Abstract
Lipoxins (LXs) display unique pro-resolving and anti-inflammatory functions in a variety of inflammatory conditions. The present study was undertaken to investigate the effects of BML-111 (5(S),6(R),7-trihydroxyheptanoic acid methyl ester), the agonist of lipoxin A4 receptor, in a model of Lipopolysaccharides (LPS) and d-Galactosamine (d-GalN) induced acute liver injury, and to explore the mechanisms. Histopathological analyses were carried out to quantify liver injury degree. The activities of myeloperoxidase (MPO) were examined to evaluate the levels of neutrophil infiltration. The activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum were detected to evaluate the functions of the liver. The amounts of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and interleukin-1β (IL-1β) were measured using enzyme-linked immunosorbent assay (ELISA), and the expression levels of transforming growth factor-β1(TGF-β1) and cyclooxygenase-2 (COX-2) were examined using Western blotting. The antioxidant capacity, the activities of inducible nitric oxide synthase (iNOS), the contents of malondialdehyde (MDA) and nitric oxide (NO) were analyzed with the kits via biochemical analysis. We established the model of acute liver injury with lipopolysaccharide and d-Galactosamine (LPS/d-GalN): (1) histopathological results and MPO activities, with the activities of AST and ALT in serum, consistently demonstrated LPS and d-GalN challenge could cause severe liver damage, but BML-111 could prevent pathological changes, inhibit neutrophil infiltration, and improve the hepatic function; (2) LPS/d-GalN increased TNF-α, IL-1β, COX-2, and IL-10, while decreasing TGF-β1. However, BML-111 could repress LPS/d-GalN -induced TNF-α, IL-1β and COX-2, meanwhile increasing the expression levels of TGF-β1 and IL-10; (3) LPS/d-GalN inhibited the activities of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and hydroxyl radical-scavenging ability, simultaneously increasing the levels of MDA and NO, so also the activity of iNOS. Otherwise, BML-111 could reverse all the phenomena. In a word, BML-111 played a protective role in acute liver injury induced by LPS and d-GalN in rats, through improving antioxidant capacity and regulating the balance of inflammatory cytokines.
Highlights
Our study showed BML-111 exerted a protective effect on liver injury, by improving antioxidant capacity and regulating the inflammatory cytokine balance
Rat tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) interleukin-10 (IL-10) enzyme-linked immunosorbent assay (ELISA) kits were from BD Biosciences (Bedford, OH, USA)
Assay kits for alanine aminotransferase (ALT), aspartate aminotransferase (AST), myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide (NO), the activation of inducible nitric oxide synthase, catalase (CAT), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) and hydroxyl radical-scavenging ability were purchased from Nanjing Jiancheng Bioengineering Institute (Nanjing, China)
Summary
Lipoxins (LXs) are biologically active productions of arachidonic acid, and are typically generated via ce1.llInintrtoedruacttiioonns, which is called the transcellular synthesis pathway [1,2]. LXs exert potent pro-resolvLiinpogxainnsd(LaXnsti)-ianrfleabmiomloagtiocarlylyfuanctcivtieonpsropdruimctiaornislyo[f3,a4r]a.chTihdoenriac paicdidi,naanctdivaarteiotnypkiicnaleltyics of LXs hgaevneercaotemd pvliiacacetelldinttheerairctaionnasl,ywsehsicihn ivsivcaol,leadndthpe rtoramnspcteeldlultahressyynnthtehseissipsaothf wbiaoylo[1g,i2c]a. NBcMtioLn-s11p1ri(m5(aSri)l,y6([R3,)4,7].-Ttrhihe yradpriodxiynhaectpivtaantioinckaicniedtimcsethyl ester)o,fthLeXsaghoanviestcoomf lpipliocaxtiendAth4eriercaenpatloyrse(sAiLnXv)i,vios,tahnedmporsotmwpitdedelythue sseydntLhXesaisnoaflobgiouleo,gaicnadllywaacstiivneitially showLnXisna1n9a9lo1gtuoesbeweitqhueinachtainvceewd cithhemlipicoaxl isntaAbi4lit(yLX[5A].4B)MwLit-1h1r1e(s5p(eSc),t6t(Ro)t,h7-etriinhhydibriotxioynheopftaLnToBic4-aicnidduced neutrmopethhiyl lmeisgterar)t,iothne[6a]g.oSnuisbtseoqf uliepnotxsintuAdi4ersehceapvteorde(AmLoXn)s, trisattehde pmootestntwaindteil-yinuflsaemd mLXatoanryalpogroupe,erties of BManLd-11w1aisnianivtiaalrliyetsyhoofwinnflinam1m99a1totorybceoneqduitiiaocntivs,einwciltuhdliinpgoxaicnutAe4lu(LnXgAi4n)juwriyth[7r–e1s1p]e,cat rttohrtihties [12], sepsiiasnn[ht1ii-3bi]int,fiiolsancmhomef mLatToiBar/y4-ripenrpdoeuprceferudtisenisoenouftirnBoMjpuhLriy-l1m[111i4gi]rn,aatainovdna[ri6sie]c.thySeuombfsiiecnqfsultaermnotkmseatut[o1dr5iye].scWohnaevdeiatnidodenmso,otihnnsectrlrusadtheinadvgpeaocrtueenptetorted that lBuMngL-i1n1ju1ryals[7o–1p1r]o, taercttherditisag[a1i2n],stsehpespisat[i1c3fi],birsocshiesm[i1a6/r]epaenrdfushioenpaitnojcuerlylu[l1a4r],caarncdiniosmchaem[1ic7–19]. NTdhedaiismcuosfs tthhies mstuedcyhawnaismtos.observe the effects of BML-111 on Lipopolysaccharides and Holoywsaevccehr,atrhiedeefsfeacntsdoDf -BGMaLla-1c1to1soanmaicnuete(LlivPeSr/inDj-uGryalaNre) sintildl uced liver uinnjculerayra. nTdhedaiismcuosfs tthhies mstuedcyhawnaismtos.observe the effects of BML-111 on Lipopolysaccharides and
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