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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 | Digital Converter for Differential Capacitive Sensors 显示文摘 | Mohan N M Shet A R Kedamath S | 2008 | IEEE Transactions on Instrumentation and Measurement(S0018-9456)2008，57，11： | 1 |
| 3 | Induction of micropartiele and cell-associated intravascular tissue factor in human endotoxemia显示文摘 | Aras O Shet A Bach RR | 2004 | Blood2004，103，12： | 1 |
| 4 | Neonatal & maternal group B streptococcal infections : A comprehensive review 显示文摘 | SHET A FERRIERI P | 2004 | Indian J Med Res2004，120，： | 1 |
| 5 | A numerical study of division of flow in open channels显示文摘 | SHET'FAR A S MURTH K | 1996 | Journal of Hydraulic Research1996，34，5： | 1 |
| 6 | Endothelial cell ex- pression of tissue factor in sickle mice is augmented by hy- poxia/reoxygenation and inhibited by lovastatin显示文摘 | Solovey A Kollander R Shet A | 2004 | Blood2004，104，3： | 1 |
| 7 | Congenital and perinatal infections:throwing new light with an old TORCH显示文摘 | Shet A | | 0，，01： | 1 |
| 8 | Endothelial cell expression of tissue factor in sickle mice is augmented by hypoxia/reoxygenation and inhibited by lovastatin显示文摘 | Solovey A Kollander R Shet A | 2004 | Blood2004，104，3： | 1 |
| 9 | Neonatal & maternal group B strep- tococcal infections: a comprehensive review显示文摘 | SHET A FERRIERI P | 2004 | Indian J Med Res2004，120，3： | 1 |
| 10 | Tracking the prevalence of transmitted antiretroviral drug-resistant HIV-I: a decade of experience显示文摘 | Shet A BetTy L Mohri H | 2006 | J Acquir Immune Defic Syndr2006，41，4： | 1 |
| 11 | Analysis of individval platelet-derived microparticles, comparing flow cytometry and capillary electrophoresis with laser-induced fluorescence detection 显示文摘 | Aras O Shet A | 2003 | Analyst2003，128，6： | 1 |
| 12 | 显示文摘 | Aras O Shet A Bach RR | 2004 | Blood2004，103，12： | 1 |
| 13 | Malignant pilar tumor of the scalp: A case report and review of literature 显示文摘 | Siddha M Budrukkar A Shet T | 2007 | J Cancer Res Ther2007，3，： | 1 |
| 14 | Novel therapies for chronic myelogenous leukemia 显示文摘 | Jahagirdar B N Miller J S Shet A | 2001 | Exp Hematol2001，29，5： | 1 |
| 15 | Induction of microparticle-and cell-associated intravascular tissue factor in human endotoxemia 显示文摘 | Aras O Shet A Bach RR | 2004 | Blood2004，103，： | 1 |
| 16 | Neonatal & maternal group B streptococcal infections : a comprehensive review 显示文摘 | Shet A Ferrieri P | 2004 | Indian J Med Res2004，120，3： | 1 |
| 17 | Sickle blood contains tissue factor positive microparticles derived from endothelial cells and monocytes显示文摘 | Shet A Aras O Gupta K | 2003 | Blood2003，102，7： | 1 |
| 18 | Changes in the tumor grade and biological markers in locally advanced breast cancer after chemotherapy-implications for a pathologist 显示文摘 | Shet T Agrawal A Chinoy R | 2007 | Breast J2007，13，5： | 1 |
| 19 | Induction of microparticle and cell associated intravascular tissue factor in human endotoxemia显示文摘 | Aras O Shet A Bach RR | 2004 | Blood2004，103，12： | 1 |
| 20 | Transmitted multidrug resistant HIV-1:new and investigational therapeutic approaches显示文摘 | Shet A Markowitz M | 2006 | Curr Opin Investig Drugs2006，7，8： | 1 |
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