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| 1 | Plecanatide and dolcanatide, novel guanylate cyclase-C agonists, ameliorate gastrointestinal inflammation in experimental models of murine colitis显示文摘AIM: To evaluate the effect of orally administeredplecanatide or dolcanatide, analogs of uroguanylin, on amelioration of colitis in murine models.METHODS: The cyclic guanosine monophosphate(cG MP) stimulatory potency of plecanatide and dolcanatide was measured using a human colon carcinoma T84 cellbased assay. For animal studies all test agents were formulated in phosphate buffered saline. Sulfasalazine or 5-amino salicylic acid(5-ASA) served as positive controls. Effect of oral treatment with test agents on amelioration of acute colitis induced either by dextran sulfate sodium(DSS) in drinking water or by rectal instillation of trinitrobenzene sulfonic(TNBS) acid, was examined in BALB/c and/or BDF1 mice. Additionally, the effect of orally administered plecanatide on the spontaneous colitis in T-cell receptor alpha knockout(TCRα-/-) mice was also examined. Amelioration of colitis was assessed by monitoring severity of colitis, disease activity index and by histopathology. Frozen colon tissues were used to measure myeloperoxidase activity.RESULTS: Plecanatide and dolcanatide are structurally related analogs of uroguanylin, which is an endogenous ligand of guanylate cyclase-C(GC-C). As expected from the agonists of GC-C, both plecanatide and dolcanatide exhibited potent cG MP-stimulatory activity in T84 cells. Once-daily treatment by oral gavage with either of these analogs(0.05-0.5 mg/kg) ameliorated colitis in both DSS and TNBS-induced models of acute colitis, as assessed by body weight, reduction in colitis severity(P < 0.05) and disease activity index(P < 0.05). Amelioration of colitis by either of the drug candidates was comparable to that achieved by orally administered sulfasalazine or 5-ASA. Plecanatide also effectively ameliorated colitis in TCRα-/- mice, a model of spontaneous colitis. As dolcanatide exhibited higher resistance to proteolysis in simulated gastric and intestinal juices, it was selected for further studies. CONCLUSION: This is the first-ever study reporting the therapeutic utility of GC-C agonists as a new class of orally delivered and mucosally active drug candidates for the treatment of inflammatory bowel diseases. | Kunwar Shailubhai Vaseem Palejwala Krishna Priya Arjunan Sayali Saykhedkar Bradley Nefsky John A Foss Stephen Comiskey Gary S Jacob Scott E Plevy | 2015 | World Journal of Gastrointestinal Pharmacology and Therapeutics2015，6，4： | 5 |
| 2 | Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models显示文摘AIM To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeability, integrity of tight junctions and on suppression of visceral hypersensitivity. METHODS Transport of fluorescein isothiocyanate(FITC)-dextran was measured to assess permeability across cell monolayers and rat colon tissues. Effects of plecanatide and dolcanatide on the integrity of tight junctions in Caco-2 and T84 monolayers and on the expression and localization of occludin and zonula occludens-1(ZO-1) were examined by immunofluorescence microscopy. Anti-nociceptive activity of these agonists was evaluated in trinitrobenzene sulfonic acid(TNBS)-induced inflammatory as well as in non-inflammatory partial restraint stress(PRS) rat models. Statistical significance between the treatment groups in the permeability studies were evaluated using unpaired t-tests.RESULTS Treatment of T84 and Caco-2 monolayers with lipopolysaccharide(LPS) rapidly increased permeability, which was effectively suppressed when monolayers were also treated with plecanatide or dolcanatide. Similarly, when T84 and Caco-2 monolayers were treated with LPS, cell surface localization of tight junction proteins occludin and ZO-1 was severely disrupted. When cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, occludin and ZO-1 were localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells. Treatment of cell monolayers with plecanatide or dolcanatide without LPS did not alter permeability, integrity of tight junctions and cell surface localization of either of the tight junction proteins. In rat visceral hypersensitivity models, both agonists suppressed the TNBS-induced increase in abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity, and both agonists also reduced colonic hypersensitivity in the PRS model. CONCLUSION Our results suggest that activation of GC-C signaling might be involved in maintenance of barrier function, possibly through regulating normal localization of tight junction proteins. Consistent with these findings, plecanatide and dolcanatide showed potent antinociceptive activity in rat visceral hypersensitivity models. These results imply that activation of GC-C signaling may be an attractive therapeutic approach to treat functional constipation disorders and inflammatory gastrointestinal conditions. | Illona-Marie Boulete Anusha Thadi Catherine Beaufrand Viren Patwa Apoorva Joshi John A Foss E Priya Eddy Helene Eutamene Vaseem A Palejwala Vassilia Theodorou Kunwar Shailubhai | 2018 | World Journal of Gastroenterology2018，24，17： | 5 |
| 3 | Optimising islet engraftment is critical for successful clinical islet transplantation显示文摘 | O Korsgren T Lundgren M Felldin A Foss B Isaksson J Permert N H Persson E Rafael M Rydén K Salmela A Tibell G Tufveson B Nilsson | 2008 | Diabetologia2008，，2： | 2 |
| 4 | Pathways of organic carbon oxidation in three continental margin sediments 显示文摘 | Canfield D E J? rgensen B B Fossing H | 1993 | Marine Geology1993，113，： | 1 |
| 5 | Compensa- tory growth in Atlantic halibut: effect of starvation and subsequent feeding on growth, maturation, feed utilization and flesh quality显示文摘 | Foss A Imsland A K Vikingstad E | 2009 | Aquaculture2009，290，34： | 1 |
| 6 | Pathways oforganic carbon oxidation in three continental margin sedi- ments显示文摘 | Canfield D E Jorgensen B B Fossing H | 1993 | Mar Geol1993，113，： | 1 |
| 7 | Autonomic neuropathy in nondiabetic offspring of type 2 diabetic subjects is associated with urinary albumin excretion rate and 24-h ambulatory blood pressure:The Frederica Study显示文摘 | Foss GH Vestbo E Froland A | 2001 | Diabetes2001，50，3： | 1 |
| 8 | High and low heparin dose with heparin - coated CPB: activation of complement and granulocyte显示文摘 | Mollnes TE Fosse E | 1995 | Ann Thorac Surg1995，60，： | 1 |
| 9 | Gated importation of prothymocytes by adult mouse thymus is coordinated with their periodic mobilization from bone marrow显示文摘 | Donskoy E Foss D Goldschneider I | 2003 | J Immunol2003，171，7： | 1 |
| 10 | Reduced complement and granulocyte activation with heparin - coated CPB 显示文摘 | Moen O Johnson E | 1994 | Ann Thorac Surg1994，58，： | 1 |
| 11 | Ellipsometric study of the influence of chemical etching on thin porous sili- con structures显示文摘 | Selj J ThqSgersen A Foss S E | 2011 | Thin Solid Films2011，519，9： | 1 |
| 12 | Pathways of organic carbon oxidation in three continental margin sediments显示文摘 | Canfield D E Jorgensen B B Fossing H | 1993 | Marine Geology1993，113，12： | 1 |
| 13 | Reduc- ing social inequalities in health in Norway:Concerted action at state and local levels 显示文摘 | Tallarek nee Grimm M J Helgesen M K Fosse E | 2013 | Health Policy2013，113，3： | 1 |
| 14 | High and low heparin dose w ith heparin-coated cardiopulmonary bypass: Activation of complement and granulocytes 显示文摘 | Mollnes TE Fosse E | 1995 | Ann Thorac Surg1995，60，6： | 1 |
| 15 | Reduced complement activation with heparin- coated oxygenator and tubing in coronary bypass operation 显示文摘 | Svennevig JL Fosse E | 1992 | J Thorac Cardiovasc Surg1992，103，： | 1 |
| 16 | Thick etch-through macroporous Si membrane from p-and n-Si, and fast pore etching and tuning the pore size from n-Si 显示文摘 | Kan P Y Y Foss S E Finstad T G | 2007 | Materials Science and Engineering B-Solid State Materials for Advanced Technology2007，137，13： | 1 |
| 17 | Leading and supporting the imple- mentation of the Norwegian network of health promotion schools显示文摘 | Viig NG Fosse E Samdal O | 2012 | Scandinavian Journal of Educational Research2012，56，6： | 1 |
| 18 | The Relationship of Hamstrings and Quadriceps Strength to Anterior Cruciate Ligament Injury in Female Athletes显示文摘 | Gregory D Myer Kevin R Ford Kim D Barber Foss Chunyan Liu Todd G Nick Timothy E Hewett | 2009 | Clinical Journal of Sport Medicine2009，，1： | 1 |
| 19 | Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the tromso study显示文摘 | JOHNSEN S H MATHIESEN E B FOSSE E etal | 2005 | Circulation2005，112，： | 1 |
| 20 | Silk Fibroin/HyaluronicAcid 3D Matrices for Cartilage Tissue Engineering 显示文摘 | Foss G Merzari E Migliaresi C | 2013 | Bionuicro-molecules2013，14，1： | 1 |
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