5,7,2',4',5'-Pentamethoxyflavanone regulates M1/M2 macrophage phenotype and protects the septic mice
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摘要
Flavonoids have been reported to exert protective effect against many inflammatory diseases, while the underlying cellular mechanisms are still not completely known. In the present study, we explored the anti-inflammation activity of 5, 7, 2', 4', 5'-pentamethoxyflavanone(abbreviated as Pen.), a kind of polymethoxylated flavonoid, both in vitro and in vivo experiments. Pen. was showed no obvious toxicity in macrophages even at high dosage treatment. Our results indicated that Pen. significantly inhibited both mR NA and protein level of proinflammatory cytokines, IL-1β, IL-6, TNF-α and iN OS, which was characteristic expressed on M1 polarized macrophages. These effects of Pen. were further confirmed by diminished expression of CD11c, the M1 macrophage surface marker. Further researches showed that the mechanism was due to that Pen. downregulated the activity of p65, key transcription factor for M1 polarization. On the other hand, Pen. also enhanced M2 polarization with upregulation of anti-inflammatory factors and increase of M2 macrophage surface markers, which lead to the balance of M1 and M2 macrophages. Moreover, in vivo research verified that Pen. treatment alleviated LPS-induced sepsis in mice by increasing survival rate, decreasing inflammatory cytokines and improving lung tissue damage. In summary, our results suggested that Pen. modulated macrophage phenotype via suppressing p65 signal pathway to exert the anti-inflammation activity.
Flavonoids have been reported to exert protective effect against many inflammatory diseases, while the underlying cellular mechanisms are still not completely known. In the present study, we explored the anti-inflammation activity of 5, 7, 2', 4', 5'-pentamethoxyflavanone(abbreviated as Pen.), a kind of polymethoxylated flavonoid, both in vitro and in vivo experiments. Pen. was showed no obvious toxicity in macrophages even at high dosage treatment. Our results indicated that Pen. significantly inhibited both mR NA and protein level of proinflammatory cytokines, IL-1β, IL-6, TNF-α and iN OS, which was characteristic expressed on M1 polarized macrophages. These effects of Pen. were further confirmed by diminished expression of CD11c, the M1 macrophage surface marker. Further researches showed that the mechanism was due to that Pen. downregulated the activity of p65, key transcription factor for M1 polarization. On the other hand, Pen. also enhanced M2 polarization with upregulation of anti-inflammatory factors and increase of M2 macrophage surface markers, which lead to the balance of M1 and M2 macrophages. Moreover, in vivo research verified that Pen. treatment alleviated LPS-induced sepsis in mice by increasing survival rate, decreasing inflammatory cytokines and improving lung tissue damage. In summary, our results suggested that Pen. modulated macrophage phenotype via suppressing p65 signal pathway to exert the anti-inflammation activity.
Flavonoids have been reported to exert protective effect against many inflammatory diseases, while the underlying cellular mechanisms are still not completely known. In the present study, we explored the anti-inflammation activity of 5, 7, 2', 4', 5'-pentamethoxyflavanone(abbreviated as Pen.), a kind of polymethoxylated flavonoid, both in vitro and in vivo experiments. Pen. was showed no obvious toxicity in macrophages even at high dosage treatment. Our results indicated that Pen. significantly inhibited both mR NA and protein level of proinflammatory cytokines, IL-1β, IL-6, TNF-α and iN OS, which was characteristic expressed on M1 polarized macrophages. These effects of Pen. were further confirmed by diminished expression of CD11c, the M1 macrophage surface marker. Further researches showed that the mechanism was due to that Pen. downregulated the activity of p65, key transcription factor for M1 polarization. On the other hand, Pen. also enhanced M2 polarization with upregulation of anti-inflammatory factors and increase of M2 macrophage surface markers, which lead to the balance of M1 and M2 macrophages. Moreover, in vivo research verified that Pen. treatment alleviated LPS-induced sepsis in mice by increasing survival rate, decreasing inflammatory cytokines and improving lung tissue damage. In summary, our results suggested that Pen. modulated macrophage phenotype via suppressing p65 signal pathway to exert the anti-inflammation activity.
引文
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[22]Liu-Smith F,Meyskens FL.Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma[J].Mol Nutr Food Res,2016,60(6):1264-1274.
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[24]Feng L,Song P,Zhou H,et al.Pentamethoxyflavanone regulates macrophage polarization and ameliorates sepsis in mice[J].Biochem Pharmacol,2014,89(1):109-118.
[25]Kilkenny C,Browne W,Cuthill IC,et al.Animal research:reporting in vivo experiments-the ARRIVE guidelines[J].JCereb Blood Flow Metab,2011,31(4):991-993.
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[29]Hayden MS,Ghosh S.NF-kappaB in immunobiology[J].Cell Res,2011,21(2):223-244.
[30]Acharyya S,Villalta SA,Bakkar N,et al.Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy[J].J Clin Invest,2007,117(4):889-901.
[2]Medzhitov R.Inflammation 2010:new adventures of an old flame[J].Cell,2010,140(6):771-776.
[3]Nathan C.Points of control in inflammation[J].Nature,2002,420(6917):846-852.
[4]Kotas ME,Medzhitov R.Homeostasis,inflammation,and disease susceptibility[J].Cell,2015,160(5):816-827.
[5]Stearns-Kurosawa DJ,Osuchowski MF,Valentine C,et al.The pathogenesis of sepsis[J].Ann Rev pathol,2011,6:19-48.
[6]Benoit M,Desnues B,Mege JL.Macrophage polarization in bacterial infections[J].J Immunol(Baltimore,Md:1950),2008,181(6):3733-3739.
[7]Sindrilaru A,Peters T,Wieschalka S,et al.An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice[J].J Clin Invest,2011,121(3):985-997.
[8]Sica A,Mantovani A.Macrophage plasticity and polarization:in vivo veritas[J].J Clin Invest,2012,122(3):787-795.
[9]Gordon S,Martinez FO.Alternative activation of macrophages:mechanism and functions[J].Immunity,2010,32(5):593-604.
[10]Noy R,Pollard JW.Tumor-associated macrophages:from mechanisms to therapy[J].Immunity,2014,41(1):49-61.
[11]Biswas SK,Mantovani A.Macrophage plasticity and interaction with lymphocyte subsets:cancer as a paradigm[J].Nature Immunol,2010,11(10):889-896.
[12]Murray PJ,Allen JE,Biswas SK,et al.Macrophage activation and polarization:nomenclature and experimental guidelines[J].Immunity,2014,41(1):14-20.
[13]Wang N,Liang H,Zen K.Molecular mechanisms that influence the macrophage m1-m2 polarization balance[J].Front Immunol,2014,5:614.
[14]Martinez FO,Gordon S.The M1 and M2 paradigm of macrophage activation:time for reassessment[J].F1000Prime Rep,2014,6:13.
[15]Lucas T,Waisman A,Ranjan R,et al.Differential roles of macrophages in diverse phases of skin repair[J].J Immunol(Baltimore,Md:1950),2010,184(7):3964-3977.
[16]Laskin DL,Sunil VR,Gardner CR,et al.Macrophages and tissue injury:agents of defense or destruction?[J]Ann Rev Pharmacol Toxicol,2011,51:267-288.
[17]Vinayagam R,Xu B.Antidiabetic properties of dietary flavonoids:a cellular mechanism review[J].Nutr Metab,2015,12:60.
[18]Eghbaliferiz S,Iranshahi M.Prooxidant activity of polyphenols,flavonoids,anthocyanins and carotenoids:Updated review of mechanisms and catalyzing metals[J].Phytother Res,2016,30(9):1379-1391.
[19]Shen CY,Jiang JG,Yang L,et al.Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine:pharmacological mechanisms and implications for drug discovery[J].Br J Pharmacol,2017,174(11):1395-1425.
[20]Wu L,Li P,Wang X,et al.Evaluation of anti-inflammatory and antinociceptive activities of Murraya exotica[J].Pharm Biol,2010,48(12):1344-1353.
[21]George VC,Dellaire G,Rupasinghe HPV.Plant flavonoids in cancer chemoprevention:role in genome stability[J].J Nutr Biochem,2017,45:1-14.
[22]Liu-Smith F,Meyskens FL.Molecular mechanisms of flavonoids in melanin synthesis and the potential for the prevention and treatment of melanoma[J].Mol Nutr Food Res,2016,60(6):1264-1274.
[23]Ayatollahi AM,Ghanadian M,Att-Ur-Rahman R,et al.Methoxylated flavones from Salvia mirzayanii Rech.f.and esfand with immunosuppressive properties[J].Iran J Pharm Res,2015,14(3):955-960.
[24]Feng L,Song P,Zhou H,et al.Pentamethoxyflavanone regulates macrophage polarization and ameliorates sepsis in mice[J].Biochem Pharmacol,2014,89(1):109-118.
[25]Kilkenny C,Browne W,Cuthill IC,et al.Animal research:reporting in vivo experiments-the ARRIVE guidelines[J].JCereb Blood Flow Metab,2011,31(4):991-993.
[26]Wang W,Sun C,Mao L,et al.The biological activities,chemical stability,metabolism and delivery systems of quercetin:A review[J].Trends Food Sci Tech,2016,56:21-38.
[27]Cassidy A,Minihane AM.The role of metabolism(and the microbiome)in defining the clinical efficacy of dietary flavonoids[J].Am J Clin Nutr,2017,105(1):10-22.
[28]Martinon F,Burns K,Tschopp J.The inflammasome:a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta[J].Mol Cell,2002,10(2):417-426.
[29]Hayden MS,Ghosh S.NF-kappaB in immunobiology[J].Cell Res,2011,21(2):223-244.
[30]Acharyya S,Villalta SA,Bakkar N,et al.Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy[J].J Clin Invest,2007,117(4):889-901.