INTRODUCTION
Neolignans are secondary plant metabolites that are oxidative products of phenylpropanoids, a large family of organic compounds synthesized by plants from amino acids such as phenylalanine and tyrosine (Zálešák et al., 2019). They are phenolic compounds with dimeric structures linking two units via a C-C or C-O linkage. Neolignans with C-O linkages are sometimes referred to as oxyneolignans (Teponno et al., 2016). Among Magnolia species, well-reviewed neolignans are honokiol (Ong et al., 2020; Rauf et al., 2018) and magnolol (Chen et al., 2011; Lin et al., 2021). Neolignans possess biological activities such as anticancer, estrogenic, antiviral, antimicrobial, neuroprotective, antihypersensitive, and antioxidant properties. Other classes of compounds isolated from Magnolia species are flavonoids, phenylpropanoids, coumarins, alkaloids, terpenoids, and lignans (Lee et al., 2011a).
Most of the studies on the pharmacological properties of neolignans from Magnolia are from three species. The species are described below.
Magnolia officinalis Rehder & E. Wilson is native to China, occurring at altitudes of 300–1,500 m (Xia et al., 2008; TSO, 2021). The species is a deciduous tree that reaches 20 m in height and produces a thick, brown, but not fissured bark. Young shoots are downy and yellowish grey. Leaves are obovate, rounded at the apex, pale green above, and downy beneath. Flowers are white, fragrant, and cup-shaped (Fig. 1). Fruits are elongated with a rounded tip. In China, the dried bark of M. officinalis (Houpo) is an important medicinal herb having a wide range of biological and pharmacological properties (Luo et al., 2019).
Magnolia obovata Thunb. is a deciduous tree species that is native to the deciduous broad-leaved temperate forests of Hokkaido in Japan (Kikuzawa and Mizui, 1990). The species is cultivated in China (Xia et al., 2008) and has naturalized in Korea (Kwon and Oh, 2015). In Japan, M. obovata is a beautiful tree that reaches 20 m in height (TSO, 2021). Its bark is thick, brown, and not fissured. Leaves are large, leathery, obovate, green above, and bluish-white beneath. Flowers are large, strongly fragrant, and cup-shaped, and they produce petals that are creamy white with purplish-red filaments and yellow anthers (Fig. 1). Fruits are red and cone-shaped with a tapering tip.
 | Figure 1. Flowers of M. officinalis (left), M. obovata (middle), and M. grandiflora (right). [Click here to view] |
 | Figure 2. The chemical structure of 4-O-methylhonokiol. [Click here to view] |
Magnolia grandiflora L. is a medium to large evergreen tree that is native to North America, up to 30 m in height with a dense pyramidal crown (Lim, 2014). The bark is greyish brown, scaly, and fissured. Leaves are leathery, broadly ovate, dark green above, and yellowish brown with tomentose beneath. Flowers are large, showy, fragrant, and white (Fig. 1). Fruits are cylindrical to ovoid with greyish-yellow tomentose. They contain seeds that are ovoid, glossy, and bright red.
4-O-METHYLHONOKIOL
MH (3,5'-diallyl-2'-hydroxy-4-methoxybiphenyl) is a neolignan with the molecular formula of C19H20O2 and molecular weight of 280 g/mol (Lee et al., 2011a). Its IUPAC name is 2-(4-methoxy-3-prop-2-enylphenyl)-4-prop-2-enylphenol. Structurally, MH has a biphenyl skeleton linked by a C-C bridge at C1 and C1- (Fig. 2). There is a methylene (-CH2) group at C3 and at C5- (diallyl moiety), a methoxy (-OCH3) group at C4 of the A ring, and a hydroxy (-OH) group at C2- of the B ring. MH has a chemical structure that is similar to that of honokiol (3,5′-diallyl-4,2′-dihydroxybiphenyl) which has a -OH group at C4, instead of a -OCH3 group. Both MH and honokiol have a -OH group at C2-.
MH has been isolated and identified from Magnolia species. They include M. officinalis (Luo et al., 2019; Poivre and Duez, 2017), M. obovata (Chan et al., 2021; Min, 2008), M. grandiflora (Clark et al., 1981; Schühly et al., 2007), M. virginiana (Chandra and Nair, 1995; Nitao et al., 1991), and M. garrettii (Schuehly et al., 2010). MH was first reported in the seeds of M. grandiflora by El-Feraly and Li (1978). In the seeds of M. grandiflora (Fig. 3), MH (~10%) was found to be the major neolignan, followed by magnolol (1%–2%) and honokiol (1%–2%) (Schühly et al., 2009b). From 20 kg of M. obovata stem bark, 8.5 g of MH was obtained (Singha et al., 2019). In M. officinalis bark (Fig. 3), the content of MH was 16.6% with 16.5% of honokiol and 12.9% of magnolol (Lee et al., 2009a).
The pharmacokinetics of MH was first studied in rabbit plasma using an oral dose of 0.6 mg/kg (Li et al., 2011). Results showed that MH was absorbed at 0.85 hours and had a short half-life of 0.35 hours. A more recent study investigated the pharmacokinetics and metabolism of MH in rats (Yu et al., 2014). As a drug candidate, MH possessed a pharmacokinetic profile characterized by poor oral absorption and high systemic clearance. These results suggest that the pharmacokinetic properties of MH can be optimized by synthetizing analogs with improved metabolic stability.
PHARMACOLOGICAL PROPERTIES
Anticancer
When tested against HeLa cervical, A549 lung, and HCT116 colon cancer cells, MH from the stem bark of M. obovata was reported to be cytotoxic with IC50 values of 12.4, 14.1, and 14.4 μg/ml, respectively (Youn et al., 2008). In comparison, honokiol and magnolol displayed stronger cytotoxicities, 7.7-8.6 and 11.1-11.4 μg/ml, respectively.
 | Figure 3. Seeds of M. grandiflora (left) and bark of M. officinalis (right). [Click here to view] |
Among the three key bioactive compounds of the M. officinalis bark, MH, honokiol, and magnolol showed antiproliferative activities in SCC-9 and Cal-27 oral squamous cancer cells (Bui et al., 2020). Against SCC-9 cancer cells, MH (5.2 μg/ml) and honokiol (5.5 μg/ml) had significantly stronger cytotoxicity than magnolol (7.8 μg/ml), based on IC50 values and a 72 h treatment period. Against Cal-27 cells, cytotoxicities of all three compounds were comparable with IC50 values of 5.6, 6.6, and 5.1 μg/ml, respectively. Related in vivo studies showed that MH suppressed oral tumors in mice more effectively than honokiol and magnolol did (Zhang et al., 2020). While these three neolignans displayed efficacy in inhibiting oral cancer cells, their anticancer effects were enhanced when combined as in natural extracts (Zhang et al., 2020).
MH inhibited colon cancer cell growth of SW620 and HCT116 (Oh et al., 2012) and prostate cancer cells of PC-3 and LNCap (Lee et al., 2013) via apoptotic cell death, p21-mediated suppression of nuclear factor (NF)-κB activity, and cell cycle arrest. MH inhibited cell growth and induced apoptosis in HN22 and HSC4 oral squamous cancer cells and in xenograft tumors (Cho et al., 2015). Significant apoptotic effects were observed following MH treatment of 20-40 μM for both types of cancer cells. MH inhibited the growth of SiHa human cervical cancer cells by triggering the intrinsic apoptosis pathway and inhibiting the PI3K/Akt survival pathway (Hyun et al., 2015). MH induced cytotoxicity against PE/CA-PJ41 oral squamous cancer cells with an IC50 value of 1.25 μM (Xiao et al., 2017). The antitumor activity was mediated via reactive oxygen species (ROS) generation, mitochondrial membrane potential disruption, and cell cycle arrest, including the modulation of Bcl-2/Bax proteins.
Overall, MH exerts anticancer properties via molecular mechanisms of nuclear factor -κB (NF-κB) suppression (Oh et al., 2012), activation of PPARγ (Lee et al., 2013), induction of ROS (Xiao et al., 2017), disruption of mitochondrial membrane potential (Xiao et al., 2017), the PI3K/Akt survival pathway inhibition (Hyun et al., 2015), modulation of Bcl-2/Bax proteins (Xiao et al., 2017), and induction of p21 protein expression (Oh et al., 2012). A study by Han and Van Anh (2012) showed that MH downregulated P-glycoprotein expression and could serve as an effective agent for reducing the multidrug resistance of cancer cells.
Anti-inflammatory
The results of in vitro and in vivo experiments showed that MH possessed anti-inflammatory properties by inhibiting NF-κB (Oh et al., 2009). The neolignan inhibited nitric oxide (NO) generation in RAW 264.7 macrophage cells with an IC50 value of 9.8 μM. When topically applied, MH inhibited ear edema inflammation in rats. Similar tests conducted earlier also showed the anti-inflammatory activity of MH (Zhou et al., 2008). The anti-inflammatory activity of MH involved the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase- (COX)-2 expression by downregulating signaling pathways of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) and inactivation of NF-κB.
The anti-inflammatory activity of MH was accompanied by COX-2 inhibition with an IC50 value of 1.5 µg/ml (Schühly et al., 2007). Compared to its derivatives, MH displayed the strongest inhibition of 95% for COX-2 and 96% for leukotriene B4 (Schühly et al., 2009a). From the seeds of M. grandiflora, the strongest inhibition was displayed by MH (1.2 µg/ml) compared to honokiol (1.7 µg/ml) and magnolol (2.0 µg/ml) (Schühly et al., 2009b). MH strongly inhibited COX-2 activity (IC50 value of 0.06 µM) and prostaglandin production mediated by COX-2 (IC50 value of 0.10 µM) in zymosan-injected mice (Kim et al., 2015).
Derivatives of MH also possess anti-inflammatory properties in a lipopolysaccharide- (LPS-) induced neuroinflammation mouse model (Sivak et al., 2019). The anti-inflammatory effect of a novel derivative of MH in the brains of rats with LPS-induced neuroinflammation was four times that of control rats (Kiseleva et al., 2020). Recently, an assessment of novel structural honokiol analogs with a 4'-O-(2-fluoroethyl) moiety showed potent anti-inflammatory activity (Vaulina et al., 2021). The anti-inflammatory activity of MH involved the inhibition of COX-2 (Chicca et al., 2015) and cannabinoid receptor type 2 (Gertsch and Anavi-Goffer, 2012).
Attenuation of memory impairment
A group of scientists from the Chungbuk National University in Korea studied MH and its effects on memory impairment in mice. The following are some of the results in chronological order:
MH attenuated scopolamine-induced memory impairment function in mice by inhibiting acetylcholinesterase activity (IC50 value of 12 nM) (Lee et al., 2009a). This value was more than 11 times stronger than that of tacrine, used as a positive control.
MH suppressed beta-amyloid (Aβ)-induced memory impairment in male ICR mice via the inhibition of neuronal cell death and ROS generation (Lee et al., 2010).
Memory impairment in an Alzheimer’s disease (AD) mouse model was attenuated by MH through modulation of oxidative damage of enzymes by reducing Aβ generation and accumulation (Choi et al., 2011).
MH attenuated memory impairment in presenilin 2 mutant mice through the reduction of oxidative damage, inactivation of astrocytes, and suppression of the ERK pathway (Lee et al., 2011b).
β-Amyloid-induced memory impairment in mice was attenuated by MH via reduction of oxidative damage and inactivation of the p38 MAP kinase pathway (Lee et al., 2011c).
MH ameliorated LPS-induced memory deficiencies and checked neuroinflammation (Lee et al., 2012a).
MH ameliorated memory impairment in a transgenic mice model of AD by downregulating secretase activity and inhibiting oxidative stress and neuroinflammatory responses (Lee et al., 2012b).
Anxiolytic effect
Anxiety disorders are common among adults and adolescents, and anxiolytic or antianxiety drugs are in great demand and are prescribed to manage such mental disorders. Interestingly, MH has been found to possess such psychopharmacological properties. A study reported that, after 7 d of treatment, MH exerted anxiolytic-like effects on male ICR mice, and the process might be mediated by the transmission of γ-aminobutyric acid (GABA) followed by an increase in chloride channel opening (Han et al., 2011). Another study reported that MH at 3 μM potentiated GABAA receptors 20 times stronger than honokiol, both at the same concentration (Baur et al., 2014). This affirms the potential of MH to be developed into an anxiolytic agent.
Antidiabetes
Diabetic nephropathy and diabetic cardiomyopathy are long-term disorders of type 2 diabetes. A study on the effect of treatment with MH for three months on diabetic nephropathy progression in a type 2 diabetes murine model showed that MH prevented renal oxidative stress and inflammation (Ma et al., 2019). The protection might be attributed to oxidative stress attenuation and lipid metabolic improvement. Results of another study revealed that MH protected male C57BL/6J mice against diabetic cardiomyopathy by activation of AMP-activated protein kinase (AMPK) and improvement in cardiac lipid metabolism (Zheng et al., 2019).
Antiobesity
MH protected against high-fat diet-induced obesity and systemic insulin resistance in male C57BL/6J mice (Zhang et al., 2014a). Lipid accumulation and inflammation in adipose tissue, hepatic steatosis, and insulin resistance were ameliorated in the treated mice. In addition, MH significantly lowered plasma triglyceride, cholesterol levels, reduced alanine transaminase (ALT), liver weight, and hepatic triglyceride level, and also ameliorated hepatic steatosis. In comparison, the Magnolia extract only significantly reduced ALT and hepatic triglyceride level. MH prevented cardiac hypertrophy in male obese mice via suppression of lipid accumulation, oxidative stress, and inflammation (Zhang et al., 2014b). In addition, MH prevented cardiac pathogenesis and attenuated cardiac insulin signaling impairment in these obese mice (Zhang et al., 2015).
Hair growth promotion
At a dose of 30 nM and applied for 14 days, MH significantly increased hair growth in rat vibrissa follicles by 2.5 times that of the control group (Kim et al., 2011). MH promoted hair growth via the downregulation of transforming growth factors and the proliferation of dermal papilla cells. In immortalized human keratinocyte HaCaT cells, the hair-growing mechanisms of MH may involve the modulation of cell cycle arrest and ROS production (Kang et al., 2011) and the suppression of cell growth via the inhibition of both canonical and noncanonical pathways (Kim et al., 2017).
 | Table 1. Other bioactivities of 4-O-methylhonokiol from Magnolia species. [Click here to view] |
Influence on embryo anomalies
Studies have shown that MH has influence on teratogenesis or embryo anomalies. In cultured mouse embryos, MH inhibited nicotine-induced teratogenesis. Reduction in anomalies of the cultured embryos was attributed to modulation of apoptosis, oxidative stress, and inflammation (Lin et al., 2014; Yon et al., 2013). Results suggested that MH can be developed into a protective agent against teratogenesis caused by maternal smoking during pregnancy. However, another study showed that MH was found to cause adverse changes in the cells and morphology of medaka embryos, characterized by inflammation, thrombosis, and spinal and cardiac deformities (Singha et al., 2019).
Other properties
Other pharmacological properties of MH include inhibition of antiseizure, neuroprotection, osteoclastogenesis, protection against liver injury, treatment of cannabis dependence, alleviation of blood–brain barrier dysfunction, amelioration of cognitive dysfunction, and reception of cannabinoid 2 (Table 1).
Abbreviations: AEA = anandamide, BBB = blood-brain barrier, CB2 = cannabinoid type 2, CD = cognitive dysfunction, EKP = ethylketopentenoate, ERK = extracellular signal-regulated kinases, HSC = hepatic stellate cells, MMP = matrix metalloproteinases, NAEs = N-acetylethanolamines, OCG = osteoclastogenesis, PPAR = peroxisome proliferator-activated receptor, RANKL = receptor activator of NF-κB ligand, and RSA = radical scavenging activity.
CONCLUSION
From Magnolia, neolignans such as honokiol and magnolol are well studied. MH is lesser known and has tremendous prospects for new and further research. Further studies warranted are the cellular and molecular mechanisms underlying the effects of MH on various types of cancer and on neurodegenerative diseases, notably AD. Some research needs to be repeated as the results are either questionable or conflicting. MH has been reported to exert anticancer properties towards cervical, colon, lung, oral, and prostate cancer cells. Studies that yielded negative results using other cancer cell lines should also be published. The neuropharmacological benefits of MH in the prevention and/or treatment of neuroinflammation, anxiety, memory impairment, and cognitive dysfunction present promising research opportunities. Structure–activity relationship studies of MH are lacking. Finally, opportunities for multidisciplinary research exist whereby scientists in natural products chemistry, biochemistry, and pharmacology can work together to produce more in-depth and meaningful results. Finally, the perspectives of MH have the potential for development into agents for reducing or overcoming anxiety, multidrug resistance of cancer cells, teratogenesis caused by maternal smoking during pregnancy, memory deficiencies, and neuroinflammation.
CONFLICT OF INTEREST
The author has no funding or any other conflict of interest in this work.
AUTHOR CONTRIBUTIONS
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.
FUNDING
There is no funding to report
ETHICAL APPROVALS
This study does not involve experiments on animals or human subjects.
DATA AVAILABILITY
All data generated and analyzed are included within this research article.
PUBLISHER’S NOTE
This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.
REFERENCES
Baur R, Schuehly W, Sigel E. Moderate concentrations of 4-O-methylhonokiol potentiate GABAA receptor currents stronger than honokiol. Biochim Biophy Acta, 2014; 1840(10):3017-21. CrossRef
Bui D, Li L, Yin T, Wang X, Gao S, You M, Singh R, Hu M. Pharmacokinetic and metabolic profiling of key active components of dietary supplement Magnolia officinalis extract for prevention against oral carcinoma. J Agric Food Chem, 2020; 68(24):6576-87. CrossRef
Chan EWC, Wong SK, Chan HT. A short review on the chemistry, pharmacological properties and patents of obovatol and obovatal (neolignans) from Magnolia obovata. Nat Prod Sci, 2021; 27(3):141-50.
Chandra A, Nair MG. Supercritical carbon dioxide extraction and quantification of bioactive neolignans from Magnolia virginiana flowers. Planta Med, 1995; 61(2):192-5. CrossRef
Chen YH, Huang PH, Lin FY, Chen WC, Chen YL, Yin WH, Man KM, Liu PL. Magnolol: A multi-functional compound isolated from the Chinese medicinal plant Magnolia officinalis. Eur J Integr Med, 2011; 3(4):317-24. CrossRef
Chicca A, Gachet MS, Petrucci V, Schuehly W, Charles RP, Gertsch J. 4′-O-Methylhonokiol increases levels of 2-arachidonoyl glycerol in mouse brain via selective inhibition of its COX-2-mediated oxygenation. J Neuroinflammation, 2015;12(1):1-16. CrossRef
Cho JH, Lee RH, Jeon YJ, Shin JC, Park SM, Choi NJ, Seo KS, Yoon G, Cho SS, Kim KH, Cho JJ, Cho YS, Kim DH, Hong JT, Lee TH, Park HJ, Jung S, Seo JM, Chen H, Dong Z, Chae JI, Shim JH. Role of transcription factor Sp1 in the 4-O-methylhonokiol-mediated apoptotic effect on oral squamous cancer cells and xenograft. Int J Biochem Cell Biol, 2015; 64:287-97. CrossRef
Choi IS, Lee YJ, Choi DY, Lee YK, Lee YH, Kim KH, Kim YH, Jeon YH, Kim EH, Han SB, Jung JK. 4-O-Methylhonokiol attenuated memory impairment through modulation of oxidative damage of enzymes involving amyloid-β generation and accumulation in a mouse model of Alzheimer’s disease. J Alzhiemer’s Dis, 2011; 27(1):127-41. CrossRef
Clark AM, El-Feraly AS, Li WS. Antimicrobial activity of phenolic constituents of Magnolia grandiflora L. J Pharm Sci, 1981; 70(8):951-2. CrossRef
Coppola M, Mondola R. Potential use of Magnolia officinalis bark polyphenols in the treatment of cannabis dependence. Med Hypotheses, 2014; 83(6):673-6. CrossRef
El-Feraly FS, Li WS. Phenolic constituents of Magnolia grandiflora L. seeds. Lloydia, 1978; 41(5):442-9.
Gertsch J, Anavi-Goffer S. Methylhonokiol attenuates neuro-inflammation: A role for cannabinoid receptors- J Neuroinflammation, 2012; 9(1):1-5. CrossRef
Han H, Jung JK, Han SB, Nam SY, Oh KW, Hong JT. Anxiolytic-like effects of 4-O-methylhonokiol isolated from Magnolia officinalis through enhancement of GABAergic transmission and chloride influx. J Med Food, 2011; 14:724-31. CrossRef
Han HK, Van Anh LT. Modulation of P-glycoprotein expression by honokiol, magnolol and 4-O-methylhonokiol, the bioactive components of Magnolia officinalis. Anticancer Res, 2012; 32(10):4445-52.
Han JY, Ahn SY, Yoo JH, Nam SY, Hong JT, Oh KW. Alleviation of kainic acid-induced brain barrier dysfunction by 4-O-methylhonokiol in in vitro and in vivo models. BioMed Res Int, 2015; Article ID 893163. CrossRef
Han Y, Liu J, Ahn S, An S, Ko H, Shin JC, Jin SH, Ki MW, Lee SH, Lee KH, Shin SS. Diallyl biphenyl-type neolignans have a pharmacophore of PPARα/γ dual modulators. Biomol Therapeut, 2020; 28(5):397-404. CrossRef
Hyun S, Kim MS, Song YS, Bak Y, Ham SY, Lee DH, Hong J, Yoon DY. Peroxisome proliferator-activated receptor-gamma agonist 4-O-methylhonokiol induces apoptosis by triggering the intrinsic apoptosis pathway and inhibiting the PI3K/Akt survival pathway in SiHa human cervical cancer cells. J Microbiol Biotechnol, 2015; 25(3):334-42. CrossRef
Jung YY, Lee YJ, Choi DY, Hong JT. Amelioration of cognitive dysfunction in APP/PS1 double transgenic mice by long-term treatment of 4-O-methylhonokiol. Biomol Ther, 2014; 22(3):232-8. CrossRef
Kang J, Kim S, Kim E, Park D, Koh Y, Yoo E, Kang H. Regulatory effect of 4-O-methylhonokiol on TGF-β1-induced cell cycle arrest in human keratinocyte cell line (HaCaT). Planta Med, 2011; 77(12):PM161. CrossRef
Kikuzawa K, Mizui N. Flowering and fruiting phenology of Magnolia hypoleuca. Plant Species Biol, 1990; 5(2):255-61. CrossRef
Kim HS, Ryu HS, Kim JS, Kim YG, Lee HK, Jung JK, Kwak YS, Lee K, Seo SY, Yun J, Kang JS. Validation of cyclooxygenase-2 as a direct anti-inflammatory target of 4-O-methylhonokiol in zymosan-induced animal models. Arch Pharm Res, 2015; 38(5):813-25. CrossRef
Kim SC, Kang JI, Hyun JW, Kang JH, Koh YS, Kim YH, Kim KH, Ko JH, Yoo ES, Kang HK. 4-O-Methylhonokiol protects HaCaT cells from TGF-β1-induced cell cycle arrest by regulating canonical and non-canonical pathways of TGF-β signaling. Biomol Ther, 2017; 25(4):417-26. CrossRef
Kim SC, Kang JI, Kim MK, Boo HJ, Park DB, Lee YK, Kang JH, Yoo ES, Kim YH, Kang HK. The hair growth promoting effect of 4-O-methylhonokiol. Eur J Dermatol, 2011; 21(6):1012-4. CrossRef
Kiseleva MM, Vaulina DD, Sivak KV, Alexandrov AG, Kuzmich NN, Viktorov NB, Kuznetsova OF, Gomzina NA. Radiosynthesis of a novel 11C-labeled derivative of 4’-O-methylhonokiol and its preliminary evaluation in an LPS rat model of neuroinflammation. ChemistrySelect, 2020; 5(9):2685-9. CrossRef
Kwon OJ, Oh CH. Naturalization of landscaping woody plant, Magnolia obovata potentially invasive species. J Mt Sci, 2015; 12(1):30-8. CrossRef
Lee JW, Lee YK, Lee BJ, Nam SY, Lee SI, Kim YH, Kim KH, Oh KW, Hong JT. 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. CrossRef
Lee NJ, Oh JH, Ban JO, Shim JH, Lee HP, Jung JK, Ahn BW, Yoon DY, Han SB, Ham YW, Hong JT. 4-O-Methylhonokiol, a PPARγ agonist, inhibits prostate tumor growth: p21-mediated suppression of NF-κB activity. Br J Pharmacol, 2013; 168(5):1133-45. CrossRef
Lee YJ, Choi DY, Choi IS, Kim KH, Kim YH, Kim HM, Lee K, Cho WG, Jung JK, Han SB, Han JY. Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models. J Neuroinflammation, 2012a; 9(1):1-19. CrossRef
Lee YJ, Choi DY, Lee YK, Lee YM, Han, SB, Kim YH, Kim KH, Nam SY, Lee BJ, Kang JK, Yun YW. 4-O-Methylhonokiol prevents memory impairment in the Tg2576 transgenic mice model of Alzheimer’s disease via regulation of β-secretase activity. J Alzhiemer’s Dis, 2012b; 29(3):677-90. CrossRef
Lee YJ, Lee YM, Lee CK, Jung JK, Han SB, Hong JT. Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther, 2011a; 130(2):157-76. CrossRef
Lee YJ, Choi IS, Park MH, Lee YM, Song JK, Kim YH, Kim KH, Hwang DY, Jeong JH, Yun YP, Oh KW. 4-O-Methylhonokiol attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway. Free Radic Biol Med, 2011b; 50(1):66-77. CrossRef
Lee YK, Choi IS, Ban JO, Lee HJ, Lee US, Han SB, Jung JK, Kim YH, Kim KH, Oh KW, Hong JT. 4-O-Methylhonokiol attenuated β-amyloid-induced memory impairment through reduction of oxidative damages via inactivation of p38 MAP kinase. J Nutr Biochem, 2011c; 22(5):476-86. CrossRef
Lee YK, Choi IS, Kim YH, Kim KH, Nam SY, Yun YW, Lee MS, Oh KW, Hong JT. Neurite outgrowth effect of 4-O-methylhonokiol by induction of neurotrophic factors through ERK activation. Neurochem Res, 2009b; 34(12):2251-60. CrossRef
Lee YK, Yuk DY, Kim TI, Kim YH, Kim KT, Kim KH, Lee BJ, Nam SY, Hong JT. Protective effect of the ethanol extract of Magnolia officinalis and 4-O-methylhonokiol on scopolamine-induced memory impairment and the inhibition of acetylcholinesterase activity. J Nat Med, 2009a; 63(3):274-82. CrossRef
Li J, Copmans D, Partoens M, Hunyadi B, Luyten W, de Witte P. Zebrafish-based screening of anti-seizure plants used in traditional Chinese medicine: Magnolia officinalis extract and its constituents magnolol and honokiol exhibit potent anticonvulsant activity in a therapy-resistant epilepsy model. ACS Chem Neurosci, 2020; 11(5):730-42. CrossRef
Li MY, Tang YH, Liu X, Lü HY, Shi XY. Sensitive determination of 4-O-methylhonokiol in rabbit plasma by high performance liquid chromatography and application to its pharmacokinetic investigation. J Pharm Anal, 2011; 1(2):108−12. CrossRef
Lim TK. Edible medicinal and non-medicinal plants. Science+Business Media, Dordrecht, The Netherlands, vol. 8, pp 243-75, 2014. CrossRef
Lin C, Yon JM, Hong JT, Lee JK, Jeong J, Baek IJ, Lee BJ, Yun YW, Nam SY. 4-O-Methylhonokiol inhibits serious embryo anomalies caused by nicotine via modulations of oxidative stress, apoptosis, and inflammation. Birth Defects Res, 2014; 101(2):125-34. CrossRef
Lin Y, Li Y, Zeng Y, Tian B, Qu X, Yuan Q, Song Y. Pharmacology, toxicity, bioavailability, and formulation of magnolol: An update. Front Pharmacol, 2021; 12:632767. CrossRef
Luo H, Wu H, Yu X, Zhang X, Lu Y, Fan J, Tang L, Wang Z. A review of the phytochemistry and pharmacological activities of Magnoliae officinalis cortex. J Ethnopharmacol, 2019; 236:412-42. CrossRef
Ma T, Zheng Z, Guo H, Lian X, Rane MJ, Cai L, Kim KS, Kim KT, Zhang Z, Bi L. 4-O-Methylhonokiol ameliorates type 2 diabetes-induced nephropathy in mice likely by activation of AMPK-mediated fatty acid oxidation and Nrf2-mediated anti-oxidative stress. Toxicol Appl Pharmacol, 2019; 370:93-105. CrossRef
Min BS. Anti-complement activity of phenolic compounds from the stem bark of Magnolia obovata. Nat Prod Sci, 2008; 14(3):196-201.
Nitao JK, Nair MG, Thorogood DL, Johnson KS, Scriber JM. Bioactive neolignans from the leaves of Magnolia virginiana. Phytochemistry, 1991; 30(7):2193-5. CrossRef
Oh JH, Ban JO, Cho MC, Jo M, Jung JK, Ahn B, Yoon DY, Han SB, Hong JT. 4-O-Methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF-κB activity. J Nutr Biochem, 2012; 23(7):706-15. CrossRef
Oh JH, La Kang L, Ban JO, Kim YH, Kim KH, Han SB, Hong JT. Anti-inflammatory effect of 4-O-methylhonokiol, a novel compound isolated from Magnolia officinalis through inhibition of NF-κB. Chem-Biol Interact, 2009;180(3):506-14. CrossRef
Ong CP, Lee WL, Tang YQ, Yap WH. Honokiol: A review of its anticancer potential and mechanisms. Cancers, 2020; 12(1):48. CrossRef
Park KR, Kim JY, Kim EC, Yun HM, Hong JT. RANKL-induced osteoclastogenesis is suppressed by 4-O-methylhonokiol in bone marrow-derived macrophages. Arch Pharm Res, 2017; 40(8):933-42. CrossRef
Patsenker E, Chicca A, Petrucci V, Moghadamrad S, De Gottardi A, Hampe J, Gertsch J, Semmo N, Stickel F. 4-O-Methylhonokiol protects from alcohol/carbon tetrachloride-induced liver injury in mice. J Mol Med, 2017; 95(10):1077-89. CrossRef
Poivre M, Duez P. Biological activity and toxicity of the Chinese herb Magnolia officinalis Rehder & E. Wilson (Houpo) and its constituents. J Zhejiang Univ - Sci B, 2017; 18(3):194-214. CrossRef
Rauf A, Patel S, Imran M, Maalik A, Arshad MU, Saeed F, Mabkhot YN, Al-Showiman SS, Ahmad N, Elsharkawy E. Honokiol: An anticancer lignan. Biomed Pharmacother, 2018; 107:555-62. CrossRef
Schuehly W, Paredes JM, Kleyer J, Huefner A, Anavi-Goffer S, Raduner S, Altmann KH, Gertsch J. Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB2 receptor inverse agonists. Chem Biol, 2011; 18(8):1053-64. CrossRef
Schuehly W, Voith W, Teppner H, Kunert O. Substituted dineolignans from Magnolia garrettii. J Nat Prod, 2010; 73(8):1381-4. CrossRef
Schühly W, Hüfner A, Wenzig EM, Kunert O, Haslinger E, Bauer R. Investigations on the main neolignan constituent methylhonokiol of Magnolia grandiflora as a new anti-inflammatory lead compound. Planta Med, 2007; 73(9):SL27. CrossRef
Schühly W, Hüfner A, Pferschy-Wenzig EM, Prettner E, Adams M, Bodensieck A, Kunert O, Oluwemimo A, Haslinger E, Bauer R. Design and synthesis of ten biphenyl neolignan derivatives and their in vitro inhibitory potency against cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4-formation. Bioorg Med Chem, 2009a; 17(13):4459-65. CrossRef
Schühly W, Khan SI, Fischer NH. Neolignans from North American Magnolia species with cyclooxygenase 2 inhibitory activity. Inflammopharmacology, 2009b; 17(2):106-10. CrossRef
Singha SK, Muhammad I, Ibrahim MA, Wang M, Ashpole NM, Shariat-Madar Z. 4-O-Methylhonokiol influences normal cardiovascular development in medaka embryo. Molecules, 2019; 24(3):475. CrossRef
Sivak KV, Stosman KI, Muzhikyan AA, Alexandrov AG, Viktorov NB, Vaulina DD, Gomzina NA. Evaluation of anti-inflammatory activity of 4’---methylhonokiol derivatives in a neuroinflammation model. Russ J Bioorg Chem, 2019; 45(5):425-9. CrossRef
Teponno RB, Kusari S, Spiteller M. Recent advances in research on lignans and neolignans. Nat Prod Rep, 2016; 33(9):1044-92. CrossRef
TSO. Magnolia L. From trees and shrubs online. Available via treesandshrubsonline.org/ articles/magnolia (Accessed 10 May 2021).
Vaulina DD, Stosman KI, Sivak KV, Aleksandrov AG, Viktorov NB, Kuzmich NN, Kiseleva MM, Kuznetsova OF, Gomzina NA. Preliminary assessment of the anti-inflammatory activity of new structural honokiol analogs with a 4′-O-(2-Fluoroethyl) moiety and the potential of their 18F-labeled derivatives for neuroinflammation imaging. Molecules, 2021; 26(21):6630. CrossRef
Xia N, Liu Y, Nooteboom HP. Magnolia L. Flora China, 2008; 7:64-6.
Xiao S, Chen F, Gao C. Antitumor activity of 4-O-methylhonokiol in human oral cancer cells is mediated via ROS generation, disruption of mitochondrial potential, cell cycle arrest and modulation of Bcl-2/Bax proteins. J BUON, 2017; 22:1577-81.
Yon JM, Lin C, Lee BJ, Yun YW, Nam SY. Effects of 4-O-methylhonokiol for nicotine-induced toxicities in cultured mouse fetuses. Reprod Toxicol, 2013; 41:25. CrossRef
Youn U, Chen QC, Lee IS, Kim H, Yoo JK, Lee J, Na M, Min BS, Bae K. Two new lignans from the stem bark of Magnolia obovata and their cytotoxic activity. Chem Pharm Bull, 2008; 56(1):115-7. CrossRef
Yu HE, Oh SJ, Ryu JK, Kang JS, Hong JT, Jung JK, Han SB, Seo SY, Kim YH, Park SK, Kim HM. Pharmacokinetics and metabolism of 4-O-methylhonokiol in rats. Phytother Res, 2014; 28(4):568-78. CrossRef
Zálešák F, Bon DJ, Pospíšil J. Lignans and neolignans: Plant secondary metabolites as a reservoir of biologically active substances. Pharmacol Res, 2019; 146:104284. CrossRef
Zhang Q, Cheng G, Pan J, Zielonka J, Xiong D, Myers CR, Feng L, Shin SS, Kim YH, Bui D, Hu M. Magnolia extract is effective for the chemoprevention of oral cancer through its ability to inhibit mitochondrial respiration at complex I. Cell Commun Signal, 2020; 18(1):1−4. CrossRef
Zhang Z, Chen J, Jiang X, Wang J, Yan X, Zheng Y, Conklin DJ, Kim KS, Kim KH, Tan Y, Kim YH. The magnolia bioactive constituent 4-O-methylhonokiol protects against high-fat diet-induced obesity and systemic insulin resistance in mice. Oxid Med Cell Longev, 2014a; Article ID 965954. CrossRef
Zhang Z, Wang S, Zhou S, Yan X, Zheng Y, Tan Y, Cai L, Kim YH. 4-O-Methylhonokiol prevent cardiac hypertrophy via suppression of lipid accumulation, oxidative stress and inflammation in obesity mice induced by high fat diet. J Am Coll Cardiol, 2014b; 64:C66. CrossRef
Zhang Z, Chen J, Zhou S, Wang S, Cai X, Conklin DJ, Kim KS, Kim KH, Tan Y, Zheng Y, Kim YH. Magnolia bioactive constituent 4-O-methylhonokiol prevents the impairment of cardiac insulin signaling and the cardiac pathogenesis in high-fat diet-induced obese mice. Int J Biol Sci, 2015; 11(8):879-91. CrossRef
Zheng Z, Ma T, Guo H, Kim KS, Kim KT, Bi L, Zhang Z, Cai L. 4-O-Methylhonokiol protects against diabetic cardiomyopathy in type 2 diabetic mice by activation of AMPK-mediated cardiac lipid metabolism improvement. J Cell Mol Med, 2019; 23(8):5771-81. CrossRef
Zhou HY, Shin EM, Guo LY, Youn UJ, Bae K., Kang SS, Zou LB, Kim YS. Anti-inflammatory 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; 586:340-9. CrossRef