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麦角甾-7,9(11),22-三烯-3β-醇通过抑制丝裂原活化蛋白激酶/活化蛋白-1诱导的白细胞介素-6/ Janus激酶/信号转导和转录激活因子途径以及激活脂多糖刺激的巨噬细胞样细胞中的核因子E2相关因子2/血红素加氧酶-1信号来减轻炎症反应。

Ergosta-7,9(11),22-trien-3β-ol Attenuates Inflammatory Responses via Inhibiting MAPK/AP-1 Induced IL-6/JAK/STAT Pathways and Activating Nrf2/HO-1 Signaling in LPS-Stimulated Macrophage-like Cells.

作者信息

Huang Yi-Ping, Chen Dar-Ren, Lin Wen-Jen, Lin Yu-Hsien, Chen Jiann-Yeu, Kuo Yueh-Hsiung, Chung Jing-Gung, Hsia Te-Chun, Hsieh Wen-Tsong

机构信息

Department of Physiology, China Medical University, Taichung 404333, Taiwan.

Comprehensive Breast Cancer Center, Changhua Christian Hospital, Changhua 50006, Taiwan.

出版信息

Antioxidants (Basel). 2021 Sep 8;10(9):1430. doi: 10.3390/antiox10091430.

DOI:10.3390/antiox10091430
PMID:34573062
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8464970/
Abstract

Chronic inflammation induces autoimmune disorders and chronic diseases. Several natural products activate nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, attenuating inflammatory responses. Ergosta-7,9(11),22-trien-3β-ol (EK100) isolated from showed anti-inflammatory and antioxidative activity, but those mechanisms are still unclear. This study is the first to investigate EK100 on antioxidant Nrf2 relative genes expression in LPS-stimulated macrophage-like cell lines. The results showed that EK100 reduced IL-6 (interleukin-6) and tumor necrosis factor-α production. EK100 also attenuated a mitogen-activated protein kinase/activator protein-1 (MAPK/AP-1) pathway and interleukin-6/Janus kinase/signal transducer and activator of transcription (IL-6/JAK/STAT) pathway in LPS-stimulated cells. Toll-like receptor 4 (TLR4) inhibitor CLI-095 and MAPK inhibitors can synergize the anti-inflammatory response of EK100 in LPS-stimulated cells. Moreover, EK100 activated Nrf2/HO-1 (heme oxygenase-1) signaling in LPS-stimulated murine macrophage-like RAW 264.7 cells, murine microglial BV2 cells, and human monocytic leukemia THP-1 cells. However, Nrf2 small interfering RNA (Nrf2 siRNA) reversed EK100-induced antioxidative proteins expressions. In conclusion, EK100 showed anti-inflammatory responses activating the antioxidative Nrf2/HO-1 signaling and inhibiting TLR4 related MAPK/AP-1 induced IL-6/JAK/STAT pathways in the LPS-stimulated cells . The results suggest EK100 acts as a novel antioxidant with multiple therapeutic targets that can potentially be developed to treat chronic inflammation-related diseases.

摘要

慢性炎症会诱发自身免疫性疾病和慢性疾病。几种天然产物可激活核因子红细胞2相关因子2（Nrf2）信号通路，减轻炎症反应。从[具体来源未给出]中分离出的麦角甾-7,9(11),22-三烯-3β-醇（EK100）具有抗炎和抗氧化活性，但其作用机制尚不清楚。本研究首次探讨EK100对脂多糖（LPS）刺激的巨噬细胞样细胞系中抗氧化Nrf2相关基因表达的影响。结果表明，EK100可降低白细胞介素-6（IL-6）和肿瘤坏死因子-α的产生。EK100还可减弱LPS刺激细胞中的丝裂原活化蛋白激酶/活化蛋白-1（MAPK/AP-1）信号通路和白细胞介素-6/Janus激酶/信号转导及转录激活因子（IL-6/JAK/STAT）信号通路。Toll样受体4（TLR4）抑制剂CLI-095和MAPK抑制剂可增强EK100在LPS刺激细胞中的抗炎反应。此外，EK100可激活LPS刺激的小鼠巨噬细胞样RAW 264.7细胞、小鼠小胶质细胞BV2细胞和人单核细胞白血病THP-1细胞中的Nrf2/血红素加氧酶-1（HO-1）信号通路。然而，Nrf2小干扰RNA（Nrf2 siRNA）可逆转EK100诱导的抗氧化蛋白表达。总之，EK100通过激活抗氧化Nrf2/HO-1信号通路并抑制LPS刺激细胞中TLR4相关的MAPK/AP-1诱导的IL-6/JAK/STAT信号通路而表现出抗炎反应。结果表明，EK100作为一种具有多个治疗靶点的新型抗氧化剂，有望被开发用于治疗慢性炎症相关疾病。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/4cdae168dbca/antioxidants-10-01430-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/9f139630d703/antioxidants-10-01430-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/4500a4733b66/antioxidants-10-01430-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/dff7f851c08a/antioxidants-10-01430-g003a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/de2fbb82b819/antioxidants-10-01430-g004a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/292758e0ec31/antioxidants-10-01430-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/380ba729b486/antioxidants-10-01430-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/4cdae168dbca/antioxidants-10-01430-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/9f139630d703/antioxidants-10-01430-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/4500a4733b66/antioxidants-10-01430-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/dff7f851c08a/antioxidants-10-01430-g003a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/de2fbb82b819/antioxidants-10-01430-g004a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/292758e0ec31/antioxidants-10-01430-g005a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/380ba729b486/antioxidants-10-01430-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13a0/8464970/4cdae168dbca/antioxidants-10-01430-g007.jpg

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