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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 | 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 |
| 3 | Pediatric pituitary adenomas显示文摘 | Kunwar S Wilson C B | 1999 | J Clin Endocrinol Metab1999，84，12： | 1 |
| 4 | Poly-β-hydroxybutyrate (PHB) increases growth perform- ance and intestinal bacterial range-weighted richness in ju- venile European sea bass, Dicentrarchus labrax显示文摘 | De Schryver P Sinha A K Kunwar P S | 2010 | Appl Microbiol Biotechnol2010，86，5： | 1 |
| 5 | The effects of aldosterone antagonists in pa-tients with resistant hypertension : a meta-analysis of randomized and nonran-domized studies显示文摘 | Dahal K Kunwar S Rijal J | 2015 | Am J Hypertens2015，28，11： | 1 |
| 6 | Apparatus dependence of normal brain tissue dose in stereotactic radiosurgery for multiple brain metastases显示文摘 | Ma L Petti P Wang B Descovich M Chuang C Barani IJ Kunwar S Shrieve DC Sahgal A Larson DA | 2011 | 中国神经肿瘤杂志2011，9，1： | 1 |
| 7 | Automatic image registration using evolutionary algorithm显示文摘 | MALIK S A KUNWAR R S HAQUE M E | | 0，，01： | 1 |
| 8 | Single- and multi-component adsorption of cadmium and zinc using activated carbon derived from bagasse-an agricultural waste显示文摘 | DINESH M KUNWAR P S | 2002 | Water Research2002，36，12： | 1 |
| 9 | Multivariate Statistical Techniques forthe Evaluation of Spatial and Temporal Variations in Water Quality of Gomti Riv-er(India):A Case Study显示文摘 | Kunwar P S Amrita M Dinesh M | 2004 | Water Research2004，，18： | 1 |
| 10 | Liquid-phase adsorption of phenols using activated carbons derived from agricultural waste material 显示文摘 | Kunwar P Singh A M Sarita S | 2008 | Journal of Hazardous Materials2008，150，3： | 1 |
| 11 | Studies on distribution and fractionation of heavy metals in Gomti river sediments--a tributary of the Ganges,India显示文摘 | Kunwar P S Dinesh M Vinod K S | 2005 | Journal of Hydrology2005，312，： | 1 |
| 12 | Clinical management ofpituitary carcinoma?显示文摘 | OH MC TIHAN T KUNWAR S | 2012 | Neurosurg Clin N Am2012，23，4： | 1 |
| 13 | Stereotactic radiosurgery and interstitial brachytherapy for glial neoplasms显示文摘 | McDermott MW Berger MS Kunwar S | 2004 | J Neurooncol2004，69，13： | 1 |
| 14 | Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma:a report by the Cintredekin Besudotox Intraparenchymal Study Group显示文摘 | Kunwar S Prados MD Chang SM | 2007 | J Clin Oncol2007，25，7： | 1 |
| 15 | Convection enhanced delivery of IL-13-PE38QQR for treatment of recurrent malignant glioma:presentation of interim findings from ongoing phase I studies 显示文摘 | Kunwar S | 2003 | Acta Neuroehir Suppl2003，88，： | 1 |
| 16 | Endoscopic adjuncts to intraventricular surgery显示文摘 | Kunwar S | 2003 | Neurosurg Clin N Am2003，14，4： | 1 |
| 17 | Multivariate Statisti-cal Techniques for the Evaluation of Spatial and Temporal Vartionsin Water Quality of Gomti River(India):A Case Study显示文摘 | KUNWAR P S AMRITA M DINESH M | 2004 | WaterResearch2004，38，18： | 1 |
| 18 | Anti-apop- totic,anti-inflammatory,and immunomodulatory activi- ties of 3,3'-diselenodipropionic acid in mice exposed to whole body 7-radiation显示文摘 | Kunwar A Bag P P Chattopadhyay S | 2011 | Archives of Toxicology2011，85，11： | 1 |
| 19 | Clinical management of pituitary carcinomas 显示文摘 | Oh MC Tihan T Kunwar S | 2012 | Neurosurg Clin N Am2012，23，4： | 1 |
| 20 | Multivariate statistical techniques for the evaluation of spatial and temporal variations in water quality of Gomti River显示文摘 | Kunwar P S Amrita M Dinesh M | 2004 | Water Research2004，38，18： | 1 |
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