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Bakuchiol: A Retinol-Like Functional Compound,
Modulating Multiple Retinol and Non-Retinol Targets
Ratan K. Chaudhuri
Background
Bakuchiol (Figure 1.1; Phenol, 4-[1E, 3S]-3-ethenyl-3, 7-dimethyl-1, 6-octadienyl) was rst isolated by
Mehta etal. from the Psoralea corylifolia seed in 1973.1 Absolute conguration of bakuchiol was estab-
lished in the same year by Parakasarao etal.2 Bakuchiol has one asymmetric center and is shown to
possess (S)-chirality.3 Mechanistically, both the 4-hydroxystyryl and terpenic moieties of the compound
seem to be important for its bioactivity. Total synthesis was also accomplished in 1973.4 Banerji and
Chintalwar reported the biosynthesis of bakuchiol and established the pathway by using phenylalanine
and mevalonic acid as substrates.5,6
Bakuchiol is mainly obtained from the seeds of the plant Psoralea corylifolia, which is widely used in
Indian as well as in Chinese medicine to treat a variety of diseases.7 Traditional medicine practition ers
in India and China have utilized the plant for centuries. Psoralea corylifolia is known by a wide variety
of names, suggesting its widespread use. For example, babchi, baguchi, babachi, Bakchi in Hindi and
by many other names depending on the Indian languages; Ravoli in Sri Lanka; Boh-gol zhee in Korea;
Buguzhi in Chinese.7 A recent chapter on P. corylifolia describes its botany, phytochemistry, and ethno-
pharmacology, along with the various pharmacological activities of the plant.8 Bakuchiol has also been
isolated from other plants, such as P. grandulosa,9,10 P. drupaceae,11 Ulmus davidiana,12 Otholobium
pubescens,13 Piper longum,14 and Aerva sangulnolenta Blum.15
Structurally, bakuchiol (Figure 1.1) belongs to the family of meroterpenes. Meroterpenes are ter-
penes having an aromatic ring in the chemical structure. The term meroterpenoid was rst applied by
Cornforth, in 1968, to describe natural products of mixed biosynthetic origin which are partially derived
from terpenoids.16 They are typically derived from higher plants though they have also been obtained
from fungi17 as well as having been produced synthetically. Meroterpenes are also widely distributed
in marine organisms. They are particularly abundant within brown algae, but other important sources
include microorganisms and invertebrates.18 Interestingly, the 4-hydroxystyryl functionality present in
bakuchiol is also present in resveratrol (Figure 1.2).19
Bakuchiol possesses antioxidant,20–23 anti-inammatory24,10,25,26, anti-bacterial,27 anti-tumor,28,29 cyto-
toxic,30 heptaprotective,31 and caspase-3 dependent apoptosis32 properties. The cytotoxicity of bakuchiol
is mainly due to its DNA polymerase 1 inhibiting activity.33 Although bakuchiol has shown many physi-
ological properties and has been known since 1973, its rst commercial use in topical applications did
not occur until 2007 when it was introduced to the market under the trade name Sytenol® A by Sytheon
Ltd. of Boonton, New Jersey. The focus of this chapter is twofold. The rst is to show evidence of
bakuchiol’s functional resemblance to retinol (Figure 1.3). The second is to provide an overview of the
important physiological and biological properties of bakuchiol as they relate to three key skin care appli-
cations—(1) preventative & restorative anti-aging; (2) anti-acne; and (3) skin lightening/even toning—
and the mechanisms by which it provides these benets. Additionally, this chapter has been extended to
include a few key targets that may have applications beyond skin care, as well as provide an overview of
bakuchiol’s antibacterial properties.
2Cosmeceuticals and Active Cosmetics
Bakuchiol, a Functional Analog of Retinol
From the perspective of topically applied compositions, a small molecule that safely mimics the proper-
ties of retinol34 (Figure 1.3) in reversing signs of aging, providing skin protection from sun-induced dam-
age, providing solutions to problem skin, like acne and rosacea, and modulating pigmentation control,
is a greatly sought after ingredient. Recently, Chaudhuri, using a simple comparative gene expression
proling of retinol and bakuchiol in a reconstituted full thickness skin substitute model, established a
basis for making a claim that bakuchiol is a functional analog of retinol.35 The journey from gene to pro-
tein is complex and tightly controlled within each cell. It consists of two major steps: transcription and
translation. Together, transcription and translation are known as gene expression. Figure 1.4 illustrates
the molecular signatures of retinol and bakuchiol through the volcano plot presentation of a DNA micro-
array experiment. The comparison of the volcano plots for bakuchiol (Figure 1.4a) and retinol (Figure
1.4b) shows similar overall shape, indicating similar overall modulation of gene expression in the skin
substitute model. The effects of both compounds on specic pathways relevant to retinol functionality
were then compared. First, a similar modulation of many (however, not all) genes coding for retinoid
binding and metabolizing proteins was observed. A brief description of these genes as well as the impact
of retinol and bakuchiol on each is presented in Table 1.1. Similarly, many genes involved in the genera-
tion and maintenance of the extracellular matrix (ECM) and the dermal-epidermal junction (DEJ) were
similarly modulated by both retinol and bakuchiol.36 Based on this and other data, Chaudhuri concluded
that bakuchiol can function as a retinol-like compound through retinol-like regulation of gene expression.
Preventative and Restorative Anti-Aging
Targeting skin concerns early on can effectively prevent damage to the skin’s surface and improve skin
quality. Slowing down the aging process can be achieved by (i) antioxidant protection to limit direct oxi-
dative damage to the cells, proteins, and DNA, (ii) controlling inammation to minimize inammation-
induced skin damage, and (iii) use of sunscreen protection to prevent photodamage. The mechanisms and
the sequence of events by which free radicals, the main culprit of oxidative damage, interfere with cellular
HO
OH
OH
FIGURE 1.2 Structure of resveratrol.
CH
3
CH3
OH
CH3
H
3C
CH
3
FIGURE 1.3 Structure of retinol.
CH
3
HO
CH
3
CH
3
H2C
FIGURE 1.1 Structure of bakuchiol.
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3Bakuchiol
functions are not fully understood; but one of the most important events seems to be lipid peroxidation,
which results in cellular membrane damage. This cellular damage causes a shift in the net charge of the
cell, changing the osmotic pressure, leading to swelling and eventually cell death.37
Antioxidant
Multiple lines of compelling evidence substantiate the benecial effects provided by the use of antioxi-
dants. Direct application of antioxidants to skin has the added advantage of targeting antioxidants to
those areas of the skin needing the protection most and, obviously, can easily be achieved. Topical appli-
cation adds low molecular-weight antioxidants to the skin reservoir where they are available to protect
the skin against oxidative stress. Psoralea corylifolia has a number of antioxidative components; baku-
chiol is one of the most abundant and powerful antioxidants present in this plant.21 Bakuchiol not only
interferes with different free radical-producing systems, which are described below; but it also increases
the function and effectiveness of endogenous antioxidants.
Haraguchi etal. have reported that bakuchiol inhibited NADPH-, ascorbate-, t-BuOOH-, and CCl(4)-
induced lipid peroxidation in microsomes.21 Indeed, bakuchiol was the most potent antioxidant in micro-
somes and its inhibition of oxygen consumption induced by lipid peroxidation was time-dependent.
Bakuchiol also inhibits microsomal lipid peroxidation in a concentration-dependent manner showing
74.7% protection at a concentration of 10 µM. Bakuchiol also prevented NADH-dependent and ascor-
bate-induced mitochondrial lipid peroxidation. In view of its solubility in lipid and water (at higher
pH), bakuchiol is expected to be distributed in both of these phases. This may account for its low
IC50 = 6.1 ± 0.2 µM value against lipid peroxidation.20,38
Bakuchiol has also been found to protect human red blood cells against oxidative hemolysis and to
protect against oxidative stress-induced retinal damage. With respect to the latter, bakuchiol attenuated
optic nerve crush (ONC)-induced up-regulation of apoptotic proteins, including cleaved poly ADP ribose
polymerase (PARP), cleaved caspase-3, and cleaved caspase-9.39 Bakuchiol also signicantly inhibited
translocation of mitochondrial apoptosis induced factor (AIF) into the nuclear fraction and release of
mitochondrial cytochrome c into the cytosol.
In validation of the foregoing effect, Chaudhuri and Marchio have recently shown that bakuchiol has
broad-spectrum antioxidant activity (in vitro) and effectively quenches superoxide-, hydroxy-, peroxy-,
peroxynitrile radicals, and singlet oxygen non-radical in addition to inhibiting lipid peroxidation.23 As
0
2
4
6
–3 –2 –1 0
log2 (fold change)
Retinol
123
–log (p value)
0
2
4
6
–3 –2 –1 01
23
log2 (fold change)
Bakuchiol
–log (p value)
(a)
(b
)
FIGURE 1.4 (a) Volcanic plot of DNA microarray data—Retinol. (b) Volcanic plot of DNA microarray data—Bakuchiol.
(From Chaudhuri RK, Bojanowski K. Int J Cosmet Sci 2014;36(3):221–30. With permission.)
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4Cosmeceuticals and Active Cosmetics
presented in Table 1.2, its antioxidant prole, especially with respect to lipid peroxidation inhibitory
activity, is far superior to natural tocopherol, a common topical antioxidant. Bakuchiol was found to be
60-fold more effective in inhibiting squalene than natural tocopherol (IC50 for bakuchiol 0.5 µg/mL vs.
natural tocopherol 30 µg/mL). Squalene is particularly prone to photooxidation during sun exposure.40
Hence, bakuchiol is expected to protect squalene and other skin lipids from oxidation due to its excellent
lipid peroxidation inhibitory activity.
The protective activity of bakuchiol against oxidative damage to lipids and proteins has been investi-
gated and rationalized based on the scavenging activity of bakuchiol against various oxidizing radicals
including Cl(3)CO(2)(*), linoleic acid peroxyl radicals, LOO(*), DPPH radicals, (*)OH, and glutathiyl
radicals by Adhikari et al.20 The rate constants of the scavenging reactions, the transients formed in
these reactions, and their mechanistic pathways have been probed using an optical pulse radiolysis tech-
nique. The methyl ether derivative of bakuchiol was also shown to prevent lipid peroxidation in rat
brain homogenate, indicating participation of the terpenoid chain in scavenging LOO(*). In their study,
TABLE 1.1
Fold Change in the DNA Microarray Experiment, and Role of Modulated Retinoid Binding and
Metabolizing Genes (R: retinol; B: bakuchiol)
Gene Full Name Function and Comments
CRBP I;
CRBP II;
CRBP IV
Cellular retinol
binding protein I, II
and IV
CRBP I:R = 2.6; B = 4.2
CRBP II: R = NS; B = 4.1
CRBP IV: R = NS; B = 3.1
CRBP I mediates the cellular uptake of retinol, solubilizes and detoxies it for
further transport within the cytoplasm, and presents it to the appropriate
enzymes to biosynthesize retinoic acid.
N6AMT2 N-6 adenine-specic
DNA
methyltransferase 2
R = NS; B = −2.1
Retinoic acid resistance might be overcome by the use of epigenetic modifying
agents such as DNA methyl transferase inhibitors. Down-regulation provided by
bakuchiol may reduce retinoic acid-induced toxicity.
TIG1 Tazarotene-inducible
gene 1
R = 13.2; B = 12.9
Retinoid acid (RA) receptor-responsive gene. The expression of this gene is
found to be down-regulated in a variety of human cancers as well as in acne,
rosacea, and psoriasis. Up-regulation by bakuchiol may provide a solution to
problem skin. Anti-acne clinical study results of bakuchiol has recently been
reported (40).
DHRS9 Dehydrogenase/
reductase SDR
family member 9
precursor
R = 5.5; B = 11.6
DHRS9 is involved in converting retinol to retinal and then to retinoic acid, the
rate-limiting step for the biosynthesis of retinoic acid.
RETSAT All-trans-
13,14-dihydroretinol
saturase
R = –2.9; B = −2.8
RETSAT expression is involved in adipocyte differentiation.
LRAT Lecithin-retinol
acyltransferase
R = 12.3; B = 82.2
Retinol esterication with long-chain fatty acid by LRAT is the key step in both
absorption and storage of retinol.
CYP1A1;
CYP1A2
Cytochrome P450 CYP1A1: R = 4.0; B = 4.9
CYP1A2: R = 3.6; B = 6.7
In addition to retinol dehydrogenase, P450s 1A1 and 1A2 genes are the major
human P450s that catalyze the reaction of retinol to retinal.
RARB;
RARG
Retinoic acid receptor
beta -1; Retinoic
acid receptor
gamma-1
RARB: R = 5.6; B = NS
RARG: R = 1.8; B = NS
The actions of retinoids are generally mediated by the retinoic acid receptors
(RARs alpha, beta, and gamma) and the retinoid X receptors (RXRs alpha, beta,
and gamma). Both RARB and RARG are up-regulated, as expected, by retinol
but not with bakuchiol.
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5Bakuchiol
Adhikari etal. were able to demonstrate that the allylic radical formed initially was transformed into
the phenoxyl radical at a later stage. These ndings revealed the importance of the terpenoid moiety of
bakuchiol in controlling its antioxidant action via radical scavenging.
Many studies have established that oxidative stress and mitochondrial dysfunction are two central
factors contributing to the aging process. Bakuchiol was shown by Haraguchi etal. to be very effective
in protecting mitochondrial functions against oxidative stress.22 As noted earlier, bakuchiol prevented
mitochondrial lipid peroxidation, inhibiting oxygen consumption originating in lipid peroxidation, in a
time-dependent manner. Bakuchiol was also found to protect mitochondrial respiratory enzyme activi-
ties against both NADPH-dependent and dihydroxyfumarate-induced peroxidation injury.
ATP generation is an essential function in mitochondria. Recently, Seo etal. examined the effect of
Psoralea corylifolia seed (PCS) extract on ATP synthesis. They found that both PCS extract and baku-
chiol increased ATP synthesis in the hepatocytes of old mice whose ATP synthesis had been reduced by
H2O2 treatment. Seo etal. further examined the impact of PCS extract on the integrity of the mitochon-
drial membrane structure which, according to Tsujimoto and Shimizu,41 is involved in ATP energy pro-
duction and mitochondrial function. According to their ndings, PCS extract treatment led to a recovery
in the mitochondrial membrane potential whose reduction had been induced by oxidative stress, evidenc-
ing a stimulation of mitochondrial respiration and restoration of mitochondrial energy metabolism.42
These authors were also able to demonstrate that PCS extract and bakuchiol guarded against mitochon-
drial genome damage.
Another possible mechanism by which bakuchiol acts in addressing oxidative damage and stress is
through interaction with various enzyme systems, especially those associated with the endogenous anti-
oxidant defense system. Efcacy may, at least in part, manifest from a two pronged effort involving both
radical scavenging and an interaction with enzyme functions. As presented in Table 1.3, in a side-by-side
comparison with retinol, bakuchiol has been shown to stimulate the endogenous antioxidant defense
system using a reconstituted full thickness skin substitute model. As indicated, with one exception,
TABLE 1.2
Antioxidant Prole of Bakuchiol and Natural Tocopherol
UnitaPeroxyl Hydroxyl Superoxide Peroxynitrite Singlet Oxygen Lipid Peroxidationb
Bakuchiol 15,165 569 204 130 1,325 0.5
Tocopherol
natural
813 Not detected Not detected 1 1,110 30
a µmole Trolox equivalent/g.
b Squalene was used as a substrate for lipid peroxidation inhibitory activity; data is expressed in IC50 in µg/mL.
TABLE 1.3
Gene Expression Prole of Bakuchiol and Retinol Related to Endogenous Antioxidant System
Gene Gene Description Function
Fold Change vs. Control
Retinol Bakuchiol
GPX3 Glutathione peroxidase 3
precursor/extracellular
glutathione peroxidase
Protect organism from oxidative damage.
Reduce lipid hydroperoxides → alcohols
and hydrogen peroxide → water
+2.5 +3.2
GSTT1 Glutathione S-transferase
theta −1
Involved in the detoxication of endogenous
compounds, such as peroxidized lipids, as
well as the metabolism of xenobiotics.
+2.9 +3.0
GSTP1 Glutathione S-transferase P 1 Same as above +2.8 +3.0
NQO1 NAD(P)H dehydrogenase
[quinone]
This protein’s enzymatic activity prevents the
one electron reduction of quinones that
results in the production of radical species
No effect +5.0
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6Cosmeceuticals and Active Cosmetics
bakuchiol and retinol showed a remarkably similar gene expression pattern with a very high statistical
signicance (p ≤ 0.05). The only exception was that retinol had no effect on the NQO1 gene whereas
bakuchiol had a vefold stimulatory effect. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a cytosolic
protein that catalyzes metabolic detoxication of quinones, thereby protecting cells against quinone-
induced oxidative stress, cytotoxicity, and mutagenicity.43
Inflammation
Skin aging and inammation are critically linked. Enzymes associated with inammation and the
inammatory responses, particularly chronic inammation, are known to accelerate skin aging and
degradation. Among the enzymes that synthesize pro-inammatory mediators from the arachidonic acid
pathway are the cyclo- and lipo-oxygenases.44 Bakuchiol has moderate inhibitory activities against both
5-lipooxygenase (IC50 23.5 µM)24 and cyclooxygenase-1 and -2 (IC50 14.7 and 514 µg /mL).23 Studies
have revealed that bakuchiol is a weak inhibitor of secretory and intracellular phospholipase A2 (PLA2)
but dose-dependently reduced the formation of leukotirene B4 (LTB4) and thrombaxane B2 (TXB2) by
human neutrophils and platelet microsomes, respectively.24 Additionally, bakuchiol inhibited degran-
ulation in human neutrophils, whereas superoxide generation was not affected. In mice, bakuchiol
decreased cell migration, myeloperoxidase activity, and eicosanoid levels in the air pouch inammation
induced by zymosan. Applied topically, bakuchiol was also found to be effective as an inhibitor of edema
and myeloperoxidase activity in the 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced ear edema
and signicantly reduced the PGE2 content and ear edema in the arachidonic acid-induced response.
Bakuchiol is a natural anti-inammatory agent that, among others, is able to control leukocytic functions
such as eicosanoid production, migration, and degranulation in the inammatory site. Inhibitory effects
of bakuchiol in pro-inammatory arachidonic acid pathway are summarized in Figure 1.5.
Diacylglycerol or phospholipid
Arachldonic acid
Bakuchiol
Bakuchiol
HPETE (hydroperoxy
eicosatetraenoic acid)
Phospho-
lipase A2
Phospho-
lipase C
Prostaglandin H2 (PGH2)
PGH2 synthase
(COX-1 or -2 and
peroxidase
PGD
synthase
PGD2PGD
synthase
PGE2
PGF2
LTB4
Prostacyclin synthas
e
Thromboxane synthas
e
Prostacyclin
(PGL2)Thromboxane
(TXA2)
Thromboxane
(TXA2)
Platelets
Endothelium
6-keto
PGF1a
Lipooxygenese
(FLAP, Alox5)
H2O
Leukotriene A4
Glutathione
Leukotriene D4
Leukotriene C4
Leukotriene E4
Glutamic acid
Glutathione-
S-transferase
Bakuchiol
Bakuchiol
FIGURE 1.5 Bakuchiol inhibits multiple sites in pro-inammatory arachidonic acid pathway.
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7Bakuchiol
Validating the anti-inammatory effect of bakuchiol, Chaudhuri conducted comparative gene expres-
sion proles of bakuchiol and retinol on several pro-inammatory genes using a reconstituted full thick-
ness skin substitute model. As presented in Table 1.4, with the exception of two genes, phospholipase
A-2-activating protein (PLAA) and 15-hydroxy prostaglandin dehydrogenase (HPGD) (15-PGDH),
bakuchiol and retinol showed remarkable similarity in the down-regulation of the inammatory genes.
In the case of PLAA, bakuchiol produced a sevenfold down-regulation whereas retinol had no effect
on PLAA. With HPGD, bakuchiol showed a 22-fold up-regulation in comparison to retinol’s fourfold
up-regulation. The HPGD gene encodes the enzyme HPDG, a member of the short-chain non-metallo-
enzyme alcohol dehydrogenase protein family, which is a catabolic enzyme controlling the biological
activities of prostaglandins by converting them into inactive keto-metabolites. Reduced expression of
HPGD contributes to the elevated levels of prostaglandins found in the skin following UVR exposure as
demonstrated by Judson etal.45 Following on their ndings, these authors speculated that agents which
prevent UVR-mediated down-regulation of HPGD could affect the acute or the long-term consequences
of UVR exposure, including nonmelanoma skin cancer.
Erythema, a common form of inammation, is the most obvious clinical sign of UV radiation exposure
and becomes readily apparent within 6 h or less of UV exposure and is maximal at about 24 h.46 COX
dependent prostaglandin E2 (PGE2) is believed to be one of the mediators of UVR-induced erythema.
Phospholipase A2 (PLA2), whose synthesis occurs only when skin is exposed to UV doses sufcient to
cause erythema, is considered a rate limiting step in the generation of leukotrienes and prostaglandins.
Hence, the two are intertwined in regards to erythema and their impact thereon.
Building upon the results attained in the above-mentioned investigation of the impact of baku-
chiol and retinol on inammation-related gene expression, Chaudhuri conducted a clinical study
(unpublished) to assess the skin protection property of bakuchiol against erythema.47 In this study,
Chaudhuri determined the average L-, a-, and ITA (Individual Typology Angle) values of treated (with
TABLE 1.4
Pro-Inammatory Gene Modulation by Bakuchiol and Retinol
Gene Gene Description Function
Fold Change vs. Control
Bakuchiol Retinol
COX-1/PTGS1 Cyclooxygenase-1
(prostaglandin G/H
synthase precursor)
Prostaglandin biosynthesis; acts as both
a dioxygenase and a peroxidase −3.6 −3.4
PLAA Phospholipase A-2-
activating protein
PLAA releases fatty acids from the
second carbon group of glycerol.
Upon downstream modication by
cyclooxygenases, arachidonic acid is
modied into eicosanoids. Eicosanoids
include prostaglandins and
leukotrienes, which are categorized as
inammatory mediators.
−7.7 No effect
PLA2G4A Cytosolic phospholipase A2 Catalyzes hydrolysis of membrane
phospholipids to release arachidonic
acid, which is subsequently
metabolized into eicosanoids
−2.6 −3.1
PTGER2 Prostaglandin E2 receptor
EP2 subtype
Inammatory reaction via the EP2
receptor through its regulation of
TNF-alpha and IL-6
−2.4 −2.2
PTGER4 Prostaglandin E2 receptor
EP4 subtype
Inammatory reaction via the EP4
receptor through its regulation of
TNF-alpha and IL-6
−6.1 −3.0
HPGD/15PGDH 15-Hydroxy prostaglandin
dehydrogenase
HPGD is a catabolic enzyme
controlling the biological activities of
prostaglandins by converting them
into inactive keto-metabolites
+21.8 +4.1
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8Cosmeceuticals and Active Cosmetics
a 1% bakuchiol lotion) and untreated skin of 10 human volunteers prior to irradiation/UV exposure
(“Pre-Irr”) and following irradiation/UV exposure (“Post-Irr”). As presented in Table 1.5, the results
clearly showed a marked reduction in the manifestation of erythema, as evidenced by the signicant
difference in the delta or change in the L-, a-, and ITA values in those areas that were treated with the
bakuchiol containing lotion as compared to the untreated areas.
More recently the role of nitric oxide (NO) as a contributor to the UV erythema response has been
established.48 NO is produced in the skin by NO synthase that can combine with superoxide to form
peroxynitrite, a highly reactive oxidant and mediator of tissue injury. Similarly, large amounts of nitric
oxide (NO) production following the induction of an inducible NO synthase (iNOS) gene has also been
implicated in the pathogenesis of various inammatory diseases. Bakuchiol has been shown to inhibit
NO production in RAW 264.7 macrophages activated with interferon-γ and lipopolysaccharide. The
mechanistic studies showed that bakuchiol inhibited the expression of iNOS mRNA through the inacti-
vation of NF-κB.25 Thus, bakuchiol is also expected to protect skin from UV induced erythema as well
as from damage due to sun-induced iNOS gene over-expression.
Matrix Metalloprotease (MMP)
A major characteristic of aged and prematurely aged skin is a high degree of fragmentation of the der-
mal collagen matrix.49 MMPs play a major role in protein and collagen degradation, which affects the
structural integrity of the dermis. In normal skin, its production is in balance with their natural inhibitors
tissue inhibitors of metalloproteinases (TIMPs); however, UV light is reported to enhance the synthesis
of MMP in human skin in vivo leading to MMP-mediated collagen destruction. Sun exposure, especially
substantial sun exposure, leads to an imbalance between the active enzymes, the MMPs, and their natu-
ral inhibitors (TIMPs) resulting in the accelerated destruction of connective tissues50 and photoaging.50
Therefore, protection of extracellular matrix proteins, such as collagens, in aged or photoaged human
skin by the reduction of MMPs would be expected to retard the clinical manifestations of skin aging.
In this regard, it is well documented that retinol treatment (human clinical) reduces matrix metallo-
protease expression and stimulates collagen synthesis in naturally aged, sun-protected skin and, perhaps
more importantly, in photodamaged skin.51 Given the many similar targets of retinol and bakuchiol,
Chaudhuri compared the performance of bakuchiol and retinol on two key matrix metalloproteases,
MMP-1 and MMP-12. As presented in Table 1.6, bakuchiol has a signicant inhibitory effect on MMP-1
TABLE 1.5
Reduction in Erythema Using 1% Bakuchiol Lotion
Pre-Irr Post-Irr Δ L or ΔITA Value or Δa-Value
L-value (with bakuchiol) 65.69 66.25 −0.56
L-value (without bakuchiol) 66.45 60.71 −5.74 (Statistically signicant p < 0.001)
ITA (with bakuchiol) 43.97 46.83 +2.86
ITA (without bakuchiol) 46.05 36.76 −9.29 (Statistically signicant p < 0.001)
a-value (with bakuchiol) 8.53 8.38 −0.15
a-value (without bakuchiol) 8.17 16.32 +8.15 (Statistically signicant p < 0.001)
TABLE 1.6
Matrix Metalloprotease Inhibitory Activity of Bakuchiol and Retinol
Matrix Metalloprotease Methods Used Bakuchiol Retinol
MMP-1 (collagenase) Enzcheck collagenase assay kit
(molecular probe)
50% inhibition at 1 mg/mL Not determined
MMP-12 (elastase) Calbiochem human neutrophile
elastase kit (Cat # 324681)
70% inhibition at 1 µg/mL 8% inhibition at 1 µg/mL
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9Bakuchiol
and a markedly stronger inhibitory effect on MMP-12, far exceeding the effect of retinol (Ta ble 1.6).
Thus, based on retinol’s known effectiveness and these results, it is expected that bakuchiol will provide
an even stronger protection to the extracellular matrix proteins in vivo.
Extracellular Matrix Proteins
Emerging evidence indicates that intrinsic, chronological aging of the skin shares several mechanistic
features with photoaging.48 For example, collagen fragmentation is responsible for the loss of struc-
tural integrity and the impairment of broblast function in aged as well as photoaged human skin. In
aged skin, collapsed broblasts produce low levels of collagen and high levels of collagen-degrading
enzymes. This imbalance advances the aging process in a self-perpetuating, never-ending deleterious
cycle. Treatments that stimulate production of new, non-fragmented collagen are, therefore, expected
to provide substantial improvement in the appearance, health, and integrity of aged skin. Indeed, treat-
ments such as topical retinol or retinoic acid have been clinically proven to stimulate production of new,
undamaged collagen.49 The attachment of broblasts to this new collagen allows stretch, which in turn
balances collagen production and degradation, thereby slowing, if not reversing, the aging process.
Numerous studies have shown the restorative effects of topical application of all-trans retinoic acid
(RA) on aging skin, including the partial restoration of collagens I, III,47 and VII52 and the restoration
of the brillin-rich microbrillar network.53 These extracellular matrix (ECM) changing together with
reduced MMP expression may, in part, explain the clinical improvement of photoaged skin produced
by topical retinoids. In light of the similarities in targets of retinol and bakuchiol, one may also expect
similar performance of bakuchiol in this regard as well.
In an effort to validate their DNA microarray analysis of the comparative effects of bakuchiol and
retinol on collagen stimulation, Chaudhuri and Bojanowski measured collagen stimulation by ELISA
and histochemistry methods. The ELISA assessment employed cell-culture conditioned media from neo-
natal (type I and IV collagens) or mature (type III collagen) broblasts.36 Their ndings, as summarized
in Table 1.7, not only conrmed the up-regulation of types I and IV collagen in the DNA microarray
study and the stimulation of type III collagen in the mature broblast model, but also demonstrated a
signicant improvement in collagen stimulation as compared to retinol. Hence, even greater restorative
properties may be found with bakuchiol.
Skin Hydration and Barrier Homeostasis
Water homeostasis of the epidermis is essential for the normal function of the skin and for normal stra-
tum corneum (SC) hydration. Dehydration of the SC is a typical characteristic of skin aging, especially
in photoaged skin, and of many diseases associated with dry skin.54 Water homeostasis is a determinant
of skin appearance, mechanical properties, barrier function, and metabolism. In addition, it is indis-
pensable in maintaining proper water balance of the body itself. One of the key genes associated with
skin hydration and barrier homeostasis is CDH1, epidermal cadherin. Epidermal cadherin (E-cadherin)
is essential for water barrier formation and is required for correct tight junction formation. Loss of
E-cadherin in the epidermis in vivo results in prenatal death of mice due to the inability to retain a
functional epidermal water barrier. E-cadherin regulates claudin-1, claudin-4, and ZO-1 localization by
activating aPKC, which is implicated in tight junction formation and is considered to be a key protein
for maintaining skin homeostasis.55 Using EpiDermFT skin substitute, Chaudhuri and Bojanowski36
have shown that both retinol and bakuchiol increased expression of CDH1 as well as AQP3, another
TABLE 1.7
Comparative Collagen Stimulatory Effects of Bakuchiol and Retinol
Test Material (10 µg/mL) Collagen I Collagen III Collagen IV
Bakuchiol 147 150 119
Retinol 119 148 100
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10 Cosmeceuticals and Active Cosmetics
gene associated with water transport and whose expression is decreased during aging.56 As indicated in
Table 1.8, while the two had similar effects on AQP3, bakuchiol produced a marked increase in the gene
expression of E-cadherin.
Following on the gene expression study, Chaudhuri and Bojanowski also conducted a clinical study
demonstrating the anti-aging efcacy of a topical composition containing just 0.5% bakuchiol.36 In that
study, the composition was applied to the face of 17 healthy female subjects ranging in age from 40 to
65 years and who showed outward evidence of photoaging, including wrinkles, sagging, spots, and a
dull complexion on the face, twice a day for 12 weeks. (One subject was removed from the study due to
protocol violation.) Each subject’s facial skin was evaluated through self-assessment, clinical grading,
and instrument measurements, over the course of the treatment to assess any changes in the appear-
ance of ne lines and wrinkles, elasticity, rmness, even toning, and overall signs of photodamage.
Although some improvement was noted in most of the parameters after just four weeks, signicantly
more improvement was noted after the eighth week. These improvements continued to increase, even
faster through the twelfth week of product application, indicating, perhaps, a certain degree of cumula-
tive benecial effect over time. These results were consistent amongst all three evaluation methodologies
employed. Additionally, these results provided the ultimate validation of the in vitro results noted previ-
ously and were in line with the retinoid-type functionality of bakuchiol.
Anti-Acne
Acne is a complex, chronic, and common skin disorder of pilosebaceous units. There are four major
targets presently governing acne therapy as follows: correcting the altered pattern of follicular kerati-
nization; decreasing sebaceous gland activity; decreasing the follicular bacterial population, especially
P.acnes; and producing an anti-inammatory effect by inhibiting the production of extracellular inam-
matory products through the inhibition of these microorganisms.57 Dihydrotesterone (DHT) is not only
involved in sebum production but also involved in the production of pro-inammatory cytokines in
acne.58 In recent years there has been an increasing focus on the extent to which oxidative stress is
involved in the pathophysiology of acne. Emerging studies have shown that patients with acne are under
increased cutaneous and systemic oxidative stress. Indeed, there are indications that lipid peroxidation
itself triggers the inammatory cascade in acne.59
Chaudhuri and Marchio have demonstrated that bakuchiol effectively reduces acne and is more effec-
tive when combined with salicylic acid.23 Table 1.9 sets forth their ndings presented as percent reduc-
tion in acne using the Global Acne Grading System.60 Based on the results, formulations containing the
combination of 1% bakuchiol and 2% salicylic acid showed a nearly 70% reduction in acne lesions and
inammation, as judged by the acne grading system. The next best results was attained with the 1%
bakuchiol by itself, which reduced acne by a score of about 57%; whereas 2% salicylic acid only reduced
acne by about 48%. As expected, practically no improvement in the reduction of acne was evident in the
control group. None of the subjects observed or reported any adverse reaction using these formulated
products. These results clearly show that bakuchiol is an effective ingredient, especially when combined
with an exfoliating agent like salicylic acid, for the treatment of acne.
TABLE 1.8
Gene Expression Prole of Bakuchiol and Retinol Related to Skin Hydration and Barrier Homeostasis
Gene Gene Description Function
Fold Change vs. Control
Bakuchiol Retinol
AQP3 Aquaporin 3 Aquaporin 3 is the water/glycerol transporting channel
protein expressed in the epidermis which helps maintain
the right level of skin hydration, elasticity, and barrier
recovery.
4.3 3.5
CDH1 E-cadherin Essential for water barrier formation and is required for
correct tight junction formation
21.6 9.4
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11Bakuchiol
Based on their ndings, Chaudhuri and Marchio also concluded that bakuchiol is a multitasking
product for mitigating acne-affected skin. It works by down-regulating 5α-reductase; inhibiting, if not
killing, P. acne and other bacteria and fungus present in acne-affected skin; quenching radicals and
non-radicals, especially inhibiting lipid peroxidation; reducing pro-inammatory activity; and inhibiting
matrix metalloprotease activity. Interestingly, these authors also reported that tazarotene-inducible gene
1 (TIG1) is signicantly up-regulated by both bakuchiol and retinol (see Table 1.1), and the expression of
TIG1 is found to be down-regulated in a variety of human cancers as well as acne, rosacea, and psoriasis.
Thus, it is quite conceivable to assume that the up-regulation of TIG1 gene by bakuchiol may provide a
solution to many skin problems in addition to acne.23
Skin Lightening and Even Toning
Photoaging is also associated with a dysregulation in melanin synthesis and distribution and with a
general increase in the inammatory status of the skin leading to the appearance of brown spots and
an increase in skin redness. Recently, bakuchiol was shown to inhibit melanin production in a dose-
dependent manner without showing strong cytotoxicty.14 The results of that study, which included a com-
parison to arbutin, a known skin lightening agent, are summarized in Table 1.10. As noted, bakuchiol
showed more than a 10-fold increase in activity as compared to arbutin.
These authors’ ndings also indicated that the addition of bakuchiol to the cells prior to stimulation
with α-MSH markedly decreased the production of melanin in a dose-dependent manner. By applying
the bakuchiol prior to α-MSH stimulation, the authors effectively showed that, at least in this regard,
the effect is not due to tyrosinase inhibition: the primary mode of action of arbutin and other key skin
whitening agents. Independently, Chaudhuri found that bakuchiol and retinol are very weak tyrosinase
inhibitors. At 10 µg/mL level, bakuchiol and retinol have shown tyrosinase (mushroom) inhibitory activ-
ity of about 10% and 25%, respectively. EC50 could not be determined due to cytotoxicity at higher doses.
It has also been found that human skin exposed to UVB irradiation with a dose of 2 MED manifests
a signicant increase in the expression of Endothelin-1 (ET-1) and tyrosinase mRNA signals ve days
after irradiation.61 In these studies, low levels of ET-1 secreted by keratinocytes in response to UVB
radiation was shown to down-regulate E-cadherin in melanocytic cells. ET-1 is a potent down-regulator
of E-cadherin in human melanocytes and also melanoma cells.62 An independent and unpublished study
by Chaudhuri has shown a sixfold up-regulation of CDH-1 gene coding for E-cadherin as compared to
TABLE 1.9
Percent Reduction in Acne after Bakuchiol Treatment
Group # Type of Lotions
Number of
Volunteers
% Reduction in Acne after Treatment
2 weeks 4 weeks 6 weeks
1 1% bakuchiol 13a30 42 57
2 2% salicylic acid 14b21 34 48
31% bakuchiol +2% salicylic acid 14a26 48 67
4 control 15 5 5 11
a Two dropped out due to protocol violation.
b One dropped out due to protocol violation.
TABLE 1.10
Effects of Bakuchiol on Melanin Production and Cell Viability in B16
Melanoma Cells
Compounds Melanin/EC50 in µg/mL Cell Viability/IC50 in µg/mL
Bakuchiol 1.8 5.9
Arbutin 24.0 >1000
Source: Adapted from Jamal S, Schneider RJ. J Clin Invest 2002;110:443–52.
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12 Cosmeceuticals and Active Cosmetics
a control in UV-B irradiated normal human keratinocytes treated with bakuchiol using 0.5 µg/mL. In
light of the foregoing, it is quite tempting to propose that bakuchiol also reduces UV-induced hyper-
pigmentation by modulating E-cadherin. Additionally, in a small, open-label, pilot study by Shalita,
it was found that 0.6% bakuchiol cream was effective and very well tolerated in reducing acne related
post-inammatory hyper-pigmentation. In light of the foregoing, it would seem that the combination
of several skin lightening agents, targeting different pathways, may have additive or synergistic effects
with bakuchiol at doses that may confer cost-effective and safe even toning as well as anti-aging effects.
Antimicrobial
Bakuchiol has shown bactericidal effects against Streptococcus mutans, S. sanguis, S. salivarius, S sob-
rinus, Enterococcus faecalis, E. faecium, Lactobacillus acidophilus, L. casei, L. plantarum, Actinomyces
viscosus, and Porphyromonas gingivalis, with minimum inhibitory concentrations (MICs) ranging from 1
to 4 µg/mL and the sterilizing concentration (15 min exposure) ranging from 5 to 20 µg/mL.27 In another
study, an ether extract of P. corylifolia seed showed antimicrobial activity against various strains of
bacteria. This study concluded that the antimicrobial activity was due to the presence of bakuchiol which,
among other effects, inhibited the cell growth of S. mutans in a concentration dependent-manner and
completely prevented growth at 20 µg/mL of bakuchiol.63 Similarly, an in vitro screening of crude metha-
nolic seed extract of P. corylifolia showed signicant antimycobacterial activity against Mycobacterium
aurum and M. smegmatis at a MIC of 62.5 µg/mL.64 Recently, a new source of bakuchiol was found by
bioassay-guided isolation from dried leaves of Aerva sangulnolenta Blume and shown to have good
antibacterial activity against S. mutans, A. viscosus, S. sanguis, and moderate antifungal activity against
Malassezia furfur.15
Chaudhuri has also demonstrated excellent antimicrobial activities of bakuchiol in an, as yet, unpub-
lished work. Specically, Chaudhuri conducted an evaluation to assess the minimum inhibitory con-
centration values (MIC in µg/mL) of bakuchiol against various organisms relevant to personal care
applications in accordance with U.S. Pharmacopeia’s Compendia Products procedure for Category 2
(USP 26–87, pp. 2022–2026). The results are given in Table 1.11. The data clearly shows that bakuchiol
is an effective antimicrobial ingredient for use in personal care products. Additionally, a comparative
study was done of the effectiveness of several commercial antimicrobial additives against E. coli and
S.aureus: the results of that study are presented in Table 1.12. As indicated, bakuchiol is comparative
with, if not a superior option to, current commercial antimicrobial additives.
TABLE 1.11
Minimum Inhibitory Concentration (MIC) Values of
Bakuchiol Against Various Organisms
Organisms MIC Value (µg/mL)
Bacteria
E. coli 1.0
S. aureus 2.0
S. epidermidis 1.5
Streptococcus 4.0
Lactobacillus 3.0
P. gingivalis 1.0
P. acne 1.2
Pseudomonas aeruginosa 8.5
Fungi
Aspergillus niger 0.8
Candida albican 1.5
P. ovale 25.8
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13Bakuchiol
Other Targets
Protein Tyrosine Phosphatases (PTPs)
Phosphorylation and dephosphorylation of structural and regulatory proteins are major intracellular
control mechanisms in eukaryotes. PTPs are a group of enzymes that remove phosphate groups from
phosphorylated tyrosine residues on proteins.33 Protein tyrosine (pTyr) phosphorylation is a common
post-translational modication that can create novel recognition motifs for protein interactions and
cellular localization, affect protein stability, and regulate enzyme activity. These enzymes are key regu-
latory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle
control, and are important in the control of cell growth, proliferation, differentiation, and transforma-
tion. As a consequence, maintaining an appropriate level of protein tyrosine phosphorylation is essen-
tial for many cellular functions.
Bioassay-guided fractionation of the EtOAc-soluble extract of the seeds of P. corylifolia afforded two
protein tyrosine phosphatase (PTP) 1B inhibitory compounds, psoralidin and bakuchiol, along with
inactive corylin. Psoralidin and bakuchiol inhibited PTP1B activity in a dose-dependent manner, dis-
playing IC50 values of 9.4 ± 0.5 µM and 20.8 ± 1.9 µM , respectively.65 Thus, this is an area ripe for con-
tinued investigation.
DNA Polymerases
DNA polymerases are enzymes that are essential for DNA replication and are involved in a number of
related cell processes, good and bad. DNA polymerase inhibitors, as their name suggests, are compounds
that inhibit DNA polymerase activity. One key DNA polymerase inhibitor, resveratrol (Figure 1.2), was
tested by Sun etal. and was found to have an inhibitory activity of 10 µM in an SV40 viral DNA repli-
cation assay.66 More detailed structure–function analysis showed that resveratrol, whose structure has
a 4-hydroxystyryl moiety in a trans conformation with respect to the m-hydroquinone, inhibits DNA
polymerases α and δ (IC50 3.3 and 5 µM, respectively) and, by comparison with structurally related
resveratrol derivatives, demonstrated the absolute requirement of the 4-hydroxystyryl moiety for inhibi-
tion to occur.67 Interestingly, both corylifolin and bakuchiol also possess the 4-hydroxystyryl moiety.
Additionally, bioassay-directed purication of P. corylifolia ethanol extracts led to the identication of
corylifolin and bakuchiol as DNA polymerase inhibitors.66 Hence, inhibition of DNA synthesis provides
yet another molecular mechanism for the chemopreventive activity of bakuchiol.
Tumor Suppressor p53
Anti-tumor activity of bakuchiol was investigated on the human lung adenocarcinoma A549 cell line.
MTT assay revealed that the IC50 of bakuchiol at 72 h was 9.58 ± 1.12 µmol/L, much more effective than
TABLE 1.12
Comparative Inhibitory Activity of Bakuchiol vs. Leading
Antimicrobial Ingredients
MIC in µg/mL MIC in µg/mL
Ingredients S. aureus E. coli
Bakuchiol 2.0 1.0
Chlorhexidine 0.5–1.0 1.0
Hexachlorophene 0.5 12.5
Cetrimide 4.0 16.0
Triclosan 0.1 5.0
Benzalkonium chloride 0.5 50.0
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14 Cosmeceuticals and Active Cosmetics
that of resveratrol (33.02 ± 2.35 µmol/L). Bakuchiol has also been shown to reduce the mitochondrial
membrane potential of cells in a concentration- and time-dependent manner. In fact, bakuchiol is shown
to be more potent in many respects than resveratrol, producing/inducing a much higher level of apop-
totic cells than resveratrol.29 Additionally, p53 up-regulation, S phase arrest, caspase 9/3 activation, Bax
up-regulation, and Bcl-2 down-regulation were observed in bakuchiol-treated A549 cells. These results
suggest that S phase-related cell cycle regulation and, more importantly, reactive oxygen species-related
apoptosis, might contribute to the anticancer properties of bakuchiol.
In another study, Russo etal.* showed that P. glandulosa extracts inhibited the growth of cancer cells
after 48 h of treatment (IC50 of 10.5 µg/mL). The authors demonstrated that the extract induced apoptotic
cell death, which they could attribute to the overall action of the meroterpenes present in the extract: the
most active meroterpenes being bakuchiol, 12-hydroxy-iso-bakuchiol, 3-hydroxy-bakuchiol, and baku-
chiol acetate. To a large extent, apoptotic cell death corresponded to a high level of DNA fragmentation,
which, in turn, correlated to a signicant increase in caspase-3 enzyme activity and Bax protein levels
and a decrease in Bcl-2. This work supports the premise of the authors for the use of P. glandulosa as
a potential source of anticancer agents, including, especially bakuchiol, for the treatment of melanoma.
Cellular tumor antigen p53, which is also known as phosphoprotein p53, tumor suppressor p53, and,
simply p53, is a protein that, in humans, is encoded by the TP53 gene. The p53 protein is crucial in
multicellular organisms where it regulates the cell cycle and, thus, functions as a tumor suppressor, pre-
venting cancer. As such, p53 has been described as “the guardian of the genome” because of its role in
conserving stability by preventing genome mutation. In its anti-cancer role, p53 works through several
mechanisms: activating DNA repair proteins when DNA has sustained damage; arresting growth by
holding the cell cycle at the G21/S regulation point on DNA damage recognition (if it holds the cell here
for long enough, the DNA repair proteins will have time to x the damage and the cell will be allowed
to continue the cell cycle); and initiating apoptosis—programmed cell death—if DNA damage proves to
be irreparable.68 Thus, bakuchiol’s up-regulation of p53, as noted above, adds further support to the use
of this compound in preventing and/or treating cancer.
Signal Transducer and Activator of Transcription 3(STAT3)
Inhibiting interleukin-6 (IL-6) has been postulated as an effective therapy in the pathogenesis of several
inammatory diseases. Lee etal. have shown that bakuchiol has an inhibitory effect on IL-6-induced
STAT3 promoter activity in Hep3B cells with an IC50 value of 4.57 ± 0.45.69 In response to cytokines
and growth factors, STAT family members are phosphorylated by receptor-associated kinases and then
form homo- or heterodimers that translocate to the cell nucleus, where they act as transcription activa-
tors. STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in
a variety of autoimmune diseases.70
Hypoxia Inducible Factor 1 (HIF-1)
A methanol extract of the seeds of P. corylifolia potently inhibited hypoxia inducible factor-1 (HIF-1)
activation induced by hypoxia (100% inhibition at 20 µg/mL) in a HIF-1-mediated reporter gene assay.71
Interestingly, bakuchiol is the only HIF-1 inhibitory agent (IC50 value 6.1 µM) found in this plant. In
an effort to better understand the structural/performance relationship, the authors prepared few simple
bakuchiol analogs and evaluated their HIF-1 inhibitory activities. Based on the results, the authors con-
cluded that the phenolic hydroxyl group and the 12,13-double bond of bakuchiol play important roles in
the biological activity of bakuchiol in HIF-1 inhibition.
HIF-1 is primarily involved in the sensing and adapting of cells to changes in the O2 level, which
is essential for their viability. A body of evidence indicates that oxygen deciency clearly inuences
some major intracellular pathways such as those involved in cell proliferation, cell cycle progression,
apoptosis, cell adhesion, and others.71 HIF-1 is considered a central regulator of the adaptation response
* This work was presented by A Russo etal. at the 36 Congresso Nazionale Della Societa Italiana di Farmacologica held
in Torino, 2013.
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15Bakuchiol
of cancer cells to hypoxia that makes it a therapeutic target in solid tumors. Hypoxia may induce
changes in gene expression. Many genes involved in extracellular matrix remodeling are induced by
hypoxic exposure. Matrix metalloproteases (MMPs) have also been implicated in metastatic progres-
sion, because MMPs can degrade all constituents of the basement membrane as well as structural
components of the stroma.72
Conclusion
In summary, it is quite clear from the author’s own work and the current literature that bakuchiol mimics
and, in some cases, exceeds the activity of retinol towards various retinol targets and shows signicant
activity with respect to a number of non-retinol targets as well. Mechanistically, both the 4-hydroxystyryl
and terpenic moieties of bakuchiol seem to be important, if not critical, with respect to the determination
of its bioactive and physiological properties. Individual properties or effects, many of which are similar
to retinol, may depend on the interplay between bakuchiol and very specic cellular targets that are
upstream controllers of many cellular events. Overall, the complex and expansive biological action of
bakuchiol and its capacity to modulate multiple different and distinct physiological pathways support the
hypothesis of a mechanism involving multiple molecular targets. Thus, future studies on the properties
of bakuchiol should evaluate the impact of bakuchiol on the maximal number of reported targets and
their implications in topical as well as other modes of delivery.
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