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首页> 外文期刊>The FASEB Journal >Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo
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Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo

机译：氨基噻唑抑制微粒体前列腺素E合酶-1可降低体外前列腺素E2的合成，并改善体内实验性牙周炎

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The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1β and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1β-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 μM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis.—Kats, A., B?ge, T., Georgsson, P., J?nsson, J., Quezada, H. C., Gustafsson, A., Jansson, L., Lindberg, C., N?sstr?m, K., Yucel-Lindberg, T. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo.
机译：有效的炎症介质前列腺素E2（PGE2）与几种慢性炎症（包括牙周炎）的发病机理有关。诱导酶微粒体前列腺素E合酶1（mPGES-1），催化PGE2生物合成的最终步骤，是选择性PGE2抑制的有吸引力的目标。为了鉴定mPGES-1抑制剂，我们使用细胞因子IL-1β刺激的人牙龈成纤维细胞和无细胞mPGES-1活性测定方法，研究了氨基噻唑类药物在体外对炎症诱导的PGE2合成的影响，以及对炎症-使用结扎诱导的实验性牙周炎在Sprague-Dawley大鼠中诱导体内骨吸收。氨基噻唑4-（[4-（2-萘基）-1,3-噻唑-2-基]氨基）苯酚（TH-848）和4-（3-氟-4-甲氧基苯基）-N-（4-苯氧基苯基） ）-1,3-噻唑-2-胺（TH-644）减少了成纤维细胞中IL-1β诱导的PGE2生成（分别为IC50 1.1和1.5μM）以及重组mPGES-1活性，而不会影响其活性或上游酶环氧合酶-2。在结扎诱发的实验性牙周炎中，与载体相比，通过X射线成像评估的局部肺泡骨损失通过TH-848局部治疗可减少46％，而对PGE2、6-酮PGF1α，LTB4或细胞因子无全身性影响水平。总之，这些结果表明，氨基噻唑类代表了新型mPGES-1抑制剂，可抑制实验性牙周炎中PGE2的产生并减少骨吸收，并可作为潜在的抗炎药治疗包括牙周炎在内的慢性炎症性疾病。 Kats，A.，B？ge，T.，Georgsson，P.，J？nsson，J.，Quezada，HC，Gustafsson，A.，Jansson，L.，Lindberg，C.，N？sstr？m，K ，Yusel-Lindberg，T。氨基噻唑抑制微粒体前列腺素E合酶-1降低了体外前列腺素E2的合成，并改善了体内实验性牙周炎。

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