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).|
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|Figure 2. The chemical structure of 4-O-methylhonokiol.|
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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.
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.
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).|
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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.
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).
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.
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).
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.|
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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 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.
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.
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.
There is no funding to report
This study does not involve experiments on animals or human subjects.
All data generated and analyzed are included within this research article.
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