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Cellular and molecular aspects involved in the inflammatory response induced by carrageenan in healthy or diabetic mice

Grant number: 12/06652-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): October 01, 2012
Effective date (End): September 30, 2014
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Joilson de Oliveira Martins
Grantee:Fernanda Peixoto Barbosa Nunes
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:10/02272-0 - Effect of insulin on lung inflammation in animal with sepsis, innate immunit,activation of insulin gene (BGK) and insulin receptors (IR)-A and IR-B, AP.JP

Abstract

Diabetes mellitus is a metabolic disorder associated with an increased risk of infections affecting the soft tissue and mucous. Insulin regulates cellular metabolism by modulating the activity of proteins involved in intracellular signaling. This project aims to assess the role of insulin on the expression of chemical mediators pro and anti-inflammatory, as well as its effect on the expression of adhesion molecules, on the function of peritoneal macrophages and the expression of cell signaling proteins activated in the presence of inflammation in the peritoneal cavity (peritonitis) induced by carrageenan in mice, focusing on MAPK pathways, ERK and NF-kB, besides evaluating the effect of insulin on the activation of its gene (BetaGK) and its receptors IR-A and IR-B. Thus, it will be evaluated: a) the number of cells in the peritoneal fluid, the white blood count and blood glucose (glucose monitor), b) serum levels of corticosterone and insulin (ELISA), c) the concentrations of cytokines (IL-1Beta, TNF-alpha, IL-6, MIF-1, IFN-gamma, IL-4, IL-10, IL-12, CINC-1 and CINC-2) in peritoneal fluid by ELISA d) the expression of COX-2 and iNOS, molecules involved in intracellular signaling (p38 MAPK, ERK1 / 2, p65, NF-kB, AP-1, IRF-3, IRR, trifluoromethyl, TRAM) and the expression of the TLR-4 receptor in peritoneal macrophages (MPs) by Western blot e) the expression of adhesion molecules (P-selectin, ICAM-1 and PECAM-1) on mesenteric vascular endothelium by immunohistochemistry; f) the expression of adhesion molecule (Mac-1) on leukocytes by flow citometry; g) the phagocytic index and nitric oxide production by peritoneal macrophages; i) the cytokines and intracellular signaling pathways altered in the presence of inflammation or diabetes will also be analyzed for their mRNA expression by RT-PCR in real time; i) besides evaluating the activation that the insulin promotes on its gene "Beta Cell glucokinase gene"(BetaGK) and its receptors (isoforms A and B), by confocal microscopy. Since diabetes is one of the ten diseases that most victimization causes in the world population, increasing knowledge about the inflammatory and immune response resulting from common inflammatory agents (carrageenan) in diabetic individuals is of fundamental importance. A better understanding of how insulin works in the inflammatory response, innate immune receptors, the activation of its own gene, their receptors and how the different signaling pathways interfere with each other would not only contribute to the discussion on the use of insulin in patients with trauma victims, but also increase the natural immunity against pathogenic microorganisms or inhibit the deleterious effects of inflammation.

Scientific publications
(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)
KNOX DE SOUZA, PAULA R.; FERREIRA, SABRINA S.; NUNES, FERNANDA P. B.; CASAGRANDE, FELIPE B.; TESSARO, FERNANDO H. G.; SILVA, MARIANA C. F.; MIRANDA COSTA CRUZ, JOSE WALBER; MAMIZUKA, ELSA M.; MARTINS, JOILSON O. Cytokine and Adhesion Molecule Expression Induced by Different Strains of Staphylococcus aureus in Type 1 Diabetic Rats: Role of Insulin. FRONTIERS IN IMMUNOLOGY, v. 9, JAN 17 2019. Web of Science Citations: 0.
CASAGRANDE, FELIPE BECCARIA; FERREIRA, SABRINA DE SOUZA; BARBOSA NUNES, FERNANDA PEIXOTO; DAL'MAS ROMERA, LAVINIA MARIA; DOS SANTOS, SUELEN SILVANA; GALVAO TESSARO, FERNANDO HENRIQUE; KNOX DE SOUZA, PAULA REGINA; ALMEIDA, SANDRO ROGERIO; MARTINS, JOILSON OLIVEIRA. Insulin Modulates Paracoccidioides brasiliensis-Induced Inflammation by Restoring the Populations of NK Cells, Dendritic Cells, and B Lymphocytes in Lungs. JOURNAL OF DIABETES RESEARCH, 2018. Web of Science Citations: 0.

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