Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, PR China.
Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, PR China; Department of Inspection and Quarantine, School of Medical Technology, Shanghai University of Medicine & Health Sciences, Shanghai, China.
J Ethnopharmacol. 2022 Aug 10;294:115368. doi: 10.1016/j.jep.2022.115368. Epub 2022 May 16.
ETHNOPHARMACOLOGICAL RELEVANCE: The genus Glycyrrhiza is a small perennial herb that has been traditionally used to treat many diseases across the world. Licorice (Gancao in Chinese) is the dried root and rhizome of G. glabra, G. uralensis or G. inflata. Licorice plays an important role in traditional Chinese medicine (TCM), and is the most frequently used in Chinese herbal formulas. Isoliquiritigenin (ISL) is a flavonoid extracted from licorice, and has been evaluated for its various biological activities, including anti-inflammatory, anti-tumor and anti-oxidant activities. Excessive and persistent inflammation in the Mycobacterium tuberculosis (Mtb) infection is not conducive to the elimination of Mtb, but contributes to serious pulmonary dysfunction. AIM OF THE STUDY: This study aimed to examine the anti-inflammatory effects of ISL in the Mtb infection. METHODS: In vitro models of Mtb-infected macrophages were established. Murine macrophage Raw 264.7 cells and primary peritoneal macrophages were used in this study. Cell viability was determined by the cell counting kit-8 (CCK-8) assay. The effects of ISL on the secretion levels of interleukin -1β (IL-1β), tumor necrosis factor -α (TNF-α), and interleukin -6 (IL-6) were detected by the enzyme-linked immunosorbent assay (ELISA). The expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) were measured by the real time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. Western blot was used to assess the effects of ISL on the activation of NLRP3 inflammasome and Notch1/NF-κB and MAPK signaling pathways. Immunofluorescence assays was used to detected the translocation of phosphorylation of p65 subunit of NF-κB. RESULTS: It was revealed that ISL inhibited the secretion of IL-1β and the activation of pore-forming protein (gasdermin D, GSDMD) by suppressing the activation of NLPR3 inflammasome induced by Mtb infection. ISL was also shown to have promising inhibitory effects on inflammatory factors, such as TNF-α, IL-6, iNOS and COX2. Regarding the anti-inflammatory mechanism of ISL, it was found that ISL exerted its anti-inflammatory effects by inhibiting the activation of Notch1/NF-κB and MAPK signaling pathways. CONCLUSION: ISL reduced Mtb-induced inflammation through the Notch1/NF-κB and MAPK signaling pathways. ISL might be used as a potential adjuvant drug to treat tuberculosis by adjusting host immune responses.
民族药理学相关性：甘草属是一种小型多年生草本植物，在世界各地传统上被用于治疗许多疾病。甘草（中文为“甘草”）是甘草、乌拉尔甘草或胀果甘草的干根和根茎。甘草在中药（TCM）中起着重要作用，是中草药配方中最常用的药物。异甘草素（ISL）是从甘草中提取的一种类黄酮，已对其多种生物活性进行了评估，包括抗炎、抗肿瘤和抗氧化活性。分枝杆菌（Mtb）感染中持续和过度的炎症不利于消除 Mtb，反而会导致严重的肺功能障碍。 研究目的：本研究旨在研究 ISL 在 Mtb 感染中的抗炎作用。 方法：建立了 Mtb 感染的巨噬细胞体外模型。本研究使用了小鼠巨噬细胞 Raw 264.7 细胞和原代腹腔巨噬细胞。通过细胞计数试剂盒-8（CCK-8）测定细胞活力。通过酶联免疫吸附试验（ELISA）检测 ISL 对白细胞介素 -1β（IL-1β）、肿瘤坏死因子 -α（TNF-α）和白细胞介素 -6（IL-6）分泌水平的影响。通过实时定量逆转录聚合酶链反应（RT-qPCR）和 Western blot 测定诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX2）的表达水平。Western blot 用于评估 ISL 对 NLRP3 炎性体和 Notch1/NF-κB 和 MAPK 信号通路激活的影响。免疫荧光法检测 NF-κB p65 亚单位磷酸化的易位。 结果：结果表明，ISL 通过抑制 Mtb 感染诱导的 NLPR3 炎性体的激活，抑制 IL-1β 的分泌和孔形成蛋白（gasdermin D，GSDMD）的激活。ISL 对 TNF-α、IL-6、iNOS 和 COX2 等炎症因子也有很好的抑制作用。关于 ISL 的抗炎机制，研究发现 ISL 通过抑制 Notch1/NF-κB 和 MAPK 信号通路的激活发挥抗炎作用。 结论：ISL 通过 Notch1/NF-κB 和 MAPK 信号通路减轻 Mtb 诱导的炎症。ISL 可能通过调节宿主免疫反应被用作治疗结核病的潜在辅助药物。
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