Gutiérrez-Venegas Gloria, Kawasaki-Cárdenas Perla, Arroyo-Cruz Santa Rita, Maldonado-Frías Silvia
Laboratorio de Bioquímica de la División de Estudios de Posgrado de la Facultad de Odontología, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, D.F., México.
Eur J Pharmacol. 2006 Jul 10;541(1-2):95-105. doi: 10.1016/j.ejphar.2006.03.069. Epub 2006 Apr 5.
Periodontal disease comprises a group of infections that lead to inflammation of the gingiva, periodontal tissue destruction, and in severe cases is accompanied by alveolar bone loss with tooth exfoliation. Actinobacillus actinomycetemcomitans is a Gram-negative microorganism, which possesses and produces lipopolysaccharide (LPS) molecules that play a key role in disease development. Human gingival fibroblasts are the major constituents of gingival connective tissue and may interact directly with bacteria and bacterial products including LPS. Flavonoids possess antioxidant and anti-inflammatory properties that reduce inflammatory molecule expression in macrophages and monocytes. In this study, we evaluated the ability of diverse flavonoids to regulate nitric oxide production of LPS-stimulated human gingival fibroblasts, and studied the effect of luteolin on diminish phosphorylation in mitogen-activated protein kinase (MAPK) family members as well as in protein kinase B (Akt), nuclear factor kappa B (NF-kappaB) activation, inducible nitric oxide synthase (NOS) expression, and nitric oxide (NO) synthesis. We also found that pretreatment with three flavonoids, including quercetin, genistein, and luteolin, blocked nitric oxide synthesis in a dose-dependent fashion. Luteolin exerted the strongest blocking action on expression of this inflammatory mediator. Luteolin pretreatment attenuated LPS-induced extracellular signal-regulated kinase, p38, and Akt phosphorylation. LPS treatment of human gingival fibroblasts resulted in NF-kappaB translocation. Cell pretreatment with luteolin abolished LPS effects on NF-kappaB translocation. In addition, luteolin treatment blocked LPS-induced cellular proliferation inhibition without affecting genetic material integrity. We concluded that luteolin interferes with LPS signaling pathways, reducing activation of several mitogen-activated protein kinase family members, and inhibits inflammatory mediator expression.
牙周病是一组感染性疾病，可导致牙龈炎症、牙周组织破坏，严重时伴有牙槽骨丧失和牙齿脱落。伴放线放线杆菌是一种革兰氏阴性微生物，它拥有并产生脂多糖（LPS）分子，这些分子在疾病发展中起关键作用。人牙龈成纤维细胞是牙龈结缔组织的主要成分，可能直接与细菌及包括LPS在内的细菌产物相互作用。黄酮类化合物具有抗氧化和抗炎特性，可减少巨噬细胞和单核细胞中炎症分子的表达。在本研究中，我们评估了多种黄酮类化合物调节LPS刺激的人牙龈成纤维细胞产生一氧化氮的能力，并研究了木犀草素对丝裂原活化蛋白激酶（MAPK）家族成员以及蛋白激酶B（Akt）磷酸化的影响，还研究了其对核因子κB（NF-κB）激活、诱导型一氧化氮合酶（NOS）表达和一氧化氮（NO）合成的影响。我们还发现，用槲皮素、染料木黄酮和木犀草素这三种黄酮类化合物预处理，可剂量依赖性地阻断一氧化氮的合成。木犀草素对这种炎症介质的表达具有最强的阻断作用。木犀草素预处理可减弱LPS诱导的细胞外信号调节激酶、p38和Akt的磷酸化。用LPS处理人牙龈成纤维细胞会导致NF-κB易位。用木犀草素对细胞进行预处理可消除LPS对NF-κB易位的影响。此外，木犀草素处理可阻断LPS诱导的细胞增殖抑制，而不影响遗传物质的完整性。我们得出结论，木犀草素干扰LPS信号通路，减少几种丝裂原活化蛋白激酶家族成员的激活，并抑制炎症介质的表达。
