Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents

Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents 厚朴及其成分的生物活性和毒性 first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:pierre.duez@umons.ac.be †E-mail:pierre.duez@umons.ac.be pierre.duez@umons.ac.be Unit of Therapeutic Chemistry and Pharmacognosy, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons–UMONS, Mons, Belgium Unit of Therapeutic Chemistry and Pharmacognosy, Faculty of Medicine and Pharmacy, Research Institute for Health Sciences and Technology, University of Mons–UMONS, Mons, Belgium 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. 中草药已在中国药典中使用了数千年。木兰属的厚朴，主要用于治疗焦虑、哮喘、抑郁症、胃肠道疾病、头痛。其树皮提取物是目前市售的食品补充剂和化妆品的主要成分。厚朴及其主要成分具有多种药理活性，具有抗氧化、抗炎、抗生素和抗痉挛作用。然而，相关机制尚未明确，临床试验也鲜有报道。体外和体内毒性研究已经发现了一些有趣的特征。本文旨在总结关于厚朴的成分、利用、药理学和安全性的文献。 Magnolia bark Houpo Chinese herb Traditional Chinese medicine 木兰树皮 厚朴 中草药 中药 Introduction 1 Traditional Chinese medicine (TCM) has a more than 2500-year history and consists of the development of major theories and clinical investigations carried out by generations of practitioners and researchers (Fazel, 1995 1995 ; Unschuld, 1999 1999 ; Wang and Li, 2005 2005 ; Tang et al., 2008 2008 ; Xu et al., 2013 2013 ). Different Magnolia have been traditionally used in Chinese and Japanese medicine for thousands of years (Liu et al., 2007 2007 ) and are now widely used internationally. There are three basic materials of frequent application and described in the Chinese pharmacopoeia 2010 (CPC, 2010 2010 ): the bark of Magnolia officinalis Rehder & E. Wilson, called “Houpo” or “Houpu” in Chinese (Houpu, refers to the thick (“hou”) bark that is the unadorned (“pu”) portion of the plant. The herb is sometimes called “Chuan houpu”, because it originally came from the Sichuan area of China. Tuhoupu (“tu” is especially used in Guangxi Province, China) is sometimes used as a substitute (Dharmananda, 2002 2002 ), the flower bud of M . officinalis , called “Houpohua”, and the flower bud of Magnolia biondii Pamp., Magnolia denudate Desr., or Magnolia sprengeri Pamp. called “Xinyi” or “Xinyihua”. A non-official species, Magnolia obovata Thunb., is sometimes described as source material for Magnolia bark (Liu et al., 2007 2007 ). In some literature, the flower is wrongly assigned to a non-botanically defined species, erroneously called Magnolia lactiflora . Magnolia trees are mainly distributed in East and Southeast Asia (Cui et al., 2013 2013 ) and are generally very attractive thanks to their fragrant and dazzling flowers (Lee et al., 2011 2011 ). The root and branch bark are collected from April to June and dried in the shade; the stem bark is slightly decocted in boiling water and piled up in a wet place until its inner surface becomes purplish-brown or dark brown, softened by steaming, and rolled and dried (CPC, 2010 2010 ). The dried bark is gray-brown in color with oval lenticles in a longitudinal striation (Fig. 1 1 ) and has a fragrant odor, a pungent taste, and is slightly bitter (EPCNF, 2009 2009 ). The current taxonomic description of the plant is summarized below: Kingdom: Viridiplantae; Phylum: Streotophyta; Class: Eukaryota; Order: Magnoliales; Family: Magnoliaceae; Genus: Magnolia Species: Magnolia officinalis , Magnolia obovata ; Pharmaceutical name: Magnoliae cortex, Magnolia officinalis cortex, Magnolia officinalis bark; TCM name: Hou Po or Houpo. Magnolia bark has been used as a constituent of various traditional Chinese formulas such as “Banxia Houpo Tang” (Table 1 1 ), “Xiao Zhengai Tang”, “Ping Wei San”, and “Shenmi Tang”. In China, a number of prescriptions containing Houpo are still in use in modern clinical practice (Yu et al., 2012 2012 ). In Japan, two prescriptions containing Magnolia bark, Hange-Koboku-To (Japanese name for Banxia Houpo Tang) (Iwasaki et al., 2000 2000 ) and Saiboku-To (Table 1 1 ), are also still in use in modern clinical practice (Li N. et al., 2007 2007 ; Lee et al., 2011 2011 ). Although these herbs are part of herbal formulae implicated in hepatotoxicities (Teschke et al., 2014 2014 ; 2015 2015 ; 2016 2016 ; Zhu et al., 2016 2016 ), the causality assessment is most often lacking Traditional Chinese and Japanese formulas Plants Banxia Houpo Tang (Chinese) (Iwasaki et al., 2000 2000 ) Pinellia a a ( Pinellia ternate Thunb.): 6. Hoelen a a ( Poria cocos Wolf): 3.0 g Magnolia ( Magnolia obovata Thunb.): 3.0 g Perilla ( Perilla frutescens Britton var. acuta Kudo): 2.0 g Ginger a a ( Zingiber officinale Roscoe): 1.0 g Saiboku-To (Japanese) (Bielory et al., 2004 2004 ) Bupleuri a a ( Bupleurum falcatum L.): 7.0 g Pinellia a a ( Pinellia ternata Thunb.): 5.0 g Hoelen a a ( Poria cocos Wolf): 5.0 g Scutellaria a a ( Sculellaria baicalensis Georgi): 3.0 g Magnolia ( Magnolia obovata Thunb.): 3.0 g Zizyphi a a ( Zizyphus jujuba Miller var. inermis Rehder): 3.0 g Ginseng a a ( Panax ginseng C.A. Meyer): 3.0 g Glycyrrhiza a a ( Glycyrrhiza uralensis Fisch.): 2.0 g Perilla ( Perilla frutescens Britton var. acuta Kudo): 2.0 g Zingiberis a a ( Zingiber officinale Roscoe): 1.0 g Herbal preparations containing Magnolia bark are typically used as decoctions with intakes ranging from 3 to 10 g per person. Various Magnolia bark extracts (MBEs) can also be found in the marketplace as ingredients of both dietary supplements, typical recommended use levels ranging from 200 to 800 mg/d per person (EPCNF, 2009 2009 ), and cosmetic products (Liu et al., 2007 2007 ). The flower bud is used almost exclusively for the treatment of sinus congestion and sinus headaches, and is taken orally or applied topically. Magnolia bark, on the other hand, has a very wide range of applications as will be detailed in the present review; it has been used in Chinese and Japanese traditional medicines for the treatment of gastrointestinal (GI) disorders, anxiety, depression, nervous disorders, asthma, and allergic disease, as well for the alleviation of headaches, muscular pain, and fever (Dharmananda, 2002 2002 ; Amblard et al., 2007 2007 ; Li N. et al., 2007 2007 ; Liu et al., 2007 2007 ; Lee et al., 2011 2011 ). Phytochemicals isolated from Magnolia 1 Up till now, more than 250 kinds of ingredients have been isolated from the cones, bark, flowers, and leaves of the genus Magnolia (Cui et al., 2013 2013 ). Chemical investigations of the cortex of M. officinalis and M. obovata led to the isolation of several major phenolic compounds, notably the neolignan derivatives magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) and honokiol (5,3'-diallyl-2,4'-dihydroxybiphenyl) (Table 2 2 ), which are considered the two principal phenolic compounds in the bark and the main active constituents (Dharmananda, 2002 2002 ; Li N. et al., 2007 2007 ; EPCNF, 2009 2009 ). ppm: 1 ppm=1 mg/L Component Parts where found Essential oil Bark (3000–10 000 ppm) * *  Bornyl-acetate Essential oil (terpene)  Camphene Essential oil (terpene)  Caryophyllene epoxide Essential oil (terpene)  Eudesmols Bark  α-Eudesmol Essential oil (terpene)  β-Eudesmol Essential oil (terpene)  γ-Eudesmol Essential oil (terpene)  Cryptomeridiol Essential oil (terpene)  α-Pinene Whole plant (terpene)  β-Pinene Whole plant (terpene) Polyphenol  Bornyl-magnoliol Whole plant (lignan)  Caffeic acid Whole plant  Cyanidin Whole plant (anthocyanidin)  Honokiol Whole plant (lignan)  Quercetin Whole plant (flavonoid)  Kaempferol Whole plant (flavonoid)  Magnolol Bark (lignan) Alkaloid About 1% of the bark  Anonaine Whole plant (aporphine)  Liriodenine Whole plant (aporphine)  Magnocurarine Whole plant (benzyltetrahydroisoquinoline)  Magnoflorine Whole plant (benzyltetrahydroisoquinoline)  Michelalbine Whole plant (aporphine)  Salicifoline Whole plant (phenethylamine) Mineral  Copper Bark (8 ppm)  Calcium Bark (6350 ppm)  Iron Bark (120 ppm)  Magnesium Bark (690 ppm)  Manganese Bark (120 ppm)  Potassium Bark (2560 ppm)  Sodium Bark (27 ppm)  Zinc Bark (9 ppm) As well as these well-known lignans magnolol and honokiol, alkaloids are a group of interesting secondary metabolites of this species, which produces mainly isoquinoline-type alkaloids, the majority of which are aporphine and benzylisoquinoline derivatives (Yan et al., 2013 2013 ). Magnolia bark also contains volatile oils, the major constituents of which are the sesquiterpenoid alcohols, α-, β-, and γ-eudesmol (about 95% of the essential oil). Specific components in the bark and the proportions of those constituents significantly differ depending on harvesting sites and period (EPCNF, 2009 2009 ). Lignans 2 Major significant bioactive components isolated from the bark of M. officinalis or M. obovata appear to be the polyphenolic neolignans, magnolol and honokiol (Kong et al., 2005 2005 ; Amblard et al., 2007 2007 ; Lin et al., 2011 2011 ). Magnolol was named after its source, genus Magnolia plants, and honokiol was named after “Honoki”, a Japanese name of M. obovata Thunb. (Maruyama and Kuribara, 2000 2000 ). Magnolol and honokiol are two hydroxylated biphenolic isomers (neolignans, C 18 H 18 O 2 ) (Lin et al., 2007 2007 ), the ortho - ortho -C-C and ortho - para -C-C dimers of 4-allyl-phenol, respectively (Kong et al., 2005 2005 ) (Table 3 3 ). Commercially available Magnolia bark extracts appear to be marketed based on their high phenolic content, with magnolol and honokiol ranging from 40% to 90% of total polyphenols; the evaluation of the quality of commercial Houpo samples, according to region, harvesting, and processing, is effectively based on a quantitative determination of the levels of magnolol and honokiol in the bark (EPCNF, 2009 2009 ). The Chinese (CPC, 2010 2010 ) and European pharmacopoeia (Council of Europe, 2013 2013 ) require a minimum of 2.0% of the total amount of honokiol and magnolol, with reference to the dried drug. Other neolignans include 4- O -methylhonokiol (0.012% in M. obovata and 0.0003% in M. officinalis bark) and obovatol (only found in M. obovata at 0.33%) (Lee et al., 2011 2011 ). Alkaloids 2 Other bioactive polar compounds from Magnolia bark are alkaloids (about 1% of the bark), mainly benzyltetrahydroisoquinoline and aporphine types (Yu et al., 2012 2012 ), based on the precursor amino acids tyrosine and dopa. Alkaloids that possess an isoquinoline skeleton are among the most common of all alkaloids. From the bark of M. officinalis , different tertiary and quaternary alkaloids have been isolated and structurally elucidated (Yan et al., 2013 2013 ), including (1) the aporphine alkaloids N -methylcoxylonine, ( S )-magnoflorine, magnofficine, ( R )-asimilobine, corytubérine, anonaine, liriodenine and (2) the benzyltetrahydroisoquinoline alkaloids ( R )-magnocurarine, ( S )-tembetarine, lotusine, ( R )-oblongine, reticuline (Guo et al., 2011 2011 ; Yan et al., 2013 2013 ). Magnoflorine and magnocurarine are considered as the major and most potent of Magnolia bark alkaloids (Dharmananda, 2002 2002 ) (Tables 4 4 and 5 5 ). Species Collection site Magnocurarine (% (w/w) in bark) Magnolia officinalis Zhenping, Shaanxi 0.150 Magnolia officinalis Hanzhong, Shaanxi 0.103 Magnolia officinalis Ansi, Hubei 0.127 Magnolia officinalis Nanjiang, Sichuan 0.060 Magnolia officinalis var. biloba Jinggangshan, Jiangxi 0.060 Magnolia officinalis var. biloba Guilin, Guangxi 0.025 Magnolia officinalis var. biloba Lishui, Zhejiang 0.201 Alkaloids are found in leaves (at full maturation or beginning of fall), branches, and bark of Magnolia species (Ziyaev et al., 1999 1999 ). These alkaloids include tertiary and the highly polar quaternary ammoniums. Biological activity 1 Magnolia bark has not only been used historically in traditional Chinese and Japanese medicine, but also in American and Indian medicine; the bark has been listed in the American Pharmacopeia as bitter tonic and antimalarial (Davis, 1981 1981 ; Li N. et al., 2007 2007 ). More recently, Magnolia bark has been used as a component of dietary supplements and topically applied cosmetics (Li N. et al., 2007 2007 ; Liu et al., 2007 2007 ). Various pharmacological activities (anti-cancer, anti-stress, anti-anxiety, antidepressant, antioxidant, anti-inflammatory, and hepatoprotective) have been investigated for Magnolia bark and its constituents. However, most often the mechanisms underlying these pharmacological effects have not been elucidated (Lee et al., 2011 2011 ) (Fig. 2 2 ). Cytotoxic activity: eventual therapeutic application in cancer 2 Cancer represents a major health problem worldwide. In 2012, the World Health Organization (WHO) recorded 14 million new cases of cancer and 8.2 million cancer-related deaths, with 4.3 million under the age of 70 years (WHO, 2016 2016 ). Significant progress in the fight against cancer still calls for both advances in cancer diagnosis and development of preventive and therapeutic strategies (Arora et al., 2012 2012 ). Herbal therapies from alternative and complementary medicines may hold a key to such advances; for example, TCM proposes preparations to treat cancers, but the effective component(s) or their mode of action at cellular and molecular levels is largely unknown (Yang et al., 2003 2003 ). Studies in in vitro and animal models have shown that Magnolia components, especially the neolignans honokiol and magnolol, are able to target many pathologically relevant pathways (Arora et al., 2012 2012 ). These findings have increased interest in using neolignans as possible novel chemotherapeutic agents; notably, mechanistic studies have been carried out on honokiol to assist the development of novel synthetic analogues and to provide clues for rational combinations with conventional chemo-or radiotherapy (Fried and Arbiser, 2009 2009 ). 3.1.1 Mechanisms of action As Arora et al. ( 2012 2012 ) recapped, cancer progresses through a series of genetic and epigenetic aberrations leading to dysregulation of key cell signaling pathways involved in growth, malignant behavior, and therapy-resistance. Honokiol and its analogs target multiple signaling pathways, including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), epidermal growth factor (EGFR, also called ErbB1), mammalian target of rapamycin (mTOR, a protein kinase centrally involved in the control of cell metabolism, growth, and proliferation), and the caspase-mediated common pathway, which modulate cancer initiation and progression (Kumar et al., 2013 2013 ). Also, to fight cancer, lignans-induced apoptosis seems to be a key feature (Lee et al., 2011 2011 ). The ubiquitous transcription factors, NF-κB and STAT3, control the expression of a wide array of genes notably involved in development, cell growth, and differentiation, immunity, metabolism, inflammation, and cancer (Grivennikov and Karin, 2010 2010 ). Aberrant activation of these transcription factors is not only common in many malignancies, in both the early and late developmental steps (Arora et al., 2012 2012 ), but also in tumorigenesis, metastasis, and angiogenesis through the induction of genes participating in malignant conversion and tumor promotion (Lee et al., 2011 2011 ). In many tumors, a constitutive activation of NF-κB modulates the expression of anti-apoptotic (upregulation) and pro-apoptotic (downregulation) genes and activates cell cycle and proliferation (Garg and Aggarwal, 2002 2002 ; Karin, 2006 2006 ; Lee et al., 2011 2011 ; Arora et al., 2012 2012 ). STATs notably participate in oncogenesis, through upregulation of genes encoding apoptosis inhibitors and cell cycle regulators (Yu et al., 1995 1995 ; Buettner et al., 2002 2002 ). Lignans, especially honokiol, have been shown to affect NF-κB signaling, not through a direct effect on NF-κB-DNA binding, but upstream of NF-κB activation, at the level of IKK, the inhibitor of κB (IκB) kinase (Fried and Arbiser, 2009 2009 ). They inhibit NF-κB activation through the suppression of protein kinase B (AKT), which prevents IKK activation, IκBα phosphorylation, and NF-κB nuclear translocation. STAT3 can be inhibited by lignans through interleukin-6 (IL-6), one of the many growth factors that modulate its expression, and by the repression of upstream protein tyrosine kinases, cellular sarcoma (c-Src), Janus kinase 1 (JAK1), and JAK2 (Fried and Arbiser, 2009 2009 ; Arora et al., 2012 2012 ). EGFR is a membrane receptor, a glycoprotein with tyrosine kinase activity, which is frequently overexpressed and/or amplified in various cancer types. Aberrant EGFR signaling has been shown to promote cell survival and proliferation (Arora et al., 2012 2012 ). Failure to attenuate receptor signaling by receptor downregulation can also lead to cellular transformation; the mechanisms by which EGFR becomes oncogenic are numerous, often specific for each cancer type (Zandi et al., 2007 2007 ). Studies in several human cells, obtained from breast cancer, melanoma, and head and neck squamous cell carcinoma, indicate that a growth inhibitory effect of lignans is associated with down-modulation of EGFR signaling and phosphorylation (Fried and Arbiser, 2009 2009 ; Arora et al., 2012 2012 ; Kaushik et al., 2012 2012 ). In most cancer cells, but also in the carcinogenic process, an aberrant activation of mTOR is primarily caused by the activation of the phosphatidyl-inositol 3-kinase (PI3K)-AKT pathway (Guertin and Sabatini, 2007 2007 ). It is suggested that lignans, and especially honokiol, may suppress the activation of mTOR and its downstream signaling, resulting in apoptosis induction, by inhibiting the extracellular signal-regulated kinases (ERK) and AKT pathways or by upregulating phosphatase and tensin homolog (PTEN) (Liu et al., 2008 2008 ; Fried and Arbiser, 2009 2009 ; Lee et al., 2011 2011 ; Arora et al., 2012 2012 ; Kaushik et al., 2012 2012 ). 3.1.2 Cytotoxic activity of Magnolia lignans Several constituents of M. officinalis , mainly lignans, have been widely reported to be cytotoxic, which is a possible clue to new anti-cancer compounds (Lee et al., 2011 2011 ). At low concentrations (up to 3 µmol/L), they can induce apoptosis in human cancer cell lines, whereas they do not inhibit the growth of human untransformed cells (Kong et al., 2005 2005 ). Honokiol was reported to possess higher activity than magnolol in the induction of apoptosis (Kong et al., 2005 2005 ). Obovatol increased the susceptibility to chemotherapeutic agents at low concentrations, around 5 µmol/L (Lee S.Y. et al., 2009 2009 ) (Table 6 6 ). IC 50 : concentrations for 50% inhibition of cell growth Compound Cell line or animal model IC 50 (μ mol/L) Reference  Magnolol COLO-205 (human colon carcinoma cell line) 50–100 Lin et al., 2001 2001 HCT116 (human colorectal carcinoma cell line) 60 Lee D.H. et al., 2009 2009 HeLa (human cervix adenocarcinoma cell line) 12.4–49.9 Syu et al., 2004 2004 HepG2 (human liver cancer cell line) 100 Lin et al., 2001 2001 RKO (human rectal carcinoma cell line) 47.8 Chen et al., 2004 2004 H460 (human lung carcinoma cell line) 20–40 Li H.B. et al., 2007 2007 OVCAR-3 (human ovarian carcinoma cell line) 12.4–49.9 Syu et al., 2004 2004 PC-3 (human prostate metastatic cell line) 60 Lee D.H. et al., 2009 2009  Honokiol RKO (human rectal carcinoma cell line) 38.8 Wang et al., 2004 2004 H460 (human lung carcinoma cell line) 41.1 Yang et al., 2002 2002 SW480 (human colorectal carcinoma cell line) 48.7 Yang et al., 2002 2002 LS180 (intestinal human colon adenocarcinoma cell line) 41.9 Yang et al., 2002 2002 CH27 (human lung squamous carcinoma) 40.9 Yang et al., 2003 2003 PC-3 (human prostate metastatic cell line) 20–40 Hahm and Singh, 2007 2007 MCF-7 (human breast adenocarcinoma cell line) 15–20 Li L. et al., 2007 2007 SCC4 (human tongue squamous cell carcinoma) 25 Ahn et al., 2006 2006 MKN45 (human gastric cancer cell line) 20–40 Sheu et al., 2007 2007  Obovatol SW620 (human colon metastatic cell line) 5 Lee S.Y. et al., 2009 2009 HCT116 (human colorectal carcinoma cell line) 5 Lee S.Y. et al., 2009 2009 LNCaP (androgen-sensitive human prostate adenocarcinoma cell line) 5 Lee S.Y. et al., 2009 2009 PC-3 (human prostate metastatic cell line) 5 Lee S.Y. et al., 2009 2009 HT1080 (fibrosarcoma cell line) 20 Lee et al., 2007 2007  Magnoflorine HepG2 (human liver cancer cell line) 1.2 Mohamed et al., 2010 2010 Anti-inflammatory activity 2 Inflammation, a protective response involving immune cells, blood vessels, and molecular mediators, is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants (Ferrero-Miliani et al., 2007 2007 ). Generally, the production of inflammatory molecules is triggered by mitogenic stimulation with various bacterial products, such as lipopolysaccharides (LPS). Various signaling cascades composed of pattern recognition receptors (e.g. Toll-like receptor 4 (TLR4)), non-receptor type tyrosine kinases (eg. Src and Syk), serine/threonine kinases (protein kinase C (PKC), PKA, PI3K, and AKT), MAPK, and various redox-sensitive transcription factors, such as NF-κB, are regarded as critical components participating in the process (Kim and Cho, 2008 2008 ; Simmonds and Foxwell, 2008 2008 ). Nitric oxide (NO·), a physiological mediator of endothelial cell relaxation, also plays a key role in the inflammatory pathway. Synthesised by many cell types involved in immunity and inflammation, through the inducible NO· synthase (iNOS), in response to pro-inflammatory cytokines and bacterial LPS, NO· is a major defense molecule, toxic against infectious organisms, and is a key player in the pathogenesis of a variety of inflammatory diseases (Lee et al., 2011 2011 ). NO· notably regulates the functional activity, growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils, and natural killer cells (Coleman, 2001 2001 ; Ricciardolo et al., 2004 2004 ; Garcia and Stein, 2006 2006 ; Tripathi et al., 2007 2007 ). The factor NF-κB (Section 3.1) promotes the transcription of genes involved in pro-inflammatory responses. In macrophages, NF-κB is activated by inflammatory extracellular signals such as LPS, IL-1 and tumor necrosis factor α (TNF-α), and regulates a number of inflammatory genes, inducing further inflammatory mediators, including NO· and cytokines (Zhang et al., 2013 2013 ). A second major transcription factor, the activator protein 1 (AP-1), an ubiquitous dimeric protein complex composed of Jun and Fos subfamilies (Curran and Franza, 1988 1988 ), is also activated by many pathophysiological stimuli, including LPS, reactive oxygen species (ROS), mitogenic growth factors, inflammatory cytokines, growth factors of the transforming growth factor-β (TGF-β family, ultraviolet (UV) and ionizing irradiation, cellular stress, antigen binding, and neoplastic transformation. In response to different stimuli, AP-1 is able to activate different sets of genes for differentiation, proliferation, apoptosis (Wisdom, 1999 1999 ), and inflammation (Newton and Dixit, 2012 2012 ) responses. Within the repertoire of protein kinase cascade networks, the MAPK family contains at least 3 protein kinases in series that culminate in the activation of a multifunctional MAP kinase (Pearson et al., 2001 2001 ). MAP kinases are major components of pathways controlling embryogenesis, cell differentiation, cell proliferation and cell death (Pearson et al., 2001 2001 ), and play a significant role in carcinogenesis and in leukocytes’ recruitment to sites of inflammation (Herlaar and Brown, 1999 1999 ). As for AP-1, the MAPKs differentially activate inflammatory pathways, depending on the stimuli and cell types (Lee et al., 2011 2011 ). The cyclooxygenase 2 (COX2), induced in cells by proinflammatory cytokines and growth factors, is also increased in certain inflammatory states. COX2 is a key enzyme in the synthesis of pro-inflammatory eicosanoids (prostaglandins (PGs), thromboxanes (TBXs), leukotrienes, etc.). As discussed in the previous section, the NO production, the expressions of iNOS, IL-1β, TNF-α and COX, and the generation of eicosanoids, in addition to the activation levels of MAPKs, AP-1, and NF-κB pathways, may reflect the degree of inflammation and have become important indicators with which to assess inflammatory and anti-inflammatory processes (Lee et al., 2011 2011 ). An impressive series of studies has shown that all of these major indicators are positively impacted by Magnolia lignans, even if the full anti-inflammatory mechanisms have not yet been elucidated (Choi et al., 2007 2007 ; Lin et al., 2007 2007 ; Munroe et al., 2007 2007 ; Kang et al., 2008 2008 ; Lee et al., 2011 2011 ). Upregulating signaling cascades composed of Ras, Raf, and MAPK, downregulating the activation of NF-κB, and blocking NF-κB activation mediated by CD40 and latent membrane protein 1 are speculated to be the action mechanism of Magnolia lignans (Lin et al., 2007 2007 ; Kim and Cho, 2008 2008 ; Lee et al., 2011 2011 ). Among the lignans (Table 7 7 ), honokiol and magnolol were notably shown to inhibit the formation of eicosanoids (prostaglandin D2 (PGD2), PGE2, leukotriene C4 (LTC4), LTB4, and thromboxane B2 (TXB2)), probably through inhibition of phospholipase A2, COX, 5-lipoxygenase, LTC4 synthase, and LTA4 hydrolase activities (Lin et al., 2007 2007 ). Compound Cell line In vivo Concentration/dose Reference 4-Methoxyhonokiol Mice 20–100 mg/kg Zhou et al., 2008 2008 Honokiol Mice 3 mg/mouse Munroe et al., 2007 2007 Magnolol Mice 10 mg/kg Wang et al., 1992 1992 4-Methoxyhonokiol RAW (murine macrophage cell line) 1–30 μ mol/L Zhou et al., 2008 2008 Obovatol RAW (murine macrophage cell line) 1–5 μ mol/L Choi et al., 2007 2007 Therapeutic activity in asthma 2 Asthma is a chronic disease characterized by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person (WHO, 2016 2016 ). According to WHO estimates, 235 million people suffer from asthma, with prevalences ranging from 1% to 18% across countries. Moreover, it represents one of the most prevalent chronic conditions among children. In addition to large financial burdens, asthma also leads to serious health consequences and compromises life quality (Lin et al., 2015 2015 ). The causes of asthma are not completely understood and the pathology cannot be cured, but appropriate management can control the disorder (WHO, 2016 2016 ). In China as well as throughout Asia, myths and misconceptions on Western medicine and corticosteroids are prevalent, resulting in non-adherence to conventional treatments and in the recourse to traditional herbal medicines (Hon et al., 2015 2015 ). For example, Saiboku-To, a Japanese mixture of ten different herbal extracts (Table 1 1 ) that include M. officinalis , has been investigated for corticosteroid-dependent severe asthma to reduce the maintenance doses of corticosteroids. This herbal complex medicine is also known for its use in general bronchial asthma (Lee et al., 2011 2011 ) and the TCM herb “Houpo” (bark of M. obovata and/or M. officinalis ), is widely used for the treatment of chest tightness and asthma (Ko et al., 2003 2003 ). Homma et al. ( 1993 1993 ) suggested that magnolol, as an inhibitor of 11β-hydroxysteroid dehydrogenase and T-lymphocyte proliferation, might be responsible for the therapeutic effect of Saiboku-To resulting in corticosteroid-sparing. The effects of Magnolia on asthma are from two types: (1) M. officinalis (as well as Saiboku-To) inhibits human lymphocyte blastogenesis, in vitro, in a dose-dependent way. It seems to have anti-asthmatic effect through suppression of type IV (lymphocyte-mediated) allergic reaction (Lee et al., 2011 2011 ); (2) Magnolia extracts induce bronchodilatation by a muscle relaxation that is associated with a Ca 2+ antagonist effect, probably due to magnolol and honokiol. Moreover, alkaloids such as ( R )-coclaurine and ( S )-reticuline inhibit acetylcholine (ACH)-induced contraction of muscles (Ko et al., 2003 2003 ; Lee et al., 2011 2011 ). The effects of honokiol and magnolol on muscular contractile responses and intracellular Ca 2+ mobilization were investigated in the non-pregnant rat uterus; both lignans (at concentrations 1–100 μ mol/L) inhibited spontaneous and uterotonic agonists (carbachol, PGF-2α, and oxytocin), and an experimental Ca 2+ channel activator in a concentration-dependent manner. The inhibition rate of honokiol on spontaneous contractions appeared to be slower than that of magnolol-induced responses (Lu et al., 2003 2003 ) (Table 8 8 ). IC 50 : concentrations for 50% inhibition of cell growth Compound Dose Effect Reference Magnolol and 8,9-dihydroxydihydromagnolol 11.26–26.29 μ mol/L (IC 50 ) Inhibition of lymphocytes blastogenesis Taniguchi et al., 2000 2000 Magnolol and honokiol 0.1–100.0 μ mol/L Muscle relaxation (through Ca 2+ channels) Ko et al., 2003 2003 ( R )-coclaurine and ( S )-reticuline 0.25–0.50 mmol/L Muscle relaxation (through Ca 2+ channels) Kimura et al., 1989 1989 Treatment of gastrointestinal disorders 2 Diseases of the GI tract are highly common and varied, including irritable bowel syndrome, functional dyspepsia, abdominal pain, abdominal bloating, nausea, vomiting, diarrhoea, constipation, etc., which have a substantial effect on quality of life and health-care costs (Hu et al., 2009 2009 ). M. officinalis is commonly used in TCM for treating such GI disorders, probably through an antispasmodic effect that results in relaxation of GI tract smooth muscles (Chan et al., 2008 2008 ; Lee et al., 2011 2011 ). Among various regulatory factors that modulate smooth muscle motility in GI tracts, ACH and serotonin (5-hydroxytryptamine, 5-HT) are considered as major neurotransmitters that regulate the GI motility. Magnolol and honokiol significantly inhibit the contractility of isolated gastric fundus strips of rats treated with ACH or serotonin, and of isolated ileum in guinea pigs treated with ACH or CaCl 2 ; both behave as non-competitive muscarinic antagonists. Magnolol and honokiol inhibited contractions induced by ACH (in Ca 2+ -free medium) and extracellular Ca 2+ -dependent contractions induced by ACH; this Ca 2+ blockade effect is also discussed for anti-asthmatic effects in Section 3.3 (Lu et al., 2003 2003 ; Chan et al., 2008 2008 ; Jeong et al., 2009 2009 ; Lee et al., 2011 2011 ; Herrmann et al., 2014 2014 ). Alkaloids may also confer some of the antispasmodic effect of Magnolia bark when used in high-dose decoctions to alleviate bronchiole spasms and intestinal spasms. Magnocurarine was investigated as a potential muscle relaxant drug in Japan (Dharmananda, 2002 2002 ) (Table 9 9 ). Compound Dose Effect Reference Magnolol and honokiol 0.1–100.0 μ mol/L (human prostate stromal cells WPMY-1 and porcine trachea); 1–1000 μ mol/L (guinea pig) Muscle relaxation (through Ca 2+ voltage-operated channels) Ko et al., 2003 2003 ; Herrmann et al., 2014 2014 ( R )-coclaurine and ( S )-reticuline 0.25–0.50 mmol/L (isolated guinea pig papillary muscle) Muscle relaxation (through Ca 2+ voltage-operated channels) Kimura et al., 1989 1989 Magnocurarine 13.8 mg/kg (rabbit) Muscle relaxation (through Ca 2+ voltage-operated channels) Chang and But, 1987 1987 Treatment of diabetes 2 Magnolia plants have been used as Korean and Brazilian complementary and alternative medicines for the treatment of diabetes and diabetic complications; it has been shown that long-term supplementation of honokiol and magnolol ameliorates body fat accumulation, insulin resistance, and adipose inflammation in high-fat fed mice (Kim et al., 2013 2013 ). Honokiol and magnolol reduce fasting blood glucose and plasma insulin levels in type 2 diabetic rats without altering body weight, and induce glucose uptake in adipocytes. Honokiol also enhances insulin signaling pathways such as the Ras/ERK1/2 and phosphoinositide-3-kinase/AKT signaling pathways, and ameliorates alcoholic steatosis by blocking fatty acid synthesis regulated by the sterol regulatory element-binding protein 1c (SREBP1c) (Kim et al., 2013 2013 ). An ethanolic extract of the Magnolia cortex showed an in vitro inhibitory effect on the formation of advanced glycation endproducts (AGEs), which play an important role in the development of diabetic complications. Furthermore, magnolol inhibits AGE formation and sorbitol accumulation in streptozotocine-induced diabetic rats (Sohn et al., 2007 2007 ). Honokiol and magnolol also improve both glucose and lipid metabolisms and inhibit acyl-CoA cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesteryl esters from cholesterol and long-chain fatty acyl-CoA. Magnolol can activate the peroxisome proliferator-activated receptor γ (PPARγ) as a ligand, induce adipocyte differentiation, and enhance insulin-stimulated glucose uptake in animal models (Lee et al., 2015 2015 ). Effects on neuronal disease 2 The bark of M. officinalis is one of the most important traditional herbal medicines in China and Japan used to treat clinical depression and anxiety-related disorders (Nakazawa et al., 2003 2003 ). Even the oldest known TCM book, Shennong Bencao Jing , mentions this tranquilizing action (Tachikawa et al., 2000 2000 ). Kampo preparations, such as Hange-Koboku-To, Yoku-Kan-san, Saiboku-To, and Kami-Kihi-To, have been historically prescribed for conditions akin to clinical depression, anxiety-related disorders, such as anxiety neurosis, insomnia, and anxiety hysteria, as well as for thrombotic stroke and GI complaints (Maruyama et al., 1998 1998 ). The ingredients that have been reported to possess pharmacological effects on the nervous systems are β-eudesmol, α-and β-pinenes, and bornyl acetate, as essential oils; magnolol and honokiol, as diphenyl compounds; and magnocurarine and magnoflorine, as alkaloids (Tachikawa et al., 2000 2000 ). Metabolites formed by the gut flora have been proposed as the actual active agents (Nakazawa et al., 2003 2003 ). 3.6.1 Treatment of anxiety Anxiety disorders are considered the most common psychiatric diagnoses affecting between 10% and 30% of the general population. Excess anxiety can be debilitating and lower the quality of life (Wittchen and Hoyer, 2001 2001 ; Lee et al., 2011 2011 ). Despite well-known side effects such as sedation, muscle relaxation, amnesia, and dependence, benzodiazepines are extensively used for the treatment of several forms of anxiety (Wittchen and Hoyer, 2001 2001 ). Various herbal medicines, traditionally used for tranquillo-sedative effects, are now being investigated as anxiolytic drugs, including the bark of M. officinalis (Lee et al., 2011 2011 ). The central depressant effects of lignans may contribute not only to an anticonvulsant effect but also, at low doses, to an anxiolytic activity. This can be partially attributed to their interaction with the γ-aminobutyric acid receptor A (GABA A ), a known target for benzodiazepines and other anxiolytics. The activity of hippocampal glutamic acid decarboxylase (GAD), an enzyme involved in GABA synthesis, is significantly increased in honokiol-treated mice, suggesting that honokiol may alter the brain’s synthesis of GABA. GABA A receptors have subunit heterogeneity that influences their function; magnolol and honokiol were found to modulate all receptors, regardless of their sub-units, but receptors with the δ-subunit were 2 to 3 times more sensitive (Alexeev et al., 2012 2012 ; Chen et al., 2012 2012 ; Woodbury et al., 2013 2013 ). 3.6.2 Treatment of depression Depression is a mood-altering disease affecting energy, sleep, appetite, libido, and the ability to function. The symptoms of depression include an intense feeling of sadness, hopelessness, despair, and the inability to experience pleasure in usual activities (Lee et al., 2011 2011 ). Most common anti-depressant drugs (tricyclic/polycyclic antidepressants, selective serotonin reuptake inhibitor, monoamine oxidase inhibitors, serotonin-norepinephrine reuptake inhibitors, lithium) potentiate the action of monoamines (norepinephrine, dopamine, and serotonin) in the brain, an observation that resulted in the so-called “theory of monoamines” that postulates an association between depression and monoamine depletion. Efforts in the field are still sorely needed, as recent studies indicate that about 30% of depressive patients fail to respond satisfactorily to antidepressant treatment. In vitro radioligand binding and cellular functional assays revealed that Magnolia bark supercritical carbon dioxide extracts interact with the adenosine A1 receptor, dopamine transporter, and dopamine D5 receptor (antagonist activity), serotonin receptors (5-HT1B and 5-HT6, antagonist activity) and the GABA benzodiazepine receptor at a concentration of 100 μg/ml or lower (Koetter et al., 2009 2009 ). Honokiol and magnolol exhibit neurotrophic function by enhancing hippocampal ACH release, and magnolol modulates the central serotonergic activity (Nakazawa et al., 2003 2003 ). Major receptors of biogenic amine neurotransmitters (dopamine, noradrenaline, serotonin, and histamine) are coupled with G-proteins, activating or inhibiting adenylate cyclase. Honokiol and magnolol could normalize the biochemical abnormalities in brain serotonin and its metabolites, serum corticosterone levels, and platelet adenylate cyclase activity via up-regulating the cyclic adenosine monophosphate pathway (Waymire, 1997 1997 ; Lee et al., 2011 2011 ). 3.6.3 Effects on Alzheimer’s disease Alzheimer’s disease (AD) is the most common form of dementia. There are no available treatments that stop or reverse the progression of the disease, which worsens as it progresses, and eventually leads to death (WHO, 2016 2016 ). Studies of patients with AD have revealed ACH-depleted cerebral regions; centrally acting cholinergic drugs have been reported to increase the ACH levels in these brain regions affected by AD and to improve cognition and memory. Maintaining ACH levels in brain, by antagonizing the activity of acetylcholinesterase (ACHE), the enzyme that degrades ACH, is one of the few therapeutic options in AD patients, which could be important to delay the aggravation of the disease (Lee et al., 2011 2011 ). However, ACHE inhibitors have limitations, including short half-lives, peripheral cholinergic side effects, and notable hepatotoxicity (Lee et al., 2011 2011 ). Beside ACH depletion, abnormal phosphorylation of the protein tau, oxidative stress, and altered protein processing resulting in abnormal β-amyloid peptide (Aβ) accumulation are associated with the progressive development of AD, leading to neuronal cell death (Zaki et al., 2014 2014 ). Ethanol extracts of M. officinalis and 4- O -methylhonokiol were found to dose-dependently attenuate the scopolamine-induced increase in ACHE activity in the cortex and hippocampus of mice and inhibited ACHE activity in vitro (Lee et al., 2010 2010 ). Beside ACH depletion, oxidative damages are also associated in the progressive development of AD. Actually, oxidative stress-induced neuronal cell death by accumulation of Aβ is a critical pathological mechanism in AD. The antioxidants honokiol, magnolol, and 4- O -methylhonokiol significantly decrease Aβ-induced cell death; these neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase-3 activity (Hoi et al., 2010 2010 ; Woodbury et al., 2013 2013 ). Lignans are also able to decrease the activity of β-secretase, preventing the release of Aβ from amyloid precursor protein (APP) (Lee et al., 2010 2010 ). Therapeutic activity in cardiovascular diseases 2 Cardiovascular diseases (CVDs), a group of disorders of the heart and blood vessels, are the prime cause of death worldwide (WHO, 2016 2016 ). The cardiovascular protection potentiality of M. officinalis due to its antioxidant components was described around the 1990s (Lo et al., 1994 1994 ). A role for oxidative stress has been postulated in many CVDs as ROS contribute to cardiovascular lesions by promoting inflammation, altering vasomotion, inducing cell death, causing platelet aggregation, and stimulating vascular smooth muscle cell (VSMC) proliferation; induced vascular stenosis, cell death, and inflammation are major progressive factors in cardiovascular dysfunctions (Lee et al., 2011 2011 ). The potential of M. officinalis to afford cardiovascular protection was attributed to its antioxidant components, including lignans and, notably, honokiol and magnolol. Those effects are dose-related, and are the consequence of different molecular mechanisms’ regulation (Ho and Hong, 2012 2012 ). 3.7.1 Effects in atherosclerosis Atherosclerosis is a condition, in which plaques made of cholesterol, fatty substances, cellular waste products, calcium, and fibrin build up inside the arteries (AHA, 2016 2016 ). Oxidized low-density lipoproteins (LDL) induce arterial wall cells to produce chemotactic factors, adhesion molecules, cytokines, and growth factors that play a role in the development of these plaques (Young and Woodside, 2001 2001 ; Lee et al., 2011 2011 ). Honokiol was shown to alleviate the detrimental effects of oxidized LDL, reducing the expression of endothelial iNOS and adhesion molecules, and attenuating the induced cytotoxicity, apoptosis, ROS generation, intracellular calcium accumulation, the subsequent mitochondrial membrane potential collapse, cytochrome c release, and activation of caspase-3 in human umbilical vein endothelial cells (HUVECs) (Ou et al., 2006 2006 ). Moreover, magnolol effects include protection of the cardiovascular system by interfering with ROS generation (Lee et al., 2011 2011 ). Magnolia compounds with an anti-atherosclerosis effect were listed in Table 10 10 (Lee et al., 2011 2011 ). Compound Dose (μ mol/L) Subject Reference 2  Honokiol 2.5–20.0 HUVEC (human umbilical vein endothelial cell) Ou et al., 2006 2006 25–150 HASMC (human aortic smooth muscle cell) Lee et al., 2006 2006  Magnolol 1–10 Rat cardiac fibroblasts Chen et al., 2006 2006  Obovatol 1–5 Rat VSMC (vascular smooth muscle cell) Lim et al., 2010 2010 3.7.2 Anti-platelet activity Magnolia compounds have been known for more than 20 years to interfere in some major pathways of platelet activation/inhibition: (1) TBXs, some of the most powerful agonists for platelet activation and major contributors to thrombus formation; TXB2, whether induced by collagen, arachidonic acid, or thrombin, is inhibited by magnolol and honokiol; also five aporphine alkaloids isolated from leaves of M. obovata , N -acetylanonaine, N -acetylxylopine, N -formylanonaine, liriodenine, and lanuginosine, show potent antiplatelet activities, probably by interfering with TXA2 production and/or binding (Teng et al., 1988 1988 ; Pyo et al., 2003 2003 ; Ho and Hong, 2012 2012 ); (2) the activation of PPAR isoforms (α, β/δ, and γ), a pathway known to inhibit platelet aggregation; magnolol (20–60 μmol/L) dose-dependently enhances the activity and intracellular level of PPAR-β/γ in platelets (Shih and Chou, 2012 2012 ); and (3) the cytosolic Ca 2+ influx and/or mobilization from intracellular stores that plays a crucial role in the platelet responses to various agonists (Lee et al., 2011 2011 ); the rise of intracellular calcium caused by arachidonic acid or collagen is suppressed by both magnolol and honokiol (Teng et al., 1988 1988 ; Pyo et al., 2003 2003 ; Lee et al., 2011 2011 ). Antimicrobial activities 2 Antibiotic treatments have become a cornerstone for human health; however, due to long, wide, and irrational applications of antibacterial agents in treatments in various fields other than in the clinic, resistant strains have evolved as problematic pathogens and now pose a serious challenge. In the fight against these resistant pathogens, plant extracts heavily exploited in different civilizations (Amblard et al., 2007 2007 ; Zuo et al., 2015 2015 ) could yield clues to new therapeutic options (Okusa et al., 2014 2014 ; Rasamiravaka et al., 2014 2014 ; Ngezahayo et al., 2015 2015 ; Ngezahayo et al., 2016 2016 ). The antimicrobial activities of honokiol and magnolol, the main constituents of M. officinalis , were effective against Gram-positive bacteria, such as Streptococcus mutans (Bang et al., 2000 2000 ), Staphylococcus aureus , Listeria monocytogenes , Streptococcus faecalis , Escherichia coli , Salmonella typhimurium , Bacillus anthracis , Actinobacillus actinomycetemcomitans , Porphyromonas gingivalis , Prevotella intermedia , Micrococcus luteus , Bacillus subtilis , Capnocytophaga gingivalis , Veillonella disper , but also against fungal strains such as Candida albicans as a representative fungus for candidiasis, Trichophyton mentagrophytes for superficial dermatomycosis and Cryptococcus neoformans for deep dermatomycosis. The lignans showed a significant antimicrobial activity against these microorganisms with minimum inhibitory concentrations (MICs) ranging 10–240 μ mol/L (Chang et al., 1998 1998 ; Bang et al., 2000 2000 ; Ho et al., 2001 2001 ; Hu et al., 2011 2011 ). Lignans, mainly honokiol and magnolol, have marked dose-dependent antimicrobial effects (Table 11 11 ) (Kim et al., 2015 2015 ). Previous studies have shown that phenolic compounds can affect microbial growth by altering microbial cell permeability and permitting the loss of macromolecules. Once the phenolic compounds have crossed the cell membrane, interactions with membrane enzymes and proteins will cause an opposite flow of protons, affecting cellular activity. It has also been suggested that phenols react primarily with the phospholipid components of the cell membrane, causing an increase in permeability (Hu et al., 2011 2011 ; Zuo et al., 2015 2015 ). For antiviral activity of aporphine alkaloids, they were shown to interfere with the viral replicative cycle. Although DNA synthesis was reduced, their exact target remains to be elucidated (Boustie et al., 1998 1998 ). Compound Concentration Microorganisms Reference 3 Honokiol 94–188 μ mol/L C. albicans , T. mentagrophytes , and C. neoformans Funga strains Bang et al., 2000 2000 11–15 μ mol/L Propionibacterium acnes bacteria strain (Gram+) Zuo et al., 2015 2015 60–240 μ mol/L Staphylococcus aureus bacteria strain (Gram +) Zuo et al., 2015 2015 3 Magnolol 94–188 μ mol/L C. albicans , T. mentagrophytes , and C. neoformans fungal strains Bang et al., 2000 2000 34 μ mol/L Propionibacterium acnes bacteria strain (Gram+) Park et al., 2004 2004 60–240 μ mol/L Staphylococcus aureus bacteria strain (Gram+) Zuo et al., 2015 2015 Aporphine alkaloids 1.1 μ g/ml Herpes simplex virus (HSV-1) Poliovirus Mohamed et al., 2010 2010 Toxicity 1 All effective drugs may produce adverse drug reactions, and herbal medicines are no exception. Their long-standing use as traditional medicines has probably allowed the elimination of the most toxic drugs but special attention must be paid to insidious toxicities which are not easily detectable by tradipraticians or pharmacovigilance, including genotoxicity, carcinogenicity, and developmental toxicity (Ouédraogo et al., 2012 2012 ; Zhang et al., 2012 2012 ; Williamson et al., 2015 2015 ). With the current worldwide increase in the use of herbal products, increasing numbers of side effects, some of them very serious, are emerging, raising concerns about the general safety of herbal products (Liu et al., 2014 2014 ). Magnolia toxicity has been studied in vitro and in vivo. Results from these studies are summarized in Tables 12 12 , 13 13 , 14 14 (Li N. et al., 2007 2007 ). Assay Subject Effects Reference Ames test Salmonella typhimurium strains (TA98, TA100, TA1535, TA1537) with and without S9 fraction MBE did not increase the mean number of revertants with or without metabolic activation, for both S. thyphimirium and E. coli strains, in comparison to the spontaneous reversion rate in the negative control at concentrations from 18.75 to 300 μ g/plate 2 Li N. et al., 2007 2007 Tryptophan-requiring Escherichia coli mutant WP2 uvrA with and without S9 fraction The number of revertants could not be counted for S. typhimurium strains TA1535 and TA1537 at concentrations of 150 and 300 μ g/plate due to excessive cytotoxicity 2 Chromosomal aberration assays CHO (Chinese hamster ovary cell) Exposure for 3 h to MBE at concentrations of 0–30 μ g/ml in the absence of a metabolic activation system (S9) and 0–7 μ g/ml with S9 did not induce chromosomal aberrations, whereas higher concentrations were cytotoxic and did not allow for analysis of aberrations. Extended exposure for 18 h without metabolic activation at concentrations up to 15 μ g/ml also resulted in a negative response 2 Zhang et al., 2008 2008 V79 cell (derived from Chinese hamster lung tissue) Treatment for 6 and 24 h, with concentrations up to 52 and 59 μ g/ml, in the absence and presence of S9, did not increase the incidence of chromosomal aberrations compared to negative controls Measurement of H2AX histone phosphorylation (DNA double strand break detection) FHs 74 Int (human intestinal epithelial cells) Magnolia officinalis aqueous extract (1 mg/ml) caused DNA damages detected by immunofluorescence but not by whole-cell ELISA assay Nachtergael et al., 2015 2015 Measurement of DNA degradation (by staining and quantifying DNA with PI) HK-2 (human proximal tubule epithelial cell) Treatments of HK-2 cells with 10 μ mol/L magnolol or honokiol alone increased DNA degradation Bunel et al., 2016 2016 Assay Subject Effects Reference Genotoxicity assessment (micronucleus test) Swiss Albino (CD-1) mice No statistically significant increase in the number of micronucleated polychromatic erythrocytes in any of the MBE-treated groups compared to the negative control group at either time point Li N. et al., 2007 2007 3 Acute toxicity Mice Oral LD 50 of MBE > 50 g/kg Liu et al., 2007 2007 Swiss Albino (CD-1) mice No mortalities and no clinical signs of toxicity were observed in animals given 2500 mg MBE/kg body weight (BW) Li N. et al., 2007 2007 Dogs (1 g/kg i.v.) No mortality Chang and But, 1986 1986 Short-term toxicity Sprague-Dawley rats (animals received orally MBE at levels of 0, 60, 120, or 240 mg/kg BW per day during 21 d) Increase of absolute and relative thyroid weight and increase of relative kidney weight in female of high-dose group compared to their respective controls Slight fatty degeneration of the liver in 5/10 of the 240 mg/kg BW per day group (4 females and 1 male) Food consumption significantly reduced in Week 3 in females from the high-dose group Lack of toxicity following dietary administration of MBE at doses up to 480 mg/kg BW per day Liu et al., 2007 2007 Subchronic toxicity Sprague-Dawley rats (animals received orally MBE at levels of 0, 60, 120, or 240 mg/kg BW per day during 90 d) No mortality, ophthalmic abnormalities were found In males, significantly higher weight gains in the 120 and 240 mg/kg BW groups were observed Significant increase of blood total bilirubin and sodium values in all groups compared to the control group Slight fatty degeneration and sporadic focal necrosis in the liver of 11/40 animals (4 females and 7 males) in the 240 mg/kg BW group Lack of toxicity following dietary administration of MBE at doses up to 240 mg/kg BW per day Liu et al., 2007 2007 Magnolia preparation Subject Observation Reference Dietary supplement containing extracts of M. officinalis and Phellodendron amurense (for weight management) 22 subjects Only 1/22 subjects reported side effects such as heartburn, shaking hands, perilabial numbness, sexual dysfunction and thyroid dysfunction. No explanation for the evaluation of these effects as being possibly related to treatment was provided Garrison and Chambliss, 2006b Preparation containing 60 mg Magnolia bark extract and 50 mg magnesium (24-week period) 89 menopausal women Preparation was well tolerated by 94% of subjects Mucci et al., 2006 2006 Chinese multi-herbal preparations Some mixtures containing Magnolia are reported to be hepatotoxic Teschke et al., 2014 2014 ; 2015 2015 ; 2016 2016 Clinical research on Magnolia 1 Despite a well-documented use of Magnolia in TCM and a wealth of in vitro and in vivo pharmacological studies, there are practically no clinical studies published in English. A PubMed database search with the terms “Magnolia” [MESH] AND “Clinical Study” [Publication Type] yields only 10 papers (in Feb.2017). Most of them deal with oral cavity applications of Magnolia bark extracts, as dentifrice (Hellstrom and Ramberg, 2014 2014 ), tablets (Porciani et al., 2014 2014 ). or chewing gum (Porciani and Grandini, 2012 2012 ). In menopausal women, the addition of a Magnolia bark extract to isoflavones, lactobacilli, calcium, and vitamin D 3 induced positive effects on insomnia, irritability, anxiety, depressed mood, asthenia, and loss of libido; adverse events were comparable in treated (334 women) and control (300 women) groups (Agosta et al., 2011 2011 ). In a similar group of women, Magnolia extract and magnesium alleviated psycho-affective and sleep disturbances (Mucci et al., 2006 2006 ). On 26 healthy, overweight (BMI 25 to 34.9 kg/m 2 ), premenopausal female adults, a proprietary blend of extracts of M. officinalis and Phellodendron amurense reduced temporary, transitory anxiety but was not effective in reducing long-standing feelings of anxiety or depression; no adverse effects were observed (Kalman et al., 2008 2008 ). This mixture was investigated in a similar woman group for weight management (Garrison and Chambliss, 2006 2006 ). In a non-comparative study, as an add-on therapy in 148 patients with mild to moderate asthma using inhaled corticosteroids, an extract of Magnoliae flos had a beneficial effect on asthma control (Park et al., 2012 2012 ). The well-demonstrated pharmacological properties of Magnolia constituents probably warrant further clinical studies; the cytotoxicities and cell cycle activities of lignans represent, however, an attention point. It would be interesting to evaluate the Chinese literature for study designs and results, notably in terms of safety. Conclusions 1 Traditional Chinese herbal drugs have been used for thousands of years of Chinese history. Currently they still serve as one of the most important available health resources, prescribed in tandem with Western medical treatment. In general, the therapeutic benefits of TCM from established combination prescriptions have survived the test of time (Yang and Chen, 1997 1997 ). Magnolia bark has been used historically in traditional Asian remedies for thousands of years without apparent indications of safety concern. Various extracts derived from Magnolia bark are also widely available in dietary supplement products at recommended doses of 200 to 800 mg/d per person. Magnolia ingredients have indisputably a wide variety of pharmaceutical properties. It is now necessary to identify the constituents, delineate possible mechanisms, and justify routes and formulations (Lee et al., 2011 2011 ). Considering previous studies about Magnolia bark extract toxicity, its security seems to be assured. However, the high potentiation of aristolochic acid (AA) genotoxicity by M. officinalis was recently demonstrated. This co-genotoxicity of Magnolia and Aristolochia may lead to an explanatory factor for the “Chinese herb nephropathy” cases, rapid onset and tragic intoxications observed specifically in Belgium in the 1990s (Vanherweghem et al., 1993 1993 ). Since the recognition of the high nephrotoxicity and carcinogenicity of AAs, Aristolochia species have been classified as human carcinogens (International Agency for Research on Cancer, 2002 2002 ); banned from many markets, they should no longer be used. Nevertheless, this potentiation warrants further studies as it could bring regulatory authorities to take into account indirect genotoxicities in their safety assessment schemes (Nachtergael et al., 2015 2015 ; Bunel et al., 2016 2016 ). It is now necessary to establish suitable modern standards, techniques, and methods to evaluate the safety of such herbal products alone and in association. Herbal preparations will thereby be used more safely and effectively. References C Agosta , M Atlante , C Benvenuti . Randomized controlled study on clinical efficacy of isoflavones plus Lactobacillus sporogenes , associated or not with a natural anxiolytic agent in menopause . Minerva Ginecol , 2011 . 63 ( 1 ): 11 - 17 . 26358608 . Randomized controlled study on clinical efficacy of isoflavones plus Lactobacillus sporogenes, associated or not with a natural anxiolytic agent in menopause AHA . American Heart Association , 2016 . http://www.heart.org/HEARTORG , . American Heart Association KS Ahn , G Sethi , S Shishodia , 等 . Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-κB activation pathway . Mol Cancer Res , 2006 . 4 ( 9 ): 621 - 633 . (Available from: http://dx.doi.org/10.1158/1541-7786.MCR-06-0076 http://dx.doi.org/10.1158/1541-7786.MCR-06-0076 ) 3615803 . Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-κB activation pathway M Alexeev , DK Grosenbaugh , DD Mott , 等 . The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABA A receptors . Neuropharmacology , 2012 . 62 ( 8 ): 2507 - 2514 . (Available from: http://dx.doi.org/10.1016/j.neuropharm.2012.03.002 http://dx.doi.org/10.1016/j.neuropharm.2012.03.002 ) 18039344 . The natural products magnolol and honokiol are positive allosteric modulators of both synaptic and extra-synaptic GABAA receptors F Amblard , B Govindarajan , B Lefkove , 等 . Synthesis, cytotoxicity, and antiviral activities of new neolignans related to honokiol and magnolol . Bioorg Med Chem Lett , 2007 . 17 ( 16 ): 4428 - 4431 . (Available from: http://dx.doi.org/10.1016/j.bmcl.2007.06.024 http://dx.doi.org/10.1016/j.bmcl.2007.06.024 ) 21246247 . Synthesis, cytotoxicity, and antiviral activities of new neolignans related to honokiol and magnolol S Arora , S Singh , GA Piazza , 等 . Honokiol: a novel natural agent for cancer prevention and therapy . Curr Mol Med , 2012 . 12 ( 10 ): 1244 - 1252 . (Available from: http://dx.doi.org/10.2174/156652412803833508 http://dx.doi.org/10.2174/156652412803833508 ) 17055251 . Honokiol: a novel natural agent for cancer prevention and therapy KH Bang , YK Kim , BS Min , 等 . Antifungal activity of magnolol and honokiol . Arch Pharm Res , 2000 . 23 ( 1 ): 46 - 49 . (Available from: http://dx.doi.org/10.1007/BF02976465 http://dx.doi.org/10.1007/BF02976465 ) 25745004 . Antifungal activity of magnolol and honokiol L Bielory , J Russin , G Zuckerman . Clinical efficacy, mechanisms of action, and adverse effects of complementary and alternative medicine therapies for asthma . Allergy Asthma Proc , 2004 . 5 ( 5 ): 283 - 291 . . Clinical efficacy, mechanisms of action, and adverse effects of complementary and alternative medicine therapies for asthma J Boustie , J Stigliani , J Montanha , 等 . Antipoliovirus structure-activity relationships of some aporphine alkaloids . J Nat Prod , 1998 . 61 ( 4 ): 480 - 484 . (Available from: http://dx.doi.org/10.1021/np970382v http://dx.doi.org/10.1021/np970382v ) 18175410 . Antipoliovirus structure-activity relationships of some aporphine alkaloids R Buettner , LB Mora , R Jove . Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention . Clin Cancer Res , 2002 . 8 ( 4 ): 945 - 954 . 20495024 . Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention V Bunel , MH Antoine , C Stévigny , 等 . New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity . Food Chem Toxicol , 2016 . 87 77 - 87 . (Available from: http://dx.doi.org/10.1016/j.fct.2015.11.020 http://dx.doi.org/10.1016/j.fct.2015.11.020 ) 24806817 . New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity S Chan , M Zhao , L Lao , 等 . Magnolol and honokiol account for the anti-spasmodic effect of Magnolia officinalis in isolated Guinea pig ileum . Planta Med , 2008 . 74 ( 4 ): 381 - 384 . (Available from: http://dx.doi.org/10.1055/s-2008-1034320 http://dx.doi.org/10.1055/s-2008-1034320 ) 24073633 . Magnolol and honokiol account for the anti-spasmodic effect of Magnolia officinalis in isolated Guinea pig ileum B Chang , Y Lee , Y Ku , 等 . Antimicrobial activity of magnolol and honokiol against periodontopathic microorganisms . Planta Med , 1998 . 64 ( 4 ): 367 - 369 . (Available from: http://dx.doi.org/10.1055/s-2006-957453 http://dx.doi.org/10.1055/s-2006-957453 ) . Antimicrobial activity of magnolol and honokiol against periodontopathic microorganisms HM Chang , PPH But . Pharmacology and Applications of Chinese Materia-Medica (Volume I) , 1986 . : Philadelphia Word Scientific Philadelphia , (Available from: http://dx.doi.org/10.1142/0284 http://dx.doi.org/10.1142/0284 ) . Pharmacology and Applications of Chinese Materia-Medica (Volume I) HM Chang , PPH But . Pharmacology and Applications of Chinese Materia Medica (Volume II) , 1987 . : Philadelphia Word Scientific , (Available from: http://dx.doi.org/10.1142/0377 http://dx.doi.org/10.1142/0377 ) . Pharmacology and Applications of Chinese Materia Medica (Volume II) CR Chen , XZ Zhou , YJ Luo , 等 . Magnolol, a major bioactive constituent of the bark of Magnolia officinalis , induces sleep via the benzodiazepine site of GABA A receptor in mice . Neuropharmacology , 2012 . 63 ( 6 ): 1191 - 1199 . (Available from: http://dx.doi.org/10.1016/j.neuropharm.2012.06.031 http://dx.doi.org/10.1016/j.neuropharm.2012.06.031 ) . Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, induces sleep via the benzodiazepine site of GABAA receptor in mice F Chen , T Wang , YF Wu , 等 . Honokiol: a potent chemotherapy candidate for human colorectal carcinoma . World J Gastroenterol , 2004 . 10 ( 23 ): 3459 - 3463 . (Available from: http://dx.doi.org/10.3748/wjg.v10.i23.3459 http://dx.doi.org/10.3748/wjg.v10.i23.3459 ) . Honokiol: a potent chemotherapy candidate for human colorectal carcinoma YH Chen , SJ Lin , YL Chen , 等 . Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules . Cardiovasc Haematol Disord , 2006 . 6 ( 4 ): 279 - 304 . (Available from: http://dx.doi.org/10.2174/187152906779010737 http://dx.doi.org/10.2174/187152906779010737 ) . Anti-inflammatory effects of different drugs/agents with antioxidant property on endothelial expression of adhesion molecules MS Choi , SH Lee , HS Cho , 等 . 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 , 2007 . 556 ( 1-3 ): 181 - 189 . (Available from: http://dx.doi.org/10.1016/j.ejphar.2006.10.054 http://dx.doi.org/10.1016/j.ejphar.2006.10.054 ) . Inhibitory effect of obovatol on nitric oxide production and activation of NF-κB/MAP kinases in lipopolysaccharide-treated RAW 264.7 cells JW Coleman . Nitric oxide in immunity and inflammation . Int Immunopharmacol , 2001 . 1 ( 8 ): 1397 - 1406 . (Available from: http://dx.doi.org/10.1016/S1567-5769(01)00086-8 http://dx.doi.org/10.1016/S1567-5769(01)00086-8 ) 17122388 . Nitric oxide in immunity and inflammation Council of Europe European Pharmacopoeia 8.1 , 2013 . : Strasbourg Council of Europe , 3949 - 3950 . . European Pharmacopoeia 8.1 CPC (Chinese Pharmacopoeia Commission) Pharmacopoeia of the People’s Republic of China (English Edition) , 2010 . : Beijing, China China Medical Science Press , 22750884 . Pharmacopoeia of the People’s Republic of China (English Edition) W Cui , Y Wang , Q Chen , 等 . Magnolia extract (BL153) ameliorates kidney damage in a high fat diet-induced obesity mouse model . Oxid Med Cell Longev , 2013 . 2013 367040 (Available from: http://dx.doi.org/10.1155/2013/367040 http://dx.doi.org/10.1155/2013/367040 ) 22099498 . Magnolia extract (BL153) ameliorates kidney damage in a high fat diet-induced obesity mouse model T Curran , BJ Franza . Fos and Jun: the AP-1 connection . Cell , 1988 . 55 ( 3 ): 395 - 397 . (Available from: http://dx.doi.org/10.1016/0092-8674(88)90024-4 http://dx.doi.org/10.1016/0092-8674(88)90024-4 ) 21474611 . Fos and Jun: the AP-1 connection TL Davis . Chemistry of Magnolia grandiflora L , 1981 . University of Florida , . Chemistry of Magnolia grandiflora L S Dharmananda . Safety Issues Affecting Chinese Herbs: Magnolia alkaloids , 2002 . Institute for Traditional Medicine, Oregon. http://www.itmonline.org/arts/magsafe.htm , 23010539 . Safety Issues Affecting Chinese Herbs: Magnolia alkaloids EPCNF (European Parliament Concerning Novel Foods and Novel Food Ingredients) Application for the Approval of Magnolia Bark Supercritical Carbon Dioxide Extract (MBSE) from Magnolia officinalis , 2009 . : Chicago The William Wrigley Jr. Company , 24157058 . Application for the Approval of Magnolia Bark Supercritical Carbon Dioxide Extract (MBSE) from Magnolia officinalis M Fazel . Now show me your tongue: a taste of medicine in China . Lancet , 1995 . 346 ( 8991-8992 ): 1687 - 1688 . (Available from: http://dx.doi.org/10.1016/S0140-6736(95)92847-2 http://dx.doi.org/10.1016/S0140-6736(95)92847-2 ) . Now show me your tongue: a taste of medicine in China L Ferrero-Miliani , OH Nielsen , PS Andersen , 等 . Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation . Clin Exp Immunol , 2007 . 147 ( 2 ): 227 - 235 . (Available from: http://dx.doi.org/10.1111/j.1365-2249.2006.03261.x http://dx.doi.org/10.1111/j.1365-2249.2006.03261.x ) . Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1β generation LE Fried , JL Arbiser . Honokiol, a multifunctional antiangiogenic and antitumor agent . Antioxid Redox Signal , 2009 . 11 ( 5 ): 1139 - 1148 . (Available from: http://dx.doi.org/10.1089/ars.2009.2440 http://dx.doi.org/10.1089/ars.2009.2440 ) . Honokiol, a multifunctional antiangiogenic and antitumor agent X Garcia , F Stein . Nitric oxide . Semin Pediatr Infect Dis , 2006 . 17 ( 2 ): 55 - 57 . (Available from: http://dx.doi.org/10.1053/j.spid.2006.04.002 http://dx.doi.org/10.1053/j.spid.2006.04.002 ) 4086867 . Nitric oxide A Garg , BB Aggarwal . Nuclear transcription factor-κB as a target for cancer drug development . Leukemia , 2002 . 16 ( 6 ): 1053 - 1068 . (Available from: http://dx.doi.org/10.1038/sj.leu.2402482 http://dx.doi.org/10.1038/sj.leu.2402482 ) 12384365 . Nuclear transcription factor-κB as a target for cancer drug development R Garrison , WG Chambliss . Effect of a proprietary Magnolia and Phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial . Altern Ther Health Med , 2006 . 12 ( 1 ): 50 - 54 . 22846131 . Effect of a proprietary Magnolia and Phellodendron extract on weight management: a pilot, double-blind, placebo-controlled clinical trial S Grivennikov , M Karin . Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalkin cancer . Cytokine Growth Factor Rev , 2010 . 21 ( 1 ): 11 - 19 . (Available from: http://dx.doi.org/10.1016/j.cytogfr.2009.11.005 http://dx.doi.org/10.1016/j.cytogfr.2009.11.005 ) 25076986 . Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalkin cancer DA Guertin , DM Sabatini . Defining the role of mTOR in cancer . Cancer Cell , 2007 . 12 ( 1 ): 9 - 22 . (Available from: http://dx.doi.org/10.1016/j.ccr.2007.05.008 http://dx.doi.org/10.1016/j.ccr.2007.05.008 ) 16056220 . Defining the role of mTOR in cancer Z Guo , XB Wang , JG Luo , 等 . A novel aporphine alkaloid from Magnolia officinalis . Fitoterapia , 2011 . 82 ( 4 ): 637 - 641 . (Available from: http://dx.doi.org/10.1016/j.fitote.2011.01.021 http://dx.doi.org/10.1016/j.fitote.2011.01.021 ) . A novel aporphine alkaloid from Magnolia officinalis ER Hahm , SV Singh . Honokiol causes G 0 -G 1 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 , 2007 . 6 ( 10 ): 2686 - 2695 . (Available from: http://dx.doi.org/10.1158/1535-7163.MCT-07-0217 http://dx.doi.org/10.1158/1535-7163.MCT-07-0217 ) 26255032 . 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 MK Hellstrom , P Ramberg . The effect of a dentifrice containing Magnolia extract on established plaque and gingivitis in man: a six-month clinical study . Int J Dent Hyg , 2014 . 12 ( 2 ): 96 - 102 . (Available from: http://dx.doi.org/10.1111/idh.12047 http://dx.doi.org/10.1111/idh.12047 ) 23070160 . The effect of a dentifrice containing Magnolia extract on established plaque and gingivitis in man: a six-month clinical study E Herlaar , Z Brown . p38 MAPK signalling cascades in inflammatory disease . Mol Med Today , 1999 . 5 ( 10 ): 439 - 447 . (Available from: http://dx.doi.org/10.1016/S1357-4310(99)01544-0 http://dx.doi.org/10.1016/S1357-4310(99)01544-0 ) 21776081 . p38 MAPK signalling cascades in inflammatory disease D Herrmann , A Schreiber , A Ciotkowska , 等 . Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death . Prostate Int , 2014 . 2 ( 3 ): 140 - 146 . (Available from: http://dx.doi.org/10.12954/PI.14055 http://dx.doi.org/10.12954/PI.14055 ) 24666701 . Honokiol, a constituent of Magnolia species, inhibits adrenergic contraction of human prostate strips and induces stromal cell death JHC Ho , CY Hong . Cardiovascular protection of magnolol: cell-type specificity and dose-related effects . J Biomed Sci , 2012 . 19 70 (Available from: http://dx.doi.org/10.1186/1423-0127-19-70 http://dx.doi.org/10.1186/1423-0127-19-70 ) . Cardiovascular protection of magnolol: cell-type specificity and dose-related effects KY Ho , CC Tsai , CP Chen , 等 . Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis . Phytother Res , 2001 . 15 ( 2 ): 139 - 141 . (Available from: http://dx.doi.org/10.1002/ptr.736 http://dx.doi.org/10.1002/ptr.736 ) 23564252 . Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis CP Hoi , YP Ho , L Baum , 等 . Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis , on beta-amyloid-induced toxicity in PC12 cells . Phytother Res , 2010 . 24 ( 10 ): 1538 - 1542 . (Available from: http://dx.doi.org/10.1002/ptr.3178 http://dx.doi.org/10.1002/ptr.3178 ) . Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells M Homma , K Oka , H Kobayashi , 等 . Impact of free magnolol excretions in asthmatic patients who responded well to Saiboku-To, a Chinese herbal medicine . J Pharm Pharmacol , 1993 . 45 ( 9 ): 844 - 846 . (Available from: http://dx.doi.org/10.1111/j.2042-7158.1993.tb05699.x http://dx.doi.org/10.1111/j.2042-7158.1993.tb05699.x ) . Impact of free magnolol excretions in asthmatic patients who responded well to Saiboku-To, a Chinese herbal medicine KL Hon , CK Fung , AK Leung , 等 . Complementary and alternative medicine for childhood asthma: an overview of evidence and patents . Recent Pat Inflamm Allergy Drug Discov , 2015 . 9 ( 1 ): 66 - 79 . (Available from: http://dx.doi.org/10.2174/1872213X09666150302105225 http://dx.doi.org/10.2174/1872213X09666150302105225 ) 9879963 . Complementary and alternative medicine for childhood asthma: an overview of evidence and patents J Hu , WY Gao , NS Ling , 等 . Antidiarrhoeal and intestinal modulatory activities of Wei-Chang-An-Wan extract . J Ethnopharmacol , 2009 . 125 ( 3 ): 450 - 455 . (Available from: http://dx.doi.org/10.1016/j.jep.2009.07.027 http://dx.doi.org/10.1016/j.jep.2009.07.027 ) . Antidiarrhoeal and intestinal modulatory activities of Wei-Chang-An-Wan extract Y Hu , J Qiao , X Zhang , 等 . Antimicrobial effect of Magnolia officinalis extract against Staphylococcus aureus . J Sci Food Agric , 2011 . 91 ( 6 ): 1050 - 1056 . (Available from: http://dx.doi.org/10.1002/jsfa.4280 http://dx.doi.org/10.1002/jsfa.4280 ) 23315267 . Antimicrobial effect of Magnolia officinalis extract against Staphylococcus aureus International Agency for Research on Cancer Some traditional herbal medicines, some mycotoxins, naphthalene and styrene . IARC Monogr Eval Carcinog Risks Hum , 2002 . 82 1 - 556 . . Some traditional herbal medicines, some mycotoxins, naphthalene and styrene K Iwasaki , Q Wang , H Seki , 等 . The effects of the traditional Chinese medicine Banxia Houpo Tang on the swallowing reflex in Parkinson’s disease . Phytomedicine , 2000 . 7 ( 4 ): 259 - 263 . (Available from: http://dx.doi.org/10.1016/S0944-7113(00)80042-2 http://dx.doi.org/10.1016/S0944-7113(00)80042-2 ) 23538992 . The effects of the traditional Chinese medicine Banxia Houpo Tang on the swallowing reflex in Parkinson’s disease SI Jeong , YS Kim , MY Lee , 等 . Regulation of contractile activity by magnolol in the rat isolated gastrointestinal tracts . Pharmacol Res , 2009 . 59 ( 3 ): 183 - 188 . (Available from: http://dx.doi.org/10.1016/j.phrs.2008.11.008 http://dx.doi.org/10.1016/j.phrs.2008.11.008 ) 25510495 . Regulation of contractile activity by magnolol in the rat isolated gastrointestinal tracts DS Kalman , S Feldman , R Feldman , 等 . Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial . Nutr J , 2008 . 7 11 (Available from: http://dx.doi.org/10.1186/1475-2891-7-11 http://dx.doi.org/10.1186/1475-2891-7-11 ) . Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial JS Kang , KH Lee , MH Han , 等 . Antiinflammatory activity of methanol extract isolated from stem bark of Magnolia kobus . Phytother Res , 2008 . 22 ( 7 ): 883 - 888 . (Available from: http://dx.doi.org/10.1002/ptr.2386 http://dx.doi.org/10.1002/ptr.2386 ) . Antiinflammatory activity of methanol extract isolated from stem bark of Magnolia kobus M Karin . NF-κB and cancer: mechanisms and targets . Mol Carcinog , 2006 . 45 ( 6 ): 355 - 361 . (Available from: http://dx.doi.org/10.1002/mc.20217 http://dx.doi.org/10.1002/mc.20217 ) . NF-κB and cancer: mechanisms and targets G Kaushik , S Ramalingam , D Subramaniam , 等 . Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells . Am J Surg , 2012 . 204 ( 6 ): 868 - 873 . (Available from: http://dx.doi.org/10.1016/j.amjsurg.2012.09.001 http://dx.doi.org/10.1016/j.amjsurg.2012.09.001 ) . Honokiol induces cytotoxic and cytostatic effects in malignant melanoma cancer cells BH Kim , JY Cho . Anti-inflammatory effect of honokiol is mediated by PI3K/Akt pathway suppression . Acta Pharmol Sin , 2008 . 29 ( 1 ): 113 - 122 . (Available from: http://dx.doi.org/10.1111/j.1745-7254.2008.00725.x http://dx.doi.org/10.1111/j.1745-7254.2008.00725.x ) . Anti-inflammatory effect of honokiol is mediated by PI3K/Akt pathway suppression SY Kim , J Kim , SI Jeong , 等 . Antimicrobial effects and resistant regulation of magnolol and honokiol on methicillin-resistant Staphylococcus aureus . Biomed Res Int , 2015 . 2015 283630 (Available from: http://dx.doi.org/10.1155/2015/283630 http://dx.doi.org/10.1155/2015/283630 ) 11057514 . Antimicrobial effects and resistant regulation of magnolol and honokiol on methicillin-resistant Staphylococcus aureus YJ Kim , MS Choi , BY Cha , 等 . 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 , 2013 . 57 ( 11 ): 1988 - 1998 . (Available from: http://dx.doi.org/10.1002/mnfr.201300113 http://dx.doi.org/10.1002/mnfr.201300113 ) 21571938 . Long-term supplementation of honokiol and magnolol ameliorates body fat accumulation, insulin resistance, and adipose inflammation in high-fat fed mice I Kimura , LH Chui , K Fujitani , 等 . 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 , 1989 . 50 ( 1 ): 75 - 78 . (Available from: http://dx.doi.org/10.1254/jjp.50.75 http://dx.doi.org/10.1254/jjp.50.75 ) . 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 CH Ko , HH Chen , YR Lin , 等 . Inhibition of smooth muscle contraction by magnolol and honokiol in porcine trachea . Planta Med , 2003 . 69 ( 6 ): 532 - 536 . (Available from: http://dx.doi.org/10.1055/s-2003-40654 http://dx.doi.org/10.1055/s-2003-40654 ) 16902031 . Inhibition of smooth muscle contraction by magnolol and honokiol in porcine trachea U Koetter , M Barrett , S Lacher , 等 . Interactions of Magnolia and Ziziphus extracts with selected central nervous system receptors . J Ethnopharmacol , 2009 . 124 ( 3 ): 421 - 425 . (Available from: http://dx.doi.org/10.1016/j.jep.2009.05.040 http://dx.doi.org/10.1016/j.jep.2009.05.040 ) . Interactions of Magnolia and Ziziphus extracts with selected central nervous system receptors ZL Kong , SC Tzeng , YC Liu . Cytotoxic neolignans: an SAR study . Bioorg Med Chem Lett , 2005 . 15 ( 1 ): 163 - 166 . (Available from: http://dx.doi.org/10.1016/j.bmcl.2004.10.011 http://dx.doi.org/10.1016/j.bmcl.2004.10.011 ) 18684121 . Cytotoxic neolignans: an SAR study A Kumar , UK Singh , A Chaudhary . Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities . Future Med Chem , 2013 . 5 ( 7 ): 809 - 829 . (Available from: http://dx.doi.org/10.4155/fmc.13.32 http://dx.doi.org/10.4155/fmc.13.32 ) 24158950 . Honokiol analogs: a novel class of anticancer agents targeting cell signaling pathways and other bioactivities B Lee , CH Kim , SK Moon . 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 , 2006 . 580 ( 22 ): 5177 - 5184 . (Available from: http://dx.doi.org/10.1016/j.febslet.2006.08.064 http://dx.doi.org/10.1016/j.febslet.2006.08.064 ) . 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 DH Lee , MJ Szczepanski , YJ Lee . Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells . J Cell Biochem , 2009 . 106 ( 6 ): 1113 - 1122 . (Available from: http://dx.doi.org/10.1002/jcb.22098 http://dx.doi.org/10.1002/jcb.22098 ) . Magnolol induces apoptosis via inhibiting the EGFR/PI3K/Akt signaling pathway in human prostate cancer cells JW Lee , YK Lee , BJ Lee , 等 . 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 , 2010 . 95 ( 1 ): 31 - 40 . (Available from: http://dx.doi.org/10.1016/j.pbb.2009.12.003 http://dx.doi.org/10.1016/j.pbb.2009.12.003 ) . Inhibitory effect of ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on memory impairment and neuronal toxicity induced by beta-amyloid SK Lee , HK Chun , JY Yang , 等 . Inhibitory effect of obovatal on the migration and invasion of HT1080 cells via the inhibition of MMP-2 . Bioorg Med Chem , 2007 . 15 ( 12 ): 4085 - 4090 . (Available from: http://dx.doi.org/10.1016/j.bmc.2007.03.081 http://dx.doi.org/10.1016/j.bmc.2007.03.081 ) . Inhibitory effect of obovatal on the migration and invasion of HT1080 cells via the inhibition of MMP-2 SY Lee , JS Cho , DY Yuk , 等 . Obovatol enhances docetaxel-induced prostate and colon cancer cell death through inactivation of nuclear transcription factor-κB . J Pharm Sci , 2009 . 111 ( 2 ): 124 - 136 . (Available from: http://dx.doi.org/10.1254/jphs.09048FP http://dx.doi.org/10.1254/jphs.09048FP ) . Obovatol enhances docetaxel-induced prostate and colon cancer cell death through inactivation of nuclear transcription factor-κB YJ Lee , YM Lee , CK Lee , 等 . Therapeutic applications of compounds in the Magnolia family . Pharmacol Ther , 2011 . 130 ( 2 ): 157 - 176 . (Available from: http://dx.doi.org/10.1016/j.pharmthera.2011.01.010 http://dx.doi.org/10.1016/j.pharmthera.2011.01.010 ) . Therapeutic applications of compounds in the Magnolia family YS Lee , SS Choi , T Yonezawa , 等 . Honokiol, magnolol, and a combination of both compounds improve glucose metabolism in high-fat diet-induced obese mice . Food SciBiotechnol , 2015 . 24 ( 4 ): 1467 - 1474 . (Available from: http://dx.doi.org/10.1007/s10068-015-0189-6 http://dx.doi.org/10.1007/s10068-015-0189-6 ) . Honokiol, magnolol, and a combination of both compounds improve glucose metabolism in high-fat diet-induced obese mice HB Li , X Yi , JM Gao , 等 . Magnolol-induced H460 cells death via autophagy but not apoptosis . Arch Pharm Res , 2007 . 30 ( 12 ): 1566 - 1574 . (Available from: http://dx.doi.org/10.1007/BF02977326 http://dx.doi.org/10.1007/BF02977326 ) . Magnolol-induced H460 cells death via autophagy but not apoptosis L Li , W Han , Y Gu , 等 . Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore . Cancer Res , 2007 . 67 ( 10 ): 4894 - 4903 . (Available from: http://dx.doi.org/10.1158/0008-5472.CAN-06-3818 http://dx.doi.org/10.1158/0008-5472.CAN-06-3818 ) . Honokiol induces a necrotic cell death through the mitochondrial permeability transition pore N Li , Y Song , W Zhang , 等 . Evaluation of the in vitro and in vivo genotoxicity of magnolia bark extract . Regul Toxicol Pharmacol , 2007 . 49 ( 3 ): 154 - 159 . (Available from: http://dx.doi.org/10.1016/j.yrtph.2007.06.005 http://dx.doi.org/10.1016/j.yrtph.2007.06.005 ) . Evaluation of the in vitro and in vivo genotoxicity of magnolia bark extract Y Lim , JS Kwon , DW Kim , 等 . Obovatol from Magnolia obovata inhibits vascular smooth muscle cell proliferation and intimal hyperplasia by inducing p21Cip1 . Atherosclerosis , 2010 . 210 ( 2 ): 372 - 380 . (Available from: http://dx.doi.org/10.1016/j.atherosclerosis.2009.11.037 http://dx.doi.org/10.1016/j.atherosclerosis.2009.11.037 ) . Obovatol from Magnolia obovata inhibits vascular smooth muscle cell proliferation and intimal hyperplasia by inducing p21Cip1 SI Lin , TH Tsai , YJ Chou , 等 . 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 . 2015 108961 (Available from: http://dx.doi.org/10.1155/2015/108961 http://dx.doi.org/10.1155/2015/108961 ) . Characteristics associated with utilization of asthma-related traditional Chinese medicine services among asthma children in Taiwan: a nationwide cohort study SP Lin , SY Tsai , PDL Chao , 等 . Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats . Planta Med , 2011 . 77 ( 16 ): 1800 - 1805 . (Available from: http://dx.doi.org/10.1055/s-0030-1271159 http://dx.doi.org/10.1055/s-0030-1271159 ) . Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats SY Lin , YT Chang , JD Liu , 等 . Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells . Mol Carcinog , 2001 . 32 ( 2 ): 73 - 83 . (Available from: http://dx.doi.org/10.1002/mc.1066 http://dx.doi.org/10.1002/mc.1066 ) . Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells YR Lin , HH Chen , CH Ko , 等 . Effects of honokiol and magnolol on acute and inflammatory pain models in mice . Life Sci , 2007 . 81 ( 13 ): 1071 - 1078 . (Available from: http://dx.doi.org/10.1016/j.lfs.2007.08.014 http://dx.doi.org/10.1016/j.lfs.2007.08.014 ) . Effects of honokiol and magnolol on acute and inflammatory pain models in mice H Liu , C Zang , A Emde , 等 . Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer . Eur J Pharmacol , 2008 . 591 ( 1-3 ): 43 - 51 . (Available from: http://dx.doi.org/10.1016/j.ejphar.2008.06.026 http://dx.doi.org/10.1016/j.ejphar.2008.06.026 ) . Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer X Liu , Q Wang , G Song , 等 . The classification and application of toxic Chinese materia medica . Phytother Res , 2014 . 28 ( 3 ): 334 - 347 . (Available from: http://dx.doi.org/10.1002/ptr.5006 http://dx.doi.org/10.1002/ptr.5006 ) . The classification and application of toxic Chinese materia medica Z Liu , X Zhang , W Cui , 等 . Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats . Regul Toxicol Pharmacol , 2007 . 49 ( 3 ): 160 - 171 . (Available from: http://dx.doi.org/10.1016/j.yrtph.2007.06.006 http://dx.doi.org/10.1016/j.yrtph.2007.06.006 ) . Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats YC Lo , CM Teng , CF Chen , 等 . Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation . Biochem Pharmacol , 1994 . 47 ( 3 ): 549 - 553 . (Available from: http://dx.doi.org/10.1016/0006-2952(94)90187-2 http://dx.doi.org/10.1016/0006-2952(94)90187-2 ) . Magnolol and honokiol isolated from Magnolia officinalis protect rat heart mitochondria against lipid peroxidation YC Lu , HH Chen , CH Ko , 等 . The mechanism of honokiol-induced and magnolol-induced inhibition on muscle contraction and Ca 2+ mobilization in rat uterus . Naunyn-Schmiedeberg’s Arch Pharmacol , 2003 . 368 ( 4 ): 262 - 269 . (Available from: http://dx.doi.org/10.1007/s00210-003-0802-8 http://dx.doi.org/10.1007/s00210-003-0802-8 ) . The mechanism of honokiol-induced and magnolol-induced inhibition on muscle contraction and Ca2+ mobilization in rat uterus Y Maruyama , H Kuribara . Overview of the pharmacological features of honokiol . CNS Drug Rev , 2000 . 6 ( 1 ): 35 - 44 . (Available from: http://dx.doi.org/10.1111/j.1527-3458.2000.tb00136.x http://dx.doi.org/10.1111/j.1527-3458.2000.tb00136.x ) . Overview of the pharmacological features of honokiol Y Maruyama , H Kuribara , M Morita , 等 . Identification of magnolol and honokiol as anxiolytic agents in extracts of Saiboku-To, an oriental herbal medicine . J Nat Prod , 1998 . 61 ( 1 ): 135 - 138 . (Available from: http://dx.doi.org/10.1021/np9702446 http://dx.doi.org/10.1021/np9702446 ) . Identification of magnolol and honokiol as anxiolytic agents in extracts of Saiboku-To, an oriental herbal medicine SM Mohamed , EM Hassan , NA Ibrahim . Cytotoxic and antiviral activities of aporphine alkaloids of Magnolia grandiflora L . Nat Prod Res , 2010 . 24 ( 15 ): 1395 - 1402 . (Available from: http://dx.doi.org/10.1080/14786410902906959 http://dx.doi.org/10.1080/14786410902906959 ) . Cytotoxic and antiviral activities of aporphine alkaloids of Magnolia grandiflora L M Mucci , C Carraro , P Mancino , 等 . Soy isoflavones, lactobacilli, Magnolia bark extract, vitamin D3 and calcium. Controlled clinical study in menopause . Minerva Ginecol , 2006 . 58 ( 4 ): 323 - 334 . . Soy isoflavones, lactobacilli, Magnolia bark extract, vitamin D3 and calcium. Controlled clinical study in menopause ME Munroe , JL Arbiser , GA Bishop . Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis . J Immunol , 2007 . 179 ( 2 ): 753 - 763 . (Available from: http://dx.doi.org/10.4049/jimmunol.179.2.753 http://dx.doi.org/10.4049/jimmunol.179.2.753 ) . Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis A Nachtergael , M Poivre , A Belayew , 等 . In vitro genotoxicity tests point to an unexpected and harmful effect of a Magnolia and Aristolochia association . J Ethnopharmacol , 2015 . 174 178 - 186 . (Available from: http://dx.doi.org/10.1016/j.jep.2015.07.045 http://dx.doi.org/10.1016/j.jep.2015.07.045 ) . In vitro genotoxicity tests point to an unexpected and harmful effect of a Magnolia and Aristolochia association T Nakazawa , T Yasuda , K Ohsawa . Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice . J Pharm Pharmacol , 2003 . 55 ( 11 ): 1583 - 1591 . (Available from: http://dx.doi.org/10.1211/0022357022188 http://dx.doi.org/10.1211/0022357022188 ) . Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice NCBI (National Center for Biotechnology Information) PubChem Compound Database , 2016 . http://pubchem.ncbi.nlm. nih.gov , . PubChem Compound Database K Newton , VM Dixit . Signaling in innate immunity and inflammation . Cold Spring Harb Perspect Biol , 2012 . 4 ( 3 ): a006049 (Available from: http://dx.doi.org/10.1101/cshperspect.a006049 http://dx.doi.org/10.1101/cshperspect.a006049 ) . Signaling in innate immunity and inflammation J Ngezahayo , F Havyarimana , L Hari , 等 . Medicinal plants used by Burundian traditional healers for the treatment of microbial diseases . J Ethnopharmacol , 2015 . 173 338 - 351 . (Available from: http://dx.doi.org/10.1016/j.jep.2015.07.028 http://dx.doi.org/10.1016/j.jep.2015.07.028 ) . Medicinal plants used by Burundian traditional healers for the treatment of microbial diseases J Ngezahayo , L Pottier , SO Ribeiro , 等 . Plastotoma rotundifolium aerial tissue extract has antibacterial activities . Ind Crops Prod , 2016 . 86 301 - 310 . (Available from: http://dx.doi.org/10.1016/j.indcrop.2016.04.004 http://dx.doi.org/10.1016/j.indcrop.2016.04.004 ) . Plastotoma rotundifolium aerial tissue extract has antibacterial activities PN Okusa , C Stévigny , M Névraumont , 等 . Ferulaldehyde and lupeol as direct and indirect antimicrobial compounds from Cordia gilletii (Boraginaceae) root barks . Nat Prod Commun , 2014 . 9 ( 5 ): 619 - 622 . . Ferulaldehyde and lupeol as direct and indirect antimicrobial compounds from Cordia gilletii (Boraginaceae) root barks HC Ou , FP Chou , TM Lin , 等 . Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells . Chem-Biol Interact , 2006 . 161 ( 1 ): 1 - 13 . (Available from: http://dx.doi.org/10.1016/j.cbi.2006.02.006 http://dx.doi.org/10.1016/j.cbi.2006.02.006 ) . Protective effects of honokiol against oxidized LDL-induced cytotoxicity and adhesion molecule expression in endothelial cells M Ouédraogo , T Baudoux , C Stévigny , 等 . Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms . J Ethnopharmacol , 2012 . 140 ( 3 ): 492 - 512 . (Available from: http://dx.doi.org/10.1016/j.jep.2012.01.059 http://dx.doi.org/10.1016/j.jep.2012.01.059 ) . Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms CS Park , TB Kim , JY Lee , 等 . Effects of add-on therapy with NDC-052, an extract from Magnolia e flos , in adult asthmatic patients receiving inhaled corticosteroids . Korean J Intern Med , 2012 . 27 ( 1 ): 84 - 90 . (Available from: http://dx.doi.org/10.3904/kjim.2012.27.1.84 http://dx.doi.org/10.3904/kjim.2012.27.1.84 ) . Effects of add-on therapy with NDC-052, an extract from Magnoliae flos, in adult asthmatic patients receiving inhaled corticosteroids J Park , J Lee , E Jung , 等 . In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp . Eur J Pharmacol , 2004 . 496 ( 1-3 ): 189 - 195 . (Available from: http://dx.doi.org/10.1016/j.ejphar.2004.05.047 http://dx.doi.org/10.1016/j.ejphar.2004.05.047 ) . In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp G Pearson , F Robinson , TB Gibson , 等 . Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions . Endocr Rev , 2001 . 22 ( 2 ): 153 - 183 . (Available from: http://dx.doi.org/10.1210/er.22.2.153 http://dx.doi.org/10.1210/er.22.2.153 ) . Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions PF Porciani , S Grandini . 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 , 2012 . 23 ( 3 ): 76 - 79 . . The effect of zinc acetate and magnolia bark extract added to chewing gum on volatile sulfur-containing compounds in the oral cavity PF Porciani , S Grandini , M Chazine . The effect of zinc lactate and magnolia bark extract added tablets on volatile sulfur-containing compounds in the oral cavity . J Clin Dent , 2014 . 25 ( 3 ): 53 - 56 . . The effect of zinc lactate and magnolia bark extract added tablets on volatile sulfur-containing compounds in the oral cavity MK Pyo , HS Yun-Choi , YJ Hong . Antiplatelet activities of aporphine alkaloids isolated from leaves of Magnolia obovata . Planta Med , 2003 . 69 ( 3 ): 267 - 269 . (Available from: http://dx.doi.org/10.1055/s-2003-38493 http://dx.doi.org/10.1055/s-2003-38493 ) . Antiplatelet activities of aporphine alkaloids isolated from leaves of Magnolia obovata T Rasamiravaka , OM Vandeputte , L Pottier , 等 . 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 , 2014 . 10 ( 7 ): e0132791 (Available from: http://dx.doi.org/10.1371/journal.pone.0132791 http://dx.doi.org/10.1371/journal.pone.0132791 ) . 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 FL Ricciardolo , PJ Sterk , B Gaston , 等 . Nitric oxide in health and disease of the respiratory system . Physiol Rev , 2004 . 84 ( 3 ): 731 - 765 . (Available from: http://dx.doi.org/10.1152/physrev.00034.2003 http://dx.doi.org/10.1152/physrev.00034.2003 ) . Nitric oxide in health and disease of the respiratory system ML Sheu , SH Liu , KH Lan . Honokiol induces calpain-mediated glucose-regulated protein-94 cleavage and apoptosis in human gastric cancer cells and reduces tumor growth . PLoS ONE , 2007 . 2 ( 10 ): e1096 (Available from: http://dx.doi.org/10.1371/journal.pone.0001096 http://dx.doi.org/10.1371/journal.pone.0001096 ) . Honokiol induces calpain-mediated glucose-regulated protein-94 cleavage and apoptosis in human gastric cancer cells and reduces tumor growth CY Shih , TC Chou . The antiplatelet activity of magnolol is mediated by PPAR-β/γ . Biochem Pharmacol , 2012 . 84 ( 6 ): 793 - 803 . (Available from: http://dx.doi.org/10.1016/j.bcp.2012.06.022 http://dx.doi.org/10.1016/j.bcp.2012.06.022 ) . The antiplatelet activity of magnolol is mediated by PPAR-β/γ RE Simmonds , BM Foxwell . Signalling, inflammation and arthritis: NF-κB and its relevance to arthritis and inflammation . Rheumatology (Oxford) , 2008 . 47 ( 5 ): 584 - 590 . (Available from: http://dx.doi.org/10.1093/rheumatology/kem298 http://dx.doi.org/10.1093/rheumatology/kem298 ) . Signalling, inflammation and arthritis: NF-κB and its relevance to arthritis and inflammation EJ Sohn , CS Kim , YS Kim , 等 . Effects of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) on diabetic nephropathy in type 2 diabetic Goto-Kakizaki rats . Life Sci , 2007 . 80 ( 5 ): 468 - 475 . (Available from: http://dx.doi.org/10.1016/j.lfs.2006.09.037 http://dx.doi.org/10.1016/j.lfs.2006.09.037 ) . Effects of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) on diabetic nephropathy in type 2 diabetic Goto-Kakizaki rats WJ Syu , CC Shen , JJ Lu , 等 . Antimicrobial and cytotoxic activities of neolignans from Magnolia officinalis . Chem Biodivers , 2004 . 1 ( 3 ): 530 - 537 . (Available from: http://dx.doi.org/10.1002/cbdv.200490046 http://dx.doi.org/10.1002/cbdv.200490046 ) . Antimicrobial and cytotoxic activities of neolignans from Magnolia officinalis E Tachikawa , M Takahashi , T Kashimoto . Effects of extract and ingredients isolated from Magnolia obovata Thunberg on catecholamine secretion from bovine adrenal chromaffin cells . Biochem Pharmacol , 2000 . 60 ( 3 ): 433 - 440 . (Available from: http://dx.doi.org/10.1016/S0006-2952(00)00343-9 http://dx.doi.org/10.1016/S0006-2952(00)00343-9 ) . Effects of extract and ingredients isolated from Magnolia obovata Thunberg on catecholamine secretion from bovine adrenal chromaffin cells JL Tang , BY Liu , KW Ma . Traditional Chinese medicine . Lancet , 2008 . 372 ( 9654 ): 1938 - 1940 . (Available from: http://dx.doi.org/10.1016/S0140-6736(08)61354-9 http://dx.doi.org/10.1016/S0140-6736(08)61354-9 ) . Traditional Chinese medicine C Taniguchi , M Homma , O Takano , 等 . Pharmacological effects of urinary products obtained after treatment with saibokuto, a herbal medicine for bronchial asthma, on type IV allergic reaction . Planta Med , 2000 . 66 ( 7 ): 607 - 611 . (Available from: http://dx.doi.org/10.1055/s-2000-8626 http://dx.doi.org/10.1055/s-2000-8626 ) . Pharmacological effects of urinary products obtained after treatment with saibokuto, a herbal medicine for bronchial asthma, on type IV allergic reaction CM Teng , CC Chen , FN Ko , 等 . Two antiplatelet agents from Magnolia officinalis . Thromb Res , 1988 . 50 ( 6 ): 757 - 765 . (Available from: http://dx.doi.org/10.1016/0049-3848(88)90336-2 http://dx.doi.org/10.1016/0049-3848(88)90336-2 ) . Two antiplatelet agents from Magnolia officinalis R Teschke , A Wolff , C Frenzel , 等 . Review article: herbal hepatotoxicity–an update on traditional Chinese medicine preparations . Aliment Pharmacol Ther , 2014 . 40 ( 1 ): 32 - 50 . (Available from: http://dx.doi.org/10.1111/apt.12798 http://dx.doi.org/10.1111/apt.12798 ) . Review article: herbal hepatotoxicity–an update on traditional Chinese medicine preparations R Teschke , L Zhang , H Long , 等 . Traditional Chinese medicine and herbal hepatotoxicity: a tabular compilation of reported cases . Ann Hepatol , 2015 . 14 ( 1 ): 7 - 19 . . Traditional Chinese medicine and herbal hepatotoxicity: a tabular compilation of reported cases R Teschke , D Larrey , D Melchart , 等 . Traditional Chinese medicine (TCM) and herbal hepatotoxicity: RUCAM and the role of novel diagnostic biomarkers such as microRNAs . Medicines , 2016 . 3 ( 3 ): 18 (Available from: http://dx.doi.org/10.3390/medicines3030018 http://dx.doi.org/10.3390/medicines3030018 ) . Traditional Chinese medicine (TCM) and herbal hepatotoxicity: RUCAM and the role of novel diagnostic biomarkers such as microRNAs P Tripathi , L Kashyap , V Singh . The role of nitric oxide in inflammatory reactions . FEMS Immunol Med Microbiol , 2007 . 51 ( 3 ): 443 - 452 . (Available from: http://dx.doi.org/10.1111/j.1574-695X.2007.00329.x http://dx.doi.org/10.1111/j.1574-695X.2007.00329.x ) . The role of nitric oxide in inflammatory reactions PU Unschuld . The past 1000 years of Chinese medicine . Lancet , 1999 . 354 SIV9 (Available from: http://dx.doi.org/10.1016/S0140-6736(99)90352-5 http://dx.doi.org/10.1016/S0140-6736(99)90352-5 ) . The past 1000 years of Chinese medicine JL Vanherweghem , M Depierreux , C Tielemans , 等 . Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs . Lancet , 1993 . 341 ( 8842 ): 387 - 391 . (Available from: http://dx.doi.org/10.1016/0140-6736(93)92984-2 http://dx.doi.org/10.1016/0140-6736(93)92984-2 ) . Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs JP Wang , MF Hsu , SL Raung , 等 . Antiinflammatory and analgesic effects of magnolol. Naunyn-Schmiedeberg ’ . s Arch Pharmacol , 1992 . 346 ( 6 ): 707 - 712 . (Available from: http://dx.doi.org/10.1007/BF00168746 http://dx.doi.org/10.1007/BF00168746 ) . Antiinflammatory and analgesic effects of magnolol. Naunyn-Schmiedeberg’ S Wang , Y Li . O Devinsky , S Pacia , S Shachter . Traditional Chinese medicine . Complementary and Alternative Therapies for Epilepsy , 2005 . : New York Demos Medical Publishing , 177 - 182 . . Traditional Chinese medicine T Wang , F Chen , Z Chen , 等 . Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO . World J Gastroenterol , 2004 . 10 ( 15 ): 2205 - 2208 . . Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO JC Waymire . Chapter 12: Biogenic Amine Neurotransmitters. University of Texas Medical School at Houston . 1997 . (Available from: http://neuroscience.uth.tmc.edu/s1/chapter12.html http://neuroscience.uth.tmc.edu/s1/chapter12.html ) . Chapter 12: Biogenic Amine Neurotransmitters. University of Texas Medical School at Houston WHO (World Health Organization) World Health Statistics 2016: Monitoring Health for the SDGs , 2016 . : Geneva World Health Organization, Geneva , . World Health Statistics 2016: Monitoring Health for the SDGs EM Williamson , K Chan , Q Xu , 等 . Integrated toxicological approaches to evaluating the safety of herbal medicine . Science , 2015 . 347 ( 6219 Suppl. ): S47 - S49 . . Integrated toxicological approaches to evaluating the safety of herbal medicine R Wisdom . AP-1: one switch for many signals . Exp Cell Res , 1999 . 253 ( 1 ): 180 - 185 . (Available from: http://dx.doi.org/10.1006/excr.1999.4685 http://dx.doi.org/10.1006/excr.1999.4685 ) . AP-1: one switch for many signals HU Wittchen , J Hoyer . Generalized anxiety disorder: nature and course . J Clin Psychiatr , 2001 . 62 ( Suppl. 11 ): 15 - 21 . . Generalized anxiety disorder: nature and course A Woodbury , SP Yu , L Wei , 等 . Neuro-modulating effects of honokiol: a review . Front Neurol , 2013 . 4 130 (Available from: http://dx.doi.org/10.3389/fneur.2013.00130 http://dx.doi.org/10.3389/fneur.2013.00130 ) . Neuro-modulating effects of honokiol: a review Q Xu , R Bauer , BM Hendry , 等 . The quest for modernisation of traditional Chinese medicine . BMC Complement Altern Med , 2013 . 13 132 (Available from: http://dx.doi.org/10.1186/1472-6882-13-132 http://dx.doi.org/10.1186/1472-6882-13-132 ) . The quest for modernisation of traditional Chinese medicine R Yan , W Wang , J Guo , 等 . Studies on the alkaloids of the bBark of Magnolia officinalis : isolation and on-line analysis by HPLC-ESI-MS n . Molecules , 2013 . 18 ( 7 ): 7739 - 7750 . (Available from: http://dx.doi.org/10.3390/molecules18077739 http://dx.doi.org/10.3390/molecules18077739 ) . Studies on the alkaloids of the bBark of Magnolia officinalis: isolation and on-line analysis by HPLC-ESI-MSn HY Yang , CF Chen . Subacute toxicity of 15 commonly used Chinese drugs (II) . J Food Drug Anal , 1997 . 5 ( 4 ): 355 - 380 . . Subacute toxicity of 15 commonly used Chinese drugs (II) SE Yang , MT Hsieh , TH Tsai , 等 . 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 , 2002 . 63 ( 9 ): 1641 - 1651 . (Available from: http://dx.doi.org/10.1016/S0006-2952(02)00894-8 http://dx.doi.org/10.1016/S0006-2952(02)00894-8 ) . Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiolinduced apoptosis in human squamous lung cancer CH27 cells SE Yang , MT Hsieh , TH Tsai , 等 . Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells . Br J Pharmacol , 2003 . 138 ( 1 ): 193 - 201 . (Available from: http://dx.doi.org/10.1038/sj.bjp.0705024 http://dx.doi.org/10.1038/sj.bjp.0705024 ) . Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells IS Young , JV Woodside . Antioxidants in health and disease . J Clin Pathol , 2001 . 54 ( 3 ): 176 - 186 . (Available from: http://dx.doi.org/10.1136/jcp.54.3.176 http://dx.doi.org/10.1136/jcp.54.3.176 ) . Antioxidants in health and disease C Yu , D Meyer , G Campbell , 等 . Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein . Science , 1995 . 269 ( 5220 ): 81 - 83 . (Available from: http://dx.doi.org/10.1126/science.7541555 http://dx.doi.org/10.1126/science.7541555 ) . Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein SX Yu , RY Yan , RX Liang , 等 . Bioactive polar compounds from stem bark of Magnolia officinalis . Fitoterapia , 2012 . 83 ( 2 ): 356 - 361 . (Available from: http://dx.doi.org/10.1016/j.fitote.2011.11.020 http://dx.doi.org/10.1016/j.fitote.2011.11.020 ) . Bioactive polar compounds from stem bark of Magnolia officinalis HF Zaki , MA Abd-El-Fattah , SA Amina . Naringenin protects against scopolamine-induced dementia in rats . Bull Fac Pharm Cairo Univ , 2014 . 52 ( 1 ): 15 - 25 . (Available from: http://dx.doi.org/10.1016/j.bfopcu.2013.11.001 http://dx.doi.org/10.1016/j.bfopcu.2013.11.001 ) . Naringenin protects against scopolamine-induced dementia in rats R Zandi , AB Larsen , P Andersen , 等 . Mechanisms for oncogenic activation of the epidermal growth factor receptor . Cell Signal , 2007 . 19 ( 10 ): 2013 - 2023 . (Available from: http://dx.doi.org/10.1016/j.cellsig.2007.06.023 http://dx.doi.org/10.1016/j.cellsig.2007.06.023 ) . Mechanisms for oncogenic activation of the epidermal growth factor receptor B Zhang , T Maniatis , Y Song , 等 . Evaluation of magnolia bark extract in chromosomal aberration assays . Mutat Res-Genet Toxicol Environ Mutag , 2008 . 654 ( 2 ): 133 - 137 . (Available from: http://dx.doi.org/10.1016/j.mrgentox.2008.05.009 http://dx.doi.org/10.1016/j.mrgentox.2008.05.009 ) . Evaluation of magnolia bark extract in chromosomal aberration assays L Zhang , J Yan , X Liu , 等 . Pharmacovigilance practice and risk control of TCM in China . J Ethnopharmacol , 2012 . 140 ( 3 ): 519 - 525 . (Available from: http://dx.doi.org/10.1016/j.jep.2012.01.058 http://dx.doi.org/10.1016/j.jep.2012.01.058 ) . Pharmacovigilance practice and risk control of TCM in China P Zhang , X Liu , Y Zhu , 等 . Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells . Neurosci Lett , 2013 . 534 123 - 127 . (Available from: http://dx.doi.org/10.1016/j.neulet.2012.11.052 http://dx.doi.org/10.1016/j.neulet.2012.11.052 ) . Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells HY Zhou , EM Shin , LY Guo , 等 . 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 , 2008 . 586 ( 1-3 ): 340 - 349 . (Available from: http://dx.doi.org/10.1016/j.ejphar.2008.02.044 http://dx.doi.org/10.1016/j.ejphar.2008.02.044 ) . 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 Y Zhu , M Niu , J Chen , 等 . Hepatobiliary and pancreatic: comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients . J Gastroenterol Hepatol , 2016 . 31 ( 8 ): 1476 - 1482 . (Available from: http://dx.doi.org/10.1111/jgh.13323 http://dx.doi.org/10.1111/jgh.13323 ) . Hepatobiliary and pancreatic: comparison between Chinese herbal medicine and Western medicine-induced liver injury of 1985 patients R Ziyaev , NI Shtonda , MD Sturua , 等 . Alkaloids of some Magnolia species . Life Sci , 1999 . 35 ( 3 ): 366 - 367 . . Alkaloids of some Magnolia species GY Zuo , XJ Zhang , J Han , 等 . 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 , 2015 . 15 ( 1 ): 425 (Available from: http://dx.doi.org/10.1186/s12906-015-0938-3 http://dx.doi.org/10.1186/s12906-015-0938-3 ) . In vitro synergism of magnolol and honokiol in combination with antibacterial agents against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) Compliance with ethics guidelines Mélanie POIVRE and Pierre DUEZ declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1600299 2016-03-24 2017-02-18 2016-11-07 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2017 2017 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 03 18