Mycobacterium tuberculosis (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 in vitro infection model of Mtb macrophages with H37Ra strain to seek effective anti-TB active agent. The present study showed that Guttiferone K, isolated from Garcinia yunnanensis, 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-1β (IL-1β), tumor necrosis factor-α (TNF-α), 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-κB) 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-κB 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.

中文翻译：

---

Guttiferone K 通过靶向 TLR/IRAK-1 介导的 Akt 和 NF-κB 通路对结核分枝杆菌 (H37Ra-) 感染的巨噬细胞发挥抗炎作用

结核分枝杆菌(Mtb) 仍然是对全球健康的巨大威胁，它杀死的人比任何其他单一传染源都多，并在宿主中引起无法控制的炎症。控制不佳的炎症过程可能是有害的，并导致免疫衰竭。当前的结核病 (TB) 控制面临着药物短缺的挑战，尤其是在耐多药 (MDR) 结核病日益增多的背景下。在这种情况下，替代宿主导向疗法（HDT）应运而生，可用于通过靶向宿主来提高结核病治疗效果和疾病预后。在这里，我们用 H37Ra 菌株建立了 Mtb 巨噬细胞的体外感染模型，以寻求有效的抗结核活性剂。本研究表明 Guttiferone K，从Garcinia yunnanensis可显着抑制 RAW264.7 和原发性腹膜巨噬细胞中 Mtb 诱导的炎症。它被证明的炎症介质的产生减少，包括白细胞介素1 β（IL-1 β），肿瘤坏死因子α（TNF- α），白介素-6（IL-6），诱导型一氧化氮合酶（iNOS）和环氧合酶-2 (COX-2)。进一步的免疫印迹和免疫荧光研究表明，Guttiferone K 明显抑制核因子-κB（NF- κB) RAW264.7 和依赖 TLR/IRAK-1 通路的原发性腹膜巨噬细胞。Guttiferone 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标 (mTOR) 在两种细胞系中的 Ser473 和 Ser2448 磷酸化来抑制 NLRP3 炎性体活性并诱导自噬。因此，Guttiferoneķ具有显著抗炎作用，减轻的Mtb诱导的炎症与底层机制靶向于TLR / IRAK-1途径和抑制NF-下游κ B和AKT / mTOR信号通路。总之，Guttiferone K 可以成为设计新的抗结核辅助 HDT 药物的抗炎剂候选物。