Targeted delivery of vitamin D to the colon using β-glucuronides of vitamin D: therapeutic effects in a murine model of inflammatory bowel diseaseGoff, Jesse P.; Koszewski, Nicholas J.; Haynes, Joseph S.; Horst, Ronald L.
doi: 10.1152/ajpgi.00156.2011pmid: 22114117
Abstract 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2 D) has been shown to inhibit development of dextran sodium sulfate (DSS)-induced colitis in mice but can also cause hypercalcemia. The aim of this study was to evaluate whether β-glucuronides of vitamin D could deliver 1,25(OH) 2 D to the colon to ameliorate colitis while reducing the risk of hypercalcemia. Initial studies demonstrated that bacteria residing in the lower intestinal tract were capable of liberating 1,25(OH) 2 D from 1,25-dihydroxyvitamin D 3 -25-β-glucuronide (β-gluc-1,25(OH) 2 D). We also determined that a much greater upregulation of the vitamin D-dependent 24-hydroxylase gene (Cyp24) was induced in the colon by treatment of mice with an oral dose of β-gluc-1,25(OH) 2 D than 1,25(OH) 2 D, demonstrating targeted delivery of 1,25(OH) 2 D to the colon. We then tested β-glucuronides of vitamin D in the mouse DSS colitis model in two studies. In mice receiving DSS dissolved in distilled water and treated with 1,25(OH) 2 D or β-gluc-1,25(OH) 2 D, severity of colitis was reduced. Combination of β-gluc-1,25(OH) 2 D with 25-hydroxyvitamin D 3 -25-β-glucuronide (β-gluc-25(OH)D) resulted in the greatest reduction of colitis lesions and symptoms in DSS-treated mice. Plasma calcium concentrations were lower in mice treated with β-gluc-1,25(OH) 2 D alone or in combination with β-gluc-25(OH)D than in mice treated with 1,25(OH) 2 D, which were hypercalcemic at the time of death. β-Glucuronides of vitamin D compounds can deliver 1,25(OH) 2 D to the lower intestine and can reduce symptoms and lesions of acute colitis in this model. 1,25-dihydroxyvitamin D 3 1,25-dihydroxyvitamin D 3 -25-β-glucuronide 24-hydroxylase dextran sodium sulfate Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print November 2011 , doi: 10.1152/ajpgi.00156.2011 AJP - GI February 2012 vol. 302 no. 4 G460-G469 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpgi.00156.2011v1 302/4/G460 most recent Classifications Inflammation/Immunity/Mediators Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Goff, J. P. Articles by Horst, R. L. PubMed PubMed citation Articles by Goff, J. P. Articles by Horst, R. L. Related Content Load related web page information Current Issue February 2012, 302 (4) Alert me to new issues of AJP - GI About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547
Coexpression of ecto-5′-nucleotidase/CD73 with specific NTPDases differentially regulates adenosine formation in the rat liverFausther, Michel; Lecka, Joanna; Soliman, Elwy; Kauffenstein, Gilles; Pelletier, Julie; Sheung, Nina; Dranoff, Jonathan A.; Sévigny, Jean
doi: 10.1152/ajpgi.00165.2011pmid: 22135310
Abstract Ectonucleotidases modulate purinergic signaling by hydrolyzing ATP to adenosine. Here we characterized the impact of the cellular distribution of hepatic ectonucleotidases, namely nucleoside triphosphate diphosphohydrolase (NTPDase)1/CD39, NTPDase2/CD39L1, NTPDase8, and ecto-5′-nucleotidase/CD73, and of their specific biochemical properties, on the levels of P1 and P2 receptor agonists, with an emphasis on adenosine-producing CD73. Immunostaining and enzyme histochemistry showed that the distribution of CD73 (protein and AMPase activity) overlaps partially with those of NTPDase1, -2, and -8 (protein levels and ATPase and ADPase activities) in normal rat liver. CD73 is expressed in fibroblastic cells located underneath vascular endothelial cells and smooth muscle cells, which both express NTPDase1, in portal spaces in a distinct fibroblast population next to NTPDase2-positive portal fibroblasts, and in bile canaliculi, together with NTPDase8. In fibrotic rat livers, CD73 protein expression and activity are redistributed but still overlap with the NTPDases mentioned. The ability of the observed combinations of ectonucleotidases to generate adenosine over time was evaluated by reverse-phase HPLC with the recombinant rat enzymes at high “inflammatory” (500 μM) and low “physiological” (1 μM) ATP concentrations. Overall, ATP was rapidly converted to adenosine by the NTPDase1+CD73 combination, but not by the NTPDase2+CD73 combination. In the presence of NTPDase8 and CD73, ATP was sequentially dephosphorylated to the CD73 inhibitor ADP, and then to AMP, thus resulting in a delayed formation of adenosine. In conclusion, the specific cellular cocompartmentalization of CD73 with hepatic NTPDases is not redundant and may lead to the differential activation of P1 and P2 receptors, under normal and fibrotic conditions. P1 receptors P2 receptors ATP fibrosis carbon tetrachloride intoxication nucleoside triphosphate diphosphohydrolases Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print December 2011 , doi: 10.1152/ajpgi.00165.2011 AJP - GI February 2012 vol. 302 no. 4 G447-G459 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpgi.00165.2011v1 302/4/G447 most recent Classifications Liver and Biliary Tract Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Fausther, M. Articles by Sévigny, J. PubMed PubMed citation Articles by Fausther, M. Articles by Sévigny, J. Related Content Load related web page information Current Issue February 2012, 302 (4) Alert me to new issues of AJP - GI About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547
Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expressionXu, Qing; Nakayama, Mizuho; Suzuki, Yoshinori; Sakai, Katsuya; Nakamura, Takahiro; Sakai, Yoshiki; Matsumoto, Kunio
doi: 10.1152/ajpgi.00216.2011pmid: 22159278
Abstract Previous studies have demonstrated that mice disrupted with the cyclooxygenase-2 gene showed much more severe liver damage compared with wild-type mice after liver injury, and prostaglandins (PGs) such as PGE 1/2 and PGI 2 have decreased hepatic injury, but the mechanisms by which prostaglandins exhibit protective action on the liver have yet to be addressed. In the present study, we investigated the mechanism of the protective action of PGI 2 using the synthetic IP receptor agonist ONO-1301. In primary cultures of hepatocytes and nonparenchymal liver cells, ONO-1301 did not show protective action directly on hepatocytes, whereas it stimulated expression of hepatocyte growth factor (HGF) in nonparenchymal liver cells. In mice, peroral administration of ONO-1301 increased hepatic gene expression and protein levels of HGF. Injections of CCl4 induced acute liver injury in mice, but the onset of acute liver injury was strongly suppressed by administration of ONO-1301. The increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) by CCl4 were suppressed by 10 mg/kg ONO-1301 to 39.4 and 33.6%, respectively. When neutralizing antibody against HGF was administered with ONO-1301 and CCl4, the decreases by ONO-1301 in serum ALT and AST, apoptotic liver cells, and expansion of necrotic areas in liver tissue were strongly reversed by neutralization of endogenous HGF. These results indicate that ONO-1301 increases expression of HGF and that hepatoprotective action of ONO-1301 in CCl4-induced liver injury may be attributable to its activity to induce expression of HGF, at least in part. The potential for involvement of HGF-Met-mediated signaling in the hepatotrophic action of endogenous prostaglandins generated by injury-dependent cyclooxygenase-2 induction is considerable. cyclooxygenase-2 growth factor Met ONO-1301 prostaglandin Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print December 2011 , doi: 10.1152/ajpgi.00216.2011 AJP - GI February 2012 vol. 302 no. 4 G420-G429 » Abstract Free Full Text Free to you Full Text (PDF) Free to you All Versions of this Article: ajpgi.00216.2011v1 302/4/G420 most recent Classifications Liver and Biliary Tract Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Xu, Q. Articles by Matsumoto, K. PubMed PubMed citation Articles by Xu, Q. Articles by Matsumoto, K. Related Content Load related web page information Current Issue February 2012, 302 (4) Alert me to new issues of AJP - GI About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547
Expression profiling identifies novel gene targets and functions for Pdx1 in the duodenum of mature miceChen, Chin; Sibley, Eric
doi: 10.1152/ajpgi.00314.2011pmid: 22135308
Abstract Transcription factor pancreatic and duodenal homeobox 1 (Pdx1) plays an essential role in the pancreas to regulate its development and maintain proper islet function. However, the functions of Pdx1 in mature small intestine are less known. We aimed to investigate the intestinal role of Pdx1 by profiling the expression of genes differentially regulated in response to inactivation of Pdx1 specifically in the intestinal epithelium. Pdx1 was conditionally inactivated in the intestinal epithelium of Pdx1 flox/flox ;VilCre mice. Total RNA was isolated from the first 5 cm of the small intestine from mature Pdx1 flox/flox ;VilCre and littermate control mice. Microarray analysis identified 86 probe sets representing 68 genes significantly upregulated or downregulated 1.5-fold or greater in Pdx flox/flox ;VilCre mice maintained under standard conditions. Ingenuity Pathway Analysis revealed that functions of the differentially expressed genes are significantly associated with metabolism of nutrients including lipids and iron. Network analysis examining the interactions among the differentially expressed genes further supports the notion that Pdx1 may modulate metabolism of lipids and iron from mature intestinal epithelium. Following forced oil feeding, Pdx1 flox/flox ;VilCre mice showed diminished lipid staining in the duodenal epithelium and decreased serum triglyceride levels, indicating reduced lipid absorption compared with control duodenal epithelium. Blood samples from Pdx1 flox/flox ;VilCre mice have significantly lower mean values for mean corpuscular volume and mean corpuscular hemoglobin, consistent with iron deficiency. The absence of nonheme iron in the villous epithelium and lamina propria of Pdx1 flox/flox ;VilCre duodenum indicates that the duodenal epithelium lacking Pdx1 may have defects in importing iron through enterocytes, resulting in iron deficiency in Pdx1 flox/flox ;VilCre mice. intestinal epithelium lipid metabolism iron metabolism microarray Cre-loxP Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print December 2011 , doi: 10.1152/ajpgi.00314.2011 AJP - GI February 2012 vol. 302 no. 4 G407-G419 » Abstract Free Full Text Free Full Text (PDF) Free All Versions of this Article: ajpgi.00314.2011v1 302/4/G407 most recent Classifications Mucosal Biology Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Chen, C. Articles by Sibley, E. PubMed PubMed citation Articles by Chen, C. Articles by Sibley, E. Related Content Load related web page information Current Issue February 2012, 302 (4) Alert me to new issues of AJP - GI About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547
An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explantsGustafsson, Jenny K.; Ermund, Anna; Johansson, Malin E. V.; Schütte, André; Hansson, Gunnar C.; Sjövall, Henrik
doi: 10.1152/ajpgi.00405.2011pmid: 22159279
Abstract The colon mucus layers minimize the contact between the luminal flora and the epithelial cells, and defects in this barrier may lead to colonic inflammation. We now describe an ex vivo method for analysis of mucus properties in human colon and mouse small and large intestine. Intestinal explants were mounted in horizontal perfusion chambers. The mucus surface was visualized by adding charcoal particles on the apical side, and mucus thickness was measured using a micropipette. Mucus thickness, adhesion, and growth rate were recorded for 1 h. In mouse and human colon, the ability of the mucus to act as a barrier to beads the size of bacteria was also evaluated. Tissue viability was monitored by transepithelial potential difference. In mouse ileum, the mucus could be removed by gentle aspiration, whereas in colon ∼40 μm of the mucus remained attached to the epithelial surface. Both mouse and human colon had an inner mucus layer that was not penetrated by the fluorescent beads. Spontaneous mucus growth was observed in human (240 μm/h) and mouse (100 μm/h) colon but not in mouse ileum. In contrast, stimulation with carbachol induced a higher mucus secretion in ileum than colon (mouse ileum: Δ200 μm, mouse colon: Δ130 μm, human colon: Δ140 μm). In conclusion, while retaining key properties from the mucus system in vivo, this setup also allows for studies of the highly dynamic mucus system under well-controlled conditions. mucin carbachol colon ileum mucus growth Copyright © 2012 the American Physiological Society « Previous | Next Article » Table of Contents This Article Published online before print December 2011 , doi: 10.1152/ajpgi.00405.2011 AJP - GI February 2012 vol. 302 no. 4 G430-G438 » Abstract Free Full Text Free Full Text (PDF) Free All Versions of this Article: ajpgi.00405.2011v1 302/4/G430 most recent Classifications Mucosal Biology Services Email this article to a friend Alert me when this article is cited Alert me if a correction is posted Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Download to citation manager Citing Articles Load citing article information Citing articles via Web of Science Google Scholar Articles by Gustafsson, J. K. Articles by Sjövall, H. PubMed PubMed citation Articles by Gustafsson, J. K. Articles by Sjövall, H. Related Content Load related web page information Current Issue February 2012, 302 (4) Alert me to new issues of AJP - GI About the Journal Information for Authors Submit a Manuscript Ethical Policies AuthorChoice PubMed Central Policy Reprints and Permissions Advertising Press Copyright © 2012 the American Physiological Society Print ISSN: 0193-1857 Online ISSN: 1522-1547