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| 1 | Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCC mice显示文摘AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc^(+/Min-FCCC) mice with dextran sodium sulfate(DSS)-induced inflammation. METHODS Inflammation driven colorectal carcinogenesis was induced in Apc^(+/Min-FCCC) mice by administering DSS in their drinking water. Mice were fed a diet supplemented with plecanatide(0-20 ppm) and its effect on the multiplicity of histopathologically confirmed polypoid,flat and indeterminate dysplasia was evaluated. Plecanatide-mediated activation of guanylate cyclase-C(GC-C) signaling was assessed in colon tissues by measuring cyclic guanosine monophosphate(cG MP) by ELISA, protein kinase G-II and vasodilator stimulated phosphoprotein by immunoblotting. Ki-67, c-myc and cyclin D1 were used as markers of proliferation. Cellular levels and localization of b-catenin in colon tissues were assessed by immunoblotting and immunohistochemistry, respectively. Uroguanylin(UG) and GC-C transcript levels were measured by quantitative reverse transcription polymerase chain reaction(RT-PCR). A mouse cytokine array panel was used to detect cytokines in the supernatant of colon explant cultures. RESULTS Oral treatment of Apc^(+/Min-FCCC) mice with plecanatide produced a statistically significant reduction in the formation of inflammation-driven polypoid, flat and indeterminate dysplasias. This anti-carcinogenic activity of plecanatide was accompanied by activation of cG MP/GC-C signaling mediated inhibition of Wnt/b-catenin signaling and reduced proliferation. Plecanatide also decreased secretion of pro-inflammatory cytokines(IL-6, IL-1 TNF), chemokines(MIP-1, IP-10) and growth factors(GCSF and GMCSF) from colon explants derived from mice with acute DSS-induced inflammation. The effect of plecanatidemediated inhibition of inflammation/dysplasia on endogenous expression of UG and GC-C transcripts was measured in intestinal tissues. Although GC-C expression was not altered appreciably, a statistically significant increase in the level of UG transcripts was detected in the proximal small intestine and colon, potentially due to a reduction in intestinal inflammation and/or neoplasia. Taken together, these results suggest that reductions in endogenous UG, accompanied by dysregulation in GC-C signaling, may be an early event in inflammation-promoted colorectal neoplasia; an event that can potentially be ameliorated by prophylactic intervention with plecanatide.CONCLUSION This study provides the first evidence that orally administered plecanatide reduces the multiplicity of inflammation-driven colonic dysplasia in mice, demonstrating the utility for developing GC-C agonists as chemopreventive agents. | Wen-Chi L Chang Shet Masih Anusha Thadi Viren Patwa Apoorva Joshi Harry S Cooper Vaseem A Palejwala Margie L Clapper Kunwar Shailubhai | 2017 | World Journal of Gastrointestinal Pharmacology and Therapeutics2017，8，1： | 5 |
| 2 | Yield and quality of soymilk and tofu made from soybean genotypes grown at four locations显示文摘 | BHARDWAJ H L BHAGSARI A S JOSHI J M | 1999 | Crop Sci1999，39，： | 1 |
| 3 | Unreamed interlocking nailing in open fractures of tibia显示文摘 | Joshi D Ahmed A Krishna L | 2004 | J Orthop Surg2004，12，3： | 1 |
| 4 | Novel intracellu- lar N-terminal truncated matrix metalloproteinase-2 iso-form in skeletal muscle ischemia-reperfusion injury显示文摘 | Joshi S K Lee L Lovett D H | 2015 | J Orthop Res2015，7，22： | 1 |
| 5 | Image restoration by ma-tching gradient distributions显示文摘 | Cho T S Zitnick C L Joshi N | 2012 | IEEE Transactions on Pattern Analysis and Machine Intelligence2012，34，4： | 1 |
| 6 | Kinematic analysis of 3-DOF position mechanisms for use in hybrid kinematic machines显示文摘 | Tsai L W Joshi S | 2002 | Journal of Mechanical Design2002，124，2： | 1 |
| 7 | Usability of a patient education and motivation tool using heuristic evaluation显示文摘 | Joshi A Arora M Dai L | 2009 | Med Int Res2009，11，4： | 1 |
| 8 | Preparation and characterization of Ag-ZnO powders for applications in electrical contact materials显示文摘 | Joshi P B Murti N S S Gadgeel V L | 1995 | Journal of Materials Science Letter1995，14，16： | 1 |
| 9 | Subacute combined degen-eration of the spinal cord in an adolescent girl显示文摘 | Mohanty S Shobhavat L Joshi R | | 0，，4： | 1 |
| 10 | Jacobian analysis of limited-DOF parallel manipulators 显示文摘 | Joshi S A Tsai L W | 2002 | ASME Journal of Mechanical Design2002，124，2： | 1 |
| 11 | Kinematic analysis of 3-DOF posi- tion mechanisms for use in hybrid kinematic ma- chines 显示文摘 | Tsai L W Joshi S | 2002 | ASME Trans Journal of Mechanical Design2002，124，2： | 1 |
| 12 | Periprosthetic joint infection:the incidence,timing,and predisposing factors显示文摘 | Pulido L Ghanem E Joshi A | 2008 | Clin Orhtop Relat Res2008，466，7： | 1 |
| 13 | Multinational Corporations' Corpo- rate Social and Environmental Disclosures (CSED) on Web Sites 显示文摘 | Joshi P L S S Gao | 2009 | International Journal of Commerce and Management2009，19，1： | 1 |
| 14 | Blood product transfusion and ventilator-associated pneumonia in trauma patients显示文摘 | Bochicchio GV Napolitano L Joshi M | 2008 | Surg Infect (Larchmt)2008，9，： | 1 |
| 15 | Mechanical and thermal properties of poplar wood polyacrylonitrile composites 显示文摘 | Joshi T K Zaidi M G H Sah P L | 2005 | Poly- mer International2005，54，1： | 1 |
| 16 | Knee arthroplasty in octogenarians :results at 10 years显示文摘 | Joshi AB Markovic L Gill G | 2003 | J Arthroplasty2003，18，： | 1 |
| 17 | Jacobian analysis of limited-DOF parallel manipulators显示文摘 | JOSHI S A TSAI L W | 2002 | Journal of Mechanical Design2002，，： | 1 |
| 18 | Genistein exerts estrogen-like effects in male mouse reproductive tract 显示文摘 | Strauss L Makela S Joshi S | 1998 | Mol Cell Endocrinol1998，144，： | 1 |
| 19 | Heat transfer and friction in the offset strip fin heat exchanger显示文摘 | Joshi H M Webb R L | 1987 | International Journal of Heat and Mass Transfer1987，30，： | 1 |
| 20 | A xylem - specific cellulose synthase gene from aspen ( Populus tremuloides) is responsive to mechanical stress显示文摘 | Wu Luguang Joshi Chandrashekhar P Chiang Vincent L | 2000 | Plant J2000，22，6： | 1 |
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