common bile duct exploration (LCBDE) is a reliable, reproducible and cost-effective treatment for common bile duct stones. Several techniques have been described for choledochotomy closure. To present our experience and the lessons learned in more than 200 cases of LCBDE. Between January 1999 and July 2012, 206 patients with common bile duct stones underwent LCBDE. At the beginning of the series, we performed the closure of the CBD over a T-tube (36 patients), subsequently we favoured closure over an antegrade stent (133 patients) but due to a high incidence of acute pancreatitis in the last 16 patients we have performed primary closure. The 3 closure groups were matched for age and sex. Jaundice was the most frequent presentation. A total of 185 (88,5%) patients underwent choledochotomy whereas in 17 (8,7%) patients the transcystic route was used. The group that underwent choledochotomy had a larger size of stones compared to the transcystic group (9,7 vs 7,6mm). In the stented group we found an 11,6% incidence of pancreatitis and 26,1% of hyperamylasemia. In the primary closure group we found a clear improvement of complications and hospital stay. The increased experience of the surgeon and age (younger than 75) had a positive impact on mortality and morbidity. Primary closure of the common bile duct after LCBDE seems to be superior to closure over a T tube and stents. The learning curve seems to have a positive impact on the outcomes making it a safe and reproducible technique especially for patients aged under 75. Copyright © 2013 AEC. Published by Elsevier Espana. All rights reserved.

  1. Effect of bevacizumab on acetic acid-induced ulcerative colitis in rats.

    Science.gov (United States)

    Ozsoy, Zeki; Ozsoy, Seyma; Gevrek, Fikret; Demir, Emre; Benli, Ismail; Daldal, Emin; Yenidogan, Erdinc

    2017-08-01

    The aim of this study was to examine the effect of intraperitoneally administered bevacizumab on colitis induced by acetic acid. An experimental model of acetic acid-induced colitis was introduced in rats. After the induction of colitis, bevacizumab was administered intraperitoneally at two different daily doses of low (2.5 mg/kg) or high (5 mg/kg) concentration. Control groups were included for colitis and bevacizumab. After 7 d, the rats were sacrificed, and colonic tissues were harvested for macroscopic and microscopic examination of colonic damage. Tumor necrosis factor alpha, interleukin 1 beta (IL-1β), IL-6, myeloperoxidase, malondialdehyde, glutathione, and superoxidismutase values were measured biochemically. There was no statistically significant macroscopic improvement in damage to the colon tissues (P > 0.05). The severity of inflammation was significantly reduced (0.98 ± 0.22) in the low-dose bevacizumab-treated rat group compared with the control group (P bevacizumab-treated rat group was not statistically significant (1.40 ± 0.33). In addition, although