Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China.
Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, 201318 Shanghai, China.
Mediators Inflamm. 2020 Oct 10;2020:8528901. doi: 10.1155/2020/8528901. eCollection 2020.
(Mtb) remains a great threat to global health, killing more people than any other single infectious agent and causing uncontrollable inflammation in the host. Poorly controlled inflammatory processes can be deleterious and result in immune exhaustion. The current tuberculosis (TB) control is facing the challenge of drugs deficiency, especially in the context of increasingly multidrug resistant (MDR) TB. Under this circumstance, alternative host-directed therapy (HDT) emerges timely which can be exploited to improve the efficacy of TB treatment and disease prognosis by targeting the host. Here, we established the infection model of Mtb macrophages with H37Ra strain to seek effective anti-TB active agent. The present study showed that Guttiferone K, isolated from , could significantly inhibit Mtb-induced inflammation in RAW264.7 and primary peritoneal macrophages. It was evidenced by the decreased production of inflammatory mediators, including interleukin-1 (IL-1), tumor necrosis factor- (TNF-), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Further studies with immunoblotting and immunofluorescence revealed that Guttiferone K obviously inhibits the nuclear factor-kappa B (NF-B) both in RAW264.7 and primary peritoneal macrophages relying on the TLR/IRAK-1 pathway. Guttiferone K could also suppress the NLRP3 inflammasome activity and induce autophagy by inhibiting the protein kinase B (p-Akt) and mammalian target of rapamycin (mTOR) phosphorylation at Ser473 and Ser2448 in both cell lines. Thus, Guttiferone K possesses significant anti-inflammatory effect, alleviating Mtb-induced inflammation with an underlying mechanism that targeting on the TLR/IRAK-1 pathway and inhibiting the downstream NF-B and Akt/mTOR signaling pathways. Together, Guttiferone K can be an anti-inflammatory agent candidate for the design of new adjunct HDT drugs fighting against tuberculosis.
（结核分枝杆菌）仍然对全球健康构成巨大威胁，其致死人数超过任何其他单一感染因子，并在宿主中引发无法控制的炎症。控制不良的炎症过程可能是有害的，并导致免疫衰竭。目前的结核病（TB）控制面临着药物缺乏的挑战，尤其是在日益增多的耐多药（MDR）TB 背景下。在这种情况下，及时出现了替代宿主导向治疗（HDT），可以通过针对宿主来提高 TB 治疗效果和疾病预后。在这里，我们建立了用 H37Ra 株感染的 Mtb 巨噬细胞模型，以寻找有效的抗 TB 活性药物。本研究表明，从 中分离得到的吉非替尼 K 可以显著抑制 RAW264.7 和原代腹腔巨噬细胞中由 Mtb 诱导的炎症。这表现在炎症介质（包括白细胞介素-1（IL-1）、肿瘤坏死因子-（TNF-）、白细胞介素-6（IL-6）、诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2））的产生减少。进一步的免疫印迹和免疫荧光研究表明，吉非替尼 K 明显抑制 RAW264.7 和原代腹腔巨噬细胞中的核因子-κB（NF-B），这依赖于 TLR/IRAK-1 途径。吉非替尼 K 还可以通过抑制蛋白激酶 B（p-Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）在 Ser473 和 Ser2448 的磷酸化来抑制 NLRP3 炎性体活性并诱导自噬在这两种细胞系中。因此，吉非替尼 K 具有显著的抗炎作用，通过靶向 TLR/IRAK-1 途径并抑制下游 NF-B 和 Akt/mTOR 信号通路来减轻 Mtb 诱导的炎症。总之，吉非替尼 K 可以作为一种抗炎剂候选物，用于设计新的辅助 HDT 药物来对抗结核病。
