Abstract
In this study, we investigated the anti-inflammatory effects of Licania macrocarpa Cuatrec methanol extract (Lm-ME) in vitro and in vivo and found pharmacological target proteins of Lm-ME in TLR4-mediated inflammatory signaling. This extract reduced NO production and mRNA expression of inflammatory cytokines such as iNOS, COX-2, IL-6, and IL-1β. In the NF-κB- and AP-1-mediated luciferase reporter gene assay, transcription factor activities decreased under cotransfection with MyD88 or TRIF. Phosphorylated protein levels of Src, PI3K, IKKα/β, and IκBα as well as p50 and p65 in the NF-κB signal pathway were downregulated, and phosphorylation of TAK1, MEK1/2, MKK4/7, and MKK3/6 as well as ERK, JNK, and p38 was decreased in the AP-1 signal pathway. Through overexpression of HA-Src and HA-TAK1, respectively, Lm-ME inhibited autophosphorylation of overexpressed proteins and thereby activated fewer downstream signaling molecules. Lm-ME also attenuated stomach ulcers in an HCl/EtOH-induced acute gastritis model mice, and COX-2 mRNA expression and phosphorylated TAK1 levels in gastric tissues were diminished. The flavonoids kaempferol and quercetin were identified in the HPLC analysis of Lm-ME; both are actively anti-inflammatory. Therefore, these results suggest that Lm-ME can be used for anti-inflammatory remedy by targeting Src and TAK1.
Highlights
Inflammation is the first defense against many infectious pathogens or injury, and it plays an important role in common causes of atherosclerotic cardiovascular disease, cancer, and chronic obstructive lung disease [1,2,3]
The medicinal mechanisms of the genus Licania have not been well characterized at the cellular and molecular levels. erefore, we focused on the anti-inflammatory effects of a methanol extract of L. macrocarpa Cuatrec (Lm-ME) both in vitro, by using macrophage-like RAW264.7 cells, and in vivo, by using an HCl/EtOH-induced acute gastritis mouse model
To figure out the inflammatory effects of Licania macrocarpa Cuatrec methanol extract (Lm-ME), we first checked the inhibitory effect on Nitric oxide (NO) production in LPS-induced RAW264.7 cells and peritoneal macrophages (Figure 1(a))
Summary
Inflammation is the first defense against many infectious pathogens or injury, and it plays an important role in common causes of atherosclerotic cardiovascular disease, cancer, and chronic obstructive lung disease [1,2,3]. Toll-like receptors (TLRs) are key factors of the innate immune system that recognize pathogen-associated molecular patterns (PAMPs), which are molecular motifs shared by different types of microbes [4, 5]. Four particular adapter molecules of TLRs are known to be involved in signaling: MyD88, TIRAP, TRIF, and TRAM [7]. In the case of TLR4 activation, there are two different ways to activate inflammation: a MyD88-dependent pathway and a MyD88-independent pathway. IRAK1 is associated with TRAF6, and the complex can activate TAK1, which activates the IκB kinase (IKK) and mitogen-activated protein kinase (MAPK). In the MyD88-independent pathway, TRIF takes part in late-phase NF-κB and MAPK signaling, because TRIF recruits TRAF6 and receptor-interacting protein 1 (RIP1) to Evidence-Based Complementary and Alternative Medicine activate TAK1, resulting in NF-κB activation. Additional TLR4 downstream signaling molecules PI3K and AKT activate the NF-κB pathway [11,12,13]
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