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Abstract: Traditional chinese herbal drugs have been used for thousands of years in Chinese pharmacopoeia. The bark of Magnolia officinalis Rehder & E. Wilson, known under the pinyin name “houpo”, has been traditionally used in Chinese and Japanese medicines for the treatment of anxiety, asthma, depression, gastrointestinal disorders, headache, and more. Moreover, Magnolia bark extract is a major constituent of currently marketed dietary supplements and cosmetic products. Much pharmacological activity has been reported for this herb and its major compounds, notably antioxidant, anti-inflammatory, antibiotic and antispasmodic effects. However, the mechanisms underlying this have not been elucidated and only a very few clinical trials have been published. In vitro and in vivo toxicity studies have also been published and indicate some intriguing features. The present review aims to summarize the literature on M. officinalis bark composition, utilisation, pharmacology, and safety.

厚朴及其成分的生物活性和毒性

[1]Agosta, C., Atlante, M., Benvenuti, C., 2011. Randomized controlled study on clinical efficacy of isoflavones plus Lactobacillus sporogenes, associated or not with a natural anxiolytic agent in menopause. Minerva Ginecol., 63(1):11-17.

[2]AHA, 2016. American Heart Association. http://www.heart.org/HEARTORG

[3]Ahn, K.S., Sethi, G., Shishodia, S., et al., 2006. Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-κB activation pathway. Mol. Cancer Res., 4(9):621-633.

[4]Alexeev, M., Grosenbaugh, D.K., Mott, D.D. et al., 2012. The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA_A receptors. Neuropharmacology, 62(8):2507-2514.

[5]Amblard, F., Govindarajan, B., Lefkove, B., et al., 2007. Synthesis, cytotoxicity, and antiviral activities of new neolignans related to honokiol and magnolol. Bioorg. Med. Chem. Lett., 17(16):4428-4431.

[6]Arora, S., Singh, S., Piazza, G.A., et al., 2012. Honokiol: a novel natural agent for cancer prevention and therapy. Curr. Mol. Med., 12(10):1244-1252.

[7]Bang, K.H., Kim, Y.K., Min, B.S., et al., 2000. Antifungal activity of magnolol and honokiol. Arch. Pharm. Res., 23(1):46-49.

[8]Bielory, L., Russin, J., Zuckerman, G., 2004. Clinical efficacy, mechanisms of action, and adverse effects of complementary and alternative medicine therapies for asthma. Allergy Asthma Proc., 5(5):283-291.

[9]Boustie, J., Stigliani, J., Montanha, J., et al., 1998. Antipoliovirus structure-activity relationships of some aporphine alkaloids. J. Nat. Prod., 61(4):480-484.

[10]Buettner, R., Mora, L.B., Jove, R., 2002. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res., 8(4):945-954.

[11]Bunel, V., Antoine, M.H., Stévigny, C., et al., 2016. New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity. Food Chem. Toxicol., 87:77-87.

[12]Chan, S., Zhao, M., Lao, L., et al., 2008. Magnolol and honokiol account for the anti-spasmodic effect of Magnolia officinalis in isolated Guinea pig ileum. Planta Med., 74(4):381-384.

[13]Chang, B., Lee, Y., Ku, Y., et al., 1998. Antimicrobial activity of magnolol and honokiol against periodontopathic microorganisms. Planta Med., 64(4):367-369.

[14]Chang, H.M., But, P.P.H., 1986. Pharmacology and Applications of Chinese Materia-Medica (Volume I). Word Scientific, Philadelphia.

[15]Chang, H.M., But, P.P.H., 1987. Pharmacology and Applications of Chinese Materia Medica (Volume II). Word Scientific, Philadelphia.

[16]Chen, C.R., Zhou, X.Z., Luo, Y.J., et al., 2012. Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABA_A receptor in mice. Neuropharmacology. 63(6):1191-1199.

[17]Chen, F., Wang, T., Wu, Y.F., et al., 2004. Honokiol: a potent chemotherapy candidate for human colorectal carcinoma. World J. Gastroenterol., 10(23):3459-3463.

[18]Chen, Y.H., Lin, S.J., Chen, Y.L., et al., 2006. Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules. Cardiovasc. Haematol. Disord., 6(4):279-304.

[19]Choi, M.S., Lee, S.H., Cho, H.S., et al., 2007. Inhibitory effect of obovatol on nitric oxide production and activation of NF-κB/MAP kinases in lipopolysaccharide-treated RAW 264.7 cells. Eur. J. Pharmacol., 556(1-3):181-189.

[20]Coleman, J.W., 2001. Nitric oxide in immunity and inflammation. Int. Immunopharmacol., 1(8):1397-1406.

[21]Council of Europe, 2013. European Pharmacopoeia 8.1. Council of Europe, Strasbourg, p.3949-3950.

[22]CPC (Chinese Pharmacopoeia Commission), 2010. Pharmacopoeia of the People’s Republic of China (English Edition). China Medical Science Press, Beijing, China.

[23]Cui, W., Wang, Y., Chen, Q., et al., 2013. Magnolia extract (BL153) ameliorates kidney damage in a high fat diet-induced obesity mouse model. Oxid. Med. Cell. Longev., 2013:367040.

[24]Curran, T., Franza, B.J., 1988. Fos and Jun: the AP-1 connection. Cell, 55(3):395-397.

[25]Davis, T.L., 1981. Chemistry of Magnolia grandiflora L. University of Florida.

[26]Dharmananda, S., 2002. Safety Issues Affecting Chinese Herbs: Magnolia alkaloids. Institute for Traditional Medicine, Oregon. http://www.itmonline.org/arts/magsafe.htm

[27]EPCNF (European Parliament Concerning Novel Foods and Novel Food Ingredients), 2009. Application for the Approval of Magnolia Bark Supercritical Carbon Dioxide Extract (MBSE) from Magnolia officinalis. The William Wrigley Jr. Company, Chicago.

[28]Fazel, M., 1995. Now show me your tongue: a taste of medicine in China. Lancet, 346(8991-8992):1687-1688.

[29]Ferrero-Miliani, L., Nielsen, O.H., Andersen, P.S., et al., 2007. Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation. Clin. Exp. Immunol., 147(2):227-235.

[30]Fried, L.E., Arbiser, J.L., 2009. Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid. Redox Signal., 11(5):1139-1148.

[31]Garcia, X., Stein, F., 2006. Nitric oxide. Semin. Pediatr. Infect. Dis., 17(2):55-57.

[32]Garg, A., Aggarwal, B.B., 2002. Nuclear transcription factor-κB as a target for cancer drug development. Leukemia, 16(6):1053-1068.

[33]Garrison, R., Chambliss, W.G., 2006. Effect of a proprietary Magnolia and Phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial. Altern. Ther. Health Med., 12(1):50-54.

[34]Grivennikov, S., Karin, M., 2010. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalkin cancer. Cytokine Growth Factor Rev., 21(1):11-19.

[35]Guertin, D.A., Sabatini, D.M., 2007. Defining the role of mTOR in cancer. Cancer Cell, 12(1):9-22.

[36]Guo, Z., Wang, X.B., Luo, J.G., et al., 2011. A novel aporphine alkaloid from Magnolia officinalis. Fitoterapia, 82(4):637-641.

[37]Hahm, E.R., Singh, S.V., 2007. Honokiol causes G₀-G₁ phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity. Mol. Cancer Ther., 6(10):2686-2695.

[38]Hellstrom, M.K., Ramberg, P., 2014. The effect of a dentifrice containing Magnolia extract on established plaque and gingivitis in man: a six-month clinical study. Int. J. Dent. Hyg., 12(2):96-102.

[39]Herlaar, E., Brown, Z., 1999. p38 MAPK signalling cascades in inflammatory disease. Mol. Med. Today, 5(10):439-447.

[40]Herrmann, D., Schreiber, A., Ciotkowska, A., et al., 2014. Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death. Prostate Int., 2(3):140-146.

[41]Ho, J.H.C., Hong, C.Y., 2012. Cardiovascular protection of magnolol: cell-type specificity and dose-related effects. J. Biomed. Sci., 19:70.

[42]Ho, K.Y., Tsai, C.C., Chen, C.P., et al., 2001. Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytother. Res., 15(2):139-141.

[43]Hoi, C.P., Ho, Y.P., Baum, L., et al., 2010. Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells. Phytother. Res., 24(10):1538-1542.

[44]Homma, M., Oka, K., Kobayashi, H., et al., 1993. Impact of free magnolol excretions in asthmatic patients who responded well to Saiboku-To, a Chinese herbal medicine. J. Pharm. Pharmacol., 45(9):844-846.

[45]Hon, K.L., Fung, C.K., Leung, A.K., et al., 2015. Complementary and alternative medicine for childhood asthma: an overview of evidence and patents. Recent Pat. Inflamm. Allergy Drug Discov., 9(1):66-79.

[46]Hu, J., Gao, W.Y., Ling, N.S., et al., 2009. Antidiarrhoeal and intestinal modulatory activities of Wei-Chang-An-Wan extract. J. Ethnopharmacol., 125(3):450-455.

[47]Hu, Y., Qiao, J., Zhang, X., et al., 2011. Antimicrobial effect of Magnolia officinalis extract against Staphylococcus aureus. J. Sci. Food Agric., 91(6):1050-1056.

[48]International Agency for Research on Cancer, 2002. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monogr. Eval. Carcinog. Risks Hum., 82:1-556.

[49]Iwasaki, K., Wang, Q., Seki, H., et al., 2000. The effects of the traditional Chinese medicine Banxia Houpo Tang on the swallowing reflex in Parkinson’s disease. Phytomedicine, 7(4):259-263.

[50]Jeong, S.I., Kim, Y.S., Lee, M.Y., et al., 2009. Regulation of contractile activity by magnolol in the rat isolated gastrointestinal tracts. Pharmacol. Res., 59(3):183-188.

[51]Kalman, D.S., Feldman, S., Feldman, R., et al., 2008. Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial. Nutr. J., 7:11.

[52]Kang, J.S., Lee, K.H., Han, M.H., et al., 2008. Antiinflammatory activity of methanol extract isolated from stem bark of Magnolia kobus. Phytother. Res., 22(7):883-888.

[53]Karin, M., 2006. NF-κB and cancer: mechanisms and targets. Mol. Carcinog., 45(6):355-361.

[54]Kaushik, G., Ramalingam, S., Subramaniam, D., et al., 2012. Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells. Am. J. Surg., 204(6):868-873.

[55]Kim, B.H., Cho, J.Y., 2008. Anti-inflammatory effect of honokiol is mediated by PI3K/Akt pathway suppression. Acta Pharmol. Sin., 29(1):113-122.

[56]Kim, S.Y., Kim, J., Jeong, S.I., et al., 2015. Antimicrobial effects and resistant regulation of magnolol and honokiol on methicillin-resistant Staphylococcus aureus. Biomed. Res. Int., 2015:283630.

[57]Kim, Y.J., Choi, M.S., Cha, B.Y., et al., 2013. Long-term supplementation of honokiol and magnolol ameliorates body fat accumulation, insulin resistance, and adipose inflammation in high-fat fed mice. Mol. Nutr. Food Res., 57(11):1988-1998.

[58]Kimura, I., Chui, L.H., Fujitani, K., et al., 1989. Inotropic effects of (±)-higenamine and its chemically related components, (+)-R-coclaurine and (+)-S-reticuline, contained in the traditional sino-Japanese medicines “Bushi” and “Shin-i” in isolated guinea pig papillary muscle. Jpn. J. Pharmacol., 50(1):75-78.

[59]Ko, C.H., Chen, H.H., Lin, Y.R., et al., 2003. Inhibition of smooth muscle contraction by magnolol and honokiol in porcine trachea. Planta Med., 69(6):532-536.

[60]Koetter, U., Barrett, M., Lacher, S., et al., 2009. Interactions of Magnolia and Ziziphus extracts with selected central nervous system receptors. J. Ethnopharmacol., 124(3):421-425.

[61]Kong, Z.L., Tzeng, S.C., Liu, Y.C., 2005. Cytotoxic neolignans: an SAR study. Bioorg. Med. Chem. Lett., 15(1):163-166.

[62]Kumar, A., Singh, U.K., Chaudhary, A., 2013. Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities. Future Med. Chem., 5(7):809-829.

[63]Lee, B., Kim, C.H., Moon, S.K., 2006. Honokiol causes the p21WAF1-mediated G(1)-phase arrest of the cell cycle through inducing p38 mitogen activated protein kinase in vascular smooth muscle cells. FEBS Lett., 580(22):5177-5184.

[64]Lee, D.H., Szczepanski, M.J., Lee, Y.J., 2009. Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells. J. Cell. Biochem., 106(6):1113-1122.

[65]Lee, J.W., Lee, Y.K., Lee, B.J., et al., 2010. Inhibitory effect of ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on memory impairment and neuronal toxicity induced by beta-amyloid. Pharmacol. Biochem. Behav., 95(1):31-40.

[66]Lee, S.K., Chun, H.K., Yang, J.Y., et al., 2007. Inhibitory effect of obovatal on the migration and invasion of HT1080 cells via the inhibition of MMP-2. Bioorg. Med. Chem., 15(12):4085-4090.

[67]Lee, S.Y., Cho, J.S., Yuk, D.Y., et al., 2009. Obovatol enhances docetaxel-induced prostate and colon cancer cell death through inactivation of nuclear transcription factor-κB. J. Pharm. Sci., 111(2):124-136.

[68]Lee, Y.J., Lee, Y.M., Lee, C.K., et al., 2011. Therapeutic applications of compounds in the Magnolia family. Pharmacol. Ther., 130(2):157-176.

[69]Lee, Y.S., Choi, S.S., Yonezawa, T., et al., 2015. Honokiol, magnolol, and a combination of both compounds improve glucose metabolism in high-fat diet-induced obese mice. Food Sci.Biotechnol., 24(4):1467-1474.

[70]Li, H.B., Yi, X., Gao, J.M., et al., 2007. Magnolol-induced H460 cells death via autophagy but not apoptosis. Arch. Pharm. Res., 30(12):1566-1574.

[71]Li, L., Han, W., Gu, Y., et al., 2007. Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore. Cancer Res., 67(10):4894-4903.

[72]Li, N., Song, Y., Zhang, W., et al., 2007. Evaluation of the in vitro and in vivo genotoxicity of magnolia bark extract. Regul. Toxicol. Pharmacol., 49(3):154-159.

[73]Lim, Y., Kwon, J.S., Kim, D.W., et al., 2010. Obovatol from Magnolia obovata inhibits vascular smooth muscle cell proliferation and intimal hyperplasia by inducing p21Cip1. Atherosclerosis, 210(2):372-380.

[74]Lin, S.I., Tsai, T.H., Chou, Y.J., et al., 2015. Characteristics associated with utilization of asthma-related traditional Chinese medicine services among asthma children in Taiwan: a nationwide cohort study. Evid. Based Complement. Alternat. Med., 2015:108961.

[75]Lin, S.P., Tsai, S.Y., Chao, P.D.L., et al., 2011. Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats. Planta Med., 77(16):1800-1805.

[76]Lin, S.Y., Chang, Y.T., Liu, J.D., et al., 2001. Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells. Mol. Carcinog., 32(2):73-83.

[77]Lin, Y.R., Chen, H.H., Ko, C.H., et al., 2007. Effects of honokiol and magnolol on acute and inflammatory pain models in mice. Life Sci., 81(13):1071-1078.

[78]Liu, H., Zang, C., Emde, A., et al., 2008. Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer. Eur. J. Pharmacol., 591(1-3):43-51.

[79]Liu, X., Wang, Q., Song, G., et al., 2014. The classification and application of toxic Chinese materia medica. Phytother. Res., 28(3):334-347.

[80]Liu, Z., Zhang, X., Cui, W., et al., 2007. Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats. Regul. Toxicol. Pharmacol., 49(3):160-171.

[81]Lo, Y.C., Teng, C.M., Chen, C.F., et al., 1994. Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation. Biochem. Pharmacol., 47(3):549-553.

[82]Lu, Y.C., Chen, H.H., Ko, C.H., et al., 2003. The mechanism of honokiol-induced and magnolol-induced inhibition on muscle contraction and Ca²⁺ mobilization in rat uterus. Naunyn-Schmiedeberg’s Arch. Pharmacol., 368(4):262-269.

[83]Maruyama, Y., Kuribara, H., 2000. Overview of the pharmacological features of honokiol. CNS Drug Rev., 6(1):35-44.

[84]Maruyama, Y., Kuribara, H., Morita, M., et al., 1998. Identification of magnolol and honokiol as anxiolytic agents in extracts of Saiboku-To, an oriental herbal medicine. J. Nat. Prod., 61(1):135-138.

[85]Mohamed, S.M., Hassan, E.M., Ibrahim, N.A., 2010. Cytotoxic and antiviral activities of aporphine alkaloids of Magnolia grandiflora L. Nat. Prod. Res., 24(15):1395-1402.

[86]Mucci, M., Carraro, C., Mancino, P., et al., 2006. Soy isoflavones, lactobacilli, Magnolia bark extract, vitamin D3 and calcium. Controlled clinical study in menopause. Minerva Ginecol., 58(4):323-334.

[87]Munroe, M.E., Arbiser, J.L., Bishop, G.A., 2007. Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis. J. Immunol., 179(2):753-763.

[88]Nachtergael, A., Poivre, M., Belayew, A., et al., 2015. In vitro genotoxicity tests point to an unexpected and harmful effect of a Magnolia and Aristolochia association. J. Ethnopharmacol., 174:178-186.

[89]Nakazawa, T., Yasuda, T., Ohsawa, K., 2003. Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice. J. Pharm. Pharmacol., 55(11):1583-1591.

[90]NCBI (National Center for Biotechnology Information), 2016. PubChem Compound Database. http://pubchem.ncbi.nlm.nih.gov

[91]Newton, K., Dixit, V.M., 2012. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol., 4(3):a006049.

[92]Ngezahayo, J., Havyarimana, F., Hari, L., et al., 2015. Medicinal plants used by Burundian traditional healers for the treatment of microbial diseases. J. Ethnopharmacol., 173:338-351.

[93]Ngezahayo, J., Pottier, L., Ribeiro, S.O., et al., 2016. Plastotoma rotundifolium aerial tissue extract has antibacterial activities. Ind. Crops Prod., 86:301-310.

[94]Okusa, P.N., Stévigny, C., Névraumont, M., et al., 2014. Ferulaldehyde and lupeol as direct and indirect antimicrobial compounds from Cordia gilletii (Boraginaceae) root barks. Nat. Prod. Commun., 9(5):619-622.

[95]Ou, H.C., Chou, F.P., Lin, T.M., et al., 2006. Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells. Chem.-Biol. Interact., 161(1):1-13.

[96]Ouédraogo, M., Baudoux, T., Stévigny, C., et al., 2012. Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms. J. Ethnopharmacol., 140(3):492-512.

[97]Park, C.S., Kim, T.B., Lee, J.Y., et al., 2012. Effects of add-on therapy with NDC-052, an extract from Magnoliae flos, in adult asthmatic patients receiving inhaled corticosteroids. Korean J. Intern. Med., 27(1):84-90.

[98]Park, J., Lee, J., Jung, E., et al., 2004. In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp. Eur. J. Pharmacol., 496(1-3):189-195.

[99]Pearson, G., Robinson, F., Gibson, T.B., et al., 2001. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev., 22(2):153-183.

[100]Porciani, P.F., Grandini, S., 2012. The effect of zinc acetate and magnolia bark extract added to chewing gum on volatile sulfur-containing compounds in the oral cavity. J. Clin. Dent., 23(3):76-79.

[101]Porciani, P.F., Grandini, S., Chazine, M., 2014. The effect of zinc lactate and magnolia bark extract added tablets on volatile sulfur-containing compounds in the oral cavity. J. Clin. Dent., 25(3):53-56.

[102]Pyo, M.K., Yun-Choi, H.S., Hong, Y.J., 2003. Antiplatelet activities of aporphine alkaloids isolated from leaves of Magnolia obovata. Planta Med., 69(3):267-269.

[103]Rasamiravaka, T., Vandeputte, O.M., Pottier, L., et al., 2014. Pseudomonas aeruginosa biofilm formation and persistence, along with the production of quorum sensing dependent virulence factors, are disrupted by a triterpenoid coumarate ester isolated from Dalbergia trichocarpa, a tropical legume. PLoS ONE, 10(7):e0132791.

[104]Ricciardolo, F.L., Sterk, P.J., Gaston, B., et al., 2004. Nitric oxide in health and disease of the respiratory system. Physiol. Rev., 84(3):731-765.

[105]Sheu, M.L., Liu, S.H., Lan, K.H., 2007. Honokiol induces calpain-mediated glucose-regulated protein-94 cleavage and apoptosis in human gastric cancer cells and reduces tumor growth. PLoS ONE, 2(10):e1096.

[106]Shih, C.Y., Chou, T.C., 2012. The antiplatelet activity of magnolol is mediated by PPAR-β/γ. Biochem. Pharmacol., 84(6):793-803.

[107]Simmonds, R.E., Foxwell, B.M., 2008. Signalling, inflammation and arthritis: NF-κB and its relevance to arthritis and inflammation. Rheumatology (Oxford), 47(5):584-590.

[108]Sohn, E.J., Kim, C.S., Kim, Y.S., et al., 2007. Effects of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) on diabetic nephropathy in type 2 diabetic Goto-Kakizaki rats. Life Sci., 80(5):468-475.

[109]Syu, W.J., Shen, C.C., Lu, J.J., et al., 2004. Antimicrobial and cytotoxic activities of neolignans from Magnolia officinalis. Chem. Biodivers., 1(3):530-537.

[110]Tachikawa, E., Takahashi, M., Kashimoto, T., 2000. Effects of extract and ingredients isolated from Magnolia obovata Thunberg on catecholamine secretion from bovine adrenal chromaffin cells. Biochem. Pharmacol., 60(3):433-440.

[111]Tang, J.L., Liu, B.Y., Ma, K.W., 2008. Traditional Chinese medicine. Lancet, 372(9654):1938-1940.

[112]Taniguchi, C., Homma, M., Takano, O., et al., 2000. Pharmacological effects of urinary products obtained after treatment with saibokuto, a herbal medicine for bronchial asthma, on type IV allergic reaction. Planta Med., 66(7):607-611.

[113]Teng, C.M., Chen, C.C., Ko, F.N., et al., 1988. Two antiplatelet agents from Magnolia officinalis. Thromb. Res., 50(6):757-765.

[114]Teschke, R., Wolff, A., Frenzel, C., et al., 2014. Review article: herbal hepatotoxicity—an update on traditional Chinese medicine preparations. Aliment. Pharmacol. Ther., 40(1):32-50.

[115]Teschke, R., Zhang, L., Long, H., et al., 2015. Traditional Chinese medicine and herbal hepatotoxicity: a tabular compilation of reported cases. Ann. Hepatol., 14(1):7-19.

[116]Teschke, R., Larrey, D., Melchart, D., et al., 2016. Traditional Chinese medicine (TCM) and herbal hepatotoxicity: RUCAM and the role of novel diagnostic biomarkers such as microRNAs. Medicines, 3(3):18.

[117]Tripathi, P., Kashyap, L., Singh, V., 2007. The role of nitric oxide in inflammatory reactions. FEMS Immunol. Med. Microbiol., 51(3):443-452.

[118]Unschuld, P.U., 1999. The past 1000 years of Chinese medicine. Lancet, 354:SIV9.

[119]Vanherweghem, J.L., Depierreux, M., Tielemans, C., et al., 1993. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet, 341(8842):387-391.

[120]Wang, J.P., Hsu, M.F., Raung, S.L., et al., 1992. Antiinflammatory and analgesic effects of magnolol. Naunyn-Schmiedeberg’s Arch. Pharmacol., 346(6):707-712.

[121]Wang, S., Li, Y., 2005. Traditional Chinese medicine. In: Devinsky, O., Pacia, S., Shachter, S. (Eds.), Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing, New York, p.177-182.

[122]Wang, T., Chen, F., Chen, Z., et al., 2004. Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO. World J. Gastroenterol., 10(15):2205-2208.

[123]Waymire, J.C., 1997. Chapter 12: Biogenic Amine Neurotransmitters. University of Texas Medical School at Houston. http://neuroscience.uth.tmc.edu/s1/chapter12.html

[124]WHO (World Health Organization), 2016. World Health Statistics 2016: Monitoring Health for the SDGs. World Health Organization, Geneva.

[125]Williamson, E.M., Chan, K., Xu, Q., et al., 2015. Integrated toxicological approaches to evaluating the safety of herbal medicine. Science, 347(6219 Suppl.):S47-S49.

[126]Wisdom, R., 1999. AP-1: one switch for many signals. Exp. Cell Res., 253(1):180-185.

[127]Wittchen, H.U., Hoyer, J., 2001. Generalized anxiety disorder: nature and course. J. Clin. Psychiatr., 62(Suppl. 11):15-21.

[128]Woodbury, A., Yu, S.P., Wei, L., et al., 2013. Neuro-modulating effects of honokiol: a review. Front. Neurol., 4:130.

[129]Xu, Q., Bauer, R., Hendry, B.M., et al., 2013. The quest for modernisation of traditional Chinese medicine. BMC Complement. Altern. Med., 13:132.

[130]Yan, R., Wang, W., Guo, J., et al., 2013. Studies on the alkaloids of the bBark of Magnolia officinalis: isolation and on-line analysis by HPLC-ESI-MSⁿ. Molecules, 18(7):7739-7750.

[131]Yang, H.Y., Chen, C.F., 1997. Subacute toxicity of 15 commonly used Chinese drugs (II). J. Food Drug. Anal., 5(4):355-380.

[132]Yang, S.E., Hsieh, M.T., Tsai, T.H., et al., 2002. Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiolinduced apoptosis in human squamous lung cancer CH27 cells. Biochem. Pharmacol., 63(9):1641-1651.

[133]Yang, S.E., Hsieh, M.T., Tsai, T.H., et al., 2003. Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells. Br. J. Pharmacol., 138(1):193-201.

[134]Young, I.S., Woodside, J.V., 2001. Antioxidants in health and disease. J. Clin. Pathol., 54(3):176-186.

[135]Yu, C., Meyer, D., Campbell, G., et al., 1995. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science, 269(5220):81-83.

[136]Yu, S.X., Yan, R.Y., Liang, R.X., et al., 2012. Bioactive polar compounds from stem bark of Magnolia officinalis. Fitoterapia, 83(2):356-361.

[137]Zaki, H.F., Abd-El-Fattah, M.A., Amina, S.A., 2014. Naringenin protects against scopolamine-induced dementia in rats. Bull. Fac. Pharm. Cairo Univ., 52(1):15-25.

[138]Zandi, R., Larsen, A.B., Andersen, P., et al., 2007. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell. Signal., 19(10):2013-2023.

[139]Zhang, B., Maniatis, T., Song, Y., et al., 2008. Evaluation of magnolia bark extract in chromosomal aberration assays. Mutat. Res.-Genet. Toxicol. Environ. Mutag., 654(2):133-137.

[140]Zhang, L., Yan, J., Liu, X., et al., 2012. Pharmacovigilance practice and risk control of TCM in China. J. Ethnopharmacol., 140(3):519-525.

[141]Zhang, P., Liu, X., Zhu, Y., et al., 2013. Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells. Neurosci. Lett., 534:123-127.

[142]Zhou, H.Y., Shin, E.M., Guo, L.Y., et al., 2008. Antiinflammatory activity of 4-methoxyhonokiol is a function of the inhibition of iNOS and COX-2 expression in RAW 264.7 macrophages via NF-κB, JNK and p38 MAPK inactivation. Eur. J. Pharmacol., 586(1-3):340-349.

[143]Zhu, Y., Niu, M., Chen, J., et al., 2016. Hepatobiliary and pancreatic: comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients. J. Gastroenterol. Hepatol., 31(8):1476-1482.

[144]Ziyaev, R., Shtonda, N.I., Sturua, M.D., et al., 1999. Alkaloids of some Magnolia species. Life Sci., 35(3):366-367.

[145]Zuo, G.Y., Zhang, X.J., Han, J., et al., 2015. In vitro synergism of magnolol and honokiol in combination with antibacterial agents against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). BMC Complement. Altern. Med., 15(1):425.