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Modulation of inflammatory bone resorption by a novel chemically modified curcumin: focus on osteoclastogenesis

Grant number: 12/15826-9
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): November 01, 2012
Effective date (End): March 31, 2014
Field of knowledge:Health Sciences - Dentistry - Periodontology
Principal Investigator:Carlos Rossa Junior
Grantee:Fabiana Almeida Curylofo Zotti
Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil


Curcumin (diferuloylmethane) is a polyphenol compound derived from the rhizomes of a plant, Curcuma longa, which has been shown to simultaneously inhibit the expression of various pro-inflammatory cytokines both in vitro and in vivo. Since the imbalanced expression of these biological mediators is closely linked to multiple pathologies, a number of studies have investigated the therapeutic effect of curcumin in diseases such as cancer, rheumatoid arthritis, Crohn’s disease, inflammatory bowel disease, colitis and psoriasis. The results are encouraging but variable. Our research group has recently demonstrated the anti-oinflammatory effects of systemically-administered unmodified curcumin in an in vivo model of periodontal disease and also in vitro using LPS-stimulated murine macrophages. These models are representative of inflammatory conditions associated with host-microbial interactions. The variability on the activity and biological effects of curcumin is largely due to the poor pharmacodynamic properties of curcumin, especially its insolubility in aqueous solutions and poor adsorption by the gastrointestinal tract. Since the positive characteristics of curcumin, namely its potent anti-inflammatory properties coupled with a virtual absence of toxicity and side effects support a great interest in its therapeutic applications, the laboratories of Stony Brook University (State University of New York at Stony Brook) started the development of chemically modified versions of curcumin (CMCs) in order to improve its pharmacological properties. Pilot experiments from our research group indicate the absence of cytotoxicity and the efficacy of CMCs as direct inhibitors of matrix metalloproteases in human cells. Thus, the hypothesis of this proposal is more potent in the modulation of inflammation associated with periodontal diseases and particularly on the inhibition of bone resorption. To test this hypothesis, we propose the following experiments:1) Determine, in an in vivo model of experimental periodontal disease, the influence of CMC on inflammatory bone resorption and apoptosis. In these experiments, we will use histological sections obtained from decalcified and paraffin-embedded tissue blocks including the upper molars and surrounding tissues as well as total proteins extracted from soft gingival tissues of rats submitted to experimental periodontal disease and treated with CMC by oral gavage. The outcomes of interest will be: identification of osteoclasts (TRAP-positive cells) and apoptosis (active caspase-3) by immunohistochemistry. Detection of apoptosis (DNA fragmentation) by immunofluorescence (TUNEL assay);2) Assess the effects of CMC on the moduilation of osteoclastic differentiation in vitro. For these experiments, we will use primary bone marrow-derived macrophages from C57/Bl6 mice. The purpose is to verify if CMC modulates RANKL-induced osteoclastogenesis and iddentify if this modulation occurs at early or late stages of differentiation. We will also determine the effect of CMC on the activity of mature osteoclasts. Outcomes of interest are: actin-ring formation (immunofluorescence), pit-assay and MMP-9 gene expression (osteoclast activity). (AU)

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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)
ELBURKI, MUNA S.; ROSSA, CARLOS; GUIMARAES, MORGANA R.; GOODENOUGH, MARK; LEE, HSI-MING; CURYLOFO, FABIANA A.; ZHANG, YU; JOHNSON, FRANCIS; GOLUB, LORNE M.. A Novel Chemically Modified Curcumin Reduces Severity of Experimental Periodontal Disease in Rats: Initial Observations. Mediators of Inflammation, . (10/19660-2, 12/15826-9, 09/54080-0)
ELBURKI, MUNA S.; ROSSA, JR., CARLOS; GUIMARES-STABILI, MORGANA R.; LEE, HSI-MING; CURYLOFO-ZOTTI, FABIANA A.; JOHNSON, FRANCIS; GOLUB, LORNE M.. A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor kappa B Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis. Inflammation, v. 40, n. 4, p. 1436-1449, . (10/19660-2, 12/15826-9, 10/20091-2, 09/54080-0)

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