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Bakuchiol: A Retinol-Like Functional Compound Revealed by Gene Expression

Profiling & Clinically Proven to have Anti-Aging Effects.

Article in International Journal of Cosmetic Science · January 2014

DOI: 10.1111/ics.12117 · Source: PubMed

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International Journal of Cosmetic Science, 2014, 1–10 doi: 10.1111/ics.12117

Bakuchiol: a retinol-like functional compound revealed by gene

expression profiling and clinically proven to have anti-aging effects

R. K. Chaudhuri* and K. Bojanowski†

*Sytheon Ltd., Boonton, NJ 07005, USA and †Sunny Biodiscovery, Santa Paula, CA 93060, USA

Received 04 November 2013, Accepted 25 January 2014

Keywords: anti-ageing clinical, bakuchiol, DNA microarray, histology, retinol

Synopsis m
etabolite physiologiquement actif du r
etinol qui r
egule l’expres-

OBJECTIVE: The study was undertaken to compare the skin care sion des genes par des voies d
ependantes et ind
ependantes du
related activities of retinol and bakuchiol, a potential alternative to r
ecepteur de l’acide r
etino€ıque.
retinoids. Retinol is a pivotal regulator of differentiation and

METHODES: Un profilage comparatif d’expression g
en
etique de ces
growth of developing as well as adult skin. Retinoic acid is the deux substances dans le modele substitut de la peau EpiDerm FT a
major physiologically active metabolite of retinol regulating gene
et
e entrepris. La synthese des collagenes de type I, III et IV et de
expression through retinoic acid receptor – dependant and indepen- l’aquaporine 3 dans des fibroblastes dermiques humains normaux
dent pathways. ont
et
e analys
es par ELISA et/ou en histochimie dans le modele de
METHODS: Comparative gene expression profiling of both sub- peau EpiDermTM FT.
stances in the EpiDerm FT full thickness skin substitute model

RESULTATS: Bakuchiol est un ph
enol meroterpene abondant dans
was undertaken. Furthermore, type I, III and IV collagen, as well les graines et les feuilles de la Psoralea corylifolia. Nous pr
esentons
as aquaporin 3 expression was analyzed by ELISA and/or histo- des preuves que bakuchiol, n’ayant aucune ressemblance structu-
chemistry in human dermal fibroblasts and/or Epiderm FT skin relle avec les r
etino€ıdes, peut fonctionner comme un analogue fonc-
substitutes. tionnel de r
etinol. Les diagrammes de type Volcano montrent la
RESULTS: Bakuchiol is a meroterpene phenol abundant in seeds grande similitude de l’effet du r
etinol et du bakuchiol sur l’expres-
and leaves of the plant Psoralea corylifolia. We present evidence that sion des genes. Cette ressemblance a
et
e aussi d
emontr
ee par la
bakuchiol, having no structural resemblance to retinoids, can func- comparaison de la modulation de l’expression de genes particu-
tion as a functional analogue of retinol. Volcano plots showed laires, appartenant a de diff
erentes groupes fonctionnelles. La fonc-
great overall similarity of retinol and bakuchiol effects on the gene tionnalit
e r
etinol -like a
et
e confirm
ee par la r
egulation a
 la hausse
expression profile. This similarity was confirmed by the side-by-side du collagene de type I et IV et aquaporine 3 au niveau de proteines
comparison of the modulation of individual genes, as well as on par ELISA et histochimie. Le bakuchiol a
egalement
et
e formul
e
the protein level by ELISA and histochemistry. Retinol-like func- dans un produit de soin de la peau et a
et
e test
e dans une
etude
tionality was further confirmed for the upregulation of types I and clinique avec deux applications par jour au visage. Les r
esultats
IV collagen in DNA microarray study and also show stimulation of ont montr
e que, apres le traitement de douze semaines, une
type III collagen in the mature fibroblast model. Bakuchiol was also am
elioration significative a
et
e observ
ee dans les rides et ridules, la
formulated into a finished skin care product and was tested in clini- pigmentation, l’
elasticit
e, la fermet
e et la r
eduction globale des
cal case study by twice-a-day facial application. The results showed dommages du photo-vieillissement, sans les effets ind
esirables habi-
that, after 12 weeks treatment, significant improvement in lines tuels associ
es a la th
erapie au r
etinol.
and wrinkles, pigmentation, elasticity, firmness and overall reduc- CONCLUSION: Sur la base de ces donn
ees, nous proposons que le
tion in photo-damage was observed, without usual retinol therapy- bakuchiol peut fonctionner comme un compos
e anti- vieillissement
associated undesirable effects. gr^ace a  la r
eglementation de l’expression des genes similaire au
CONCLUSION: Based on these data, we propose that bakuchiol r
etinol.
can function as an anti-ageing compound through retinol-like
regulation of gene expression.
Introduction
Retinoids have been first defined as a family of naturally occurring
Re
sume

compounds comprised of vitamin A (retinol) and its derivatives,
OBJECTIF: L’
etude a
et
e men
ee pour comparer les activit
es li
ees
such as vitamin A aldehyde (retinal) or vitamin A acid (retinoic
aux soins de la peau du r
etinol et du bakuchiol, une alternative
acid). Retinoic acid is considered to be the active form of vitamin A
potentielle aux r
etino€ıdes. Le r
etinol est un r
egulateur essentiel de
and is involved in gene regulation, leading to effects ranging from
la diff
erenciation et de la croissance de la peau en d
eveloppement
hyperplasia to differentiation and apoptosis of normal and cancer
ainsi que la peau des adultes. L’acide r
etino€ıque est le principal
cells [1, 2]. The conversion of retinol to retinal by the retinol dehy-
Correspondence: Ratan K. Chaudhuri, Sytheon Ltd., 315 Wootton drogenases is considered to be the rate-limiting step for the biosyn-
Street, Boonton, NJ 07005, USA. Tel.: +201 303 5594; fax: +1 973 thesis of retinoic acid [3]. In addition to retinol dehydrogenases,
909 9922; e-mail: [email protected] P450s 1A1, 1A2, 1B1 and 3A4 have been shown to be involved

© 2014 Society of Cosmetic Scientists and the Soci
et
e Francßaise de Cosm
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A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

A 1% BHA. Bakuchiol (Phenol, 4-[1E,3S)-3-ethenyl-3,7-dimethyl-1,6-

octadinenyl; Fig. 1B)l is a phenolic compound with a monoterpene
OH
side chain [19]. Bakuchiol belongs to a rare group of terpenoids in
which the aromatic ring system is derived from phenylpropane unit.
The material used in this study is obtained from edible seeds of Psora-
lea corylifolia, which is psoralene-depleted Bakuchiol (trade named Sy-
B tenolâ A; INCI name Bakuchiol) with a purity of about 95%.

DNA microarrays
HO
EpiDerm FT tissues were obtained from Mattek (Ashland, MA,
Figure 1 (A) Retinol. (B) Bakuchiol. U.S.A.; cat. no. EFT 212) and cultured according to the manu-
facturer’s instructions. The test materials – Retinol (50%) and
in the metabolism of retinoic acid [4]. Human dermal fibroblasts Bakuchiol (100%) were dissolved in DMSO at 10 mg mL 1 (Reti-
treated with retinol metabolize it to retinoic acid, demonstrating nol) and 5 mg mL 1 (Bakuchiol), and further dilutions were made
the bioactivity and bioavailability of retinol in the dermis [5]. in type I sterile water. Test materials were assayed at 10 lg mL 1
Retinol is found in a variety of foods such as beef, calf, chicken (Retinol) and 5 lg mL 1 (Bakuchiol) against 0.1% DMSO as a con-
liver, eggs and fish. It is also present in vegetables such as carrots, trol. The incubation time with skin tissues was 2 days. After incu-
squash, sweet potatoes, pumpkin and cantaloupe. Subsequent bation, skin tissues were harvested, frozen in liquid nitrogen and
research has resulted in a much larger class of natural and syn- subjected to total RNA extraction with Qiagen kit (Frederick, MD,
thetic compounds that are termed retinoids due to their functional U.S.A). The quality of extracted RNA was validated twice by elec-
– although not always structural – similarity to vitamin A [6]. trophoresis (after extraction and before microarray analysis).
The epidermis is one of the major targets for the retinoic acid Samples were hybridized and data were analysed using human
signalling in adult organism. Classic retinoid activities are mainly OneArray platform from Phalanx Biotech (Palo Alto, CA, U.S.A.).
achieved through the transcriptional regulation of specific genes The Excel file yielding information on over 30 000 probes was then
via two classes of nuclear hormone receptors, the retinoic acid further processed in house to retain only differences with low P
receptors (RAR) and retinoid X receptors (RXR), each with three is- values (P value cut off was 0.05) and high fold-change (the cut off
otypes (a, b, c) and multiple isoforms [7–9]. All-trans retinoic acid value for fold-change was 2.0).
preferentially binds RARs and its 9-cis isomer, 9-cis retinoic acid,
binds both RARs and RXRs. The predominant retinoid receptors
Collagen ELISA
found in skin are RARc and RXRa [10]. Retinoic acid receptors
exert their effects in epidermis through direct binding to epidermal Retinol and bakuchiol were assayed at 10 lg mL 1 on normal
genes [11, 12] or interference with signalling of other transcription human fibroblasts grown in DMEM with 5% calf serum (Hyclone,
factors [13]. Salt Lake City, UT, U.S.A.). For type I and IV collagen quantifica-
Retinoic acid and its derivatives have been used as therapeutic tion, neonatal human dermal fibroblasts (low passage; American
agents for numerous skin conditions from psoriasis to acne and Type Culture Collection, Manassas, VA, U.S.A. cat. no. PCS-201-
were also found to be clinically effective against wrinkles [14]. 010, lot no. 58243223) were used. For type III collagen quantifi-
Retinol (Fig. 1A) application is believed to be a more efficient cation, human epidermal fibroblasts from a 68-year-old female
method to deliver retinoic acid to the skin cells than direct treat- donor (p. 5, Zen-bio, cat. no. KR-F) was used. Cells were exposed
ment with retinoic acid [15]. However, retinoid therapy using to test materials for 3 days (type I collagen quantification) or
even the newer analogues is still restricted by many undesirable 7 days (type III and IV collagen quantification). Afterward, cell-
side effects, such as irritation, dryness, peeling, erythema and a culture conditioned media were harvested and assayed for type I,
sensation of burning on the skin [16, 17]. These side effects often type III or type IV collagen by sandwich ELISA using affinity-purified
result in non-compliance and discontinuation of therapy. There- antibodies, followed by streptavidin-avidin-HRP conjugate and ABTS,
fore, there is a definite need to develop improved retinoid com- according to a standard ELISA protocol [21, 22]. The colorimetric
pounds. Such compounds should have similar but not identical signal proportional to collagen content was quantified with the Bio-
gene expression pattern as compared with retinol, ideally, result- Rad microplate spectrophotometer 3550-UV at 405 nm with back-
ing in retinol-like beneficial effects, without having retinol-like ground subtraction at 660 nm and analysed with Microplate
undesirable side effects. Here, we build on our preliminary findings Manager v.2 software for Macintosh (BioRad, Hercules, CA, U.S.A.).
[18] and report that bakuchiol (Fig. 1B) – a meroterpene phenol
from seeds of the plant Psoralea corylifolia [19, 20] – exhibits such
Histochemistry
retinol-like functionality.
Fort type IV collagen and aquaporin three visualization retinol
and bakuchiol were dissolved at 50 mg mL 1 in DMSO. Test sam-
Materials and methods
ples were then further diluted in type I sterile water and tested at
final concentrations 10 lg mL 1 (Retinol) and 5 lg mL 1 (Bak-
Test materials
uchiol) using EpiDermFT tissues from Mattek. Tissues were equili-
Retinol (Fig. 1A), trade named Retinol 50 C (INCI name Retinol brated for 24 h and incubated with test materials or water
and Polysorb 20), was purchased from BASF (Florham Park, NJ, (negative control) for 96 h, afterward they were rinsed and fixed
U.S.A). This product is a yellow oil containing 50% vitamin A in in 10% buffered formalin. Paraffin sections of these tissues were
polysorbate 20 and stabilizer system consisting of 3.5% BHT and stained with a biotinylated antibody against type IV collagen (cat.

2 © 2014 Society of Cosmetic Scientists and the Soci
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A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

no. 1340-08 Southern Bio, Birmingham, AL, U.S.A.) or AQP3 allowed to dry for approximately 5 min, and the replica was
(cat. no. sc-9885, Santa Cruz Biotechnology, Santa Cruz, CA, removed gently from the site.
U.S.A.) and developed with the ABC peroxidase staining compo-
nents (Santa Cruz Biotechnology). Slides were mounted in Perm-
Product application
mount and observed on Nikon (Tokyo, Japan) Eclipse TS100
inverted microscope at 100 magnifications. Microphotographs Test Materials were distributed to the subjects. Subjects were asked to
were taken with Canon Rebel digital camera mounted on the gently massage a small amount of the test material to the crow’s feet
Nikon TS100 microscope. and eye area and then smooth over the whole face. They were asked
to apply twice a day for 12 weeks. A study diary was given to the
panelists to list the time of application, the dates and any subjective
Clinical study
comments that they might have in regard to the test product.
General
Seventeen healthy but photo-aged subjects were recruited to this
Weeks 4, 8 and 12
blind study (all females; age range 40–65 years). All subjects read,
understood and signed an informed consent. All subjects had Panellists returned to the study site after week 4, 8 and 12 of prod-
abstained from the use of moisturizing products and used only sim- uct use. At each study visit, panellists were clinically evaluated in
ple soap, for at least 1 week prior to treatment conditions. All test the same manner as at the baseline visit.
products were supplied in identical containers. Subjects were
instructed on the use of the cream – twice daily morning and even-
Statistical analysis
ing applications to the entire face for 3 months. Clinical assess-
ments of the skin of the face were performed for all participants at For each of the parameters, percent improvement from baseline
baseline and following 4, 8 and 12 weeks of product use. The fol- was calculated to express the efficacy of the product at each time
lowing parameters were assessed at each visit by an expert grader: point (4, 8 and 12 weeks). Using the t-test, the statistical signifi-
Fine Lines/Wrinkles, Roughness and Dryness, Skin Tone, Skin Elas- cance of the net change from baseline (pre-application) to each
ticity and Firmness, Radiance, Brightening and Overall Eye Area subsequent time point was assessed. Statistical significance was
Appearance. Assessment for each parameter was performed at defined at the P = 0.05 or less level (corresponding to a 95% or
baseline using the following five-point ordinal severity scale: greater confidence level).
0 = None; 1 = Minimal; 2 = Mild; 3 = Moderate; 4 = Severe.
Formulated product
Silicone analysis profilometry
At each visit, a single silicone replica was made of the target area Formulation details are given in Table V.
and a photographic record was kept of this target for subsequent
relocation. Comparative analysis of skin profilometry was con-
Results and discussion
ducted, using surface roughness and wrinkle depth analysis. The
heights of the replicated wrinkles were measured using Miyomoto Bakuchiol is a meroterpene phenol abundant in seeds and leaves of
Surftest profilometer. Ry (depth) and Ra (mean roughness) were the plant Psoralea corylifolia [19, 20] and has also been isolated
recorded at each time of measuring operation. The area scanned from other plants, such as, P. grandulosa [23, 24], P. drupaceae
from each sample was clearly mapped so as to determine the same [25], Ulmus davidiana [26], Otholobium pubescens [27] and Piper lon-
area in respective weeks 4, 8 and 12 samples. gum [28]. It is widely used in Indian as well as Chinese medicine to
treat a variety of diseases. Bakuchiol has been reported to possess
Photo booth anti-inflammatory [24, 29–31], antioxidant [32–34], anti-tumor
At each time point, a series of high resolution digital photographs [35, 36], anti-bacterial [37], cytotoxic [38], heptaprotective [39]
was collected using a photo booth equipped with Canon G7 Digital and caspase-3 depended apoptosis [40] effects. The cytotoxicity of
Camera 10 MP, 69 zoom. Subject positioning was reproduced bakuchiol is mainly due to its DNA polymerase 1-inhibiting activity
upon return visit. A light booth was used so as to provide con- [41]. Recently, anti-acne activity of bakuchiol has been reported
trolled reproducible light conditions. The booth consists of an array [42]. Here, we demonstrate the anti-ageing and retinol-like func-
of 8 equally spaced fluorescent tubes in a semicircular configura- tionalities of bakuchiol using DNA microarray, ELISA, histochemis-
tion. The software-driven system allows the position and expression try and clinical case studies.
of the test subjects to be aligned to a high degree. As human skin naturally ages, it becomes thin, lax and finely
wrinkled. Of these changes, fine lines & wrinkles and uneven pig-
mentation are most easily appreciated clinically with severity corre-
Method of assessment & product application
lating strongly with age. We have demonstrated through a pilot
clinical study that topical 0.5% bakuchiol treatment improves clini-
Baseline
cal appearance (% improvement vs. baseline) of naturally aged/
The expert grader performed assessment of the panelist’s face and photo-aged human skin.
eye area for all the parameters as described before. Photographs
were conducted using a photo booth with a three-point head
DNA microarrays
restraint with photographs taken with frontal view, 45 degrees to
the right and 45 degrees to the left at each time point (Day 0, As retinol affects the expression of a vast array of genes, compara-
Weeks 4, 8 and 12). A replica ring was used to delineate the wrin- tive gene expression profiling with retinol is a suitable method to
kle site in the crow’s feet area. Silflo was applied on the site, identify retinol-like compounds [43]. Here, we applied this method

© 2014 Society of Cosmetic Scientists and the Soci
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A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

A Retinol y- and x-axes, respectively. Data points with low P-values (highly
6 significant) appear towards the top of the plot, and with P value of
–Log (P value)

0.05 being set as the threshold for statistical significance, all points
4
situated above the value of 1.3 on the y axis are statistically signifi-
2 cant. The finding that the overall shapes of retinol and bakuchiol
volcano plots are similar was the first indication of the functional
0 analogy between the two compounds. This was further confirmed
–3 –2 –1 0 1 2 3
by the analysis of retinoid-binding and metabolizing genes; the
Log2 (fold change)
expression was often – but not always – similarly modulated
(Table I). Interestingly, both RARB and RARG are up-regulated, as
B Bakuchiol
6
expected, by retinol but not by bakuchiol, indicating a possible
–Log (P value)

advantage of the latter in terms of side effects. Also retinol had no

4 effects on CRBP II and CRBP IV, whereas bakuchiol showed signifi-
cantly higher up-regulation. Furthermore, retinol causes down reg-
2
ulation of CRABP1 gene whereas bakuchiol causes up-regulation,
0 and whereas bakuchiol showed a dramatic up-regulation (82-fold
–3 –2 –1 0 1 2 3 vs. placebo) of LRAT retinol showed 12.3-fold (still a very signifi-
Log2 (fold change) cant) increase. These results indicate that besides being a retinol
functional analogue, bakuchiol may enhance the availability of
Figure 2 (A) Volcanic plot of DNA microarray data – Retinol. (B) Volcanic endogenous retinol.
plot of DNA microarray data – Bakuchiol.
Retinol and bakuchiol also showed similar modulation of genes
implicated in ECM and DEJ (Tables II and III, respectively). ECM is
the material that forms the bulk of the dermis, excluding water and
to reveal retinol-like properties of bakuchiol. These proprieties were cells. Proteins and complex sugars form most of the dermal ECM, and
first evidenced on the whole genome scale by comparing the shapes they are arranged in an orderly network fibres and ground sub-
of volcano plots of retinol- and bakuchiol-treated skin substitutes stances organized by physical entanglements, opposing ionic
(Fig. 2A,B). Volcano plot is a scatter graph used to identify mean- charges, chemical covalent bonding and cross-linking into a
ingful changes in large datasets, such as data from DNA micro- biomechanically active polymer. This scaffolding structure with
array analysis, by plotting significance versus. fold-change on the regional tensile strength provided by collagens, elasticity by elastins,

Table I Description, fold-change in the DNA microarray experiment and role of modulated retinoid binding and metabolizing genes (R: retinol; B: bakuchiol)

Gene Full name Function & comments

CRBP I; Cellular retinol binding CRBP I:R = 2.6; B = 4.2

CRBP II; protein I, II & IV CRBP II: R = NS; B = 4.1
CRBP IV CRBP IV: R = NS; B = 3.1
CRBP I mediates the cellular uptake of retinol, solubilizes and detoxifies it for further transport within the
cytoplasm and presents it to the appropriate enzymes to biosynthesize retinoic acid
N6AMT2 N-6 adenine-specific R = NS; B = 2.1
DNA methyltransferase 2 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 R = 5.5; B = 11.6
SDR family member DHRS9 is involved in converting retinol to retinal and then to retinoic acid, the rate-limiting step for the
9 precursor biosynthesis of retinoic acid
RETSAT All-trans- 13,14-dihydroretinol R = 2.9; B = 2.8
saturase RETSAT expression is involved in adipocyte differentiation
LRAT Lecithin-retinol acyltransferase R = 12.3; B = 82.2
Retinol esterification with long-chain fatty acid by LRAT is the key step in both absorption & storage of retinol.
CYP1A1; Cytochrome P450 CYP1A1: R = 4.0; B = 4.9
CYP1A2 CYP1A2: R = 3.6; B = 6.7
In addition to retinol dehydrogenase, P450s 1A1 and 1A2 genes are the major human P450s
RARB; RARG Retinoic acid receptor beta -1; RARB: R = 5.6; B = NS
Retinoic acid receptor RARG: R = 1.8; B = NS
gamma -1 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

4 © 2014 Society of Cosmetic Scientists and the Soci
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A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

Table II Description, fold-change in the DNA microarray experiment and roles of modulated genes coding for ECM components [(R: retinol; B: bakuchiol]

Gene Full name Function & comments

COL1A2; Collagen 1A2; COL1A2: R = 3.3; B = 1.9

COL4A6; Collagen 4A6; COL4A6: R = 6.4; B = 11.2
COL9A2; Collagen 9A2; COL9A2: R = 5.6; B = 6.7
COL9A3; Collagen 9A3 COL9A3: R = 4.1; B = 5.8
Collagens provide scaffolding structure with regional tensile strength and elasticity; Degradation leads to fine lines and
wrinkles. Comparable fold-change observed with four collagen genes with the exception of COL3A1. This may be due
to the use of neonatal tissue in the skin substitutes. ELISA study with mature fibroblasts showed stimulation of type III
collagen.
EMILIN3 Elastin microfibril EMILIN3:R = 2.2 (NS); B = 9.1
EMILIN1 interface-located protein 3; EMILIN1: R = 3.4; B = 2.4
Elastin microfifibril The EMILINs are a family of glycoproteins of the extracellular matrix; Widely distributed in several tissues associated
interface-located protein 1 with elastin and localized at the interface between amorphous elastin and microfibrils
PI3 Peptidase inhibitor R = 2.5; B = 2.7
3/Elastase-specific inhibitor Bakuchiol and retinol are expected to maintain the desired level of elastin required for maintaining the connective
tissue structure due to their up-regulation of elastase-specific inhibitor gene PI3
FLRT2; Fibronectin-like FLRT2: R = NS; B = 13.9
FLRT3 domain-containing FLRT3: R = 2.8 (NS); B = 6.1
leucine-rich transmembrane Fibronectins maintain the shape of cells and matrix stability
protein 2
HAS3 Hyaluronan synthase 3 R = 10.8; B = 19.2
Hyaluronans are important for the maintenance of a highly hydrated extracellular matrix in tissues and is also involved
in cell adhesion and supports cell migration. It is synthesized by hyaluronan synthases, such as HAS-3
AQP3 Aquaporin 3 R = 3.5; B = 4.3
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. Both retinol and bakuchiol up-regulated AQP3

Table III Description, fold-change in the DNA microarray experiment and roles of modulated DEJ genes (R: retinol; B: bakuchiol)

Gene Full name Fold-change, function & comments

COL4A6 Collage alpha-6 (IV) COL4A6: R = 6.4; B = 11.2

COL17A1 Collagen alpha-1(XVII) COL17A1: R = 3.6; B = 8.7
Lamina densa mostly consists of type IV collagen, perlecan and nidogen. Through a complex inter- and intramolecular
interactions type IV collagen forms supra molecular networks that influence cell adhesion, migration, and
differentiation. Type XVII collagen is the protein component of anchoring fibrils that fortifies the attachment of the
epidermis to the dermis.
PLEC1 or Plectin I R = 2.7; B = 6.8
HD1 (Hemidesmosomal Plectin, a 500-KDa protein and a constituent of the intracellular component of hemidesmosomes, attaches intermediate
protein 1) filaments to both hemidesmosomes and plasma membranes of basal keratocytes
ITGB4; Integrin beta-4; ITGB4: R = 3.5; B = 8.0; ITGB6: R = 7.5; B = 7.7
ITGB6; Integrin beta-6; ITGB8: R = 0; B = 3.9; ITGA6: R = 0; B = 3.6
ITGB8; Integrin beta-8; Integrins are transmembrane glycoproteins and a major component of hemidesmosomes. They mediate the transfer of
ITGA6 Integrin alpha-6 information between the extracellular matrix and the interior of the cell, thereby aiding in modulating the organization of
the cytoskeleton, proliferation and differentiation. Main functions: (a) attachment of the cell to the ECM and (b) signal
transduction from ECM to the cell
LAMA3; Laminin subunit alpha-3 LAMA3: R = 4.7; B = 11.0;
LAMC2 precursor; Laminin LAMC2: R = 2.7; B = 7.8
subunit gamma-2 Laminins are the major non-collagenous proteins in lamina densa and are integral part of the structural scaffolding in
precursor almost every tissue; Involved in cell differentiation, migration, adhesion as well as phenotype and survival.
CDH1 E-Cadherin R = 9.4; B = 21.6
One of the most important and ubiquitous types of adhesive interactions required for the maintenance of solid tissues
is that mediated by E-cadherin. E-cadherin has important functions in pluripotency and maintenance of the
differentiated state of cells

adhesiveness by structural glycoproteins, compressibility by proteo- dermal extracellular matrix, provides a unique homeostatic tenseg-
glycans – hyaluronans and communicability by transmembrane rity function to the skin [44, 45]. DEJ, in turn, provides cohesion
receptors, such as integrins, which exchange information between between dermis and epidermis. With age, both, ECM and DEJ
the cytoskeleton-bound cellular elements and between cells and the gradually deteriorate resulting in skin thinning and morphological

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A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

Table IV Comparative collagen stimulatory effects of bakuchiol and retinol select collagens by ELISA and histochemistry methods to validate
as determined by ELISA in human dermal fibroblasts. The stimulatory effect the data obtained by DNA microarrays. The results, summarized in
is expressed as the % of water control (100%) the Table IV, confirm the upregulation of types I and IV collagen
in DNA microarray study and also show stimulation of type III
Test material (10 lg mL 1) Collagen I Collagen III Collagen IV collagen in this mature fibroblast model.
To determine whether the stimulation of type IV collagens in cell
culture translates into a more robust collagen expression in 3D
Bakuchiol 147 150 119 skin substitute tissue, EpiDermFT tissues were incubated with bak-
Retinol 119 148 100
uchiol or retinol at 10 lg mL 1, and histological sections were
stained with anti-type IV collagen antibodies (Fig. 3). The stain
revealed a stronger type IV collagen signal at the dermal–epidermal
flattening [46]. Retinol is a well known inhibitor of those processes, junction, as compared with the water control, further corroborat-
and the finding that bakuchiol has retinol-like functionality at the ing the DNA microarray and ELISA results. This collagen stimula-
ECM and DEJ levels makes it an interesting novel candidate for tory effect observed in cell culture seems to be due to the selective
anti-ageing applications. metabolic activation of collagen synthesis in fibroblasts, because at
10 lg/mL 1, bakuchiol or retinol did not enhance cell proliferation
(results not shown).
Validation of DNA microarray results by ELISA and histochemistry
Water homeostasis of the epidermis is essential for the normal
Collagens secreted by dermal fibroblasts are major components of function of the skin and stratum corneum (SC) hydration. It is a
the skin extracellular matrix (type I and type III collagens) and determinant of skin appearance, mechanical properties, barrier
basement membrane (type IV collagen). In aged and photodamaged function and metabolism. In addition, it is indispensable in main-
skin, the new collagen pool is decreased due to the inferior amount taining proper water balance of the body. Dehydration of SC is a
and quality of dermal fibroblasts. Therefore, we chose to measure typical feature of skin ageing, especially in photo-aged skin and of

A B C

Figure 3 Effect of Retinol (B) and Bakuchiol (C) on type IV collagen expression compared with non-treated control (A) in human EpidermFT (full thickness)
tissue substitutes. Arrows indicate dermo-epidermal juncture (basement membrane), where collagen IV is localized. Note darker band in (B) and (C) as com-
pared to (A) at this level, indicating greater type IV collagen expression.

A B C

Figure 4 Effect of Retinol (B) and Bakuchiol (C) on aquaporin-3 expression, compared with non-treated control (A) in human EpidermFT (full thickness) tissue
substitutes. Arrows indicate aquaporin-3 staining in the basal layer, where this protein is principally localized.

6 © 2014 Society of Cosmetic Scientists and the Soci
et
e Francßaise de Cosm
etologie

International Journal of Cosmetic Science, 1–10
A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

Table V Formulation details of bakuchiol Table VIII Silicone replica analysis using profilometry: % reduction vs.
baseline

Ingredient Trade name/supplier % w/w

Parameters 4 Weeks 8 Weeks 12 Weeks

Phase A
Glyceryl stearate Arlacel 165/Uniqema 1.50 Wrinkle depth 7% 13% 20%
and PEG-100 Skin roughness 2% 10% 21%
Arachidyl alcohol, Montanov 202/Seppic 4.00
Behenyl alcohol,
Arachidyl glucoside
Dimethyl isosorbide Arlasolve DMI/Uniqema 3.00
Isohexadecane Permethyl 101A/Presperse 8.00 EpiDermFT skin substitutes were incubated with retinol, bakuchiol
Dimethicone Dow Corning 200, 100 cst/Dow Corning 2.00 and compared with the negative (water) control using immunohis-
Bakuchiol Sytenol A/Sytheon 0.50
tochemistry. It was found that both retinol and bakuchiol increased
Phase B
Water 69.75
AQP3 expression (Fig. 4) as visualized by more intense brown col-
Propylene Glycol Propylene glycol/Lyondell 2.00 oration in retinol and bakuchiol – treated tissues located, as
Pentylene Glycol Hydrolite-5/Symrise 3.00 expected, at stratum spinosum and corneum level. Recently, Belle-
Xanthan Gum Vanzan NF/Vanderbilt 0.25 mere et al. [51] have shown the effects of all-trans retinoic acid
Phase C (ATRA) on AQP3 expression and function both in vitro and ex
Dicaprylylether Cetiol OE/Cognis 4.00
vivo. ATRA treatment increased a rapid accumulation of AQP3
Hydroxyethylacrylate Sepinove EMT 10/Seppic 1.00
(and) sodium transcripts in cultured normal human epidermal keratinocytes.
acryloyldimethyl Also in our model of EpiDermFT skin substitute, both retinol and
taurate copolymer bakuchiol increased AQP3 expression.
Phenoxyethanol Optiphen or Microcare PHG 1.00
(and) Caprylyl glycol
Total 100.00 Clinical study
Taken together, these results prompted us to test bakuchiol clinically.
The formulated product containing 0.5% bakuchiol (no moisturizer
Table VI Subjective evaluation by expert – % improvement vs. baseline or any other active ingredients or sunscreen included in this formu-
lated product; Table V) was applied twice daily to the whole face.
Sixteen subjects of seventeen enrolled completed the study. One sub-
Parameters 4 Weeks 8 Weeks 12 Weeks
ject discontinued due to protocol violation. Each of the parameters
was graded on a semi-quantitative scale from 0 to 4 (0, none; 1,
Roughness & dryness 65 81 90 minimal; 2, mild; 3, moderate; and 4, severe). With regard to subjec-
Fine lines/wrinkles 5 16 29 tive evaluation by experts and panelists, the obtained results for the
Skin tone 14 29 39
entire subjects are summarized in Tables VI and VII, respectively.
Skin elasticity/firmness 13 20 39
Radiance 24 40 52
Evaluations were performed at baseline and then at 4, 8 and
Skin brightening 13 35 46 12 weeks and the results compared versus. the baseline.
Eye area appearance 8 24 46 Retinol is used widely in cosmetic products for reducing the
appearance of the signs of ageing and photo-damage [52]. Retinol
is a precursor of retinoic acid. Once it penetrates skin, it is sequen-
tially oxidized to retinoic acid, causing retinoic acid-like effects, but
Table VII Subjective evaluation by panelists – % improvement vs. baseline
is notably less irritating. Currently, most of these products contain
0.1% or lower of retinol. However, even at this low concentration,
Parameters 4 Weeks 8 Weeks 12 Weeks some irritation can occur [53]. It seems that bakuchiol has accept-
able skin tolerability.
Analysing the data (Table VI vs. Table VII), it is evident that %
Roughness & dryness 35 40 48
Fine lines/wrinkles 19 25 23
improvement score for roughness & dryness and radiance given by
Skin tone 12 19 29 expert is significantly higher versus. the panelists’ self-evaluation. It
Skin elasticity/firmness 14 23 25 is interesting to note that % improvement score given by the sub-
Radiance 11 17 30 jects, on the other hand, for fine lines and wrinkles and eye area
Skin brightening 10 14 29 appearance is significantly higher than the score given by the
Eye area appearance 22 24 35
expert. Most of the parameters were improved significantly more
after 8 weeks compared to 4 weeks of application of bakuchiol,
showing a certain degree of cumulative beneficial effect over time.
Results obtained from silicone replica analysis using profilometry
several diseases, for example, eczema, atopic dermatitis, psoriasis are summarized in Table VIII. Comparison of results of day 0 (base
and hereditary ichthyosis (retinol 3.5 fold and bakuchiol 4.3 fold, line) vs. 4, 8 and 12 weeks treated skin provided 7%, 13% and
Table II) [47–50]. To determine whether the increase of the !!! 20% reduction in wrinkle depth (Ry), respectively. All three
expression of water channel AQP3 gene observed in DNA micro- results are statistically significant (P ≤ 0.01). Comparison of results
arrays translates into orthotropic increase at the protein level. of day 0 (baseline) versus. 4, 8 and 12 weeks treated skin yielded

© 2014 Society of Cosmetic Scientists and the Soci
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e Francßaise de Cosm
etologie 7

International Journal of Cosmetic Science, 1–10
A retinol-like functional compound R. K. Chaudhuri and K. Bojanowski

A The photos (Fig. 5; before and after treatment) shown here are
representative of the results that have been obtained with bakuchi-
ol treatment for 12 weeks.
Clinical grading and comparative analysis of skin profilometric
measurements were performed at baseline and after 4, 8 and
12 weeks of application. After 8 weeks of daily application, a
significant reduction in the wrinkle depth and roughness was
observed with the product vs. baseline. These changes were even
greater after 12 weeks of product application. For example, wrinkle
depth reduction (Fig. 5C) is significantly more after 8 weeks com-
pared to 4 weeks of application of bakuchiol (subject no. M572)
showing a certain degree of cumulative beneficial effect over time.
The significant improvement in fine lines and wrinkles, elasticity,
B firmness and overall reduction in signs of photodamage including
even toning effects observed after 12 weeks of treatment provided
the ultimate validation of the in vitro results and were in line with
the retinoid-type functionality of bakuchiol.

Conclusion
Given the fact that retinol and bakuchiol do not have close struc-
tural similarities, yet they exhibit a similar gene expression profile,
especially on certain key anti-ageing genes and proteins,which is
remarkable. Bakuchiol has several substantial advantages over reti-
nol, including excellent photochemical and hydrolytic stability a
good safety profile and ease to formulate due to miscibility with a
wide variety of emollients and solubilizers [18]. Bakuchiol can be
C Subject #M572
used during the day due its photostability. Interestingly, bakuchiol
20
is an excellent stabilizer of retinol under photo-oxidative as well as
18
singlet oxygen environments (not discussed here). This property
16
may help reduce oxidative stress caused by retinol when combined
14 with bakuchiol and used at concentrations higher than the physio-
12 logical limit [54].
10 This open clinical pilot study needs further confirmation of bak-
8 uchiol bioactivity in vivo, from vehicle- or benchmark-controlled
6 studies. The similarity of gene expression and protein synthesis
4 stimulation observed in the comparison of bakuchiol with retinol
2 is, however, remarkable and suggests that similar bioactivity in vivo
0 is probable. Taken together, this study demonstrates the potential
Base 4 weeks 8 weeks 12 weeks of bakuchiol, a true retinol-like functional compound, to become a
key ingredient for dermatological and skin care products.
Figure 5 (A) Subject no. M572; Right view; Pre application. (B) Subject no.
M572; Right view; 12-week treatment. (C) Change in wrinkle depth in lm.
Acknowledgements
2%, 10% and 21% reduction in skin roughness (Ra), respec- The authors would like to thank Sytheon Ltd for funding this
tively. The results at 8 and 12 weeks are statistically significant research and to Stephanie Ma for her dedicated assistance in this
(P ≤ 0.004). project.

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