Inflammatory bowel disease (IBD): new molecular markers and intestinal anti-inflammatory activity of drugs and plant products

• Grant number: 11/50512-2
• Support Opportunities: Regular Research Grants
• Duration: May 01, 2011 - July 31, 2013
• Field of knowledge: Biological Sciences - Pharmacology - Ethnopharmacology
• Principal Investigator: Luiz Claudio Di Stasi
• Grantee: Luiz Claudio Di Stasi
• Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil

Abstract

The inflammatory bowel disease (IBD), Crohn's disease and Ulcerative Colitis, are multifactorial disorders of the gut. Although the pathogenesis is poorly understood, there is evidence that it involves interactions among the immune system, genetic susceptibility, and environmental factors, mainly the bacterial flora. A major limitation in understanding the pathogenetic mechanisms responsible for IBD has been the relative lack of animal models that exhibit the human chronic inflammatory process. Therefore, studies related to elucidation and involvement of several mediators of the human IBD in experimental model of colitis are very important to characterization of new therapeutic targets. The trinitrobenzenesulphonic (TNBS) acid model of rat colitis is the easiest and most adequate experimental model used in investigations for the development and testing of therapeutic molecules that have the potential to be used in the clinic for the management of human disease. Indeed, considering that a specific causal treatment of IBD is still not available and drugs currently used for the management of human IBD are not devoid of potentially serious side effects, the development of new treatment strategies that combine efficacy and safety is an important goal in IBD therapy. Considering these data, the aim of the present proposal are: a. to evaluate the involvement of the new and important human molecular markers in TNBS model of rat colitis, mainly heat shock protein, heparanase, metalloproteinase and MAPK signaling cascades: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK as new therapeutic targets for management of IBD; b. to determine effects of classical drugs (sulfasalazine, prednisolone and azatioprine) for management of human IBD on these inflammatory mediators and, c. to determine the pharmacological activity of the previously evaluated natural products, such as natural coumarins: esculin, esculetin and 4-methyl-esculetin and some plant species from Brazilian flora: Physalis angulata L. - "camapú" (supercritic CO2 extract of aerial parts standardized in physalins) Bidens pilosa L. - "picão preto" (supercritic CO2 extract of aerial parts standardized in eicosapentanoic and α-linolenic acids), Baccharis dracunculifolia L. - "alecrim do campo" (Ethyl acetate extract of aerial parts standardized in phenolic compounds) as new potential products for IBD therapy. This was performed in two experimental settings, /.e. when the colonic mucosa is intact (preventative studies) or when the mucosa is in process of recovery after an initial insult (curative studies). Simultaneously to expression of new mediators, the effects of each treatment were evaluated macroscopically (damage score, extension of lesion, colonic weight, incidence of diarrhoea), biochemically (mieloperoxidade and phosphatase alkaline activities, glutathione content, TNF-α and IL-1ß production, and NF-κB expression), microscopically (light and electron microscopy). (AU)

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

QUAGLIO, ANA E. V.; CASTILHO, ANTHONY C. S.; DI STASI, LUIZ C.. Experimental evidence of heparanase, Hsp70 and NF-kappa B gene expression on the response of anti-inflammatory drugs in TNBS-induced colonic inflammation. Life Sciences, v. 141, p. 179-187, NOV 15 2015. (11/50512-2)

WITAICENIS, A.; LUCHINI, A. C.; HIRUMA-LIMA, C. A.; FELISBINO, S. L.; JUSTULIN, JR., L. A.; GARRIDO-MESA, N.; UTRILLA, P.; GALVEZ, J.; DI STASI, L. C.. MECHANISM AND EFFECT OF ESCULETIN IN AN EXPERIMENTAL ANIMAL MODEL OF INFLAMMATORY BOWEL DISEASE. European Journal of Inflammation, v. 11, n. 2, p. 433-446, MAY-AUG 2013. (11/50512-2)

ALMEIDA JUNIOR, LUIZ DOMINGUES; VALENCISE QUAGLIO, ANA ELISA; RODRIGUES DE ALMEIDA COSTA, CELSO ACACIO; DI STASI, LUIZ CLAUDIO. Intestinal anti-inflammatory activity of Ground Cherry (Physalis angulata L.) standardized CO2 phytopharmaceutical preparation. WORLD JOURNAL OF GASTROENTEROLOGY, v. 23, n. 24, p. 4369-4380, JUN 28 2017. (11/50512-2, 15/15267-8)

WITAICENIS, ALINE; SOUZA DE OLIVEIRA, ELLEN CRISTINA; TANIMOTO, ALEXANDRE; GONCALVES ZORZELLA-PEZAVENTO, SOFIA FERNANDA; DE OLIVEIRA, SILVIO LUIS; SARTORI, ALEXANDRINA; DI STASI, LUIZ CLAUDIO. 4-methylesculetin, a coumarin derivative, ameliorates dextran sulfate sodium-induced intestinal inflammation. Chemico-Biological Interactions, v. 280, p. 59-63, JAN 25 2018. (11/50512-2, 13/01297-7)

PEREDA, MARIA DEL CARMEN V.; DIEAMANT, GUSTAVO; NOGUEIRA, CECILIA; EBERLIN, SAMARA; FACCHINI, GUSTAVO; MUSSI, LILIAN; POLEZEL, MARCIO A.; MARTINS-OLIVEIRA, DIVINO; ROSA, PAULO T. V.; DI STASI, LUIZ C.. Sterol-standardized phytopharmaceutical from ground cherry: Corticoid-like properties on human keratinocytes and fibroblasts and its effects in a randomized double-blind placebo-controlled clinical trial. Journal of Cosmetic Dermatology, v. 18, n. 5, p. 1516-1528, OCT 2019. (11/50512-2)

VALENCISE QUAGLIO, ANA ELISA; SOUZA CASTILHO, ANTHONY CESAR; DI STASI, LUIZ CLAUDIO. Experimental evidence of MAP kinase gene expression on the response of intestinal anti-inflammatory drugs. Life Sciences, v. 136, p. 60-66, SEP 1 2015. (11/50512-2)

ALMEIDA-JUNIOR, L. D.; CURIMBABA, T. F. S.; CHAGAS, A. S.; QUAGLIO, A. E. V.; DI STASI, L. C.. Dietary intervention with green dwarf banana flour (Musa sp AAA) modulates oxidative stress and colonic SCFAs production in the TNBS model of intestinal inflammation. Journal of Functional Foods, v. 38, n. A, p. 497-504, NOV 2017. (11/50512-2, 15/15267-8)