1,4-Naphthoquinone Is a Potent Inhibitor of IRAK1 Kinases and the Production of Inflammatory Cytokines in THP-1 Differentiated Macrophages

Abstract

Quinones are a class of cyclic organic compounds that are widely distributed in nature and have been shown to exhibit anti-inflammatory, antioxidant, and anticancerous activities. However, the molecular mechanisms/signaling by which these molecules exert their effect are still not fully understood. In this study, a group of quinone-derived compounds were examined for their potential inhibitory effect against human IRAK1 and IRAK4 kinases in vitro. We have identified five compounds: 1,4-naphthoquinone, emodin, shikonin, plumbagin, and menadione (vitamin K3) as active and selective inhibitors of human IRAK1 enzyme in vitro. The biochemical binding and molecular interactions between the active compounds and IRAK1’s catalytic site were demonstrated in silico using structural-based docking and dynamic simulation analysis. Also, 1,4-naphthoquinone was found to effectively inhibit the growth of cancer cell lines overexpressing IRAK1. Furthermore, 1,4-naphthoquinone potently suppressed the production and secretion of key proinflammatory cytokine proteins IL-8, IL-1β, IL-10, TNF-α, and IL-6 in LPS-stimulated PMA-induced human THP-1 macrophages. In conclusion, 1,4-naphthoquinone is an effective inhibitor of IRAK1 kinases and their mediated inflammatory cytokines production in LPS-stimulated PMA-induced human THP-1 macrophages.

Sustainable Synthesis, Antiproliferative and Acetylcholinesterase Inhibition of 1,4- and 1,2-Naphthoquinone Derivatives

“…In particular, the results showed that both 2-aryl-1,4-NQs and 4-aryl-1,2-NQs are expected to be biologically active as kinase inhibitors (see Table S5 ). In fact, the 1,4-NQ skeleton and other quinone-derived compounds had already been reported as active against kinases, by biochemical binding and molecular interaction with the kinases catalytic sites [ 39 ]. Kinase inhibitors are a large group of antineoplastic agents targeting protein kinases, which are altered in cancer cells leading to abnormal growth; hence, kinase inhibitors are considered a promising approach for anticancer drug development [ 40 ].…”

The role of non-coding RNAs in myocarditis: a narrative review

“…The lncRNA AK085865 binds to IL enhancer-binding factor 2 (ILF2), thereby regulating the ILF2/ILF3 complex and subsequently, miR-192/IL-1 receptor-associated kinase 1 (IRAK1) function ( 78 , 79 ). IRAK1 is the main mediator of toll-like receptor 4 (TLR4) activation and binds to TRAF6, ultimately leading to the induction of NF-κB, which is essential for lipopolysaccharide-mediated inflammatory response in macrophages ( 80 - 82 ). Xue et al found that silencing of the lncRNA MEG3 inhibited M1 polarization and promoted M2 polarization in macrophages, alleviating myocarditis.…”

1,4-Naphthoquinone Induces FcRn Protein Expression and Albumin Recycling in Human THP-1 Cells

“…However, it can be surmised by the ability of 1,4-naphthoquinone to modulate the IRAK1-mediated signaling pathway. Indeed, it has been recently shown that 1,4-naphthoquinone effectively inhibits IRAK1 enzymes in vitro and potently suppresses the production and secretion of key proinflammatory cytokine proteins in THP-1 cells . Several downstream signaling cascades such as NF-κB, JNK, and MAPKs can be activated by the IRAK1-mediated pathway. , Therefore, it would be interesting to define whether these pathways are involved in the 1,4-naphthoquinone-mediated FcRn induction mechanism in the future.…”

“…1,4-Naphthoquinone is a quinone-derived compound that has been shown to exhibit anti-inflammatory activity both in vitro and in vivo . , We have recently reported the ability of 1,4-naphthoquinone to target the IRAK1 enzyme, a master regulator of the IL1R/TLR immune signaling pathway in cells . Notably, IL1R/TLR regulates key downstream signaling proteins including NF-κB .…”