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Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide

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Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide International Journal of Molecular Sciences Article Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide-Stimulated RAW264.7 Cells and Mouse Models 1, 2, 2 1 1 Seul-Ki Mun y, Kyung-Yun Kang y, Ho-Yeol Jang , Yun-Ho Hwang , Seong-Gyeol Hong , Su-Jin Kim 1, Hyun-Wook Cho 3, Dong-Jo Chang 1 , Jae-Seoun Hur 4 and Sung-Tae Yee 1,* 1 Department of Pharmacy, Sunchon National University, 255 Jungang-Ro, Suncheon 549-742, Korea; [email protected] (S.-K.M.); [email protected] (Y.-H.H.); [email protected] (S.-G.H.); [email protected] (S.-J.K.); [email protected] (D.-J.C.) 2 Suncheon Research Center for National Medicines, Suncheon 549-742, Korea; [email protected] (K.-Y.K.); [email protected] (H.-Y.J.) 3 Department of Biology, Sunchon National University, Suncheon 549-742, Korea; [email protected] 4 Department of Environmental Education, Korea Lichen Research Institute, Sunchon National University, Suncheon 549-742, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-61-750-3752; Fax: +82-61-750-3708 These authors contributed equally to this work. y Received: 26 August 2020; Accepted: 22 September 2020; Published: 25 September 2020 Abstract: Lichens, composite organisms resulting from the symbiotic association between the fungi and algae, produce a variety of secondary metabolites that exhibit pharmacological activities. This study aimed to investigate the anti-inflammatory activities of the secondary metabolite atraric acid produced by Heterodermia hypoleuca. The results confirmed that atraric acid could regulate induced pro-inflammatory cytokine, nitric oxide, prostaglandin E2, induced nitric oxide synthase and cyclooxygenase-2 enzyme expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Meanwhile, atraric acid downregulated the expression of phosphorylated IκB, extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results indicate that atraric acid has an anti-inflammatory effect, which may be the underlying molecular mechanism involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its potential therapeutic value for treating inflammatory diseases. Keywords: anti-inflammation; endotoxin shock; atraric acid; lichen; Heterodermia hypoleuca 1. Introduction Inflammation is an inherent immune mechanism that occurs as a result of pathogen invasion in the body [1,2]. During an inflammatory immune response, macrophages release pro-inflammatory mediators, such as nitric oxide (NO), prostaglandin E2 (PGE2), induced nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), as well as pro-inflammatory cytokines and chemokines [3,4]. Nuclear factor-kappa B (NFκB), which regulates the transcription of inflammatory factors induced by lipopolysaccharide (LPS) stimulation, binds to IκB in the cytoplasm and activated by phosphorylation and IκB degradation. The activation of NFκB is regulated by a mitogen-activated protein kinase (MAPK) and an extracellular signal-regulated kinase (ERK) [5–7]. Abnormally high inflammatory Int. J. Mol. Sci. 2020, 21, 7070; doi:10.3390/ijms21197070 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 7070 2 of 13 response results in severe tissue damage and endotoxin shock. Chronic inflammatory responses cause a series of diseases such as neurodegeneration, cardiovascular diseases (CVD), and cancer [3]. Endotoxin shock is a severe inflammatory reaction caused by Gram-negative bacteria infection of the bloodstream. LPS, an endotoxin on the surface of Gram-negative organisms, stimulates the release of pro-inflammatory cytokines and NO, resulting in increasing vasodilation and vascular permeability. This leads to impaired cardiovascular function, pulmonary dysfunction, acute renal impairment, septic shock and, finally, death. Many studies have demonstrated that the inhibition of NFκB and MAPK activation is an important strategy for the treatment of inflammatory diseases [8–11]. Lichens, symbiotic associations of algae and fungi, are abundantly found in the surroundings and can grow in cold and harsh environments [3,12]. In addition, lichens have been traditionally used as herbal tea and as a food ingredient in China and Japan. Their ability capacity to produce and accumulate secondary metabolites gives rise to their wide chemical diversity. Many secondary metabolites from Lichen, including atraric acid, atranorin, usnic acid and olivetoric acid, have been linked to different biological effects such as antibacterial, antioxidant and antiproliferation effects. Therefore, lichens are attracting attention as a new natural material. [13–15]. Although biological activities of numerous lichens have been studied, there is no information on hyterodermia hypoleuca (HH), a lichen native to Korea. Thus, we attempted to discover the biological activities of HH from the extract fractions using diverse solvents. The methanol (MeOH) extract exhibited a strong anti-inflammatory activity. However, there is no information for anti-inflammatory metabolites of HH, and also the mechanism underlying the anti-inflammatory activity of HH is not yet clear. Thus, we tried to discover active metabolites with anti-inflammatory activity from the MeOH extract fraction. We successfully isolated atraric acid with strong anti-inflammatory activity as a secondary metabolite with high concentration in the MeOH extract. Atraric acid is a phenolic compound, and has been reported to exhibit anti-cancer activity against prostate cancer. It serves as an antagonist of androgen receptor [16]. Atraric acid also possesses antioxidant and antibacterial [17] activities. However, it is not clear how atraric acid shows anti-inflammatory activity in vitro and in vivo. In this work, we show the in vitro and in vivo anti-inflammatory effects of atraric acid, which revealed that atratic acid has anti-inflammatory activity caused by the suppression of the MAPK-NFκB signaling pathway. 2. Results 2.1. HH Exhibited Anti-Inflammatory Effect The anti-inflammatory activity of heterodermia hypoleuca (HH) was investigated in LPS-stimulated RAW264.7 cells. At first, examining the cytotoxicity of HH extract in RAW264.7 cells using cell counting kit-8 (CCK-8), we observed that the growth of the cells was not affected by the HH extracts (Figure1a). As shown in Figure1, HH inhibited the production of NO stimulated by LPS in a concentration-dependent manner (Figure1b). In addition, the levels of pro-inflammatory, such as Tumor necrosis factor-alpha (TNF-α), interleukin l beta (IL-1β), interleukin 6 (IL-6) and granulocyte–macrophage colony-stimulating factor (GM-CSF) released in LPS-stimulated RAW 264.7 cells were significantly reduced by 20%, 30%, 58% and 45%, respectively, at 30 µg/mL of HH (Figure1c–f). Int. J. Mol. Sci. 2020, 21, 7070 3 of 13 Int.Int. J. J. Mol. Mol. Sci. Sci. 2020 2020, 21, 21, x, xFOR FOR PEER PEER REVIEW REVIEW 3 3of of 13 13 FigureFigureFigure 1.1. 1. The The screening screening ofof of anti-inflammatoryanti-inflammatory anti-inflammatory activityac activitytivity ofof of thethe the methanolmethanol methanol extractextract extract ofof of HeterodermiaHeterodermia Heterodermia hypoleucahypoleuca hypoleuca (HH).(HH).(HH). ((a a()a) The)The The cellscells cells werewere were treatedtreated treated withwith with didifferent differentfferentconcentrations concentrations concentrations ofof of HHHH HH forfor for 2424 24 h,h, h, andand and thethe the viabilityviability viability ofof of thethe the µ treatedtreatedtreated cellscells cells waswas was determineddetermined determined byby by cellcell cell countingcounting counting kit-8kit-8 kit-8 assay.assay. assay. TheThe The cellscells cells werewere were preincubatedpreincubated preincubated withwith with 11 1 μ gμg/mL/g/mLmL µ lipopolysaccharidelipopolysaccharidelipopolysaccharide (LPS) (LPS) (LPS) for for for 1 1 h 1h h andand and thenthen then treatedtreated treated withwith with 1-301-30 1-30 μ gμg/mL/g/mLmL HH HH HH for for for 24 24 24 h.h. h. ((b b()b) The)The The concentrationconcentration concentration ofofof nitricnitric nitric oxideoxide oxide inin in thethe the culturedcultured cultured mediummedium medium waswas was measuredmeasur measureded byby by usingusing using thethe the GriessGriess Griessreaction. reaction. reaction. TheThe The releaserelease release ofof of α c β d e TumorTumorTumor necrosisnecrosis necrosis factor-alphafactor-alpha factor-alpha (TNF-(TNF- (TNF-α)(α) )( c),(),c), interleukininterleukin interleukin ll betalbeta beta (IL-1(IL-1 (IL-1β)(β) )( d(),d),), interleukininterleukin interleukin 66 6 (IL-6)(IL-6) (IL-6) (( e()e) and)and and granulocyte–macrophage colony-stimulating factor (GM-CSF) (f) was determined by enzyme-linked granulocyte–macrophagegranulocyte–macrophage colony-s colony-stimulatingtimulating factor factor (GM-CSF) (GM-CSF) ( f()f )was was determined determined by by enzyme-linked enzyme-linked immunosorbent assay (ELISA). Data are presented as mean SD from three independent experiments immunosorbentimmunosorbent assay assay (ELISA). (ELISA). Data Data are are presented presented as as mean mean ± ±SD SD from from three three independent independent experiments experiments ### ± ( ###p < 0.001 versus the control group; *
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