PMID- 33100904 OWN - NLM STAT- MEDLINE DCOM- 20211004 LR - 20211004 IS - 1466-1861 (Electronic) IS - 0962-9351 (Print) IS - 0962-9351 (Linking) VI - 2020 DP - 2020 TI - Guttiferone K Exerts the Anti-inflammatory Effect on Mycobacterium Tuberculosis- (H37Ra-) Infected Macrophages by Targeting the TLR/IRAK-1 Mediated Akt and NF-kappaB Pathway. PG - 8528901 LID - 10.1155/2020/8528901 [doi] LID - 8528901 AB - 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-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), 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-kappaB) 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-kappaB 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. CI - Copyright (c) 2020 Qingwen Zhang et al. FAU - Zhang, Qingwen AU - Zhang Q AD - Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. AD - Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine & Health Sciences, 201318 Shanghai, China. FAU - Sun, Jinxia AU - Sun J AD - Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. FAU - Fu, Yan AU - Fu Y AD - Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. FAU - He, Weigang AU - He W AD - Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. FAU - Li, Yinhong AU - Li Y AD - Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. FAU - Tan, Hongsheng AU - Tan H AD - Clinical Research Center, Shanghai Jiao Tong University School of Medicine, 200240 Shanghai, China. FAU - Xu, Hongxi AU - Xu H AUID- ORCID: 0000-0001-6238-4511 AD - Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. AD - School of Pharmacy, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. FAU - Jiang, Xin AU - Jiang X AUID- ORCID: 0000-0001-7007-0483 AD - Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 201203 Shanghai, China. LA - eng PT - Journal Article DEP - 20201010 PL - United States TA - Mediators Inflamm JT - Mediators of inflammation JID - 9209001 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Benzophenones) RN - 0 (NF-kappa B) RN - 0 (guttiferone K) RN - EC 2.7.11.1 (Interleukin-1 Receptor-Associated Kinases) RN - EC 2.7.11.1 (Irak1 protein, mouse) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*therapeutic use MH - Benzophenones/*therapeutic use MH - Blotting, Western MH - Cell Survival/drug effects MH - Female MH - Immunoprecipitation MH - Interleukin-1 Receptor-Associated Kinases/*metabolism MH - Macrophages/*drug effects/*metabolism MH - Mice MH - Mycobacterium tuberculosis/*drug effects/*pathogenicity MH - NF-kappa B/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - RAW 264.7 Cells PMC - PMC7569438 COIS- The authors declare no conflict of interest. EDAT- 2020/10/27 06:00 MHDA- 2021/10/05 06:00 PMCR- 2020/10/10 CRDT- 2020/10/26 05:20 PHST- 2020/06/05 00:00 [received] PHST- 2020/08/26 00:00 [revised] PHST- 2020/09/16 00:00 [accepted] PHST- 2020/10/26 05:20 [entrez] PHST- 2020/10/27 06:00 [pubmed] PHST- 2021/10/05 06:00 [medline] PHST- 2020/10/10 00:00 [pmc-release] AID - 10.1155/2020/8528901 [doi] PST - epublish SO - Mediators Inflamm. 2020 Oct 10;2020:8528901. doi: 10.1155/2020/8528901. eCollection 2020.