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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 | 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 | The effect of predni- sone On the progression from ocular to generalized myasthema gravis显示文摘 | Morisu NT Patwa H S Knorr AM | 2004 | J Neurol Set2004，217，2： | 1 |
| 4 | Predictive modeling of laser hardening of AISI5150H steels显示文摘 | Rahul Patwa Yung C. Shin | 2006 | International Journal of Machine Tools and Manufacture2006，，2： | 1 |
| 5 | The effect of prednisone on the progression from ocular to generalized myasthenia gravis显示文摘 | Monsul NT Patwa HS Knorr AM | 2004 | J Neurol Sci2004，15，： | 1 |
| 6 | Evidence-based guideline: Intravenous immunoglobulin in the treatment of neuromuscular disorders Report of the Therapeutics and Tech- nology Assessment Subcommittee of the American Academy of Neurology 显示文摘 | Patwa HS Chaudhry V Katzberg H | 2012 | Neurology2012，78，13： | 1 |
| 7 | Laser-assisted machining of Inconel 718 with an economic analysis显示文摘 | ANDERSON M PATWA R SHIN Y C | 2006 | International Journal of Machine Tools and Manufacture2006，46，14： | 1 |
| 8 | Evidence-based guideline: intravenous irnmunoglobulin in the treatment of neuromuscular disorders=report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology显示文摘 | Patwa H$ Chaudhry V Katzberg H | | Neurology0，，02： | 1 |
| 9 | Modified Ilizarov technique for infected nonunion of the femur:the principle of distraction-compression osteogenesis显示文摘 | Krishnan A Pamecha C Patwa JJ | 2006 | J Orthop Surg (HK)2006，14，3： | 1 |
| 10 | Predictive modeling of laser hardening of AIS15150H steels显示文摘 | PATWA R SHIN Y C | 2007 | International Journal of Machine Tools and Manufacture2007，47，2： | 1 |
| 11 | Glycoprotein microarrays with multi-lectin detection:unique lectin binding patterns as a tool for classifying normal,chronic pancreatitis and pancreatic cancer sera显示文摘 | Zhao J Patwa TH Qiu W | 2007 | J Proteome Res2007，6，5： | 1 |
| 12 | The effect of prednisone on the progression from ocular to generalized myasthenia gravis显示文摘 | Monsul NT Patwa HS Knorr AM | | 0，，： | 1 |
| 13 | Evidence-basedguideline; intravenous immunoglobulin in the treatment ofneuromuscular disorders : report of the Therapeutics and Tech-nology Assessment Subcommittee of the American Academy ofNeurology显示文摘 | Patwa HS Chaudhry V Katzberg H | 2012 | Neurology2012，78，13： | 1 |
| 14 | Predictive modeling of laser hardening of AISIS150H steels 显示文摘 | R Patwa Y C Shin | 2007 | Int J Machine Tools and Manufacture2007，47，2： | 1 |
| 15 | Laser- assisted Machining of Inconel 718 with an Economic Analysis 显示文摘 | Anderson M Patwa R Shin Y C | 2006 | International Journal of Machine Tools and Manufacture2006，46，14： | 1 |
| 16 | Glycoprotein microarrays with multi-lectin detection: unique lectin binding patterns as a tool for classifying normal, chronic pancreatitis and pancreat iccancer sera显示文摘 | Zhao J Patwa TH Qiu W | 2007 | J Proteome Res2007，6，： | 1 |
| 17 | D Dimer in acute care显示文摘 | Sathe PM Patwa UD | | nt J Crit llln !nj Sci0，4，3： | 1 |
| 18 | The effect of prednisone on the progression from ocular to generalized myasthenia gravis 显示文摘 | Monsul NT Patwa HS Knorr AM | 2004 | J Neurol Sci2004，217，2： | 1 |
| 19 | Rituximab in the manage-ment of refractory myasthenia gravis显示文摘 | Zebardast N Patwa HS Novella SP | 2010 | Muscle Nerve2010，41，3： | 1 |
| 20 | Evidence-based guideline:intravenous immunoglobulin in the treatment of neuromuscular disorders:report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology显示文摘 | Patwa HS Chaudhry V Katzberg H | | 0，，13： | 1 |
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