Department of Pharmacology, Pusan National University, School of Medicine, Yangsan, Gyeongnam 50612, Republic of Korea.
Department of Biosystems and Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
Int J Mol Med. 2019 May;43(5):2177-2186. doi: 10.3892/ijmm.2019.4135. Epub 2019 Mar 18.
The epidemiological, animal and cell effects of plant metabolites suggest versatile health benefits of flavonoids. However, whether flavonoids affect the deleterious biological activity of oxygenated cholesterol molecules remains to be elucidated. The present study investigated the effects of 4'‑O‑methylalpinumisoflavone (mAI) isolated from Maclura tricuspidata (Cudrania tricuspidata) on the 27‑hydroxycholesterol (27OHChol)‑induced activation of monocytes/macrophages using human THP‑1 cells. mAI dose‑dependently impaired the expression of C‑C motif chemokine ligand (CCL)2 chemokine and the migration of monocytic cells enhanced by 27OHChol. mAI downregulated the surface and cellular levels of CD14 and inhibited the release of soluble CD14. This isoflavone significantly weakened the lipopolysaccharide responses that were enhanced in the presence of 27OHChol, and inhibited the transcription and secretion of the active gene product of matrix metalloproteinase‑9. mAI also suppressed the expression of C‑C motif chemokine receptor 5 ligands, including CL3 and CCL4, and M1‑phenotype markers induced by 27OHChol. Furthermore, mAI impaired phosphorylation of the nuclear factor‑κB p65 subunit without affecting the phosphorylation of Akt. These results indicate that mAI inhibits the activation of monocytes/macrophages to the immunostimulatory phenotype in a milieu rich in 27OHChol, suggesting potential benefits of the flavonoid for the treatment of diseases in which the pathogenesis is linked to 27OHChol‑induced inflammatory responses.
植物代谢产物的流行病学、动物学和细胞学效应表明类黄酮具有多种健康益处。然而，类黄酮是否会影响氧化胆固醇分子的有害生物学活性仍有待阐明。本研究使用人 THP-1 细胞研究了从枳（Cudrania tricuspidata）中分离出的 4'-O-甲基阿尔平异黄酮（mAI）对 27-羟胆固醇（27OHChol）诱导的单核细胞/巨噬细胞活化的影响。mAI 呈剂量依赖性地抑制了 27OHChol 增强的 C-C 基序趋化因子配体（CCL）2 趋化因子的表达和单核细胞的迁移。mAI 下调了 CD14 的表面和细胞水平，并抑制了可溶性 CD14 的释放。这种异黄酮显著减弱了在存在 27OHChol 时增强的脂多糖反应，并抑制了基质金属蛋白酶-9 的活性基因产物的转录和分泌。mAI 还抑制了由 27OHChol 诱导的 C-C 基序趋化因子受体 5 配体，包括 CL3 和 CCL4，以及 M1 表型标志物的表达。此外，mAI 抑制了核因子-κB p65 亚基的磷酸化，而不影响 Akt 的磷酸化。这些结果表明，mAI 抑制富含 27OHChol 的环境中单核细胞/巨噬细胞向免疫刺激表型的活化，提示该类黄酮在与 27OHChol 诱导的炎症反应相关的疾病的治疗中具有潜在益处。
