Abstract
Yinhuapinggan granule (YHPG), a Chinese medicine granule based on Ma-Huang-Tang (Ephedra Decoction) and the clinical experience of Professor Wan Haitong, is used in traditional Chinese medicine (TCM) for the treatment of colds, influenza, fever, inflammation and cough. This study investigated the antiviral effects of YHPG on the production of inflammatory cytokines in influenza virus (IFV)-infected mice and evaluated the effect of YHPG on the expression of NF-κB p65 and the level of key signaling molecules in the TLR4 signaling pathway. ICR mice were orally administrated YHPG at doses of 7.5, 15 and 30 g kg−1 day−1 for 2 or 6 days after IFV infection. On days 3 and 7 after infection, YHPG (15 g/kg and 30 g/kg) significantly increased levels of interleukin (IL)-2 and interferon gamma and decreased levels of IL-4, IL-5 and tumor necrosis factor (TNF) in serum compared with the IFV control group. Furthermore, the expression of TLR4, MyD88, TRAF6 and NF-κB p65 at the mRNA and protein level was significantly lower in the YHPG (15 and 30 g/kg) treatment groups than in the IFV control group. These results suggest that YHPG has antiviral effects in IFV-infected mice, which is associated with the inhibition of the TLR4−MyD88−TRAF6 signaling pathway and the expression of NF-κB p65.
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Bai GR, Chittaganpitch M, Kanai Y, Li YG, Auwanit W, Ikuta K, Sawanpanyalert P (2009) Amantadine- and oseltamivir-resistant variants of influenza A viruses in Thailand. Biochem Biophys Res Commun 390:897–901
Kunisaki KM, Janoff EN (2009) Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses. Lancet Infect Dis 9:493–504
Ruuskanen O, Lahti E, Jennings LC, Murdoch DR (2011) Viral pneumonia. Lancet 377:1264–1275
De Clercq E (2006) Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 5:1015–1025
Feng E, Ye D, Li J, Zhang D, Wang J, Zhao F, Hilgenfeld R, Zheng M, Jiang H, Liu H (2012) Recent advances in neuraminidase inhibitor development as anti-influenza drugs. ChemMedChem 7:1527–1536
Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S (2013) The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews. PLoS One 8:e60348
Downes JE, Marshall-Clarke S (2010) Innate immune stimuli modulate bone marrow-derived dendritic cell production in vitro by toll-like receptor-dependent and -independent mechanisms. Immunology 131:513–524
Marchant D, Singhera GK, Utokaparch S, Hackett TL, Boyd JH, Luo Z, Si X, Dorscheid DR, McManus BM, Hegele RG (2010) Toll-like receptor 4-mediated activation of p38 mitogen-activated protein kinase is a determinant of respiratory virus entry and tropism. J Virol 84:11359–11373
Martin TR, Wurfel MM (2008) A TRIFfic perspective on acute lung injury. Cell 133:208–210
Barton GM (2007) Viral recognition by toll-like receptors. Semin Immunol 19:33–40
Imai Y, Kuba K, Neely GG, Yaghubian-Malhami R, Perkmann T, van Loo G, Ermolaeva M, Veldhuizen R, Leung YH, Wang H et al (2008) Identification of oxidative stress and toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133:235–249
Nhu QM, Shirey K, Teijaro JR, Farber DL, Netzel-Arnett S, Antalis TM, Fasano A, Vogel SN (2010) Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo. Mucosal Immunol 3:29–39
Wu XN, Yu CH, Cai W, Hua J, Li SQ, Wang W (2011) Protective effect of a polyphenolic rich extract from Magnolia officinalis bark on influenza virus-induced pneumonia in mice. J Ethnopharmacol 134:191–194
Li L, Yu CH, Ying HZ, Yu JM (2013) Antiviral effects of modified dingchuan decoction against respiratory syncytial virus infection in vitro and in an immunosuppressive mouse model. J Ethnopharmacol 147:238–244
Nagai T, Kataoka E, Aoki Y, Hokari R, Kiyohara H (2014) Alleviative effects of a kampo (a Japanese herbal) medicine “Maoto (Ma-Huang-Tang)” on the Early phase of influenza virus infection and its possible mode of action. Evid Based Complement Alternat Med 2014:187036
Hsieh CF, Lo CW, Liu CH, Lin S, Yen HR, Lin TY, Horng JT (2012) Mechanism by which ma-xing-shi-gan-tang inhibits the entry of influenza virus. J Ethnopharmacol 143:57–67
Zhang BG, Liu QF (2007) Modern pharmacodynamic research and clinical application of Ephedra decoction. Chin Tradit Pat Med 29:415–422
Yang X, Peng WB, Yue XQ (2009) Syndrome differentiation and treatment of Taiyang disease in Shanghan Lun. Zhong Xi Yi Jie He Xue Bao 7:171–174
Mantani N, Andoh T, Kawamata H, Terasawa K, Ochiai H (1999) Inhibitory effect of Ephedrae herba, an oriental traditional medicine, on the growth of influenza A/PR/8 virus in MDCK cells. Antivir Res 44:193–200
Chen KT, Zhou WL, Liu JW, Zu M, He ZN, Du GH, Chen WW, Liu AL (2012) Active neuraminidase constituents of Polygonum cuspidatum against influenza A(H1N1) influenza virus. Zhongguo Zhong Yao Za Zhi 37:3068–3073
Kubo T, Nishimura H (2007) Antipyretic effect of Mao-to, a Japanese herbal medicine, for treatment of type A influenza infection in children. Phytomedicine 14:96–101
Kuo KK, Chang JS, Wang KC, Chiang LC (2009) Water extract of Glycyrrhiza uralensis inhibited enterovirus 71 in a human foreskin fibroblast cell line. Am J Chin Med 37:383–394
Wolkerstorfer A, Kurz H, Bachhofner N, Szolar OH (2009) Glycyrrhizin inhibits influenza A virus uptake into the cell. Antivir Res 83:171–178
Lin CJ, Lin HJ, Chen TH, Hsu YA, Liu CS, Hwang GY, Wan L (2015) Polygonum cuspidatum and its active components inhibit replication of the influenza virus through toll-like receptor 9-induced interferon beta expression. PLoS One 10:e0117602
Michaelis M, Geiler J, Naczk P, Sithisarn P, Leutz A, Doerr HW, Cinatl J Jr (2011) Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression. PLoS One 6:e19705
Song W, Si L, Ji S, Wang H, Fang XM, Yu LY, Li RY, Liang LN, Zhou D, Ye M (2014) Uralsaponins M-Y, antiviral triterpenoid saponins from the roots of Glycyrrhiza uralensis. J Nat Prod 77:1632–1643
He Y, Yu DJ, Zhang YY, Yang JH, Zhou HF, Wan HT (2014) Anti-tussive effect experiment of Yinhua Pinggan granule. Chin Arch Tradit Chin Med 32:2060–2061
Wan HT, Yu DJ, Lei Y, Bai HB, Yang JH, Bie XD (2002) Anti-inflammatory and analgesic effects experiment of Jin-Ping-Gan granule. Pharmacol Clin Chin Mater Med 18:39–40
Peng HQ, Xu ZM, Wan HT, Yu DJ (2005) Inhibitory effect of Jin-Ping-Gan granule on influenza virus. Zhejiang J Tradit Chin Med 12:87–88
Peng XQ, He Y, Zhou HF, Zhang YY, Chen JK, Lu YY, Wan HT (2015) Effects of Yinghuapinggan granule against influenza A/H1N1 virus in vivo. Zhongguo Zhong yao za zhi (to appear)
Harun A, Vidyadaran S, Lim SM, Cole AL, Ramasamy K (2015) Malaysian endophytic fungal extracts-induced anti-inflammation in Lipopolysaccharide-activated BV-2 microglia is associated with attenuation of NO production and IL-6 and TNF-alpha expression. BMC Complement Altern Med 15:166
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408
Rajasekaran D, Palombo EA, Chia Yeo T, Lim Siok Ley D, Lee TuC, Malherbe F, Grollo L (2013) Identification of traditional medicinal plant extracts with novel anti-influenza activity. PLoS One 8:e79293
Kaiser L, Fritz RS, Straus SE, Gubareva L, Hayden FG (2001) Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol 64:262–268
Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE (1998) Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 101:643–649
Loo YM, Gale M Jr (2007) Influenza: fatal immunity and the 1918 virus. Nature 445:267–268
Yu CH, Yan YL, Wu XN, Zhang B, Wang W, Wu QF (2010) Anti-influenza virus effects of the aqueous extract from Mosla scabra. J Ethnopharmacol 127:280–285
Yeo JM, Lee HJ, Kim JW, Lee JB, Park SY, Choi IS, Song CS (2014) Lactobacillus fermentum CJL-112 protects mice against influenza virus infection by activating T-helper 1 and eliciting a protective immune response. Int Immunopharmacol 18:50–54
Kawahara T, Takahashi T, Oishi K, Tanaka H, Masuda M, Takahashi S, Takano M, Kawakami T, Fukushima K, Kanazawa H, Suzuki T (2015) Consecutive oral administration of Bifidobacterium longum MM-2 improves the defense system against influenza virus infection by enhancing natural killer cell activity in a murine model. Microbiol Immunol 59:1–12
Wiley JA, Cerwenka A, Harkema JR, Dutton RW, Harmsen AG (2001) Production of interferon-gamma by influenza hemagglutinin-specific CD8 effector T cells influences the development of pulmonary immunopathology. Am J Pathol 158:119–130
Weiss ID, Wald O, Wald H, Beider K, Abraham M, Galun E, Nagler A, Peled A (2010) IFN-gamma treatment at early stages of influenza virus infection protects mice from death in a NK cell-dependent manner. J Interf Cytokine Res 30:439–449
Hussell T, Pennycook A, Openshaw PJ (2001) Inhibition of tumor necrosis factor reduces the severity of virus-specific lung immunopathology. Eur J Immunol 31:2566–2573
La Gruta NL, Kedzierska K, Stambas J, Doherty PC (2007) A question of self-preservation: immunopathology in influenza virus infection. Immunol Cell Biol 85:85–92
Abdul-Careem MF, Firoz Mian M, Gillgrass AE, Chenoweth MJ, Barra NG, Chan T, Al-Garawi AA, Chew MV, Yue G, van Roojen N et al (2011) FimH, a TLR4 ligand, induces innate antiviral responses in the lung leading to protection against lethal influenza infection in mice. Antivir Res 92:346–355
Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S (2003) TRAM is specifically involved in the toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4:1144–1150
Bradley JR, Pober JS (2001) Tumor necrosis factor receptor-associated factors (TRAFs). Oncogene 20:6482–6491
van de Sandt CE, Kreijtz JH, Rimmelzwaan GF (2012) Evasion of influenza A viruses from innate and adaptive immune responses. Viruses 4:1438–1476
Lawrence T, Fong C (2010) The resolution of inflammation: anti-inflammatory roles for NF-kappaB. Int J Biochem Cell Biol 42:519–523
Wang GF, Shi LP, Ren YD, Liu QF, Liu HF, Zhang RJ, Li Z, Zhu FH, He PL, Tang W et al (2009) Anti-hepatitis B virus activity of chlorogenic acid, quinic acid and caffeic acid in vivo and in vitro. Antivir Res 83:186–190
Hu KJ, Wang YH, Wang D (2010) The inhibited effect of chlorogenic acid from the honeysuckle on virus in vitro. Inf Tradit Chin Med 27:27–28
Utsunomiya T, Kobayashi M, Pollard RB, Suzuki F (1997) Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother 41:551–556
Acknowledgment
This work was supported by a grant from National Science Foundation of China (No. 81573868), Zhejiang Provincial Natural Science Foundation (Nos. LZ14H270001 and LR13H270001), Zhejiang Province Science and Technology Project (No. 2015C37077). We thank Professor Yi-yu Lu for technical help in the animal experiments and helpful discussion regarding this work.
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Peng, Xq., Zhou, Hf., Zhang, Yy. et al. Antiviral effects of Yinhuapinggan granule against influenza virus infection in the ICR mice model. J Nat Med 70, 75–88 (2016). https://doi.org/10.1007/s11418-015-0939-z
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DOI: https://doi.org/10.1007/s11418-015-0939-z