黄酮类化合物抗炎作用及其作用机制研究进展
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摘要
自二十世纪30年代初,黄酮类化合物被发现以来,其抗炎、抗肿瘤、抗氧化、降血压、防止骨质疏松等药理作用备受关注。由于目前临床上应用较多的甾体和非甾体抗炎药有胃肠道损伤、高血压、急性肾功能衰竭等不良反应,而黄酮类化合物不仅具有抗炎作用,又具有毒副作用小和作用范围广的特点,因此,引起了相关研究学者的重视。本文通过查阅近年来国内外发表的相关文献,从炎症产生的重要途径,如花生四烯酸,NO途径,细胞因子及受体,以及Nrf2、NF-κB、AP-1和MAPK等信号通路来探讨黄酮类化合物抗炎作用机制,以期为开发抗炎中药提供理论基础和研究思路。
Flavonoids were identified in the early 1930 s and have been a topic of interest in research because of their anti-inflammatory,anti-tumor and anti-oxidant functions,and hypotensive and osteoporosis prevention. Unlike current clinical steroidal and non-steroidal antiinflammatory drugs with adverse effects of gastrointestinal injury,hypertension,and acute renal failure of,flavonoids have little toxic side effect. Based on the analysis of related literatures published at home and abroad in recent years,the anti-inflammatory effects of flavonoids are reviewed and their mechanisms are identified including the arachidonic acid metabolism pathway,NO,cytokine and its receptor,signaling pathways of Nrf2,NF-κB,AP-1 and MAPK,so that theoretical basis for further development and research is suggested.
Flavonoids were identified in the early 1930 s and have been a topic of interest in research because of their anti-inflammatory,anti-tumor and anti-oxidant functions,and hypotensive and osteoporosis prevention. Unlike current clinical steroidal and non-steroidal antiinflammatory drugs with adverse effects of gastrointestinal injury,hypertension,and acute renal failure of,flavonoids have little toxic side effect. Based on the analysis of related literatures published at home and abroad in recent years,the anti-inflammatory effects of flavonoids are reviewed and their mechanisms are identified including the arachidonic acid metabolism pathway,NO,cytokine and its receptor,signaling pathways of Nrf2,NF-κB,AP-1 and MAPK,so that theoretical basis for further development and research is suggested.
引文
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[23]MrvováN,kandík M,KuniakováM,et al.Modulation of BV-2microglia functions by novel quercetin pivaloyl ester[J].Neurochem Int,2015,90:246-254.
[24]Kim H J,Lee W,Yun J M,et al.Luteolin inhibits hyperglycemia-induced proinflammatory cytokine production and its epigenetic mechanism in human monocytes[J].Phytother Res,2014,28:1383-1391.
[25]Leyva-López N,Nair V,Bang W Y,et al.Protective role of terpenes and polyphenols from three species of Oregano(Lippia graveolens,Lippia palmeri and Hedeoma patens)on the suppression of lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells[J].J Ethnopharmacol,2016,187:302-312.
[26]高蒙蒙,孙桂波,斯建勇,等.红车轴草总黄酮对H2O2诱导的内皮细胞损伤有明显的保护作用[J].中国药理学通报,2013,29(2):201-207.
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[28]Cherrak S A,Mokhtari-Soulimane N,Berroukeche F,et al.In Vitro antioxidant versus metal ion chelating properties of flavonoids:A structure-activity investigation[J].PLo S One,2016,11(10):e0165575.
[29]Choi E M,Lee Y S,Luteolin suppresses IL-1β-induced cytokines and MMPs production via p38 MAPK JNK NF-κB and AP-1 activation in human synovial sarcoma cell line SW982[J].Food Chem Toxicol,2010,48:2607-2611.
[30]Paredes-Gonzalez X,Fuentes F,Jeffery S,et al.Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin[J].Biopharm.Drug Dispos,2015,36:440-451.
[31]Oliveira A M,Cardoso S M,Ribeiro M,et al.Protective effects of 3-alkyl luteolin derivatives are mediated by Nrf2 transcriptional activity and decreased oxidative stress in Huntington's disease mouse striatal cells[J].Neurochem Int,2015,91:1-12.
[32]Funakoshi-Tago M,Ohsawa K,Ishikawa T,et al.Inhibitory effects of flavonoids extracted from Nepalese propolis on the LPS signaling pathway[J].Int Immunopharmacol,2016,11(40):550-560.
[33]Xiong D,Deng Y,Huang B,et al.Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB,PPARαand PPARγin rats[J].Int Immunopharmacol,2016,30:157-162.
[34]Liu D,Cao G,Han L,et al.Flavonoids from Radix Tetrastigmae inhibit TLR4/MD-2 mediated JNK and NF-κB pathway with antiinflammatory properties[J].Cytokine,2016,84:29-36.
[35]Oldfield V,Dhillon S,Plosker G L.Tocilizumab:A review of its use in the management of rheumatoid arthritis[J].Drugs,2009,69:609-632.
[36]Serafini M,Peluso I,Raguzzini A.Flavonoids as anti-inflammatory agents[J].Proc Nutr Soc,2010,69:273-278.
[37]Qiao Y,He H,Jonsson P,et al.AP-1 is a key regulator of proinflammatory cytokine TNFα-mediated triple-negative breast cancer progression[J].J Biol Chem,2016,291(10):5068.
[38]Rajeshwari H,Patil R L,Babu M,et al.Apigenin inhibits PMAinduced expression of pro-inflammatory cytokines and AP-1 factors in A549 cells[J].Mol Cell Biochem,2015,403:95-106
[39]Rosa S I,Rios-Santos F,Balogun S O,et al.Vitexin reduces neutrophil migration to inflammatory focus bydown-regulating pro-inflammatory mediators via inhibition of p38,ERK1/2 and JNK pathway[J].Phytomedicine,2016,23:9-17.
[40]刘丹丹,曹纲,张琦,等.三叶青黄酮经p38MAPK和NF-κB途径抑制老年小鼠急性肺损伤[J].中国药理学通报,2015,31(12):1725-1730.
[2]Venturelli S,Burkard M,Biendl M,et al.Prenylated chalcones and flavonoidsfor the prevention and treatment of cancer[J].Nutrition,2016,190:60-74.
[3]Agati G,Azzarello E,Pollastri S,et al.Flavonoids as antioxidants in plants:Location and functional significance[J].Plant Sci,2012,196:67-76.
[4]郑君,林晓春,陈育尧,等.甘草总黄酮抑制慢性萎缩性胃炎大鼠胃黏膜腺体萎缩及机制研究[J].中国药理学通报,2014,30(1):113-117.
[5]李剑霜,陈芝芸,蒋建平,等.胡皮柚黄酮对非酒精性脂肪性肝炎小鼠Th17/Treg平衡的调节作用[J].中国中药杂志,2015,40(30):2644-2648.
[6]Tsai Y F,Chua T C,Changa W Y,et al.6-Hydroxy-5,7-dimethoxy-avone suppresses the neutrophil respiratory burst via selective PDE4 inhibition to ameliorate acute lung injury[J].Free Radical Bio Med,2015,106(2017):379-392.
[7]孙阿宁,任改艳,邓超,等.牡荆素减轻小鼠溃疡性结肠炎的药效作用及机制研究[J].中国药理学通报,2014,30(12):1677-1681.
[8]Vane J R,Mitchell J A,Appleton I,et al.Inducible isoforms of cycloxygenase and nitric oxide synthase ininflammation[J].PNAS USA,1994,91:2046-2050.
[9]Smith W L,Garavito R M,Dewitt,D L,et al.Prostaglandin endoperoxide Hsynthases(cycloxygenase)-1 and 2[J].J Biol Chem,1996,271:33157-33160.
[10]Sumalatha M,Munikishore R,Rammohan A,et al.A selective inhibitor of cyclooxygenase-2(COX-2)from the tubers of pueraria tuberose[J].Nat Prod Commun,2015,10(10):1703-1704.
[11]Chen X M,Tait A R,Kitts D D,Flavonoid composition of orange peel and its association with antioxidant and anti-inflammatory activities[J].Food Chem,2017,218:15-21.
[12]Saldanha A A,de Siqueira J M,Castro A H,et al.Anti-inflammatory effects of the butanolic fraction of Byrsonima verbascifolia leaves:Mechanisms involving inhibition of tumor necrosis factor alpha,prostaglandin E(2)production and migration of polymorphonuclear leucocyte in vivo experimentation[J].Int Immunophar-macol,2016,31:123-131
[13]Nair V,Bang W Y,Schreckinger E,et al.Protective role of ternatinanthocyanins and quercetin glycosides from butterfly pea(clitoria ternatea leguminosae)blue flower petalsagainst lipopolysaccharide(LPS)-induced inflammation in macrophage cells[J].Agric Food Chem,2015,63:6355-6365.
[14]Liu C W,Lin H W,Yang D J,et al.Luteolin inhibitsviral-induced inflammatory response in RAW 264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1[J].Free Radic Biol Med,2016,95,180-189.
[15]Patwardhan R S,Sharma D,Thoh M.Baicalein exhibits anti-inflammatory effects via inhibition of NF-κB transactivation[J].Biochem Pharmacol,2016,108:75-89.
[16]Rahman I.Oxidative stress,chromatin remodeling and gene transcription in inflammation and chronic lung diseases[J].J Biochem Mol Biol,2003,36:95-109.
[17]Chanput W,Krueyos N,Ritthiruangdej P.Anti-oxidative assays as markers for anti-inflammatory activity of flavonoids[J].Int Immunopharmacol,2016,40:170-175.
[18]Lee K J,Oh Y C,Cho W K,et al.Antioxidant and anti-inflammatory activity determination of one hundred kinds of pure chemical compounds using offine and online screening HPLC assay[J].Evid Based Complement Alternat Med,2015,doi:10.1155/2015/165457.
[19]Cruz M P,Andrade C M,Silva K O,et al.Antinoceptive and anti-inflammatory activities of the ethanolic extract,fractions and flavones isolated from mimosa tenuiflora(Willd.)Poir(Leguminosae)[J].PLo S One,2016,11(3):e0150839.
[20]Lee Y J,Han S B,Nam S Y,et al.Inflammation and alzheimer’s disease[J].Arch Pharm,Res,2010,33:1539-1556.
[21]Mueller M,Hobiger S,Jungbauer A,et al.Anti-inflammatory activity of extracts from fruits,herbs and spices[J].Food Chem,2010,122:987-996.
[22]Oldfield V,Dhillon S,Plosker G L.Tocilizumab:A review of its use in the management of rheumatoid arthritis[J].Drugs,2009,69:609-632.
[23]MrvováN,kandík M,KuniakováM,et al.Modulation of BV-2microglia functions by novel quercetin pivaloyl ester[J].Neurochem Int,2015,90:246-254.
[24]Kim H J,Lee W,Yun J M,et al.Luteolin inhibits hyperglycemia-induced proinflammatory cytokine production and its epigenetic mechanism in human monocytes[J].Phytother Res,2014,28:1383-1391.
[25]Leyva-López N,Nair V,Bang W Y,et al.Protective role of terpenes and polyphenols from three species of Oregano(Lippia graveolens,Lippia palmeri and Hedeoma patens)on the suppression of lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells[J].J Ethnopharmacol,2016,187:302-312.
[26]高蒙蒙,孙桂波,斯建勇,等.红车轴草总黄酮对H2O2诱导的内皮细胞损伤有明显的保护作用[J].中国药理学通报,2013,29(2):201-207.
[27]Wang Y M,Zhao J Q,Yang J L,et al.Separation of antioxidant andα-glucosidase inhibitory flavonoids from the aerial parts of Asterothamnus centrali-asiaticus[J].Nat Prod Res,2016,21(10):1-5.
[28]Cherrak S A,Mokhtari-Soulimane N,Berroukeche F,et al.In Vitro antioxidant versus metal ion chelating properties of flavonoids:A structure-activity investigation[J].PLo S One,2016,11(10):e0165575.
[29]Choi E M,Lee Y S,Luteolin suppresses IL-1β-induced cytokines and MMPs production via p38 MAPK JNK NF-κB and AP-1 activation in human synovial sarcoma cell line SW982[J].Food Chem Toxicol,2010,48:2607-2611.
[30]Paredes-Gonzalez X,Fuentes F,Jeffery S,et al.Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin[J].Biopharm.Drug Dispos,2015,36:440-451.
[31]Oliveira A M,Cardoso S M,Ribeiro M,et al.Protective effects of 3-alkyl luteolin derivatives are mediated by Nrf2 transcriptional activity and decreased oxidative stress in Huntington's disease mouse striatal cells[J].Neurochem Int,2015,91:1-12.
[32]Funakoshi-Tago M,Ohsawa K,Ishikawa T,et al.Inhibitory effects of flavonoids extracted from Nepalese propolis on the LPS signaling pathway[J].Int Immunopharmacol,2016,11(40):550-560.
[33]Xiong D,Deng Y,Huang B,et al.Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB,PPARαand PPARγin rats[J].Int Immunopharmacol,2016,30:157-162.
[34]Liu D,Cao G,Han L,et al.Flavonoids from Radix Tetrastigmae inhibit TLR4/MD-2 mediated JNK and NF-κB pathway with antiinflammatory properties[J].Cytokine,2016,84:29-36.
[35]Oldfield V,Dhillon S,Plosker G L.Tocilizumab:A review of its use in the management of rheumatoid arthritis[J].Drugs,2009,69:609-632.
[36]Serafini M,Peluso I,Raguzzini A.Flavonoids as anti-inflammatory agents[J].Proc Nutr Soc,2010,69:273-278.
[37]Qiao Y,He H,Jonsson P,et al.AP-1 is a key regulator of proinflammatory cytokine TNFα-mediated triple-negative breast cancer progression[J].J Biol Chem,2016,291(10):5068.
[38]Rajeshwari H,Patil R L,Babu M,et al.Apigenin inhibits PMAinduced expression of pro-inflammatory cytokines and AP-1 factors in A549 cells[J].Mol Cell Biochem,2015,403:95-106
[39]Rosa S I,Rios-Santos F,Balogun S O,et al.Vitexin reduces neutrophil migration to inflammatory focus bydown-regulating pro-inflammatory mediators via inhibition of p38,ERK1/2 and JNK pathway[J].Phytomedicine,2016,23:9-17.
[40]刘丹丹,曹纲,张琦,等.三叶青黄酮经p38MAPK和NF-κB途径抑制老年小鼠急性肺损伤[J].中国药理学通报,2015,31(12):1725-1730.