| dc.identifier.uri | http://hdl.handle.net/11401/76591 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Periodontitis, the most common chronic inflammatory disease known to mankind, is recognized as the major cause of tooth loss in adults. Although periodontitis is initiated by anaerobic gram-negative bacteria, the destruction of the periodontium is essentially mediated by the host response. Numerous investigators have described various pharmacologic strategies to modulate the host response during periodontal disease, however only a non-antimicrobial tetracycline formulation is FDA-approved for these patients. Of interest, this formulation of sub-antimicrobial-dose doxycycline (SDD) has shown efficacy in clinical trials in other diseases also, e.g, rheumatoid arthritis. However, a significant drawback of the approved SDD is that this novel low-dose formulation cannot be increased in order to prevent the emergence of antibiotic-resistant bacteria. Therefore a search has been underway for new drug molecules which act on similar active-sites for matrix metalloproteinases (MMP) inhibition like the tetracyclines, but with a different phenolic superstructure. In this regard, our group recently designed new MMP-inhibitor compounds containing the same zinc-binding site as the tetracyclines, but which are bi- cyclic phenolic compounds rather than teracycles. In the current studies, we demonstrate that systemic administration of a newly developed chemically-modified-curcumin (CMC2.24) in three different rat models of periodontal disease [locally (LPS/endotoxin)-induced as well as systemically (type I diabetes)-induced models of periodontitis; and as a combination of both] significantly inhibited alveolar bone loss, and attenuated the severity of local and systemic inflammation. Moreover, this novel tri-ketonic phenylaminocarbonyl curcumin (CMC2.24) appears to reduce the pathologically-excessive levels of inducible MMPs to near normal levels, but appears to have no significant effect on the constitutive MMPs required for physiologic connective tissue turnover. In addition to the beneficial effects on periodontal disease, induced both locally and systemically, CMC2.24 treatment also favorably affected extra-oral connective tissues, skin and skeletal bone. Regarding molecular mechanisms, p38 MAPK and NF-κB, are both activated during the development of experimental periodontitis. Moreover, systemic treatment with CMC2.24 appeared to markedly inhibit NF-κB and p38 MAPK activation in both locally- and systemically-induced models of periodontitis. The data in this thesis support our hypothesis that CMC2.24 is a pleiotropic MMP-inhibitor, having both intracellular and extracellular effects, which, together, reduce local and systemic inflammation and prevent hyperglycemic- and bacteria-induced tissue destruction. | |
| dcterms.abstract | Periodontitis, the most common chronic inflammatory disease known to mankind, is recognized as the major cause of tooth loss in adults. Although periodontitis is initiated by anaerobic gram-negative bacteria, the destruction of the periodontium is essentially mediated by the host response. Numerous investigators have described various pharmacologic strategies to modulate the host response during periodontal disease, however only a non-antimicrobial tetracycline formulation is FDA-approved for these patients. Of interest, this formulation of sub-antimicrobial-dose doxycycline (SDD) has shown efficacy in clinical trials in other diseases also, e.g, rheumatoid arthritis. However, a significant drawback of the approved SDD is that this novel low-dose formulation cannot be increased in order to prevent the emergence of antibiotic-resistant bacteria. Therefore a search has been underway for new drug molecules which act on similar active-sites for matrix metalloproteinases (MMP) inhibition like the tetracyclines, but with a different phenolic superstructure. In this regard, our group recently designed new MMP-inhibitor compounds containing the same zinc-binding site as the tetracyclines, but which are bi- cyclic phenolic compounds rather than teracycles. In the current studies, we demonstrate that systemic administration of a newly developed chemically-modified-curcumin (CMC2.24) in three different rat models of periodontal disease [locally (LPS/endotoxin)-induced as well as systemically (type I diabetes)-induced models of periodontitis; and as a combination of both] significantly inhibited alveolar bone loss, and attenuated the severity of local and systemic inflammation. Moreover, this novel tri-ketonic phenylaminocarbonyl curcumin (CMC2.24) appears to reduce the pathologically-excessive levels of inducible MMPs to near normal levels, but appears to have no significant effect on the constitutive MMPs required for physiologic connective tissue turnover. In addition to the beneficial effects on periodontal disease, induced both locally and systemically, CMC2.24 treatment also favorably affected extra-oral connective tissues, skin and skeletal bone. Regarding molecular mechanisms, p38 MAPK and NF-κB, are both activated during the development of experimental periodontitis. Moreover, systemic treatment with CMC2.24 appeared to markedly inhibit NF-κB and p38 MAPK activation in both locally- and systemically-induced models of periodontitis. The data in this thesis support our hypothesis that CMC2.24 is a pleiotropic MMP-inhibitor, having both intracellular and extracellular effects, which, together, reduce local and systemic inflammation and prevent hyperglycemic- and bacteria-induced tissue destruction. | |
| dcterms.available | 2017-09-20T16:50:43Z | |
| dcterms.contributor | Simon, Marcia | en_US |
| dcterms.contributor | Golub, Lorne M | en_US |
| dcterms.contributor | Johnson, Francis | en_US |
| dcterms.contributor | Wolff, Mark | en_US |
| dcterms.contributor | Simon, Sanford | en_US |
| dcterms.contributor | Walker, Steven. | en_US |
| dcterms.creator | Elburki, Muna Saad | |
| dcterms.dateAccepted | 2017-09-20T16:50:43Z | |
| dcterms.dateSubmitted | 2017-09-20T16:50:43Z | |
| dcterms.description | Department of Oral Biology and Pathology. | en_US |
| dcterms.extent | 228 pg. | en_US |
| dcterms.format | Monograph | |
| dcterms.format | Application/PDF | en_US |
| dcterms.identifier | http://hdl.handle.net/11401/76591 | |
| dcterms.issued | 2015-05-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:50:43Z (GMT). No. of bitstreams: 1
Elburki_grad.sunysb_0771E_12366.pdf: 2991975 bytes, checksum: a08092418f068d54f99f0725f5f5a453 (MD5)
Previous issue date: 2015 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Dentistry | |
| dcterms.subject | Bone loss, Chemically-modified-curcumin, Diabetes, Matrix metalloproteinases (MMP), MMP-inhibitor, Periodontal disease | |
| dcterms.title | A Novel Chemically Modified Curcumin as a Pleiotropic MMP-Inhibitor: Therapeutic Potential in Locally- and Systemically-Induced Periodontal (and other) Connective Tissue Breakdown | |
| dcterms.type | Dissertation | |
