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Journal of Cosmetic and Laser Therapy

ISSN: 1476-4172 (Print) 1476-4180 (Online) Journal homepage: http://www.tandfonline.com/loi/ijcl20

Skin hyperpigmentation treatment using herbs: A


review of clinical evidences

Mayuree Kanlayavattanakul & Nattaya Lourith

To cite this article: Mayuree Kanlayavattanakul & Nattaya Lourith (2017): Skin hyperpigmentation
treatment using herbs: A review of clinical evidences, Journal of Cosmetic and Laser Therapy, DOI:
10.1080/14764172.2017.1368666

To link to this article: http://dx.doi.org/10.1080/14764172.2017.1368666

Accepted author version posted online: 30


Aug 2017.

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Download by: [University of Connecticut] Date: 31 August 2017, At: 11:37


Journal Title: Journal of Cosmetic and Laser Therapy

Skin hyperpigmentation treatment using herbs: A review of

clinical evidences

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MAYUREE KANLAYAVATTANAKUL1,2 & NATTAYA LOURITH1,2

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1
School of Cosmetic Science, Mae Fah Luang University, Chiang Rai, 57100 Thailand

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2
Phytocosmetics and Cosmeceuticals Research Group, Mae Fah Luang University, Chiang
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Rai 57100, Thailand
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Correspondence: Nattaya Lourith, School of Cosmetic Science, Mae Fah Luang University,
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Chiang Rai, 57100, Thailand.

Tel.: +66 53 916834; fax: +66 53 916831.


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E-mail address: nattayal@mfu.ac.th


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Received: 2016-11-10
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Accepted: 2017-08-14
Abstract

Hyperpigmentation of skin is caused by several factors. UV exposure, in addition to oxidative

stress elevates inflammatory mediators stimulating melanogenesis. Herbal derived

compounds for improving skin lightness are gaining interest as they are perceived to be

milder, safer and healthier than fully synthetic products. This review briefly addresses the

causes of skin hyperpigmentation and extensively summarizes the status of herbs currently

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used in skin lightening cosmetics. The properties of active compounds and their dose rate

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information is summarized where available, along with human or anamial relevant models for
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activity testing. This review will be of value to cosmetic formulators and dermatologists who

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are searching for naturally-derived ingredients for improving skin lightness, in line with
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consumer preference and expectations.
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Key Words: cosmeceutical, topical agents, hyperpigmentation, herbal cosmetics


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Introduction
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Radical and inflammatory mediators are several factors which show accumulation during the

hyperpigmentation of skin; the generating and inhibiting mechanisms relating to


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melanogenesis are the subject of reviews elsewhere (1).

UV radiation stimulates keratinocytes to secrete -melanocyte stimulating hormone (-

MSH), a small peptide hormone derived from propiomelanocortin (POMC). -MSH binds to

melanocortin 1 receptors (MC1R) expressed on the surface of melanocytes, inducing

melanogenesis via multiple signaling pathways resulting from cAMP, protein kinase A
(PKA), cAMP response element-binding protein (CREB) and microphthalmia-associated

transcription factor (MITF) activity. MITF is a key transcription factor regulating

transcription of melanogenic enzymes such as tyrosinase, tyrosinase-related protein-1 (TRP-

1) and tyrosinase-related protein-2 (TRP-2). Because tyrosinase can be endogenously

degraded by proteasomes maintaining an ideal balance between tyrosinase synthesis and

degradation is necessary for the regulation of skin, hair and eye pigmentation.

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Mitogen-activated protein kinases (MAPKs) are composed of 3 subtypes: stress-activated

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protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNK), p38, and extracellular signal-
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regulated kinases (ERK). JNK and p38 kinases are stimulated by pro-inflammatory cytokines

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and environmentally-induced stresses such as exposure to UV irradiation, heat, and hydrogen
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peroxide, resulting in DNA damage. Melanogenesis is controlled by MAPKs, with MITF

being activated by p38 phosphorylation. In contrast, ERK activation inhibits melanin


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synthesis by downregulating MITF expression. Thus, suppression of the ERK signaling

pathway induces cell differentiation and upregulation of tyrosinase activity, stimulating


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melanogenesis. In addition, the MAPK signaling pathway modulates nuclear factor E2-

related factor 2 (Nrf2), which is an important transcription factor controlling the antioxidant
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response to protect skin cells against oxidative stress, such as that occurring on exposure of
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melanocytes to UV radiation (2). A summary of melanogenesis pathways is depicted in

Figure 1.
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Clinical evaluations of skin ligtening agent conducted in animal models in concert with

histological studies are of paramount importance for identification of effective candidates.

Eventual examination in human subjects is necessary to gauge safety and efficacy of such

products, with instrumental observation being accepted as the gold standard assessment

protocol (3). In this context, herbal-derived skin lightening agents occur extensively in the list

of certified safe and efficient ingredients usable in cosmetic products. Biological activity
assessment techniques and methods are beyond the scope of this review, which is restricted to

a summary of active compounds in the literature, dose information as available, and the

relevant human or anamial models utilized in testing. The scientific names of currently used,

and candidate herbs, are listed alphabetically.

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Active ingredients for skin hyperpigmentation treatment

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Skin lightening agents, of which phenolics are the most widely used, can be employed in a
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formulation as either a single compound, or a combination of actives. The application of

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herbal extracts containing several actives acting synergistically to improve the efficacy is also
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encountered in cosmetic formulations, with such actives proving highly desirable candidates

(4-6). Commonly used agents are hydroquinone, vitamin C or ascorbic acid, arbutin, and
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kojic acid and derivatives thereof. Mulberry, artocarpus and orchid extracts are also used

(7,8) in cosmetic formulations. Hydroquinone was one of the most commonly used agents for
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treatment of skin hyperpigmentation, although due to its adverse effects (including toxicity

and mutagenicity) it is now banned from use in many countries. It inhibits the conversion of
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3,4-dehydroxyphenylalanine (DOPA) to melanin by tyrosinase inhibition, and also RNA and


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DNA synthesis in melanocytic cells, and is responsible for melanosome degradation. In some

cases, prescription treatments using hydroquinone are still available (containing between 2-
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10% active agent) although in light of its deleterious effects consumer interest is shifting to

safer, naturally derived actives (10).

A range of vitamins have been shown to exhibit skin lightening effects, with derivatives

of these having enhanced stabilities, efficacies and allowing for more facile dermal

penetration. Melanin production is inhibited by vitamin C via reduction of the ortho-quinone,

with its antioxidant activity triggering melanogenesis (10). Furthermore, vitamin C is able to
reduce the oxidized form of melanin, resulting in skin brightening. Vitamin B3 in the amide

form (niacinamide) is able to inhibit melanosome transfer from the melanocytes to the

epidermal keratinocytes. Accordingly, increased skin lightness was observed in human

subjects following application of 5% niacinamide over a 4 week period (11).

Arbutin (hydroquinone-O--D-glucopyranoside) and its phenolic derivatives (eg

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monobenzyl ether) are generally used as lightening agents in cosmetics. Kojic acid (5-

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hydroxy-2-(hydroxymethyl)-H-pyran-4-one) is a fungal metabolite which acts to inhibit the

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catecholate activity of tyrosinase through copper chelation. Furthermore, it prevents the
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cascade conversion process of O-quinone to DL-DOPA, and subsequently to dopamine and

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its corresponding melanin. Azelaic acid is a naturally metabolized dicarboxylic acid derived
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from Pityrosporum ovale. This compound inhibits tyrosinase activity and interferes with

mitochondrial oxidoreductase activity. It does not effect on abnormal melanocytes.


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In addition to the commonly used or known skin lightening agents discussed above (9),

several other phenolics are emerging as potential actives for skin lightness formulations.
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Gallic acid is non-cytotoxic to B16F10 melanoma cells at concentrations ranging from 12.5

100 M, and exhibits significant IC50 values against melanin production and tyrosinase
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activity (18.3 and 24.8 M, respectively). Downregulation of tyrosinase, TRP-1 and MITF
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expression results from activation of the ERK and AKT-GSK3 signaling pathways. A
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reduction in protein kinase A phosphorylation followed by the suppression of cAMP and

MC1R in a dose-dependent manner results in prevention of nuclear translocation of CREB,

and subsequently reduced CREB phosphorylation levels. Studies in zebrafish indicated that

exposure to gallic acid concentrations of 25 and 50 M resulted in decreased body

pigmentation (56 11 and 41 6%, respectively). Topical application of gallic acid to UVB-

hyperpigmented mice twice daily for four weeks resulted in skin whitening effects
comparable to those obtained for 50 M kojic acid. Moreover, an examination of the skin

turnover rate following UVB-induced inflammation revealed significant increases in skin

thickness (23.8 4.5 pixels) over those of the control (14.03 1.36 pixels) (12).

Resorcinol derivatives are also gaining interest as lightening agents. 4-Butylresorcinol is a

potent human tyrosinase inhibitor with an IC50 of 21 M, whereas its derivatives 4-

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hexylresorcinol and 4-phenylethylresorcinol are less effective (IC50 94 and 131 M).

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Comparative studies revealed its higher potency over kojic acid, hydroquinone and arbutin

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(IC50 500, 4400 and 6500 M). Further assessment in relation to melanin production in
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MelanoDermTM revealed the IC50 value to be 13.5 M. A randomized, single-blind clinical

study conducted in 14 female volunteers involved application of 0.3% 4-butylresorcinol,


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0.3% 4-hexylresorcinol and 0.5% 4-phenylethylresorcinol twice daily over a 12 week period.

The skin lightening efficacy as monitored by Spectropen and Epi-Flash indicated that 4-
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Butylresorcinol significantly (p < 0.05) improved skin lightness after 8 weeks. Thereafter,

more concentrated (1%) 4-butylresorcinol was clinically evaluated in 15 women;


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enhancements in skin lightening were noticeable by the end of the treatment period (16
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weeks) and were judged to be significant after 4 weeks (13).

Resveratrol has been shown to significantly decrease melanin production in B16F10


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melanomas and be non-cytotoxic, even at 100 M concentration. This phenolic suppresses


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the expression of -MSH induced tyrosinase, TRP-1 and TRP-2 including MITF. Its skin

lightening efficacy has been confirmed in animal models (guinea pigs) showing UVB-

induced pigmentation, where topical application of 1% resveratrol solution (200 l) for 2

weeks resulted in clear reductions in skin dullness. The lightening efficacy was confirmed by

assessment of the reduction of pigment index using the Dermalab combo system, with these
results being in accordance with histological studies highlighting decreased melanin

production on resveratrol treatment (14).

4-Hexyl-1,3-phenylenediol was assessed in regards to UV-induced melanogenesis in

primary human melanocytes and B16F10 melanoma cells, and was shown to suppress

melanin production (IC50 0.55 0.1 and 0.47 0.13 g/ml, respectively) with anti-tyrosinase

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activity (IC50 4.25 1.06 and 11.64 2.89 g/ml, respectively). In a randomized, double-

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blind placebo-control study, 65 female volunteers were directed to apply an assigned

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emulsion to their faces twice daily for 12 weeks. Evaluation of the results using a colorimeter
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(Konica Minolta CM-2600d) indicated that overall skin lightening was significantly

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improved, although the active incorporated into the vehicle was not mentioned (15).
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The skin lightening efficacy of resveratryl triacetate, a more stable derivative of

resveratrol, was clinically assessed in humans. Preliminary skin irritation tests of 0.1 and
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0.5% resveratyl triacetate in 33 female volunteers were shown to be negative. A further

cohort (22 female volunteers) was UV-tanned on the forearm using a solar stimulator
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equipped with a xenon arc lamp and filters (LS1000), prior to a topical study. Following an 8
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week randomized, single-blinded placebo control (involving twice daily application of 0.4%

resveratyl triacetate and control product), resveratyl triacetate resulted in significantly (p <
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0.001) improved skin lightness following 2 weeks of application with enhanced efficacy on

trial completion. Thereafter, the efficacy of facial applications of resveratyl triacetate was
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evaluated in 21 female volunteers using the same directions as per forearm testing, using

VISIA and Image-Pro. The skin lightening efficacy was confirmed by significant reduction

in hyperpigmentation spots after 4 weeks, and further improvements were evident by the end

of the trial (16).


Bisabolol, or 6-methyl-2-(4-methylcyclohex-3-en-1-yl)hept-5-en-2-ol, inhibits

melanogenesis by blocking the cAMP signaling pathway, thus reducing -MSH-induced

cAMP production and leading to inhibition of CREB phosphorylation. Furthermore, bisabolol

inhibits the production of MITF and TRP-1 (but not TRP-2), and promotes tyrosinase

downregulation as observed in B16 melanoma cells (17). Clinical evaluation of 0.5%

bisabolol cream was undertaken in 28 female Korean volunteers having skin pigmentation on

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their backs induced by a solar stimulator. Daily application of active (or placebo base cream)

for 8 weeks allowed for comparison, with skin lightness being monitored using a Konica

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Minolta CM2600d. The lightening efficacy of bisabolol cream was significantly enhanced

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over that of the base cream after 4 weeks (L = 1.81 1.3, p < 0.05), with clear

improvements in efficacy being evident by the end of the study (L = 2.24 1.2) (18).
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Fatty acids are also promising actives for the treatment of pigmented skin. Oleic acid
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(C18:1), linoleic acid (C18:2) and linolenic acid (C18:3) were shown to decrease levels of

melanin synthesis and tyrosinase activity, in contrast to palmitic acid (C16:0) and stearic acid
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(18:0). The melanin content in B16 melanoma cells was decreased to 62.4, 28.0 and 16.4% of

initial levels on treatment with 25 M oleic, linoleic or linolenic acids, respectively.


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Tyrosinase activity was also significantly suppressed (to 87.0, 31.9 and 19.5% of initial
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levels, respectively). Guinea pigs exhibiting UVB-induced hyperpigmentation were topically

applied with oleic, linoleic and linolenic acids (0.5% in EtOH, 0.01 ml/cm2) daily for 3
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weeks. A visible reduction in pigmentation was noticed after 2 weeks, with linoleic acid

treatment giving lighter skin tone than linolenic acid. Linoleic acid treatment resulted in

almost complete pigment removal affording near original skin coloration, with visual

assessment being consistent with the L* determined using a chromameter (Konica Minolta

CR-200). Skin biopsies indicated that numbers of melanocytes in untreated skin, pigmented

control and the linoleic acid treated areas were 253.1, 785.2 and 694.4/mm2. Furthermore,
linoleic and linolenic acids were found to accelerate the turnover of pigmented stratum

corneum cells (19).

Linoleic and palmitic acids were shown to have differing effects on melanogenesis in

B16F10 melanoma cells relative to the control, with linoleic acid promoting decreased levels

of cellular melanin (30%), while palmitic acid enhanced melanogenesis (150%) in a time-

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dependent manner. These activities are regulated by tyrosinase activity: linoleic acid

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suppressed 50% of the enzymatic activity, whereas palmitic acid promotes overexpression (to

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190%). However, TRP-1 and TRP-2 activities were not affected, suggesting that these actives
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should play a role in post-transcriptional events in the melanogenic enzymes. The cellular

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mechanism further revealed that the presence of linoleic acid decreases the amount of
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tyrosinase to 30% of initial levels, whereas palmitic acid results in a marked increase (to

130% of initial). Radio-labeling assays indicated that linoleic acid dramatically accelerates
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the proteolytic degradation of tyrosinase, in comparison to palmitic acid (20). Linoleic acid

effectively modulates the proteosomal degradation of tyrosinase via the selective degradation
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of a melanogenic enzyme through the ubiquitin-proteasome pathway (21).

A summary of the actives discussed above, their activities and other characteristics and
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properties are given in Table I.


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Plants for skin hyperpigmentation treatment

Treating aesthetically displeasing skin disorders using naturally-derived actives including

herbal extracts is gaining interest amongst consumers due to their perception of safety (4-6).

In this context herbs currently used and those having potential in skin lightening formulations

with clinical efficacies are discussed below.


Tea (Camellia sinensis) extract, specifically of black tea, was investigated for its skin

brightening potential. The tea leaves were boiled in water and after freeze drying the extract

was analyzed in terms of total phenolic and flavonoid content (104 and 91 mg/g,

respectively). Skin lightening efficacy of black tea extracts was assessed in guinea pigs

hyperpigmented by UVB irradiation (once weekly for 3 consecutive weeks). Ten days after

the last UVB exposure, the animals back was applied with 1, and 2% black tea extract (in

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addition to 2% hydroquinone for comparison), with continued application twice daily for 4

weeks. Levels of depigmentation were tracked as a measure of melanin index using a

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Mexameter, and results indicated that hydroquinone and black tea extracts were comparable

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(17 and 15% reduction) but significantly (p < 0.001) improved over untreated (control) skin.

Histological studies confirmed the efficacy of the topical actives, with hydroquinone and
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black tea extracts significantly (p < 0.001) lowering pigment levels to 8.7 1.4, 13.2 1.5
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and 10.3 1.7%, respectively, in accordance with immunohistochemical staining results (3.7

0.5, 7.8 0.7 and 5.2 1.2%, respectively) (22). Catechins, especially (-)-epigallocatechin-
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3-gallate (EGCG) are the key actives present in tea extracts. EGCG proved safe to Mel-Ab

cells up to a concentration of 10 M. Cellular melanin production was found to be


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significantly suppressed at low EGCG concentrations (1 M), with activity being dose-
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dependent. Moreover, the presence of EGCG also coincided with reduced MITF levels (23).

The 70% MeOH extract of Cassia fistula (golden shower tree) pods show a tyrosinase
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inhibitory effect (IC50 39.2 g/ml), and this extract could be formulated as a 5% oil in water

preparation. This formulation was able to inhibit tyrosinase (64.0 0.01%), without causing

skin irritation. A single blind, randomized placebo-controlled clinical evaluation was

undertaken in 17 human volunteers, involving twice daily facial (cheek) application of 500

mg of the product for 12 consecutive weeks. Noticeable (p < 0.0001) skin lightening as
examined using a Mexameter was observed following the first week (7.0%) with clear

improvements evident on study completion (13.0%) (24).

Rengyolone, as purified from Eurya emarginata root percolation with MeOH and

chromatography, was shown to potently inhibit melanin synthesis in melan-a cells. The active

was non-cytotoxic (LD50 >200 M) and suppressed cellular melanogenesis with an IC50 of 65

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2.5 M, significantly lower than arbutin or kojic acid (IC50 126 4.1, > 200 M).

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Moreover, zebrafish body pigmentation is effectively inhibited on exposure to 32.5 M

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rengyolone (25).
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The ethanolic extract of Gaillardia aristata flowers contains phenolics and shows

antioxidant activity as examined by DPPH (IC50 74.98 0.48 g/ml) and ABTS (IC50 110.79
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3.99 g/ml) assays, although is non-cytotoxic and suppresses cellular melanin production
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by anti-tyrosinase activity in human melanocytes (5, 10 g/ml). This activity is in accordance

with that in B16F10 melanoma cells, confirming its activity against tyrosinase, TRP-1 and
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MITF. Examination of the extract in human epidermal equivalents (human skin model)

indicated that its depigmenting activity (200 g/ml) was comparable to 2% kojic acid with no
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indication of skin irritation in 30 female volunteers (26).


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Licorice (Glycyrrhiza glabra) is widely employed for treatment of skin dullness, with its

activity due to the presence of glabridin (27). Glabridin is a more potent tyrosinase inhibitor
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(IC50 2.3 M) than kojic acid (IC50 43.7 M) (28) with additional inhibitory action in B16

melanoma cells and animal models (guinea pig) (29). In addition to glabridin, liquiritin

isolated from licorice is also efficient at reducing dark spots on skin, as examined in human

volunteers (30).
The extract from sea buckthorn (Hippophae rhamnoides) berries macerated in 70% MeOH

showed inhibitory effects against mushroom tyrosinase (IC50 45.9 g/ml). After further

incorporation into an oil in water emulsion (5% v/v) the emulsion was diluted (1.5 g in 50%

MeOH; 1:10) and the inhibitory activity assessed to be 58.6 0.4%. Clinical testing in 19

human volunteers indicated no skin irritation, therefore a single blind, randomized placebo-

controlled assessment of melanin content reduction was undertaken involving twice daily

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facial application of the formulation (500 mg) over a period of 12 weeks. Reductions in

melanin content (as monitored by Mexameter) were evident after the first week (3.5%) and

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were significantly better than the baseline (16.35%, p < 0.0001) at the conclusion of the study

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period (24). an
High levels of mushroom tyrosinase inhibition (89%) were observed in 1 mg/ml

hydroxyphenethyl alcohol, obtained from hot aqueous extraction and solvent partitioning of
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Hizikia fusiformis plant material. Cellular activities in B16F10 mouse melanoma cells

indicated no cytotoxicity over a concentration range of 1-100 g/ml with suppression of


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melanin production being similar to arbutin within this concentration range. Thereafter,

clinical evaluation was undertaken in male brown guinea pigs whose dorsal skin had been
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exposed to UVB. Treatment with 2% herbal extract was done twice daily for 60 days (with
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arbutin as comparison), with evaluation using a chromameter (Konica Minolta CR-300)

every 2 weeks. Skin lightness was significantly (p < 0.05) improved after 2 weeks of
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treatment, with the herbal active being comparable to arbutin. Visible improvement was

apparent after 8 weeks (31).

Percolation of ethanol through Lonicera japonica gave a crude extract that was further

partitioned with EtOAc and chromatographed to afford sweroside. This compound is non-

cytotoxic to melan-a cells at concentrations lower than 300 M, at which it significantly (p <
0.01) suppresses cellular melanin production by means of tyrosinase, TRP-1 and TRP-2

inhibitory effects. The cellular activity mechanism was elucidated as a consequence of

phospho-Akt being significantly enhanced, whereas phospho-ERK showed only a slight

increase. In addition, MITF was significantly reduced in a dose-dependent manner at tested

concentrations of 75, 150 and 300 M. Clinical evaluations in zebrafish highlighted that

numbers of embryo melanin spots decreased gradually with increasing concentration of

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active; more than 95% of zebrafish survived following treatment (32).

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Evening primrose (Oenothera biennis) saponified oil (12.5 g/ml) significantly inhibited
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melanin production in B16F10 melanoma cells. The bio-oil proved non-toxic at 100 g/ml,

with cells being viable with melanin content decreasing to 12.8 1.8% of initial levels. The
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mechanism of action was investigated with tyrosinase inhibition occurring at the

transcriptional level through decreased mRNA expression of TRP-1, TRP-2 and MITF. A
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trial in three healthy men having UVB-induced hyperpigmentation on their forearms showed

that visible reductions in skin pigmentation were observable after topical application of the
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oil twice daily for 2 months. Significant improvements was measurable after 1 month of

treatment (as quantified using a Mexameter), with no erythema being observed. Fatty acid
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components linoleic acid (65-75%), linolenic acid (7-10%) and oleic acid (9%) were deemed
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responsible for the skin lightening effects (33).


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Origanum vulgare (oregano) is a commonly known herb whose essential oil is believed to

show therapeutic benefits. Origanoside isolated from maceration of aerial portions of the

plant with EtOH, followed by partitioning with EtOAc prior to preparative HPLC proved

non-cytotoxic to human fibroblasts at a maximum dose of 100 g/ml. It was also non-

cytotoxic towards B16 melanoma cells and shown to inhibit cellular tyrosinase to levels of

16.9-28.6% at 10 and 20 g/ml, respectively, in comparison to control untreated cells,


although proved less active than arbutin or ascorbic acid. In addition, it was exhibited to

suppress MITF and TRP-2. Evaluations of origanoside clinical efficacy in C57BL/6J mice

after daily topical applications (0.1 g) for 10 days pinpointed improvements in skin lightness

in terms of L* (from colorimeter measurements). Immonohistochemistry confirmed the

results of non-invasive instrumental evaluations (34).

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Extracts of rice (Oryza sativa), one of the worlds important staples, have been widely

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used to treat skin disorders. Rice bran oil having a high content of essential fatty acids can be

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added to cosmetic remedies for hyperpigmentation. -Oryzanol, the key ingredient of rice
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bran oil, significantly inhibits cellular melanin production in B16F1 melanoma cells by 13

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and 28% at 3 and 30 M, respectively. Cellular tyrosinase activity was reduced in a dose-
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dependent manner on treatment with -oryzanol, although to a lesser degree than that

observed with arbutin. However, at 5 mM -oryzanol is non-cytotoxic to B16F1 cells, unlike


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arbutin. Further studies indicated that -oryzanol decreased melanogenesis enzyme activity

by 29 and 26% at 3 and 30 M in B16F1 melanoma cells, with the inhibitory effect against
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melanogenesis due to suppression of TRP-1, MITF, CREB, MC1R, cAMP and PKA activity

(35). In addition, rice phenolics such as p-coumaric acid, caffeic acid, ferulic acid and gallic
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acid are of importance in skin remedies (36,37). Rice panicles enriched with these phenolics
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inhibited mushroom tyrosinase and suppressed melanogenesis in B16F10 melanoma cells via

tyrosinase and TRP-2 inhibitory effects. Clinical evaluation of a skin lightening preparation
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containing the panicle extract in 24 volunteers was undertaken by means of a randomized,

double-blind, placebo-controlled study. Application of 0.1 and 0.2% rice panicle extract

creams twice daily for an extended period and monitoring (Mexameter) resulted in skin

lightness being significantly (p < 0.001) improved after 28 days, and more pronounced by the

end of the study (84 days). Both creams (0.1 and 0.2% extract) showed comparable effects
(38). Rice extracts rich in resveratrol (0.246 g/mg) suppressed tyrosinase expression in

melan-a cells to a greater extent than resveratrol and arbutin alone at the same concentration.

Skin lightening efficacy tests in guinea pigs presenting UVB-induced hyperpigmentation

revealed that resveratrol enriched rice exhibited greater lightening efficacy than arbutin and

resveratrol alone at the same applied concentration (1% in EtOH/propylene glycol; 3/7, 200

l) after 9 days consecutive treatment. This efficacy was confirmed by histological studies

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indicating significant decreases in melanin production via the suppression of tyrosinase,

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MITF and TRP-2 to levels of 54.6, 49.4 and 120.2% (39). Furthermore, rice callus enriched
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with resveratrol (1.8069 0.0021 g/g) was prepared in the form of nanoparticles (485.83

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6.717 nm, PDI = 0.31 0.01, -potential = -14.7 0.461 mV). The preparation (1% w/v) was
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topically applied onto the dorsal skin of UVB-irradiated guinea pigs once a day for 15 days.

Skin lightening efficacy as monitored by the Dermalab Combo system was observed to
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increase dramatically over time. Melanin content increased by 260% following UVB

exposure, but subsequently decreased by 160% following treatment at which time 1.519
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0.049 ng of resveratrol was determined in the animal skin. The mechanism of action was

proposed to relate to inhibition of trysosinase, TRP-1 and TRP-2 (40).


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Paeonol isolated from Moutan Cortex Radicis, the root cortex of Paeonia suffruticosa, is
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non-cytotoxic to B16F10 melanoma cells at concentrations of 100 M or lower. The active

significantly (p < 0.05) suppressed tyrosinase activity (22.2-30.9% at 500-1000 M),


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coinciding with a reduction in melanin content (27.4-37.2% at 100-1000 M). Topical

application of the active (3% w/w) to guinea pigs exhibiting UV-induced pigmentation once a

day for two consecutive weeks resulted in noticeably reduced melanin contents (41).

Ginseng (Panax ginseng) is a traditionally used therapeutic in Asian culture and has been

demonstrated to possess anti-melanogenic effects in B16 melanoma cells through tyrosinase


inhibition. Ginsenosides serve as the active constituents, having activities against -MSH and

cAMP. Another component, p-coumaric acid, shows anti-melanogenesis activity, with

lightening of UV-tanned human skin being noticeable following 8 weeks of topical

application (0.1% gensenoside F1) (42).

Extracts from the French maritime pine (Pinus pinaster) have long been used as traditional

t
medicines in Europe. Oligopin and Cosmythic (P. pinaster derived oligomeric

ip
proanthocyanins) containing 50 mg (or 17.9% pine bark extract) were subjected to a

cr
randomized, double-blind, placebo-control oral administration study to assess their skin
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lightening effects. Thirty five Thai female volunteers (age 46-70 years) each ingested 100 mg

of supplement per day for 56 days, with supplementation being found to significantly (p =
an
0.076 and 0.016) enhance skin lightness over this period as determined by L* and ITA

parameters (Konica Minolta CM700d) (43).


M

Pueraria tunbergiana was extracted with boiling water, or aqueous ethanol (various
ed

ratios) prior to partitioning with EtOAc. Bioassays indicated that the EtOAc, and crude 30

and 70% EtOH fractions significantly suppressed melanogenesis in B16F10 melanoma cells
pt

in a dose-dependent manner (5-100 g/ml) due to their anti-tyrosinase activity. Topical

application of cream containing 1 or 3 % of the EtOAc partition derived from 30% EtOH
ce

extraction to hairless mice previously exposed to UVB resulted in significantly superior skin
Ac

lightness over cream containing 1% kojic acid. The skin lightening efficacy was confirmed

by histochemical studies (44).

Ethanolic extracts of thyme (Thymus vulgaris) rich in rosmarinic acid were shown to

quench UVB-induced phosphorylation of ERK, p38, and JNK by 49.4, 63.1 and 81.9% as

examined in hairless mice subjected to UVB irradiation followed by application of 100 g/ml

thyme extract. As these pathways are relevant to melanogenesis measuring the degree of
inhibition allows for an appraisal of the extract skin lightening potential (45). Thus, further

study is needed to assess the potency of this traditional herb for use in cosmetic products.

Extraction of seeds of the Muscat Hamburg variety of blue-black table grape (Vitis

vinifera) using aqueous ethanol afforded a mother liquor rich in biologically active phenolics.

A water in oil emulsion containing 2% was applied in a randomized, single-blinded, placebo-

t
controlled clinical trial in 110 male volunteers, involving twice daily facial application of the

ip
product for 8 weeks. The melanin index showed significant (p < 0.05) reductions following 2

cr
weeks of treatment (relative to control), with lightening efficacy showing continuous
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improvements up to the end of the study (as assessed by Mexameter measurements) (46).

us
Sonication of corn (Zea may) bran in 80% EtOH followed by dichloromethane partitioning
an
and chromatography afforded an active principle rich in hydroxycinnamic acids. The active

principle suppressed melanin synthesis in B16F1 melamoma cells via MITF suppression.
M

Clinical assessment of extract (0.1%) infused cream was undertaken in 21 female volunteers

whose back was tanned by UV irradiation. Application of the product twice daily for 8
ed

consecutive weeks in a randomized, double-blind, placebo-controlled study indicated that the

extract skin lightening efficacy was significant over that of the control after 4 weeks (11%)
pt

and showed further improvements with time (15% after 6 weeks and 19% after 8 weeks) (47).
ce

Table II summarizes key properties and activities in relation to the botanical extracts and
Ac

actives described in this section.

Marine algae for skin hyperpigmentation treatment

Extracts from four other marine algae species (Schizymenia dubyi, Ecklonia cava, Sargassum

silquastrum and Endarachne binghamiae) were subjected to comparative mushroom

tyrosinase inhibitory screening. Extraction with water (1 g/ 100 ml) at 70C was shown to
give a more potent extract than extraction at 20C for the same time (24 h). Each extract from

the algae above exhibited inhibitory effects of greater than 50% at 0.1 mg/ml. Schizymenia

dubyi was the most potent inhibitor, followed by Ecklonia cava, Sargassum silquastrum and

Endarachne binghamiae (IC50 9.08, 18.00, 19.85 and 27.16 g/ml, respectively), as

compared to positive controls, kojic acid and arbutin (IC50 1.21 and 13.86 g/ml). E. cava and

S. silquastrum extracts were chosen for B16F10 cellular assays due to the natural abundance

t
ip
of the algae in the harvest area (Jeju Island, Korea). Their extract LD50 values (387 and 193

cr
g/ml) and cellular melanin production IC50 (58.65 and 72.68 g/ml) indicated lower potency
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than kojic acid or arbutin (IC50 36.65 and 37.36 g/ml, respectively). Studies in zebrafish

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showed that 48 and 50% of tyrosinase was inhibited by E. cava and S. silquastrum extracts
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(100 g/ml), which corresponded to 43 and 50% of melanin content, compared to the arbutin

control (57 and 61%, 20 mM) (48).


M
ed

Concluding remarks

This review summarizes herbal choices available for efficient treatment of


pt

hyperpigmentation, and those having potential for development. Appraisal of the anti-
ce

melanogenic activity of herbal extracts is a necessity, providing key information for cosmetic

formulators and dermatologists who are constantly searching for new, effective naturally-
Ac

derived skin lightness ingredients. In addition, consumer preferences and expectations are

shifting towards the use of herbal or natural skin lightening products, which are perceived as

being safer than synthetics. As herbal treatments are perceived to be milder, safer and

healthier, developing standardized, stable formulations of herbal products with proven

effectiveness is a key concern for the cosmetic industry (49).


Declaration of interest

The authors have none of conflict of interest to declare.

Acknowledgments

t
ip
Mae Fah Luang University is acknowledged regarding facility support during this manuscript

preparation.

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ed
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ce
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Figure 1. Mechaniism of melaanogenesis

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M
an
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ip
t
Table I. Active ingredients for skin hyperpigmentation treatment

Name Study Ref.


in vitro cell culture efficacy*
Hydroquinone tyrosinase melanosome degradation human 10
inhibitor
Vitamin C tyrosinase oxidized melanin reducing human 10
inhibitor
Vitamin B3 melanosomes transfer inhibition human 11
Arbutin tyrosinase human 11
inhibitor

t
Gallic acid tyrosinase, TRP-1, MITF, cAMP and CREB zebrafish, 12

ip
inhibitions and ERK activation in B16F10 mice
Resorcinol tyrosinase anti-melanogenesis in MelanoDerm RS 13
inhibitor

cr
-MSH, TRP-1, TRP-2 and MITF guinea 14
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suppression in B16F10 pig


4-Hexyl-1,3- anti-melanogenesis in human melanocytes RDP 15

us
phenylenediol and B16F10 by anti-tyrosinase
Resveratryl RSP 16
triacetate
bisabolol
an human 18
-MSH, cAMP, CREB, TRP-1 and MITF
suppression in B16
Oleic acid anti-melanogenesis by anti-tyrosinase in B16 guinea 19
and pigmented stratum corneum turnover pig
M
enhancement
Linoleic acid anti-melanogenesis by anti-tyrosinase in B16 guinea 19-
and pigmented stratum corneum turnover pig 21
ed

enhancement
Linolenic acid anti-melanogenesis by anti-tyrosinase in B16 guinea 19
and pigmented stratum corneum turnover pig
enhancement
pt

* RS: randomized single-blind, RDP: randomized double-blind and RSP: randomized single-
ce

blind placebo controlled clinical studies


Ac
Table II. Biological activity and potential of plants for skin hyperpigmentation treatment

Name Active Study Ref.


Scientific Common in vitro cell culture efficacy*
Camelia tea catechins anti- guinea pig 22,2
sinensis melanogenes 3
is in Mel-Ab
by MITF
suppression
Cassia gloden mushroo RSP 24
fistula shower m

t
tree tyrosinas

ip
e
Eurya renglyolone anti- zebrafish 25

cr
emarginat melanogenes
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a is in melan-a
Glycyrrhiz licorice glabridin, mushroo anti- anti-tyrosinase 27-

us
a glabra liquiritin m tyrosinase in in guinea pig, 30
tyrosinas B16 human
e
Hippophae sea mushroo RSP 24
an
rhamnoide buckthor m
s n tyrosinas
e
M
Hizikia mushroo anti- guinea pig 31
fusiformis m melanogenes
tyrosinas is in B16F10
e
ed

Lonicera sweroside anti- zebrafish 32


japonica melanogenes
is in melan-a
by
pt

tyrosinase,
TRP-1, TRP-
2 and MITF
ce

suppressions
with ERK
induction
Ac

Oenothera evening linoleic acid, anti- human 33


biennis primrose linolenic acid, melanogenes
oleic acid is in B16F10
by
tyrosinase,
TRP-1, TRP-
2 and MITF
suppression
Origanum origano origanoside inhibitory mouse 34
vulgare effects
against
tyrosinase,
MITF and
TRP-2 in
B16
Oryza rice -oryzanol, p- mushroo anti- animal model, 38-
sativa coumaric acid, m melanogenes RDP 40
caffeic acid, tyrosinas is in B16F1,
ferulic acid, e B16F10 and
gallic acid, melan-a by
resveratrol suppression
of tyrosinase,
TRP-1, TRP-

t
2, MITF,

ip
CREB,
MC1R,
cAMP and

cr
PKA
Downloaded by [University of Connecticut] at 11:37 31 August 2017

Paeonia paeonol anti- guinea pig 41

us
suffruticos melanogenes
a is in B16F10
Panax ginseng ginsenosides, p- anti- human 42
ginseng coumaric acid tyrosinase in
an
B16
Pinus French oligomeric RDP oral 43
pinaster maritime proanthocyanin administration
pine s
M
Pueraria kudzu anti- hairless mice 44
tunbergian melanogenes
a is in B16F10
ed

Thymus rosmarinic acid quench UVB- 45


vulgaris induced
phosphorylatio
n of ERK, p38
pt

and JNK in
hairless mice
Vitis blue- RSP 46
ce

vinifera black
table
grape
Ac

Zea may corn hydroxycinnam anti- RDP 47


ic acids melanogenes
is in B16F1
by MITF
suppression

* RS: randomized single-blind, RDP: randomized double-blind and RSP: randomized single-
blind placebo controlled clinical studies