Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Int J Rheum Dis. 2020 Jan;23(1):74-83. doi: 10.1111/1756-185X.13743. Epub 2019 Nov 25.
α-mangostin, a polyphenolic xanthone derivative of mangosteen, has been reported to possess multiple therapeutic properties, such as anti-cancer, anti-allergy and anti-inflammatory activity. However, its anti-inflammatory effects in autoimmune diseases such as lupus nephritis (LN) remain unclear. In this study, we want to investigate the therapeutic effect of α-mangostin in LN.
First, we elucidated the retinoic acid receptor related orphan receptor gamma t (RORγt) inhibitory activity of α-mangostin in cell-based assay and T helper 17 (Th17) differentiation in vitro assay. Then, we established a pristane-induced LN mouse model and randomly divided these into a normal control group, model control group, α-mangostin group and prednisone acetate group. Finally, anti-double-stranded DNA (anti-dsDNA) level in serum was detected by enzyme-linked immunosorbent assay, interleukin (IL)-17A and interferon (IFN)-γ expression in spleen cells by flow cytometry; histomorphology examination of kidneys was performed by periodic acid-Schiff staining and immunofluorescence analysis with an anti-immunoglobulin G (anti-IgG) and anti-IgM antibodies.
We found that α-mangostin inhibited RORγt transcription activity in a cell-based assay and also polarized Th17 cells in an in vitro induction experiment. Our results also showed that α-mangostin could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in the α-mangostin-treated group mice than in the model group mice.
Thus, α-mangostin demonstrated its potential as a candidate therapeutic drug for LN and other Th17-mediated autoimmune diseases by inhibiting the function of Th17.
α-倒捻子素是山竹果中的一种多酚类二氢黄酮衍生物，具有多种治疗特性，如抗癌、抗过敏和抗炎活性。然而，其在狼疮肾炎（LN）等自身免疫性疾病中的抗炎作用尚不清楚。在这项研究中，我们旨在研究 α-倒捻子素在 LN 中的治疗作用。
首先，我们在基于细胞的测定和体外 Th17 分化测定中阐明了 α-倒捻子素对维甲酸受体相关孤儿受体γ t（RORγt）的抑制活性。然后，我们建立了一个角鲨烷诱导的 LN 小鼠模型，并将其随机分为正常对照组、模型对照组、α-倒捻子素组和醋酸泼尼松龙组。最后，通过酶联免疫吸附试验检测血清中抗双链 DNA（抗-dsDNA）水平，通过流式细胞术检测脾细胞中白细胞介素（IL）-17A 和干扰素（IFN）-γ 的表达；通过过碘酸-希夫染色和抗免疫球蛋白 G（抗-IgG）和抗免疫球蛋白 M（抗-IgM）抗体的免疫荧光分析对肾脏进行组织形态学检查。
我们发现，α-倒捻子素在基于细胞的测定中抑制了 RORγt 的转录活性，并且在体外诱导实验中也极化了 Th17 细胞。我们的结果还表明，与模型组小鼠相比，α-倒捻子素治疗组小鼠的血清抗-dsDNA 抗体水平、IL-17A 和 IFN-γ 表达以及肾脏病理损伤明显降低。
因此，α-倒捻子素通过抑制 Th17 的功能，显示出作为 LN 和其他 Th17 介导的自身免疫性疾病候选治疗药物的潜力。
