Abstract
Biochanin A, one of the major isoflavonoids in red clover or cabbage, has been reported to have anti-inflammatory effects. However, the molecular mechanism underlying the anti-inflammatory effects of biochanin A has not been completely elucidated. The aim of this study was to investigate the anti-inflammatory effect and mechanism on lipopolysaccharide (LPS)-stimulated BV2 microglia. The results showed that biochanin A suppressed LPS-induced inflammatory mediators nitric oxide, prostaglandin E2 and inflammatory cytokines TNF-α and IL-1β production. LPS-induced NF-κB activation was also inhibited by biochanin A. In addition, biochanin A up-regulated the expression of PPAR-γ and the anti-inflammatory effects of biochanin A can be abolished by PPAR-γ antagonist GW9662. These results suggest that biochanin A exerts an anti-inflammatory property by activating PPAR-γ, thereby attenuating NF-κB activation and the release of pro-inflammatory mediators.
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Merighi S, Gessi S, Varani K, Fazzi D, Stefanelli A, Borea PA (2013) Morphine mediates a proinflammatory phenotype via mu-opioid receptor-PKCϵ-Akt-ERK1/2 signaling pathway in activated microglial cells. Biochem Pharmacol 86:487–496
Khatchadourian A, Bourque SD, Richard VR, Titorenko VI, Maysinger D (2012) Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia. Biochim Biophys Acta 1821:607–617
Kim EA, Han AR, Choi J, Ahn JY, Choi SY, Cho SW (2014) Anti-inflammatory mechanisms of N-adamantyl-4-methylthiazol-2-amine in lipopolysaccharide-stimulated BV-2 microglial cells. Int Immunopharmacol 22:73–83
Jeong JW, Lee HH, Han MH, Kim GY, Kim WJ, Choi YH (2014) Anti-inflammatory effects of genistein via suppression of the toll-like receptor 4-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglia. Chem Biol Interact 212:30–39
Nuzzo D, Picone P, Caruana L, Vasto S, Barera A, Caruso C, Di Carlo M (2014) Inflammatory mediators as biomarkers in brain disorders. Inflammation 37:639–648
Kubera M, Obuchowicz E, Goehler L, Brzeszcz J, Maes M (2011) In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog Neuro-Psychopharmacol 35:744–759
Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease—a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2:a006346
Tansey MG, Goldberg MS (2010) Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis 37:510–518
Whitehouse PJ (2014) The end of Alzheimer’s disease—from biochemical pharmacology to ecopsychosociology: a personal perspective. Biochem Pharmacol 88:677–681
Ekdahl CT, Kokaia Z, Lindvall O (2009) Brain inflammation and adult neurogenesis: the dual role of microglia. Neuroscience 158:1021–1029
Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27:2596–2605
Bhardwaj V, Tadinada SM, Jain A, Sehdev V, Daniels CK, Lai JC, Bhushan A (2014) Biochanin A reduces pancreatic cancer survival and progression. Anticancer Drugs 25:296–302
Tan JW, Tham CL, Israf DA, Lee SH, Kim MK (2013) Neuroprotective effects of biochanin A against glutamate-induced cytotoxicity in PC12 cells via apoptosis inhibition. Neurochem Res 38:512–518
Michaelis M, Sithisarn P, Cinatl J Jr (2014) Effects of flavonoid-induced oxidative stress on anti-H5N1 influenza a virus activity exerted by baicalein and biochanin A. BMC Res Notes 7:384
Kole L, Giri B, Manna SK, Pal B, Ghosh S (2011) Biochanin-A, an isoflavon, showed anti-proliferative and anti-inflammatory activities through the inhibition of iNOS expression, p38-MAPK and ATF-2 phosphorylation and blocking NF κB nuclear translocation. Eur J Pharmacol 653:8–15
Qiu L, Lin B, Lin Z, Lin Y, Lin M, Yang X (2012) Biochanin A ameliorates the cytokine secretion profile of lipopolysaccharide-stimulated macrophages by a PPARγ-dependent pathway. Mol Med Rep 5:217–222
Chung MJ, Sohng JK, Choi DJ, Park YI (2013) Inhibitory effect of phloretin and biochanin A on IgE-mediated allergic responses in rat basophilic leukemia RBL-2H3 cells. Life Sci 93:401–408
Ko WC, Lin LH, Shen HY, Lai CY, Chen CM, Shih CH (2011) Biochanin a, a phytoestrogenic isoflavone with selective inhibition of phosphodiesterase 4, suppresses ovalbumin-induced airway hyperresponsiveness. Evid-Based Complement Altern Med: eCAM 2011:635058
Bocchini V, Mazzolla R, Barluzzi R, Blasi E, Sick P, Kettenmann H (1992) An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res 31:616–621
Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7
Gonzalez-Scarano F, Baltuch G (1999) Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 22:219–240
Minghetti L (2005) Role of inflammation in neurodegenerative diseases. Curr Opin Neurol 18:315–321
Klegeris A, McGeer EG, McGeer PL (2007) Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol 20:351–357
Lee KH, Choi EM (2005) Biochanin A stimulates osteoblastic differentiation and inhibits hydrogen peroxide-induced production of inflammatory mediators in MC3T3-E1 cells. Biol Pharm Bull 28:1948–1953
Saviranta NMM, Veeroos L, Granlund LJ, Hassinen VH, Kaarniranta K, Karjalainen RO (2011) Plant flavonol quercetin and isoflavone biochanin A differentially induce protection against oxidative stress and inflammation in ARPE-19 cells. Food Res Int 44:109–113
Kim YA, Kim GY, Park KY, Choi YH (2007) Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia. J Med Food 10:218–224
Brown GC, Borutaite V (2002) Nitric oxide inhibition of mitochondrial respiration and its role in cell death. Free Radic Biol Med 33:1440–1450
Perry VH (2004) The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 18:407–413
Ha SK, Moon E, Kim SY (2010) Chrysin suppresses LPS-stimulated proinflammatory responses by blocking NF-κB and JNK activations in microglia cells. Neurosci Lett 485:143–147
Zhong LM, Zong Y, Sun L, Guo JZ, Zhang W, He Y, Song R, Wang WM, Xiao CJ, Lu D (2012) Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells. PLoS One 7:e32195
Hoozemans JJ, Veerhuis R, Rozemuller JM, Eikelenboom P (2006) Neuroinflammation and regeneration in the early stages of Alzheimer’s disease pathology. Int J Dev Neurosci 24:157–165
Jiao J, Xue B, Zhang L, Gong Y, Li K, Wang H, Jing L, Xie J, Wang X (2008) Triptolide inhibits amyloid-β1-42-induced TNF-α and IL-1β production in cultured rat microglia. J Neuroimmunol 205:32–36
Dheen ST, Kaur C, Ling EA (2007) Microglial activation and its implications in the brain diseases. Curr Med Chem 14:1189–1197
Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39:1–16
Uda S, Spolitu S, Angius F, Collu M, Accossu S, Banni S, Murru E, Sanna F, Batetta B (2013) Role of HDL in cholesteryl ester metabolism of lipopolysaccharide-activated P388D1 macrophages. J Lipid Res 54:3158–3169
Liu H, Wu X, Dong Z, Luo Z, Zhao Z, Xu Y, Zhang JT (2013) Fatty acid synthase causes drug resistance by inhibiting TNF-α and ceramide production. J Lipid Res 54:776–785
Yu H, Valerio M, Bielawski J (2013) Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans. J Lipid Res 54:189–201
McGrath KC, Li XH, Whitworth PT, Kasz R, Tan JT, McLennan SV, Celermajer DS, Barter PJ, Rye KA, Heather AK (2014) High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation. J Lipid Res 55:421–430
Zhao Z, Tang X, Zhao X, Zhang M, Zhang W, Hou S, Yuan W, Zhang H, Shi L, Jia H, Liang L, Lai Z, Gao J, Zhang K, Fu L, Chen W (2014) Tylvalosin exhibits anti-inflammatory property and attenuates acute lung injury in different models possibly through suppression of NF-κB activation. Biochem Pharmacol 90:73–87
Wang L, Xu Y, Yu Q, Sun Q, Xu Y, Gu Q, Xu X (2014) H-RN, a novel antiangiogenic peptide derived from hepatocyte growth factor inhibits inflammation in vitro and in vivo through PI3K/AKT/IKK/NF-κB signal pathway. Biochem Pharmacol 89:255–265
Kim MH, Son YJ, Lee SY, Yang WS, Yi YS, Yoon DH, Yang Y, Kim SH, Lee D, Rhee MH, Kang H, Kim TW, Sung GH, Cho JY (2013) JAK2-targeted anti-inflammatory effect of a resveratrol derivative 2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide. Biochem Pharmacol 86:1747–1761
Hamaguchi M, Sakaguchi S (2012) Regulatory T cells expressing PPAR-γ control inflammation in obesity. Cell Metab 16:4–6
Neri T, Armani C, Pegoli A, Cordazzo C, Carmazzi Y, Brunelleschi S, Bardelli C, Breschi MC, Paggiaro P, Celi A (2011) Role of NF-κB and PPAR-γ in lung inflammation induced by monocyte-derived microparticles. Eur Respir J 37:1494–1502
Tezera LB, Hampton J, Jackson SK, Davenport V (2011) Neisseria lactamica attenuates TLR-1/2-induced cytokine responses in nasopharyngeal epithelial cells using PPAR-γ. Cell Microbiol 13:554–568
Wang L, Waltenberger B, Pferschy-Wenzig EM, Blunder M, Liu X, Malainer C, Blazevic T, Schwaiger S, Rollinger JM, Heiss EH, Schuster D, Kopp B, Bauer R, Stuppner H, Dirsch VM, Atanasov AG (2014) Natural product agonists of peroxisome proliferator-activated receptor γ (PPARγ): a review. Biochem Pharmacol 92(1):73–89. doi:10.1016/j.bcp.2014.07.018
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Zhang, Y., Chen, Wa. Biochanin A Inhibits Lipopolysaccharide-Induced Inflammatory Cytokines and Mediators Production in BV2 Microglia. Neurochem Res 40, 165–171 (2015). https://doi.org/10.1007/s11064-014-1480-2
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DOI: https://doi.org/10.1007/s11064-014-1480-2