Bio‑IT Fusion Technology Research Institute, Pusan National University, Busan, South Gyeongsang 46241, Republic of Korea.
Department of Horticultural Bioscience, Pusan National University, Miryang, South Gyeongsang 50463, Republic of Korea.
Int J Mol Med. 2018 Mar;41(3):1683-1692. doi: 10.3892/ijmm.2017.3350. Epub 2017 Dec 28.
Abnormal neuroinflammatory responses have diverse roles in neuronal death, oxidative stress and neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Microglia regulate these responses via molecular signaling cascades that involve inflammatory cytokines and complement proteins. Bakkenolide B from Petasites japonicus exhibits significant anti‑inflammatory and anti‑allergic bioactivities. The present study investigated the anti‑neuroinflammatory effects and underlying molecular mechanisms of bakkenolide B on the lipopolysaccharide (LPS)‑mediated neuroinflammatory response in microglia. The results indicated that bakkenolide B pretreatment significantly reduced microglial production of interleukin (IL)‑1β, IL‑6, IL‑12, and tumor necrosis factor (TNF)‑α. Furthermore, this effect was associated with reduced production of reactive oxygen species. The role of bakkenolide B was then evaluated in the upregulation of nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathways. The results suggested that bakkenolide B significantly upregulated Nrf2/ARE pathway‑related downstream factors, such as NADPH dehydrogenase quinone‑1 (NQO‑1) and heme oxygenase‑1 (HO‑1). Silencing of Nrf2, HO‑1 and NQO‑1 diminished the anti‑neuroinflammatory properties of bakkenolide B. AMP‑activated protein kinase (AMPK) activates the Nrf2/ARE signaling pathway, and the results of the present study demonstrated that bakkenolide B increased AMPK phosphorylation in microglia. In addition, an AMPK inhibitor abolished the bakkenolide B‑induced increase in nuclear Nrf2, NQO‑1 and HO‑1 protein expression. Finally, an AMPK inhibitor diminished the bakkenolide B‑mediated inhibition of LPS‑stimulated TNF‑α production. Taken together, the present results demonstrate that bakkenolide B may be an effective and therapeutically relevant AMPK/Nrf2 pathway activator for suppressing abnormal neuro-inflammation in neurodegenerative diseases.
异常的神经炎症反应在神经元死亡、氧化应激和神经退行性疾病（如阿尔茨海默病和帕金森病）中具有多种作用。小胶质细胞通过涉及炎症细胞因子和补体蛋白的分子信号级联来调节这些反应。来自白头翁的白头翁内酯 B 具有显著的抗炎和抗过敏生物活性。本研究探讨了白头翁内酯 B 对脂多糖（LPS）介导的小胶质细胞神经炎症反应的抗炎作用及其潜在的分子机制。结果表明，白头翁内酯 B 预处理可显著减少小胶质细胞产生白细胞介素（IL）-1β、IL-6、IL-12 和肿瘤坏死因子（TNF）-α。此外，这种作用与活性氧的产生减少有关。然后评估了白头翁内酯 B 在核因子红细胞 2 相关因子 2（Nrf2）/抗氧化反应元件（ARE）信号通路上调中的作用。结果表明，白头翁内酯 B 显著上调 Nrf2/ARE 通路相关下游因子，如 NADPH 脱氢酶醌 1（NQO-1）和血红素加氧酶-1（HO-1）。Nrf2、HO-1 和 NQO-1 的沉默减弱了白头翁内酯 B 的抗炎作用。AMP 激活的蛋白激酶（AMPK）激活 Nrf2/ARE 信号通路，本研究结果表明，白头翁内酯 B 增加了小胶质细胞中 AMPK 的磷酸化。此外，AMPK 抑制剂消除了白头翁内酯 B 诱导的核 Nrf2、NQO-1 和 HO-1 蛋白表达增加。最后，AMPK 抑制剂减弱了白头翁内酯 B 介导的 LPS 刺激的 TNF-α 产生的抑制作用。综上所述，本研究结果表明，白头翁内酯 B 可能是一种有效的、具有治疗相关性的 AMPK/Nrf2 通路激活剂，可用于抑制神经退行性疾病中的异常神经炎症。
