히스톤 탈아세틸화 효소인 HDAC1과 HSIR2는 p53과 Sp1전사인자에 영향을 미쳐 치은섬유아세포에서 노화억제 조절자로 작용한

학위논문(박사) - 한국과학기술원 : 생물과학과, 2003.8, [ ix, 100 p. ]Recently, histone deacetylases (HDACs) such as HDAC1 and HSIR2 have been known to be involved in regulation of lifespan extension. In this study, we observed that primary human gingival fibroblasts (HGFs) from elderly donors showed features of senescence, including enlarged cell size with a considerable proportion of cells stained positive for senescence-associated beta-galactosidase (SA-beta gal), $G_0/G_1$ cell cycle arrest and gene expression pattern of senescent cell. Furthermore, it was observed that the expression levels of histone deacetylases HSIR2 and HDAC1, direct regulators of the senescence phenotype in the fibroblasts, were significantly reduced; whereas the cell cycle regulators, p53 and p21, the former in its hyperacetylated form, were significantly increased. Premature aging phenotypes were induced by either treatment of histone deacetylase inhibitors, trichostatin A (TSA) and sodium butyrate (SB), or the expression of p53 and p300 in young HGFs derived from a 9 year-old donor. Overexpression of HSIR2 and HDAC1 repressed the premature aging phenotypes induced by p53 and p300, suggesting that histone deacetylases may delay the aging process through deacetylation of p53. It was shown that Sp1 enhanced the transcriptional activation of p53 and both Sp3 and Sp1 enhanced the activation of p21 promoter; while those activations were repressed by HSIR2 and HDAC1. Moreover, coimmunoprecipitation experiments demonstrated that p53, Sp1, HDAC1, and p300 were physically associated and the DNA-binding activities of Sp1 and acetyl-p53 transcription factors were significantly enhanced in aged HGFs. Our findings suggest that histone deacetylases regulate aging in primary human gingival fibroblast, a new model for human aging, by affecting transcriptional activities of p53 and Sp1 transcription factors.한국과학기술원 : 생물과학과

우루소데옥시콜릭산이 치주질환 억제에 미치는 영향

Ursodeoxycholic acid(UDCA) is a hydrophilic gall bladder acid and has been used as a effective drug for liver disease related to in1munity. This drug inhibits secretions of IL-2, IL-4, and from T-cells and production of immunoglobulin from B-cells. Also it has been reported that UDCA inhibits production of IL-1 related to the progression of periodontal disease and activation of collagenases. The purpose of the present study was to elucidate the effects of UDCA on inhibition of periodontal disease progression using clinical, microbiological and histometrical parameters. Twelve pure bred, 16 month-old-beagle dogs were used in the study. After ligature-induced periodontal diseases were formed, experimental drugs were applied twice a day and then the results of clinical, microbiological, and histometrical parameters were measured at baselie(initiation of experiment) , 4weeks and 8weeks. The gel with UDCA(concentration 0.5%, 5% 3 dogs in each) was applied to experimental group, chlorhexidine to positive control group(3dogs) and the gel without UDCA(base) to negative control group. After induction of general anesthesia, the maxillary 2nd, 3rd premolars and 1st molar and the mandibular 2nd, 3rd, 4th premolars and 1st molar were ligated in one side selected randomly and were not ligated in the opposite side. The plaque index(PI), gingival index(GI), pocket depth(PD) and gingival crevicular fluid(GCF) volum were measured clinically. The PI and GI were measured at 3 buccal points of all experimental teeth and the GCF was measured only at the 3rd premolar in the maxilla and the 4th premolar in the mandible. In the microbiological study, the samples extracted from the 3rd premolar of the maxilla and the 4th premolar of the mandible at the center of buccal surface were analyzed aerobics, anaerobics and Streptococcus colony forming units, After clinical and microbiological examination at 8weeks, the dogs were sacrificed by carotid artery perfusion. The samples were fixed and sectioned including interproximal area, and the distance from cementoenamel junction(CEJ) to alveolar crest was measured. The results were that PI, GI and PD increased until 4 weeks and decreased at 8 weeks in three groups but the differences between all the groups were not significant. The 0.5% UDCA in non-ligated group showed remarkable decrease of GCF. The experimental group applied 5% UDCA decreased the number of aerobics and anaerobics. The distance from CEJ to alveolar crest was greater in the negative control group on both ligated and non-ligated sides, but the differences were not significant stastically