Pharmacological Research 141 (2019) 208–213

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Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Bakuchiol: A newly discovered warrior against organ damage T

a,b,1 a,1 a,1 a c d e
Zhenlong Xin , Xue Wu , Ting Ji , Baoping Xu , Yuehu Han , Meng Sun , Shuai Jiang ,
⁎
Tian Lib, Wei Hub, Chao Dengf, Yang Yanga,
a
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road,
Xi’an, 710069, China
b
Graduate School, The Fourth Military Medical University, 169 Changle West Road, Xi’an 710032, China
c
Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an 710032, China
d
Department of Cardiology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan 030001, China
e
Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi’an 710032, China
f
Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi’an, 710061, China

A R T I C LE I N FO A B S T R A C T

Keywords: Bakuchiol (BAK), [(1E,3S)-3-ethenyl-3,7-dimethyl-1,6-octadien-1-yl]phenol is a prenylated phenolic mono-

Bakuchiol terpene extracted from the fruit of Psoralea corylifolia L., which belongs to the Leguminosae plant family.
Oxidative stress Previous research has shown that BAK exerts a variety of pharmacological effects, including antioxidant, anti-
Inflammation bacterial, anti-inflammatory, antiaging and estrogen-like effects. In addition, recent studies have indicated that
Antibacterial
BAK exerts protective effects in the heart, liver, skin and other organs. BAK treatment protects the heart against
Ischemia-reperfusion injury
ischemia-reperfusion injury through modulating cardioprotective pathways. BAK also inhibits liver fibrosis via
promoting myofibroblast apoptosis and relieves the hepatotoxicity of multiple toxicants by suppressing oxidative
stress and inflammatory changes. BAK inhibits the proliferation of various cancer cells, including stomach, breast
and skin cancer cells, thereby exerting anticancer effects. Further, BAK effectively slows skin aging by preserving
skin collagen. BAK treatment can protect against bone loss and delay osteoporosis by exerting estrogen-like
effects. In addition, BAK remarkably reduces blood glucose and triglycerides and might be a potential phar-
macological agent that can be used to protect against pancreatic beta-cell damage and diabetes progression. In
this review, the pharmacological mechanisms and protective effects of BAK in human diseases are discussed,
with a focus on the protective effects of BAK in the heart, liver and other important organs.

1. Introduction
Psoralea corylifolia is a member of the Leguminosae plant family and
a traditional Chinese medicine [1]; previous research indicates that
Psoralea corylifolia contains multiple chemical substances, such as ba-
kuchiol (BAK), psoralen, psoralidin, isopsoralen, and bavachin [2]. In
1966, Mehta et al. extracted BAK from Psoralea corylifolia for the first
time, and it has now been verified that BAK can be widely derived from
the seeds of Psoralea corylifolia and other leguminous plants and but-
terfly flowers [3]. Some studies have shown that BAK is particularly
rich in Psoralea corylifolia, but the conclusions reached in other studies
are not consistent with this finding, which might be due to differences
in measurement methods [4]. Previous studies have shown that BAK,
[(1E,3S)-3-ethenyl-3,7-dimethyl-1,6-octadien-1-yl]phenol (Fig. 1), is a
main bioactive meroterpene that possesses a variety of pharmacological
activities, including antibacterial, anti-inflammatory, anticancer, anti-
depression, and hypoglycemic activities, protection against oxidation in
liver microsomes and estrogen-like effects [1,2,5–7] (Fig. 2). BAK has
also been associated with multiple diseases, such as myocardial
ischemia-reperfusion injury (IRI), liver fibrosis, cancer, osteoporosis,
diabetes, and neurodegenerative diseases [8,9]. Most importantly, BAK
exerts remarkable protective effects in important organs (Fig. 3), such

Abbreviations: BAK, bakuchiol; IRI, ischemia-reperfusion injury; SIRT1, silent information regulator 1; tBH, tert-butyl hydroperoxide; CCl4, tetrachloromethane; D-
GalN, D-galactosamine; NADH, nicotinamide adenine dinucleotide; PCE, Psoralea corylifolia extract; ROS, reactive oxygen species; ADP-Fe3+, adenosine diphosphate-
ferric iron; S., Streptococcus; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; GFP, green fluorescent protein; ERT, estrogen replacement therapy; MMP, matrix
metalloproteinase; FOXO, forkhead box O transcription factor; THC, tetrahydrocurcumin
⁎
Corresponding author at: Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest
University, 229 TaibaiNorth Road, Xi’an, 710069, China.
E-mail address: yang200214yy@163.com (Y. Yang).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.phrs.2019.01.001
Received 25 October 2018; Received in revised form 24 December 2018; Accepted 1 January 2019
Available online 02 January 2019
1043-6618/ © 2019 Elsevier Ltd. All rights reserved.
Z. Xin et al.
Fig. 1. The chemical structure of bakuchiol.
Fig. 2. Mechanisms underlying the pharmacological activities of BAK. BAK
inhibits tBH-, CCl4-, D-GalN- and NADH-induced lipid peroxidation. BAK can
also inhibit lipid peroxidation induced by various oxidizing radicals, such as
Cl3CO2, LOO−, DPPH radicals and OH−. BAK decreases NO, PE2, LTB4 and
TxB2 production to yield an anti-inflammatory effect. BAK exerts antibacterial
effects against S. mutans, S. sanguis, S. sobrinus, Enterococcus faecalis,
Lactobacillus plantarum, Actinomyces viscosus, and Porphyromonas gingivalis. BAK
can bind to ERα to exert an estrogen-like effect. tBH, tert-butyl hydroperoxide;
CCl4, carbon tetrachloromethane; D-GalN, D-galactosamine; NADH, reducing
nicotinamide adenine dinucleotide; NO, nitric oxide; PE2, prostaglandin E2; S.,
Streptococcus; ERα, estrogen receptor-α.
as the heart [10] and liver [11].
Recently, Feng et al. found that BAK upregulates the expression of
the antiapoptotic molecule Bcl2 and downregulates the expression of
the proapoptotic molecules Bax and caspase-3 by activating the silent
information regulator 1 (SIRT1) signaling pathway and thereby inhibits
mitochondrial damage and ameliorates myocardial IRI [10]. Park EJ
et al. found that BAK promotes apoptosis in hepatic astrocytes through
the caspase-3-dependent pathway and inhibits liver fibrosis [12]. These
authors also indicated that BAK exerts a protective effect against he-
patotoxicity induced by tert-butyl hydroperoxide (tBH), tetra-
chloromethane (CCl4) and D-galactosamine (D-GalN) [11]. In addition,
Zhang et al. showed that BAK (60 mg/kg) treatment significantly re-
duces edema and pathological changes in lung tissues by inhibiting
intense inflammation and exerting protective effects in the lung under
sepsis conditions [13]. This review summarizes recent progress on the
pharmacological activities of BAK and its effects in multiple human
diseases, with a focus on its protective effects on organs.
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Pharmacological Research 141 (2019) 208–213
2. Pharmacological activities
2.1. Antioxidant effects
Oxidative stress refers to an imbalance between oxidation and an-
tioxidation in an organism that results in the excessive production of
free radicals, which have multiple negative effects in vivo. Additionally,
oxidative stress is considered an important factor that leads to aging
and diseases. Haraguchi et al. found that BAK inhibits the effects of tBH,
CCl4, and D-GalN and reduces nicotinamide adenine dinucleotide
(NADH)-induced lipid peroxidation in rat liver microsomes and mi-
tochondria and can therefore be considered an effective antioxidant
[14]. Adhikari et al. investigated the antioxidant activity of BAK by
focusing on the oxidative damage to lipids and proteins induced by
various oxidizing radicals, including Cl3CO2, linoleic acid peroxyl ra-
dicals, LOO−, DPPH radicals and OH−. Using the optical pulse radi-
olysis technique, the authors demonstrated for the first time the im-
portance of radical scavenging activity in the antioxidant activity of
BAK [15]. In addition, Seo et al. found that Psoralea corylifolia extract
(PCE) can increase the activity of superoxide dismutase and inhibit
H2O2-induced reactive oxygen species (ROS) production in a human
liver cancer cell line (HepG2) and in hepatocytes from aged mice. In
H2O2-treated HepG2 cells, PCE treatment increases ATP production,
decreases the oxygen consumption rate, and inhibits the oxidative
stress-induced reduction of the mitochondrial membrane potential,
thereby improving mitochondrial function. In addition, PCE treatment
restores peroxisome proliferator-activated receptor γ coactivator 1α
and carnitine palmitoyl transferase 1 mRNA and protein expression and
inhibits damage to the mitochondrial genome. Furthermore, these au-
thors demonstrated that BAK, which is a major component of PCE, has
remarkable antioxidant activity and is capable of restoring mitochon-
drial function [16]. Moreover, Kim et al. showed that BAK exerts pro-
tective effects against oxidative stress-induced retinal damage and
might be considered as a medication for treating or preventing retinal
degeneration [17].
Lipid peroxidation, which occurs in a wide variety of cells, damages
the cytoplasmic membrane, proteins and DNA and thereby induces
changes in the structure and function of cells or organelles. The mi-
tochondrial membrane is prone to lipid peroxidation, and damage to
this membrane results in mitochondrial dysfunction; thus, the mi-
tochondrial membrane plays an important role in diseases such as IRI,
cancer and aging [15]. A previous study found that the electron
transport chain is involved in the lipid peroxidation of mitochondrial
membranes. Adenosine diphosphate-ferric iron (ADP-Fe3+) is essential
in the lipid peroxidation system and plays important roles in promoting
lipid peroxidation. BAK shows potent inhibitory activity against mi-
tochondrial lipid peroxidation induced by ADP-Fe3+/NADH, and
complete inhibition has been observed with 39 μM BAK [18]. Lipid
peroxidation is a typical chain reaction that continuously consumes
oxygen and forms many ROS, which damage mitochondria in the liver.
BAK inhibits mitochondrial oxygen consumption in a time-dependent
manner and thereby blocks this chain reaction and inhibits Fe3+-ADP-
induced lipid peroxidation. Therefore, these results indicate that BAK is
a chain-breaking antioxidant [19]. Oxygen free radicals affect the ac-
tivity of mitochondrial enzymes, and NADH-cytochrome c reductase
and succinic acid-cytochrome c reductase, which deliver electrons, are
the components most sensitive to mitochondrial oxidative damage. The
incubation of liver mitochondria with Fe3+-ADP/NADPH decreases the
activity of the two cytochrome c reductases and increases the degree of
lipid peroxidation, and BAK treatment restores the activity of these
enzymes and inhibits NADPH-dependent lipid peroxidation. In addi-
tion, BAK can inhibit lipid peroxidation induced by dilute hydrofluoric
acid and protect the activities of NADH-cytochrome c reductase and
succinate-cytochrome c reductase [15,19]. In conclusion, BAK effec-
tively reduces oxidative stress, and this effect can result in the inhibi-
tion of lipid peroxidation and the preservation of mitochondrial
Z. Xin et al.
function.
2.2. Anti-inflammatory effects
Inflammation is a defense response that occurs in organisms with
vascular systems and is involved in the development and progression of
various diseases. Sepsis is a systemic inflammatory reaction that can
lead to the injury of certain important organs. In a study conducted by
Zhang et al., male C57BL/6 mice were subjected to cecal ligation and
puncture and treated intragastrically with BAK (15, 30, and 60 mg/kg)
0 and 3 h after surgery, and the results suggested that BAK (60 mg/kg)
effectively inhibits intense inflammation and significantly reduces
edema and pathological changes in lung tissues by exerting protective
effects in the lung under sepsis conditions [13]. Choi et al. found that
BAK effectively inhibits γ-interferon- and LPS-induced nitric oxide
(53.7%) and prostaglandin E2 (84.2%) production in RAW 264.7
macrophages by inactivating nuclear factor-κB and inhibiting carbon
monoxide synthase mRNA expression, resulting in an anti-in-
flammatory effect [20]. In addition, Ferrandiz et al. confirmed that BAK
is a weak inhibitor of secretory and intracellular phospholipase A2 and
that BAK reduces the formation of leukotriene B4 and thromboxane B2
by human neutrophils and platelet microsomes in a dose-dependent
manner. Additionally, BAK inhibits various leukocytic functions, such
as eicosanoid production, migration and degranulation at the in-
flammatory site [21]. In conclusion, BAK has remarkable anti-in-
flammatory activity, and this finding deserves further exploration.
2.3. Antibacterial effects
Katsura et al. [22] investigated the antibacterial activity of BAK
against certain oral microorganisms in vitro. BAK inhibits Streptococcus
(S.) mutans growth in a concentration-dependent manner, and complete
inhibition is achieved with 20 μg/ml BAL. BAK also exerts bactericidal
effects against other tested bacteria, including S. sanguis, S. sobrinus,
Enterococcus faecalis, Enterococcus faecium, Lactobacillus casei, Lactoba-
cillus plantarum, Actinomyces viscosus, and Porphyromonas gingivalis.
Furthermore, BAK is effective against adherent S. mutans cells in water-
insoluble glucan in the presence of sucrose and inhibits the reduction of
pH in the medium. Therefore, BAK is a potential antibacterial substance
that can be used as a food additive, is antagonistic to oral pathogens
and can be incorporated into mouthwash to prevent and treat dental
caries. Sun et al. showed that BAK is an antibacterial compound that
inhibits nucleic acid synthesis through the degradation of DNA spirals
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Pharmacological Research 141 (2019) 208–213
Fig. 3. Mechanisms underlying the organ-protective ef-
fects of BAK. BAK upregulates SIRT1 and thereby increases
the level of the antiapoptotic factor Bcl2 and decreases the
levels of the proapoptotic factors caspase-3 and Bax, re-
sulting in cardioprotective effects against myocardial IRI.
BAK induces caspase-3-dependent HSC apoptosis by acti-
vating the JNK-mediated mitochondrial translocation of
Bax and thereby protects the liver. BAK can also promote
collagen synthesis and inhibit its degradation by de-
creasing MMP-1 expression and enhancing TIMP-2 ex-
pression. Through these effects, BAK delays the skin aging
process. BAK, bakuchiol; SIRT1, silent information reg-
ulator 1; IRI, ischemia-reperfusion injury; TIMP-2, matrix
metalloproteinase inhibitors 2; HSC, hepatic stellate cell.
and topoisomerase II enzyme activity, thereby hindering the bio-
synthesis of DNA and ultimately leading to bacterial death [23]. In
addition, other studies have demonstrated that BAK inhibits methi-
cillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, der-
matophytes and mycobacteria [24–26].
2.4. Estrogen-like effects
Phytoestrogens are plant compounds that exert weak estrogen-like
effects by binding to steroid estrogen receptors with low affinity. In
addition, the long-term use of estrogen might cause dependency in
patients; thus, phytoestrogens are considered an alternative to hormone
replacement therapy that reduces the risk of breast cancer in the clinic
[25]. PCE exerts estrogen-like effects against petroleum ether, ethanol
and chloroform, and a previous study showed that BAK is the active
ingredient in PCE [9]. Li et al. [25] selected transgenic medaka fish as
their research model and used liver specificity and an estrogen-sensitive
promoter to facilitate green fluorescent protein (GFP) expression. The
results showed that BAK (0–1 μg/mL) can induce the expression of GFP
in transgenic medaka fish in a dose-dependent manner and demon-
strated that BAK exerts an estrogen-like effect in vivo. in vitro assays
have shown that low doses of BAK (1 μg/mL) can bind to estrogen re-
ceptor-α to induce the proliferation of MCF-7 cells, but this effect might
be blocked by the antiestrogen ICI182780, which confirms that BAK
exerts an estrogen-like effect in vitro. In conclusion, BAK exerts es-
trogen-like effects and may play a role in hormone replacement therapy
and breast cancer treatment (Fig. 2).
3. Role of BAK in multiple diseases
3.1. Myocardial IRI
Myocardial ischemia is characterized by partial or complete
blockage of the coronary artery. Reperfusion restores the ischemic
myocardium to normal perfusion levels while exacerbating ischemia-
induced pathological changes, including changes in the myocardial
ultrastructure, energy metabolism, cardiac function and electro-
physiology, and these changes lead to arrhythmia, heart failure and
sudden death, which is known as myocardial IRI [27,28]. SIRT1 is a
histone deacetylase that relies on niacinamide adenine dinucleotide to
exert its biological effect [29], and another study confirmed that SIRT1
exerts a remarkable protective effect on the myocardial system [30].
Resveratrol is considered a natural agonist of SIRT1 [31], and a
Z. Xin et al.
previous study showed that resveratrol activates the SIRT1 signaling
pathway and inhibits oxidative stress by exerting protective effects on
mitochondrial function and myocardial IRI [32]. Notably, the mole-
cular structure of BAK is similar to that of resveratrol [33], and Feng
et al. [10] recently investigated the role of BAK in myocardial IRI. Prior
to the induction of ischemia-reperfusion, isolated rat hearts or cardio-
myocytes were exposed to BAK in the absence or presence of the SIRT1
inhibitors sirtinol and SIRT1 siRNA. The results showed the cardio-
protective effects of BAK, which were characterized by improved car-
diac function following ischemia, attenuated myocardial apoptosis, and
changes in several biochemical parameters, including upregulated ex-
pression of the antiapoptotic protein Bcl2 and downregulated protein
expression of Bax and caspase-3. In addition, BAK markedly increases
the activity of mitochondrial succinate dehydrogenase, cytochrome c
oxidase, and mitochondrial superoxide dismutase and decreases the
production of malondialdehyde. However, sirtinol and SIRT1 siRNA
abolished BAK-dependent mitochondrial effects by inhibiting SIRT1
signaling. These results indicate that BAK significantly decreases
ischemia-reperfusion-induced mitochondrial oxidative damage through
the activation of SIRT1 signaling, and as a result, BAK treatment at-
tenuates IRI and protects the heart [10].
3.2. Liver fibrosis and liver injury
Liver fibrosis is a pathological process in which excessive deposition
of extracellular matrix components occurs due to an imbalance between
matrix production and degradation. Liver fibrosis (which leads to liver
cirrhosis) is the main cause of liver disease-associated morbidity and
mortality [34]. Park et al. [12] found that BAK induces caspase-3-de-
pendent hepatic stellate apoptosis by activating the c-Jun NH2-terminal
protein kinase-mediated mitochondrial translocation of Bax in rat liver
myofibroblasts, thereby protecting the liver from fibrosis and cirrhosis.
An additional study indicated that treatment with BAK significantly
inhibits lipid peroxidation and intracellular glutathione depletion in
hepatocytes after treatment with tBH, CCl4 or D-GalN and thereby in-
duces radical scavenging. in vivo studies have proven that treatment
with BAK ameliorates fatty acid changes, hepatocyte necrosis and in-
flammatory cell infiltration in a CCl4-induced liver injury model and
reduces the levels of aspartate transaminase and alanine transaminase
in the serum [11]. In summary, BAK exerts protective effects against
tBH-, CCl4- and D-GalN-induced hepatotoxicity in vitro and in vivo
through different physiological mechanisms.
3.3. Cancer
Unlimited proliferation is the most fundamental biological behavior
of all cancer cells [35]. Lin et al. [36] indicated that BAK inhibits cell
proliferation and induces apoptosis and cell cycle arrest in SGC-7901
human gastric cancer cells. Moreover, Lv et al. [37] demonstrated that
the antitumor effects of BAK on human gastric carcinoma cell lines are
mediated by the phosphoinositide 3-kinase (PI3K)/protein kinase B
(PKB) and mitogen-activated protein kinase signaling pathways. In
addition, other studies verified that BAK suppresses the proliferation of
breast cancer cells and skin cancer cells [38,39]. Therefore, BAK has
potential for the treatment of human cancer.
3.4. Aging
Aging, an inevitable and spontaneous biological process that occurs
with the passage of time, is a complex but natural phenomenon. Aging
is usually accompanied by the degeneration of organ structure and
function, which further results in decreased adaptability and reduced
resistance to various stresses [40,41]. For example, elderly individuals
regularly suffer from neuron loss and alterations in nerve fiber con-
nectivity, leading to age-related gray and white matter shrinkage in
some important brain regions, which contributes to a decrease in neural
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Pharmacological Research 141 (2019) 208–213
functions, such as physical and cognitive abilities [42,43]. Furthermore,
the aged brain inevitably suffers from a decline in adaptability to
physical, cognitive and social environment challenges [44]. The skin is
the largest organ in the human body, and its aging process is affected by
multiple factors, resulting in partial loss of function [45]. Collagen is
one of the most important structural proteins in the human skin [46];
this protein is mainly synthesized and secreted by fibroblasts and is
important for maintaining skin tension and ameliorating aging-induced
skin shrinkage [47]. A study conducted by Yu et al. [48] suggested that
BAK can enhance human skin fibroblast activity, which promotes col-
lagen and the mRNA expression of matrix metalloproteinase (MMP)
inhibitors and inhibits mRNA MMP expression to delay skin aging.
Another study demonstrated that BAK upregulates the expression of
collagen, thereby delaying skin aging. BAK has also been designed as a
skin care product and has been tested in the clinic, and the results
demonstrated that BAK significantly improves the condition of the skin
(with almost no undesirable effects) [49]. In conclusion, BAK is effec-
tive in slowing skin aging and restoring homeostasis. To date, research
on the antiaging effects of BAK has been limited to the skin, but its
related effects in other organs deserve further study.
3.5. Osteoporosis
Estrogen replacement therapy (ERT) is presently considered the
standard regimen for the treatment of postmenopausal osteoporosis.
However, long-term estrogen supplementation can cause uterine hy-
perplasia and hypertension, leading to a high risk of endometrial cancer
and breast cancer [38]. Phytoestrogens are weak estrogen-like com-
pounds that bind to steroid estrogen receptors with low affinity and
have almost no undesirable effects. Weng et al. [38] suggested that both
BAK and bavachin exert estrogen-like effects in vivo and might thereby
prevent estrogen deficiency-induced bone loss. in vitro assays have in-
dicated that BAK and bavachin upregulate the Wnt signaling pathway
by inducing primary human osteoblast differentiation and inhibiting
bone absorption under osteoporosis conditions. Lim et al. [50] de-
monstrated that BAK treatment reduces postmenopausal bone loss by
increasing alkaline phosphatase activity, calcium and serum estradiol
concentrations and bone mineral density and by reducing the level of
inorganic phosphorus. In conclusion, treatment with BAK can protect
against bone loss and osteoporosis by exerting estrogen-like effects, and
BAK might thus become a safe estrogen-like supplement for ERT in the
future.
3.6. Diabetes
Diabetes is an endocrine disorder characterized by hyperglycemia
and long-term complications affecting the eyes, nerves, blood vessels,
skin and kidneys [51]. Krenisky et al. [52] confirmed that the oral
administration of BAK reduces blood glucose levels in db/db mice with
type 2 diabetes in a dose-dependent manner and does not exert a hy-
poglycemic effect in lean mice. These researchers further evaluated the
effects of BAK in a new rodent model of type 2 diabetes (fat-fed,
streptozotocin-treated rat model) and found that BAK lowers plasma
glucose and triglyceride levels. The results suggested that BAK effec-
tively reduces blood glucose levels and improves high triglyceride le-
vels. Additionally, Seo et al. [53] noted that PCE significantly reduces
blood glucose levels, improves glucose tolerance and increases serum
insulin levels in streptozotocin-induced diabetic mice. These re-
searchers investigated the effects of PCE on H2O2-induced apoptosis in
INS-1 cells and found that treatment with PCE inhibits cell death by
reducing ROS levels, activating antioxidant enzymes and inhibiting the
apoptosis of pancreatic beta-cells. However, the specific component of
PCE that protects INS-1 cells and exerts the observed hypoglycemic
effects has not been determined, and this question deserves further
exploration. The abovementioned studies show that BAK remarkably
reduces blood glucose and triglyceride levels and therefore represents a
Z. Xin et al.
potential pharmacological agent that can be used to protect against
pancreatic beta-cell damage and subsequent diabetes.
4. Potential future research directions
Among the many recent studies on BAK, some promising findings
indicate potential directions for future studies and demonstrate that
BAK might have potential for the treatment of organ damage and other
diseases. In this section, we focus on potential future directions for
research on BAK.
Polyphenols are a class of complex secondary metabolites with a
large number of phenolic hydroxyl groups. These compounds are ex-
tensively distributed in fruits, vegetables, cereals, and beverages.
Polyphenols in food sources have been widely studied based on their
roles in the maintenance of human health and the prevention of mul-
tiple diseases, such as cancer, cardiocerebral vascular diseases, dia-
betes, and neurodegenerative disorders [54]. Recently, various studies
have suggested that polyphenolic compounds, such as curcumin, ber-
berine, resveratrol, shikonin, and BAK, have similar structures and
properties [33] (Fig. 1), including many similar pharmacological ac-
tivities, such as antioxidant, anti-inflammatory, and antibacterial ac-
tivities [54,55]. Therefore, other polyphenolic compounds should be
used as a reference when exploring the pharmacological activities and
therapeutic effects of BAK.
Forkhead box O transcription factor (FOXO) is involved in many
biological processes, such as aging, the oxidative stress response, and
growth regulation [56]. FOXO activity is tightly controlled within cells
[56,57]. In particular, both growth factor signaling pathways and the
oxidative stress response can stimulate the nuclear translocation of
FOXO [58,59]. Xiang et al. showed that tetrahydrocurcumin (THC), a
curcumin metabolite, regulates the nuclear localization of FOXO in
cultured cells, inhibits the phosphorylation of PKB/Akt kinase, and
attenuates the oxidative stress response, and these effects are blocked in
a FOXO-mutant background [58]. Additionally, these researchers con-
firmed that the addition of resveratrol to the culture medium led to the
nuclear accumulation of FOXO, which suggests that resveratrol and
THC regulate the oxidative stress response of FOXO [58]. Reiter et al.
found that epigallocatechin gallate, which is a green tea polyphenol,
decreases endothelin-1 expression and secretion from endothelial cells
partly through Akt- and AMPK-stimulated FOXO1-mediated regulation
of the endothelin-1 promoter [60]. In conclusion, some phenolic com-
pounds have been shown to regulate FOXO during conditions of oxi-
dative stress through the induction of antioxidants and cell survival
pathways and thereby protect the heart [61]. Recent studies have in-
dicated that FOXO1/3 activation offers added protection against car-
diac diseases [62]. Due to the prominent beneficial effect of FOXO1/3
and the important roles of polyphenols in FOXO1/3 activation, we
hypothesize that BAK might also have the ability to activate FOXO1/3,
which might be one of the mechanisms through which BAK mediates its
organ-protective effects.
Autophagy is a lysosomal degradation process through which long-
lived and misfolded proteins and organelles are sequestered, degraded
by lysosomes, and eventually recycled [63]. This process is essential for
cell survival, proliferation, differentiation and homeostasis [64], and
dysfunction of this process contributes to the pathogenesis of many
human diseases, such as cardiocerebral vascular disorders [65].
Therefore, autophagy appears to be an attractive target in new treat-
ments for cardiocerebral vascular disorders. A study by Huang et al.
suggested that curcumin, a polyphenolic compound, mediates autop-
hagy via the PI3K/Akt pathway during neuroprotection against IRI
injury [66]. Other studies have indicated that resveratrol and berberine
can trigger autophagy via canonical (Beclin 1-dependent) and non-
canonical (Beclin 1-independent) pathways [67]. Song et al. indicated
that PCE exhibits anticancer activity by promoting both autophagy and
apoptosis in cancer cells [68], and because BAK is one of the most ac-
tive ingredients in PCE, BAK might modulate autophagy under multiple
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Pharmacological Research 141 (2019) 208–213
conditions. As autophagy has potent effects in various organs, it is of
great importance to explore whether BAK can modify the autophagy
process to exert organ-protective effects.
5. Conclusion
Organ damage, particularly heart, lung, liver, and kidney damage, is
common and inevitable during the development and progression of
diseases. BAK is a prenylated phenolic monoterpene extracted from the
fruit of Psoralea corylifolia L., which belongs to the Leguminosae family.
Multiple studies have proven that BAK exerts remarkable protective
effects in important organs, such as the heart and liver. Additionally,
BAK possesses a variety of pharmacological activities, including anti-
oxidant, anti-inflammatory, antibacterial and estrogen-like effects
(Fig. 2). Moreover, BAK might serve as a protective drug against mul-
tiple diseases or pathological processes, including myocardial IRI, liver
fibrosis, cancer, aging, osteoporosis and diabetes (Fig. 3). Notably, the
organ-protective effects of BAK have attracted more attention in recent
years, and clarification of the underlying mechanisms will greatly
promote its clinical application for organ protection and should be the
focus of future studies on BAK.
Disclosure
None.
Acknowledgement
This work was supported by the National Natural Science
Foundation of China (81871607, 81700236, 81600306, and 81500263)
and Natural Science Foundation of Shaanxi Province (2018JM3042).
References
[1] S.H. Lim, T.Y. Ha, J. Ahn, S. Kim, Estrogenic activities of psoralea corylifolia l. Seed
extracts and main constituents, Phytomedicine 18 (2011) 425–430.
[2] B. Chopra, A.K. Dhingra, K.L. Dhar, Psoralea corylifolia l. (buguchi) - folklore to
modern evidence: review, Fitoterapia 90 (2013) 44–56.
[3] G.N.U.R. Mehta, S. Dev, Bakuchiol, a novel monoterpenoid, Tetrahedron Lett. 7
(1966) 4561–4567.
[4] G.N.U.R. Mehta, S. Dev, Meroterpenoids: psoralea corylifolid linn-1 bakuchiol, a
novel monoterpenoid, Tetrahedron 29 (1973) 1119–1125.
[5] O. Ohno, T. Watabe, K. Nakamura, M. Kawagoshi, N. Uotsu, T. Chiba, et al.,
Inhibitory effects of bakuchiol, bavachin, and isobavachalcone isolated from piper
longum on melanin production in b16 mouse melanoma cells, Biosci. Biotechnol.
Biochem. 74 (2010) 1504–1506.
[6] S.W. Lee, B.R. Yun, M.H. Kim, C.S. Park, W.S. Lee, H.M. Oh, et al., Phenolic com-
pounds isolated from psoralea corylifolia inhibit il-6-induced stat3 activation,
Planta Med. 78 (2012) 903–906.
[7] Z. Chen, K. Jin, L. Gao, G. Lou, Y. Jin, Y. Yu, et al., Anti-tumor effects of bakuchiol,
an analogue of resveratrol, on human lung adenocarcinoma a549 cell line, Eur. J.
Pharmacol. 643 (2010) 170–179.
[8] Y.J. Kim, H.S. Lim, J. Lee, S.J. Jeong, Quantitative analysis of psoralea corylifolia
linne and its neuroprotective and anti-neuroinflammatory effects in ht22 hippo-
campal cells and bv-2 microglia, Molecules 21 (2016).
[9] D. Xin, H. Wang, J. Yang, Y.F. Su, G.W. Fan, Y.F. Wang, et al., Phytoestrogens from
psoralea corylifolia reveal estrogen receptor-subtype selectivity, Phytomedicine 17
(2010) 126–131.
[10] J. Feng, Y. Yang, Y. Zhou, B. Wang, H. Xiong, C. Fan, et al., Bakuchiol attenuates
myocardial ischemia reperfusion injury by maintaining mitochondrial function: the
role of silent information regulator 1, Apoptosis 21 (2016) 532–545.
[11] E.J. Park, Y.Z. Zhao, Y.C. Kim, D.H. Sohn, Protective effect of (s)-bakuchiol from
psoralea corylifolia on rat liver injury in vitro and in vivo, Planta Med. 71 (2005)
508–513.
[12] E.J. Park, Y.Z. Zhao, Y.C. Kim, D.H. Sohn, Bakuchiol-induced caspase-3-dependent
apoptosis occurs through c-jun nh2-terminal kinase-mediated mitochondrial
translocation of bax in rat liver myofibroblasts, Eur. J. Pharmacol. 559 (2007)
115–123.
[13] X. Zhang, N. Chang, Y. Zhang, M. Ye, Z. Han, J. Li, et al., Bakuchiol protects against
acute lung injury in septic mice, Inflammation 40 (2017) 351–359.
[14] H. Haraguchi, J. Inoue, Y. Tamura, K. Mizutani, Antioxidative components of
psoralea corylifolia (leguminosae), Phytother. Res. 16 (2002) 539–544.
[15] S. Adhikari, R. Joshi, B.S. Patro, T.K. Ghanty, G.J. Chintalwar, A. Sharma, et al.,
Antioxidant activity of bakuchiol: experimental evidences and theoretical treat-
ments on the possible involvement of the terpenoid chain, Chem. Res. Toxicol. 16
Z. Xin et al.
(2003) 1062–1069.
[16] E. Seo, Y.S. Oh, D. Kim, M.Y. Lee, S. Chae, H.S. Jun, Protective role of psoralea
corylifolia l. Seed extract against hepatic mitochondrial dysfunction induced by
oxidative stress or aging, Evid. Based Complement. Alternat. Med. 2013 (2013)
678028.
[17] K.A. Kim, S.H. Shim, H.R. Ahn, S.H. Jung, Protective effects of the compounds
isolated from the seed of psoralea corylifolia on oxidative stress-induced retinal
damage, Toxicol. Appl. Pharmacol. 269 (2013) 109–120.
[18] B. Halliwell, Antioxidant characterization. Methodology and mechanism, Biochem.
Pharmacol. 49 (1995) 1341–1348.
[19] H. Haraguchi, J. Inoue, Y. Tamura, K. Mizutani, Inhibition of mitochondrial lipid
peroxidation by bakuchiol, a meroterpene from psoralea corylifolia, Planta Med. 66
(2000) 569–571.
[20] S.Y. Choi, S. Lee, W.H. Choi, Y. Lee, Y.O. Jo, T.Y. Ha, Isolation and anti-in-
flammatory activity of bakuchiol from ulmus davidiana var. Japonica, J. Med. Food.
13 (2010) 1019–1023.
[21] M.L. Ferrandiz, B. Gil, M.J. Sanz, A. Ubeda, S. Erazo, E. Gonzalez, et al., Effect of
bakuchiol on leukocyte functions and some inflammatory responses in mice, J.
Pharm. Pharmacol. 48 (1996) 975–980.
[22] H. Katsura, R.I. Tsukiyama, A. Suzuki, M. Kobayashi, In vitro antimicrobial activ-
ities of bakuchiol against oral microorganisms, Antimicrob. Agents Chemother. 45
(2001) 3009–3013.
[23] N.J. Sun, S.H. Woo, J.M. Cassady, R.M. Snapka, DNA polymerase and topoisome-
rase ii inhibitors from psoralea corylifolia, J. Nat. Prod. 61 (1998) 362–366.
[24] Y. Cui, S. Taniguchi, T. Kuroda, T. Hatano, Constituents of psoralea corylifolia fruits
and their effects on methicillin-resistant staphylococcus aureus, Molecules 20
(2015) 12500–12511.
[25] L. Li, X. Chen, C.C. Liu, L.S. Lee, C. Man, S.H. Cheng, Phytoestrogen bakuchiol
exhibits in vitro and in vivo anti-breast cancer effects by inducing s phase arrest and
apoptosis, Front. Pharmacol. 7 (2016) 128.
[26] S.M. Newton, C. Lau, S.S. Gurcha, G.S. Besra, C.W. Wright, The evaluation of forty-
three plant species for in vitro antimycobacterial activities; isolation of active
constituents from psoralea corylifolia and sanguinaria canadensis, J.
Ethnopharmacol. 79 (2002) 57–67.
[27] H. Zhou, Q. Ma, Protective role of melatonin in cardiac ischemia-reperfusion injury:
From pathogenesis to targeted therapy, J. Pineal Res. 64 (2018).
[28] L.M. Yu, W.C. Di, X. Dong, Z. Li, Y. Zhang, X.D. Xue, et al., Melatonin protects
diabetic heart against ischemia-reperfusion injury, role of membrane receptor-de-
pendent cgmp-pkg activation, Biochim. Biophys. Acta Mol. Basis Dis. 1864 (2018)
563–578.
[29] Y. Yang, W. Duan, Y. Li, Z. Jin, J. Yan, S. Yu, et al., Novel role of silent information
regulator 1 in myocardial ischemia, Circulation 128 (2013) 2232–2240.
[30] Y. Yang, W. Duan, Y. Li, J. Yan, W. Yi, Z. Liang, et al., New role of silent information
regulator 1 in cerebral ischemia, Neurobiol. Aging 34 (2013) 2879–2888.
[31] J.H. Holthoff, K.A. Woodling, D.R. Doerge, S.T. Burns, J.A. Hinson, P.R. Mayeux,
Resveratrol, a dietary polyphenolic phytoalexin, is a functional scavenger of per-
oxynitrite, Biochem. Pharmacol. 80 (2010) 1260–1265.
[32] Y.G. Li, W. Zhu, J.P. Tao, P. Xin, M.Y. Liu, J.B. Li, et al., Resveratrol protects car-
diomyocytes from oxidative stress through sirt1 and mitochondrial biogenesis sig-
naling pathways, Biochem. Biophys. Res. Commun. 438 (2013) 270–276.
[33] N.L. Price, A.P. Gomes, A.J. Ling, F.V. Duarte, A. Martin-Montalvo, B.J. North,
et al., Sirt1 is required for ampk activation and the beneficial effects of resveratrol
on mitochondrial function, Cell Metab. 15 (2012) 675–690.
[34] Y. Lurie, M. Webb, R. Cytter-Kuint, S. Shteingart, G.Z. Lederkremer, Non-invasive
diagnosis of liver fibrosis and cirrhosis, World J. Gastroenterol. 21 (2015)
11567–11583.
[35] Z. Ma, Y. Yang, S. Di, X. Feng, D. Liu, S. Jiang, et al., Pterostilbene exerts anticancer
activity on non-small-cell lung cancer via activating endoplasmic reticulum stress,
Sci. Rep. 7 (2017) 8091.
[36] J. Lin, H.J. Yao, R.Y. Li, Bakuchiol inhibits cell proliferation and induces apoptosis
and cell cycle arrest in sgc-7901 human gastric cancer cells, J. BUON 21 (2016)
889–894.
[37] L. Lv, B. Liu, Antitumor effects of bakuchiol on human gastric carcinoma cell lines
are mediated through pi3k/akt and mapk signaling pathways, Mol. Med. Rep. 16
(2017) 8977–8982.
[38] Z.B. Weng, Q.Q. Gao, F. Wang, G.H. Zhao, F.Z. Yin, B.C. Cai, et al., Positive skeletal
effect of two ingredients of psoralea corylifolia l. On estrogen deficiency-induced
osteoporosis and the possible mechanisms of action, Mol. Cell. Endocrinol. 417
(2015) 103–113.
[39] J.E. Kim, J.H. Kim, Y. Lee, H. Yang, Y.S. Heo, A.M. Bode, et al., Bakuchiol sup-
presses proliferation of skin cancer cells by directly targeting hck, blk, and p38 map
kinase, Oncotarget 7 (2016) 14616–14627.
[40] C. Lopez-Otin, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of
aging, Cell 153 (2013) 1194–1217.
[41] J. Lv, S. Jiang, Z. Yang, W. Hu, Z. Wang, T. Li, et al., Pgc-1alpha sparks the fire of
213
Pharmacological Research 141 (2019) 208–213
neuroprotection against neurodegenerative disorders, Ageing Res. Rev. 44 (2018)
8–21.
[42] S. Ballesteros, E. Kraft, S. Santana, C. Tziraki, Maintaining older brain functionality:
a targeted review, Neurosci. Biobehav. Rev. 55 (2015) 453–477.
[43] D. Bavelier, C.S. Green, A. Pouget, P. Schrater, Brain plasticity through the life span:
learning to learn and action video games, Annu. Rev. Neurosci. 35 (2012) 391–416.
[44] J.O. Goh, Functional dedifferentiation and altered connectivity in older adults:
neural accounts of cognitive aging, Aging Dis. 2 (2011) 30–48.
[45] V.L. Newton, J.C. McConnell, S.A. Hibbert, H.K. Graham, R.E. Watson, Skin aging:
molecular pathology, dermal remodelling and the imaging revolution, G. Ital.
Dermatol. Venereol. 150 (2015) 665–674.
[46] Y. Morikiri, E. Matsuta, H. Inoue, The collagen-derived compound collagen tri-
peptide induces collagen expression and extends lifespan via a conserved p38 mi-
togen-activated protein kinase cascade, Biochem. Biophys. Res. Commun. 505
(2018) 1168–1173.
[47] P. Limtrakul, S. Yodkeeree, W. Punfa, J. Srisomboon, Inhibition of the mapk sig-
naling pathway by red rice extract in uvb-irradiated human skin fibroblasts, Nat.
Prod. Commun. 11 (2016) 1877–1882.
[48] Q. Yu, H.M. Zou, S. Wang, Y.M. Xu, J.M. Li, N. Zhang, [Regulative effect of ba-
kuchiol on esf-1 cells anti-aging gene], Zhong Yao Cai 37 (2014) 632–635.
[49] R.K. Chaudhuri, K. Bojanowski, Bakuchiol: a retinol-like functional compound re-
vealed by gene expression profiling and clinically proven to have anti-aging effects,
Int. J. Cosmet. Sci. 36 (2014) 221–230.
[50] S.H. Lim, T.Y. Ha, S.R. Kim, J. Ahn, H.J. Park, S. Kim, Ethanol extract of psoralea
corylifolia l. And its main constituent, bakuchiol, reduce bone loss in ovar-
iectomised sprague-dawley rats, Br. J. Nutr. 101 (2009) 1031–1039.
[51] R. Golan, A. Tirosh, D. Schwarzfuchs, I. Harman-Boehm, J. Thiery, G.M. Fiedler,
et al., Dietary intervention induces flow of changes within biomarkers of lipids,
inflammation, liver enzymes, and glycemic control, Nutrition 28 (2012) 131–137.
[52] J.M. Krenisky, J. Luo, M.J. Reed, J.R. Carney, Isolation and antihyperglycemic
activity of bakuchiol from otholobium pubescens (fabaceae), a peruvian medicinal
plant used for the treatment of diabetes, Biol. Pharm. Bull. 22 (1999) 1137–1140.
[53] E. Seo, E.K. Lee, C.S. Lee, K.H. Chun, M.Y. Lee, H.S. Jun, Psoralea corylifolia l. Seed
extract ameliorates streptozotocin-induced diabetes in mice by inhibition of oxi-
dative stress, Oxid. Med. Cell. Longev. 2014 (2014) 897296.
[54] R.A. Vacca, D. Valenti, S. Caccamese, M. Daglia, N. Braidy, S.M. Nabavi, Plant
polyphenols as natural drugs for the management of down syndrome and related
disorders, Neurosci. Biobehav. Rev. 71 (2016) 865–877.
[55] D. Fiorentini, L. Zambonin, F.V. Dalla Sega, S. Hrelia, Polyphenols as modulators of
aquaporin family in health and disease, Oxid. Med. Cell. Longev. 2015 (2015)
196914.
[56] S. Jiang, T. Li, Z. Yang, W. Hu, Y. Yang, Deciphering the roles of foxo1 in human
neoplasms, Int. J. Cancer (2018).
[57] Z. Ma, Z. Xin, W. Hu, S. Jiang, Z. Yang, X. Yan, et al., Forkhead box o proteins:
crucial regulators of cancer emt, Semin. Cancer Biol. 50 (2018) 21–31.
[58] L. Xiang, Y. Nakamura, Y.M. Lim, Y. Yamasaki, Y. Kurokawa-Nose, W. Maruyama,
et al., Tetrahydrocurcumin extends life span and inhibits the oxidative stress re-
sponse by regulating the foxo forkhead transcription factor, Aging (Albany NY) 3
(2011) 1098–1109.
[59] Z. Yang, S. Jiang, Y. Cheng, T. Li, W. Hu, Z. Ma, et al., Foxc1 in cancer development
and therapy: deciphering its emerging and divergent roles, Ther. Adv. Med. Oncol.
9 (2017) 797–816.
[60] C.E. Reiter, J.A. Kim, M.J. Quon, Green tea polyphenol epigallocatechin gallate
reduces endothelin-1 expression and secretion in vascular endothelial cells: roles for
amp-activated protein kinase, akt, and foxo1, Endocrinology 151 (2010) 103–114.
[61] A. Sengupta, J.D. Molkentin, J.H. Paik, R.A. DePinho, K.E. Yutzey, Foxo tran-
scription factors promote cardiomyocyte survival upon induction of oxidative
stress, J. Biol. Chem. 286 (2011) 7468–7478.
[62] Z. Xin, Z. Ma, S. Jiang, D. Wang, C. Fan, S. Di, et al., Foxos in the impaired heart:
new therapeutic targets for cardiac diseases, Biochim. Biophys. Acta 1863 (2017)
486–498.
[63] Y. Ohsumi, Historical landmarks of autophagy research, Cell Res. 24 (2014) 9–23.
[64] C. Wang, X. Zhang, Z. Teng, T. Zhang, Y. Li, Downregulation of pi3k/akt/mtor
signaling pathway in curcumin-induced autophagy in app/ps1 double transgenic
mice, Eur. J. Pharmacol. 740 (2014) 312–320.
[65] K.R. Parzych, D.J. Klionsky, An overview of autophagy: morphology, mechanism,
and regulation, Antioxid. Redox Signal. 20 (2014) 460–473.
[66] L. Huang, C. Chen, X. Zhang, X. Li, Z. Chen, C. Yang, et al., Neuroprotective effect of
curcumin against cerebral ischemia-reperfusion via mediating autophagy and in-
flammation, J. Mol. Neurosci. 64 (2018) 129–139.
[67] Y. Deng, J. Xu, X. Zhang, J. Yang, D. Zhang, J. Huang, et al., Berberine attenuates
autophagy in adipocytes by targeting becn1, Autophagy. 10 (2014) 1776–1786.
[68] H.S. Song, S. Jang, S.C. Kang, Bavachalcone from cullen corylifolium induces
apoptosis and autophagy in hepg2 cells, Phytomedicine 40 (2018) 37–47.