This document provides an overview of cosmeceutical products and their classification. It discusses moisturizers including occlusive and humectant types. It also covers photoprotection agents, sunscreen agents, skin lightening agents, antioxidants, depigmentation agents, hydroxy acids, retinoids, peptides and growth factors - all of which are important active ingredients used in cosmeceuticals. The document serves as a student paper submitted for a pharmacognosy course providing details on the mechanisms and applications of various cosmeceutical agents.

1. Cosmeceuticals
SUBMITTED BY: DEEP DAS
ROLL NO: 11121EN007
CLASS: B.PHARM, PART II, SEMESTER V
DEPARTMENT OF PHARMACEUTICS
INDIAN INSTITUTE OF TECHNOLOGY (BHU)
COURSE: PHARMACOGNOSY II, PH-3102
COURSE INSTRUCTURE: A. N. SAHU
DATE: 29/10/2013

2. CONTENTS
A. Introduction ………………………….……..…2
B. Classification of cosmeceutical products……......3
1. Moisturizers…………………………………….5
1.1 Occlusive moisturizers…………………...6
1.2 Humectant moisturizers………………….7
2. Photoprotection……...…………………………7
2.1 Luffa cylindrica…….......................…….8
2.2 Portulaca oleracea……………….…...…9
2.3 Terminalia chebula............,.........……….9
2.4 Piper longum………………......………..9
2.5 Aloe Vera………………………...……10
2.6 Emblica officinalis…………………….10
2.7 Crocus sativus………………...……….10
2.8 Peumus boldus Molina……….….…….11
3. Sunscreen Agents…….…..……………,,,,....…11
3.1 Vitamins...…………...………………..12
3.2 Vitamin A…………………,,,….……..13
3.3 Vitamin E…………………….……….13
3.4 Vitamin C…………………...……...…14
4. Skin Lightening Agents…….………...…...…..14
4.1Ascorbic acid…………….……………15
4.2 Licorice extract………………...……..15
4.3 Alpha-lipoic acid…………….……….16
4.4 Kojic acid…………,…………...……..16
4.5 Aleosin………,……………...………..16
4.6 Arbutin……….……………………….16
4.7 Hydroquinone….……………....……..17
5. Antioxidants………………………….….…….17
5.1 Carotenoids……………,…………….18
5.2 Astaxanthin………....…………….…18
5.3 Lutein………………………………..18
5.4 Lycopene……...………,…...…….….18
5.5 Retinol………………,……………....19
5.6 Flavonoids…………………………..19
5.7 Soy…………………,….………...….20
5.8 Curcumin…………,…..….…………20
5.9 Silymarin…………,….......……..…..20
5.10 Pycnogenol………,...…………..….21
5.11 Ginkgo……………,……………….21
5.12 Green tea…………,,……………….22
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5.13 Pomegranate……….………….....22
6. Other antioxidants used in post
resurfacing……………...……………………...23
6.1 Aloevera………………………….23
6.2 Ubiquinone…………………….…23
7. Depigmentation agents……..…...……...…..24
7.1 Phenolic Compounds……………..24
7.2 B Nonphenolic Compounds……...25
7.2.1 Azelaic Acid…………………....25
7.2.2 Tretinoin……………………......26
7.2.3 L-ascorbic Acid………………...26
7.2.4 Kojic Acid……………………...26
7.2.5 Arbutin…………………...…….27
8. Hydroxy Acids………………………...….…27
8.1 α-Hydroxyacids…………..……..27
8.2 β-Hydroxyacids…………..……..28
8.3 Polyhydroxy acids..............……..28
8.4 Bionic acids………………..……29
9. Retinoids……………………….………….....29
9.1 Tretinoin……………….……….30
9.2 Retinol…………………..….…..31
9.3 Retinyl-palmitate…………….....31
9.4 Retinaldehyde……….………….31
9.6 Alitretinoin……………...….......31
9.7 Tazarotene………………….…..31
9.8 Adapalene………………...……32
10. Peptides………………………………….….32
10.1 Antimicrobial peptides………..32
10.2 Defensins……………………..33
10.3 Psoriasin………………….…..33
10.4 RNase 7……………..….....….34
10.5 Dermicidin 1L………………..34
11. Peptides involved in wound healing……....35
11.1 RGD Peptides………….…….35
11.2 Copper Peptides…………...…35
11.3 Interleukins (IL)………….…..36
12. Growth Factors…………………..………...36
13. Conclusion…………………………...….….37
14. References……..……………………….…..37

3. A. INTRODUCTION
Cosmeceuticals are cosmetic products with biologically active ingredients purporting to have medical or drug
like benefits. A cosmeceutical is an ingredient with medicinal properties that manifests beneficial topical
actions and provides protection against degenerative skin conditions. The word "Cosmeceuticals" was
popularized by Albert M. Kligman in the late 1970s. It encompasses cosmetic actives with therapeutic, disease
fighting, or healing properties, serving as a bridge between personal care products and pharmaceuticals. Like
cosmetics, cosmeceuticals are topically applied, but they contain ingredients that influence the biological
function of the skin.1 Cosmeceuticals improve appearance by delivering nutrients necessary for healthy skin.
Cosmeceuticals typically claim to improve skin tone, texture, and radiance, while reducing wrinkling.
Cosmeceuticals are the fastest‐growing segment of the natural personal care industry.
For cosmetic labels, no division between active ingredients and other ingredients is required; they are all listed
together. The most important botanicals pertaining to dermatologic uses such as cosmeceuticals include teas,
soy, pomegranate, date, grape seed, pycnogenol, horse chestnut, German chamomile, curcumin, comfrey,
allantoin, and aloe; only green and black tea, soy, pomegranate, and date have been studied to the extent that
clinical trials for the treatment of parameters of extrinsic aging have been published. Few botanical‐based
cosmeceuticals have uses that are supported by evidence‐based science. Chemoprevention by oral or topical
use of dietary or pharmacologic agents to inhibit or reverse the development of cancer is a possibility. Potential
cosmeceutical agents in this category include green tea, grape seed extract, vitamin E, and beta‐carotene.
Cosmeceuticals being cosmetic products having medicinal or drug‐like benefits are able to affect the biological
functioning of skin owing to type of functional ingredients they contain. There are skin‐care products that go
beyond coloring and adorning the skin.
These products improve the functioning/texture of the skin by encouraging collagen growth by combating
harmful effects of free radicals, thus maintaining keratin structure in good condition and making the skin
healthier. Most of the eminent multinational companies engaged in cosmetics productions have introduced a
wide range of products having therapeutic effects by addition of a single or more active drug like component
to enhance the efficacy of products which later on was found to be beneficiary for the required purpose.
These products have also mended some flaws associated with existing products leading consumers to
discontinue the use of that product due to allergic reactions or excessive skin drying. Many companies add
humectants like glycerin as a soothing agent which increases the skin moisture level and keeps it hydrated.
Commonly used substances included in cosmeceutical formulations are described as follows.

4. B. CLASSIFICATIONOF COSMECEUTICAL PRODUCTS
The cosmeceuticals are mainly divided into seven categories. In choosing an effective Cosmeceuticals
regimen it is critical to match patients and their problems with the appropriate products. Most patients have
multiple needs, and they should be matched with products that offer ingredients with multifunctional benefits.
CLASSIFICATION OF COSMECEUTICALS
Also It can be broadly classified into following categories according to their daily life uses.
SL. NO
CATEGORIES
1
Creams, emulsions, lotions, gels and oils for the skin (hands face, feet, etc.).
2
Face masks (with the exception of chemical peeling products).
3
Tinted bases (liquids, pastes, powders).
4
Make-up powders, after-bath powders, hygienic powders, etc.
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5. 5
Toilet soaps, deodorant soaps, etc.
6
Perfumes, toilet waters and eau de Cologne.
7
Bath and shower preparations (salts, foams, oils, gels, etc.).
8
Depilatories.
9
Deodorants and anti-perspirants.
10
Hair care products:

Hair tints and bleaches,

Products for waving, straightening and fixing,

Setting products,

Cleansing products (lotions, powders, shampoos),

Conditioning products (lotions, creams, oils),

Hair dressing products (lotions, lacquers, brilliantine).
11
Shaving products (creams, foams, lotions, etc.).
12
Products for making-up and removing make-up from the face and the eyes.
13
Products intended for application to the lips.
14
Products for care of the teeth and the mouth.
15
Products for nail care and make-up.
16
Products for external intimate hygiene.
17
Sunbathing products.
18
Products for tanning without sun.
19
Skin-whitening products.
20
Anti-wrinkle products.
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6. Mechanisms of current cosmeceutical agents. Alpha-hydroxyacid (AHA), post-inflammatory hyperpigmentation
(PIH), ultraviolet light (UV).
1. Moisturizers
The main cutaneous function of cosmeceuticals is to enhance the barrier
function of the skin following a resurfacing procedure. Enhancing the barrier
decreases stinging and burning from a sensory standpoint and improves the
look and feel of the skin. Moisturizers can smooth down desquamating
corneocytes and fill in the gaps between the renaming corneocytes to create the
impression of tactile smoothness. This effect is temporary, of course, until the
moisturizer is removed from the skin surface by wiping or cleansing. From a
functional standpoint. Moisturizers can create an optimal environment for
healing and rninirnize the appearance of lines of dehydration by decreasing transepidermal water loss. Trans
epidermal water loss increases when the brick-and-mortar organization of the protein -rich corneocytes held
together by intercellular lipids is damaged. A well-formulated cosmeceutical moisturizer can decrease the water
loss until healing occurs following a resurfacing procedure. There are two cosmeceutical ingredient categories
that can reduce transepidermal water loss post-resurfacing: occlusive and humectants. The most common method
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7. for reducing transepidermal water loss is the application of occlusive ingredients in combination with humectant
ingredients in a thin moisturizer film.
1.1 Occlusive moisturizers
Occlusive moisturizers contain oily substances that create a barrier to water evaporation. The most popular and
effective occlusive ingredient used following resurfacing is petrolatum. Petrolatum is effective because it blocks
99% of water loss from the skin surface. This remaining 1% transepidermal water loss is necessary 10 provide
the cellular message for barrier repair initiation following wounding. If the transepidermal water loss is
completely halted. The removal of the occlusion results in failure to repair the barrier. And water loss quickly
resumes at its pre-application level. Tubs the occlusion does not initiate barrier repair. Petrolatum does not
function as an impermeable barrier. Rather it permeates throughout the interstices of the stratum corneum
allowing barrier function to be re-established.
1.2 Humectant moisturizers
Another concept in rehydrating the stratum corneum is the use of humectants.
Humectants have been used in cosmetics for many years to increase shelf life
by preventing product evaporation and subsequent thickening due to variations
in temperature and humidity. Humectants are a necessary in a11oil-in-water
creams to maintain the required water content. Substances that function as
humectants include glycerin, honey, sodium lactate. urea. propylene glycol,
sorbitol, pyrrolidone carboxylic acid, gelatin, hyaluronic acid, vitarnins and
some proteins. Following resurfacing, the barrier has been injured, and water
must be drawn to the wounded skin to prevent desiccation, which slows healing. Desiccation of the facial skin
also leads to an undesirable sensation of pulling and drawing. Humectants attract water from the deeper epidermal
and dermal tissues to rehydrate the stratum corneum. This water is trapped by the occlusive moisturizing
ingredients in a thin film on top of the stratum comeum . Humectants mayalso allow the skin to feel smoother by
filling holes in the stratum eerneum through swelling. Therefore a good moisturizer should combine both
occlusive and humectant ingredients. There is no doubt that most anti-aging cosmeceuticals are primarily well
constructed moisturizers containing occlusive and humectant ingredients. Furthermore most of the claims
associated with cosmeceuticals are moisturizer claims. Keep in mind that the moisturizer is really the vehicle for
transporting the special ingredient to the skin surface but the vehicle may actually be the active ingredient in many
cosmeceutical formulations. Thus. cosmeceuticals can be used to aid healing and maintain an excellent result
following skin resurfacing.
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8. 2. Photoprotection
Many new developments have occurred in the photoprotection cosmeceutical market to increase both efficacy
and cosmetic acceptability. Higher sun protection factor (SPF) formulations are more popular as new sunscreen
combinations arise that provide better ultraviolet B (UVB) protection. New methods of increasing the longevity
of UVA photoprotectants provide better broad-spectrum protection. These advances have improved the ability of
sunscreens to prevent post-inflammatory hyperpigmentation following resurfacing.
Sunscreen filters can be classified into two major categoties. Chemical and physical. Chemical sunscreens also
known as organic filters, undergo a chemical transformation known as resonance delocalization to absorb UV
radiation and transform it to heat. This reaction occurs within the phenol ring, which contains an electron-releasing
group in the ortho and/or para position, and is irreversible, rendering the sunscreen inactive once it has absorbed
the UV radiation. Physical sunscreens, also known as inorganic filters, are usually ground particulates that reflect
or scatter UV radiation absorbing relatively little of the energy. For this reason they have longer activity on the
skin surface.
The most important protection following facial resurfacing is from UVA radiation which is directly responsible
for pigment production. Two important UVA filters include oxybenzone and avobenzone. Oxybenzone provides
weak UVA photoprotection below 320 nm. It is commonly combined with avobenzone. Avobenzone is also
chemically incompatible with other commonly used inorganic filters, such as zinc oxide and titanium dioxide.
Another important UVA photoprotection in facial resurfacing is ecarnsule, better known as Mexoryl". Mexoryl
(L'Oreal) was originally developed to stabilize avobenzone. It is used in combination with oxybenzone and
octocrylene to provide excellent proteetion from post-inflammatory hyperpigmentation following resurfacing. It
is available in two forms: Mexoryl SX and Mexoryl XL. Mexoryl SX is a water-soluble form that is suitable for
daywear sunscreen formulations.
The inorganic UVA/UVB filters titanium dioxide and zinc oxide are also important in preventing postinflammatory hyperpigmentation following resurfacing. Titanium dioxide is usually micronized to contain
particles of many sizes to provide optimal UV scattering abilities. Unfortunately, it leaves a white film on the skin
and is used mainly for beachwear sunscreens and not cosmeceuticals. Zinc oxide is usually available in a
microfine forrn, meaning it contains small particles of one size making it appropriate for day wear. A newly
introduced colorless zinc oxide with extrernely small particles is finding its way into many post-resurfacing
cosmeceuticals, but there is concern that the nanoparticles may enter the skin through appendageal structures
creating a permanent reservoir. The cosmeceutical industry has placed a voluntary hold on nanoparticle inorganic
filters and pigments until the penetration issues are better understood.
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9. Effect of ROS on skin
2.1 Luffa cylindrica
L. cylindrica (Linn) M. Roem. is a climber with a slender, slightly hairy stem
with little furrowing. The seeds of L. cylindrica contain oil in which the fatty
acids are stearic and linoleic acids - are unsaturated fatty acids. It has been
reported that naturally occurring unsaturated fatty acids and phenolic
compounds have free radical scavenging properties In a study by Yoganandam
et al , it was concluded that the fixed oil isolated from the seed kernels of the
plant not only scavenges off the free radicals but also inhibits generation of free
radicals.
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10. 2.2 Portulaca oleracea
Portulaca oleracea (Common Purslane; also known as Verdolaga, Pigweed,
Little Hogweed or Pusley) is an annual succulent in the family Portulacaceae,
which can reach 40 cm in height. It is found throughout India and the Middle
East, but is naturalized elsewhere, and in some regions, is considered an
invasive weed. The whole plant is considered antiphlogistic (takes the heat
out), a bactericide, antidiabetic, anaphrodisiac (opposite to aphrodisiac),
emollient, calmative, diuretic, and refreshing agent. Sanja et al has proved the
antioxidant activity of the methanol extract using methods such as DPPH free radical scavenging, reducing power
estimation by FeCl3, nitric oxide free radical scavenging superoxide scavenging activity. The extract has a
tendency to scavenge the free radicals involved in the ageing process and skin wrinkling and thus may provide
some photoprotective action rejuvenate the skin. The fresh gel, juice or formulated products have been used for
medical and cosmetic purposes and to enhance general health.
2.3 Terminalia chebula
Terminalia chebula, also called Harde, belongs to the family Combretaceae. It
is used commonly in many Ayurvedic preparations as laxative, diuretic and
cardiotonic, as well as in some health supplements. Its chemical constituents
include ascorbic acid, gallic acid and ellagic acid, which are well known to exert
free radical scavenging properties.
2.4 Piper longum
Piper longum L. belonging to the family Piperaceae, is commonly found in
Indonesia, India and the Phillipines. It consists of a spike of fruits forming a
structure about 4 cm long and 6 mm in diameter. The fruit (pepper) contains 1 2.5 % volatile oil, 5 – 95 % of crystalline alkaloid piperine and piperettine, and
a resin. Piperine extracted from this plant has been used as an ingredient in
Ayurvedic formulations because of its antioxidant potency both in vitro and in
vivo in mice. Piperine, due to this antioxidant property, is used topically in a
cream base to treat sunburn diseases.
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11. 2.5 Aloe Vera
The leaves of Aloe vera (A. barbadensis) (Fam. Liliaceace) are the source of aloe
vera gel. The gel does not include the sap of Aloe vera, which contains
anthraquinones. Aloe vera gel is widely used in cosmetics and toiletries for its
moisturizing and revitalizing action. The whole leaf of Aloe vera is known to aid
cellular repair as well as digestion, assimilation of foods, vitamins, minerals and
other vital nutrients to rejuvenate the skin. The fresh gel, juice or formulated
products have been used for medical and cosmetic purposes and to enhance
general health.
2.6 Emblica officinalis
Emblica officinalis Gaertn., commonly known as amla, is a rich dietary source
of vitamin C, minerals and amino acids. It also contains various phenolic
compounds. Amla extract is known to exhibit potent antioxidant properties and
to provide protection for human dermal fibroblasts against oxidative stress and
therefore, it is assumed to be useful for natural dermal care. Recently, it was
reported that amla extract has effect on human skin fibroblasts, especially
production of procollagen and matrix metalloproteinases (MMPs). The water
extract from dried amla powder contains 2 % ascorbic acid and 29.4 % polyphenols including gallic acid and
elaeocarpusin. Amla extract elevates the mitochondrial activity of human skin fibroblasts and promotes
production of procollagen. Therefore, due to its potential mitigative, therapeutic and cosmetic applications, amla
has been used for skin treatment since ancient times.
2.7 Crocus sativus
Saffron, the dried stigma of the plant Crocus sativus L, popularly used as a spice
and food colorant, has been used in traditional medicine for the treatment of
many diseases including tumors. The chemical constituents of saffron include
the colored carotenoids - crocin and crocetin - and the monoterpene aldehydes picrocrocin and saffranol. Salomi et al reported the anti-promoting and nonmutagenic activity of saffron extract. Lin et al showed that crocins can protect
from the adverse effects of hepatocarcinogenic compounds and that crocetin, the
deglycosylated crocin derivative, can inhibit intracellular nucleic acid synthesis. The anticarcinogenic effect of
the aqueous infusion of saffron, administered orally, using a two-stage skin carcinogenesis model in mice, has
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12. been evaluated; the protective role of saffron against carcinogenic exposure was attributed to its action on the
physiological detoxification processes and this proved that saffron can prevent chemically-induced skin
carcinogenesis in Swiss albino mice.
2.8 Peumus boldus Molina
Peumus boldus belonging to the family Monimiaceae (a tree whose leaves
have been traditionally employed in folk medicine) is now widely
recognized as an herbal remedy by a number of Pharmacopoeias. Its leaves
are rich in several aporphine-like alkaloids, among them, boldine, which is
the most abundant one. Research conducted during the early 1990s claimed
that boldine is one of the most potent natural antioxidants. Its
pharmacological actions, which arise from its antioxidant properties, includes cytoprotective, anti-tumor
promoting, antiinflammatory, anti-diabetic and antiatherogenic actions; it has also shown some actions which do
not seem to be associated with these activities, e.g., vasorelaxing, anti-trypanocidal, immuno- and neuromodulator, cholagogic and/or choleretic actions. Free radicals are known to participate in either the aetiology or
the development of most UV-induced skin lesions. Through the experiments conducted on boldine, it has been
proved that boldine has a UV light-filtering property relevant to a photoprotective action. In fact, Hidalgo et al
showed boldine to be photo-unstable when irradiated at wavelengths up to 300 nm and to display a photo-protector
effect against UV-B, both in vitro and in vivo in mice. Photo-protection was evidenced by the prevention of UVinduced increase in the skin temperature of rodents.
3. Sunscreen Agents
Use of sunscreen agents and limiting the exposure to sun prevents early wrinkling
and skin cancer. Sunscreen agents are used to prevent sunburns. There are two kinds
of sunscreen agents: chemical and physical. Chemical sunscreen agents protect the
skin from the sun by absorbing the ultraviolet (UV) and visible sun rays, while
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13. physical sunscreen agents reflect, scatter, absorb, or block the rays. Sunscreen agents often may comprise more
than one ingredient. For example, products may contain an ingredient that provides protection against the
ultraviolet A (UVA) sun rays and another ingredient that protects from the ultraviolet B (UVB) sun rays, which
are more likely to cause sunburns than the UVA sun rays. Ideally, coverage should include protection against
both UVA and UVB sun rays. The sun protection factor (SPF) that is present on the label of these products reflects
the minimum amount of UVB sunlight that is needed with that product to produce redness on sunscreen protected
skin as compared with unprotected skin. Sunscreen products with high SPFs provide more protection against the
sun. The following sunscreen agents have been recommended by the U.S. Department of Health:
Cycloform (isobutyl p‐amino benzoate)
• Propylene glycol p‐amino benzoate
• Monoglyceryl p‐amino benzoate
• Digalloyl trioleate
• Benzyl salicylate and benzyl cinnamate (2% each)
Besides these, chemical sunscreens mainly based on para‐amino benzoic acid, its deivatives, cinnamates, various
salicylates and benzophenones, dibenzoylmethanes, anthraline derivatives, octocrylene and homosalate are
frequently employed as sun blocking agents. Direct physical blockers include metal containing compounds such
as iron, zinc, titanium, and bismuth. Zinc oxide and titanium dioxide are highly reflective white powders, but
submicron zinc oxide or titaniumdioxide powder particles transmit visible light while retaining their UV blocking
properties, thus rendering the sun block invisible on the skin.
3.1 Vitamins
Exposure to the UV radiations accelerates the aging effect of the skin. The
progressive telomere shortening and finally its disruption by low‐grade oxidative
damage are related to the aging. Damage is initiated by the generation of reactive
oxygen species (free radicals). It is a progressive process whose consequences are
damage to DNA. The topical treatment of acne vulgaris with vitamin A, is very
well supported by evidence. Vitamin B3, commonly known as nicotinamide or
niacinamide, is available in cosmetic and cosmeceutical products and can be used
as a complementary agent for some types of acne, as well as aging skin. Activation of toll‐like receptors may also
be involved in the scarring process by activating the metalloproteinases the retinoids arem vitamin A derivatives
constituting the most effective comedolytic agents. They function by normalizing desquamation of the follicular
epithelium, preventing the formation of new microcomedo, and minimizing the formation of comedones and
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14. inflammatory lesions. Nicotinamide is useful as a complementary drug because of its mild anti‐inflammatory
activity and its possible action in the reduction of sebum production and improvement of the skin barrier.
3.2 Vitamin A
The human epidermis contains significant amounts of vitamin A (alltrans‐
retinol). It has been observed that both UVB and UVA can damage the
metabolism and transport of vitamin A. This may lead to vitamin A deficiency
in the skin.13 Small amounts of retinol in the body gets converted to all‐trans
retinoic acid also called tretinoin (active form) & rest of the retinol is converted
into retinyl ester (storage form). Topical retinoids have successfully been used
to treat acne. The efficacy of topical tretinoin in the treatment of photoaged and
intrinsically aged skin is sufficiently established. The effects are believed to be mediated through its binding to
the nuclear retinoid acid receptors. It induces type I and type III procollagen gene expression in human skin,
resulting in increased deposition of collagen fibrils in the dermis. The effects result in an improvement in the
clinical and histologic skin appearance. Tretinoin cream in the appropriated concentrations of 0.025%, 0.05%,
and 0.1%, as well as 0.1% isotretinoin and 0.1% tazarotene, frequently produce moderate to severe skin irritation.
Retinaldehyde (0.05%) is another useful topical agent for the treatment of photoaged skin. It has a lower frequency
of irritation but less efficacy than tretinoin.16 Photosenstivity is another problem to be dealt in case of tretinoin.
The useful concentration of topical retinol ranges from 0.3% to 1%. Most of the over‐the‐counter products
available usually contain lower levels of retinol (about 0.08% or less), compared with the concentration used in
the few clinical studies available. Vitamin A (retinol) is the prototype of all other retinoids and is necessary for
proper growth, bone development, and integrity of mucosal and epithelial surfaces. In vitamin A deficiency, the
eyes and the skin are severely affected. The conjunctiva and the cornea develop metaplasia and keratinization,
leading to night blindness. Vitamin A exists in three isomeric forms among which beta form found to be more
active than alpha & gamma isomer. Its deficiency may lead to dry rough skin. The advent of synthetic analogs of
vitamin A in the 1970s brought new interest into their biological activity, especially on the skin. Since then,
vitamin A and its derivatives have been useful in the treatment of many skin disorders, including ichthyosis, acne,
and psoriasis.
3.3 Vitamin E
The physiological function of vitamin E, if applied dermally is to contribute to the
antioxidant defense of the skin, because of its tendency to absorb UV light in the
solar spectrum region that is responsible for most of the harmful biologic effects of
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15. the sun18. Vitamin E blocks lipid peroxidation in cells & tissues & it is a good antioxidant. It helps to enhance
the performance of UV filters, softens skin & moisturizes within. Vitamin E is the body's major lipid‐soluble
antioxidant, if oxidized, vitamin E can be regenerated back to its reduced form by L‐ascorbic acid. Vitamin E as
alphatocopherol or tocopherol acetate is used in topical OTC (over‐the counter) products in concentration (1% ‐
5%). Alphatocopherol has been found to be beneficial in reducing minimal erythema and the number of epidermal
sunburn cells, which marks skin damage related to oxidative stress caused by UVB19. The effect of vitamin E
after sun exposure seems to have no benefit. Vitamin E can reduce UV‐induced erythema and edema when it is
applied before UV exposure. Topical application of vitamin E may increase stratum corneum hydration and
enhance water binding capacity. Alpha‐tocopherol also shows synergistic effect with vitamins A (retinol) and C
(ascorbic acid) in combined products, providing an appreciable photo protection and antioxidant action that
suggests a potential effect in the protection against photo aging and skin cancer. Nanoemulsions have been
formulated containing palm oil esters in water with vitamin E and are promising potential nanocosmeceuticals.
3.4 Vitamin C
The increase of vitamin C in skin concentration is limited even with huge oral
supplementation. Vitamin C has become a popular topically applied
cosmeceutical because topical application of Lascorbic acid is the only way to
further increase skin concentration. Free radical scavengers have grabbed the
attention of researchers on vitamin C. L‐ascorbic acid is the active form of
vitamin‐C, which was first used as cosmeceutical creams. Previous formulations
(L‐ascorbic acid) were very unstable due to the oxidation of the vitamin exposed to air. So to overcome this
problem, esterified derivatives of L‐ascorbic acid in topical formulations have been used to improve stability. The
most commonly used derivatives are ascorbyl‐ 6‐palmitate and magnesium ascorbyl phosphate. Skin‐lightening
effect has been observed by the demonstration of Magnesium ascorbyl phosphate.
4. Skin Lightening Agents
Hyperpigmentation is the changing of colour intensity of the skin to darker hue,
which is due to an increased amount of melanin in the epidermis, the dermis, or
both. This change can be due to 2 pathophysiologic processes: melanocytosis
(increased number of melanocytes) and melanosis (increased amount of melanin).
Skin lightening agents work best when melanosis or melanocytosis is confined to
the epidermis. Patients with Fitzpatrick skin types III have advantage over type‐
IV such as type I‐III benefit from local pigment lightening for the treatment of
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16. hormonally induced melasma and postinflammatory hyperpigmentation caused by acne and trauma, whereas
those with Fitzpatrick skin types IV and darker may also seek therapy for pigmentary changes that occur around
the eyes, in the intertriginous areas, following dermatitis, or with acne and trauma. Standard dermatologic agent
for skin lightening is hydroquinone but its safety is questionable, leading to the use of alternative agents such as
retinoids, mequinol, azelaic acid, arbutin, kojic acid, aleosin, licorice extract, ascorbic acid, soy proteins, and N ‐
acetyl glucosamine.
4.1Ascorbic acid
Ascorbic acid, also known as vita min C, is used in cosmeceuticals for the
treatment and prevention of hyperpigmentation because it interrupts
melanogenesis by interacting with copper ions to reduce dopaquinone and block
dihydrochinindol-2-carboxyl acid oxidation. Ascorbic acid, an antioxidant, is
rapidly oxidized when exposed to air, with limited stability. For this reason. Many
cosmeceuticals are using the more stable magnesium ascorbyl phosphate. Which
is metabolized to ascorbic acid in the skin. High concentrations of ascorbic acid
must be used with caution, however, as the low pH can be irritating to the skin.
Pigment-lightening cosmeceuticals may contain ascorbic acid as a pH adjustor or
to function as an antioxidant preservative. It is important to recognize that
ascorbic acid is a multifunctional ingredient with very minimal pigmentlightening capabilities.
4.2 Licorice extract
Licorice extracts are found in cosmeceuticals to decrease facial redness and reduce
pigmentation. The extract contains liquiritin and isoliquertin. Which are glycosides
containing flavonoids, which induce skin lightening by dispersing melanin. To see
clinical results. The liquiritin must be applied in the dose of 1 g per day for 4 weeks.
Irritation is not a side effect, as is so frequently observed with hydroquinone and
ascorbic acid, but efficacy is Minimal.
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17. 4.3 Alpha-lipoic acid
Alpha-lipoic acid is found in a variety of anti-aging cosmeceuticals ramfunction as an
antioxidant, but it mayalso have very lirnited pigmentlightening properties. It is a
disulfide derivative of octanoic acid that is able to inhibit tyrosinase. However, it is a
large molecule and cutaneous penetration to the level of the melanocyte is
challenging, significantly reducing its efficacy.
4.4 Kojic acid
Kojic acid, chemically known as 5-hydroxymethyl-4H-pyrane-4-one, is one of the
most popular cosmeceutical skin-lightening agents found in cosmetic-counter skinlightening creams distributed worldwide. It is a hydroph.ilic fungal derivative
obtained from Aspergillus and Penicillium species. It is the agent most commonly
employed in vast Asia for the treatment of melasma, but it is highly unstable. Newer
formulations have incorporated kojic dipalmitate but the efficacy of this derivative
has not been well studied. Some research indicates that kojic acid is equivalent to hydroquinone in pigmentlightening ability. The activity of kojic acid is attributed to its ability to prevent tyrosinase activity by binding to
copper.
4.5 Aleosin
Aleosin is a low-molecular-weight glycoprotein obtained from the aloe vera plant. It is a natural
hydroxymethylchromone functioning to inhibit tyrosinase by competitive inhibition at the DOPA oxidation site.
In contrast to hydroquinone, it shows no cell cytotoxicity, but it has limited ability to penetrate the skin due to its
hydrophilic nature. The effects of aleosin have been largely demonstrated in pigmented skin equivalents. Not
human-use studies. It is sometimes mixed with arbutin to enhance its
Skin-lightening abilities.
4.6 Arbutin
Arbutin. Chemically known as 4-hydroxyphenyl-beta-glucopyranoside, is
obtained from the leaves of the Vaccinium vitis-idaea and other related plants. It
is a naturally occurring gluconopyranoside that causes decreased tyrosinase
activity without affecting messenger RNA expression. It also inhibits melanosome
maturation. Arbutin is not toxic to melanocytes and is used in a variety of pigmentlightening preparations in Japan at concentrations of 3%. Higher concentrations
14 | P a g e

18. are more efficacious than Jower concenrrauons, but a paradoxical pigment darkening may occur. Arbutin-betaglycosides have been produced that are less cytotoxic than arbutin.
4.7 Hydroquinone
The gold standard for the treatment of hyperpigmentation in the USA remains
hydroquinone. This substance is actually quite centroversial having been removed
from the aTC markets in Europe and Asia. Concern arose because oral
hydroquinone has been reported to cause cancer in mice fed large amounts of the
substance. While oral consumption probably is not related to topical application.
Hydroquinone remains controversial because, it is toxic to melanocytes. Hydroquinone, a phenolic compound
chemically known as lA-dihydroxybenzene, functions by inhibiting the enzymatic oxidation of tyrosine and
phenol oxidases. It covalently binds to histidine or interacts with copper at the active site of tyrosinase. It also
inhibits RNA and DNA synthesis and may alter melanosome formation. Thus selectively damaging melanocytes.
These activities suppress the melanocyte metabolic processes. Inducing gradual decrease of melanin pigment
production. Hydroquinone is still the best option for lightening post-inflammatory hyperpigmentation following
resurfacing.
5. Antioxidants
Antioxidants form one of the most popular categories of cosmeceutical ingredients. This is due tGthe fact that the
major cause of cutaneous aging is oxidation of skin structures from highly reactive oxygen molecules present in
our oxygen-rich environment. It is amazing tG think that the life-giving oxygen required to survive is also the
same oxygen responsible for aging the human body. The primary souree of cosmeceutical antioxidant ingredients
is botanical extracts, since all plants must protect themselves from oxidation following UV exposure. Antioxidant
botanieals function by quenching singlet oxygen and reactive oxygen species, such as superoxide anions.
hydroxyl radicals fatty peroxy radicals and hydroperoxides. There are many botanical antioxidants available. Both
from raw-material suppliers and from the cosmeceutical industry and they can be classified in three categones,
Carotenoids, flavonoids and polyphenols. Carotenoids are chemically related to retinoids, while flavonoids
possess a polyphenolic structure that accounts for their antioxidant, UVprotectant, and metal chelation abilities.
Lastly, polyphenols represent a chemical subset of flavonoids. Antioxidants are found in many skin lines for use
following resurfacing procedures. They are typically placed in moisturizing vehicles that may aid in healing
through the prevention of transepidermal water loss. Whether Cosmeceuticals the antioxidant formulation extends
the effect of a resurfacing procedure has never been documented, yet their frequent use demands a thorough
understanding of their function.
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19. 5.1 Carotenoids
Carotenoids are derivatives of vitamin A and have found widespread use in
cosmeceuticals due to the established topical anti-aging benefits associated with
the prescription retinoid tretinoin. The carotenoids are a large family of orange,
red, and yellow substances that perform vital antioxidant roles when ingested
and are less well established as topical antioxidants. The carotenoids are
discussed in detail here.
5.2 Astaxanthin
Astaxanthin is a pink carotenoid found in high concentration in salmon accounting for the
characteristic pink color of the fish. This is the rationale for anti-aging diets recommending
the ingestion of a serving of salmon fivemtimes weekly. For topical application purposes.
Astaxanthin is obtained from the marine rnicroalgae Haematococcus pluvialis. The efficacy
of astaxanth in is attributed to its cell mernbrane composed of two external lipid layers,
which has been touted to possess stronger antioxidant abilities than vitamin E. Few studies
exist to confirm the topical effect of astaxanthin, but it has been studied extensively as an oral supplement.
Astaxanthin in concentrations of 0.03-0.07% produces a pink-colored cream. This limits the concentration that
can be used, but no topical adverse reactions have been associated with this carotenoid. The topical antioxidant
benefits of astaxanthin have not been established.
5.3 Lutein
Another carotenoid found in topical cosmeceuticals is lutein. It is naturally found in green
leafy vegetables. Such as spinach and kale. Lutein is an antioxidant in the plant kingdom, also
being used for blue light absorption, in the animal kingdom, lutein is found in egg yolks,
animal fats and the corpus luteum. It is a lipophilic molecule, not soluble in water,
characterized bya long polyene side chain composed of conjugated double bonds. These
double bonds are degraded by light and heat, a universal characteristic of carotenoids to a
greater or lesser degree. The topical value of lutein in wound healing has never been evaluated.
5.4 Lycopene
Lycopene is a potent carotenoid found in most fruits and vegetables with .a red color
including tornatces, waterrnelon, pink grapefruit, papaya, gac, red beli pepper and
pink guava. Lycopene is a highly unsaturated hydrocarbon containing 11 conjugated
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20. and two unconjugated double bonds which makes it a longer molecule than any other carotenoid. This makes its
absorption into the skin doubtful. It undergoes cis-isomerization when exposed to sunlight. Even though lycopene
was the new oral supplement added to many commercial multivitarnins this year its topical value has never been
documented. It is safe for skin application, but may stain the skin in high concentration.
5.5 Retinol
Of all the topical carotenoids retinol is the best understood. Since it is necessary
for vision and possesses a weli-characterized skin receptor. It is theoretically
possible to interconvert the retinoids from one form to another. For exarnple.
retinyl palmitate and retinyl propionate. Chemically known as retinyI esters, can
become biologically active following cutaneous enzymatic cleavage of the ester
bond and subsequent conversion to retinol. mRetinol is the naturally occurring
vitamin A form found in red, yellow, and orange fruits and vegetables. It is the pigment responsible for vision but
is highly unstable. Retinol can be oxidized to retinaldehyde and then oxidized to retinoic acid, also known as
prescription tretinoin. It is this cutaneous conversion of retinol to retinoic acid that is responsible for the biologie
activity of some of the new stabilized OTC vitamin A preparations designed to irnprove the appearance of benign
photodamaged skin. Unfortunately, only small amounts of retinyl palrnitate and retinol can be converted by the
skin, accounting for the increased efficacy seen with prescription preparations containing retinoic acid. The main
problem with prescription retinoids is their irritancy. Unfortunately, as the biological efficacy of the retinoid
increases, so does the irritancy. This is also the case with the OTC retinoids. Retinol is more irritating than the
retinyl esters and also more unstable. It is for this reason that cosmeceutical formulations not manufactured under
strict oxygenfree conditions prefer to add retinyl palrnitate to moisturizing creams. However, the retinyl palrnitate
may act as an antioxidant for the lipids present in the moisturizer. The topical benefit of retinol has been
documented by weU-controlled studies. It is commonly felt among dermatologists that retinol is of benefit, but it
is difficult in moisturizer studies that do not include vehicle control to separate the retinol benefit from the
moisturizer benefit. Nevertheless of all the carotenoids available for Iermulation. Retinol has the most evidence
to support topical application efficacy following resurfacing.
5.6 Flavonoids
Flavonoids are aromatic compounds, frequently with a yellow color that occur
in higher plants. Five thousand flavonoids have been identified with a sirnilar
chemical structure, possessing 15 carbon atoms and a variety of biologie
activities. Flavonoids can be divided into flavones. Flavonols, isoflavone and
flavones. Each with a slightly different chemical structure. Currently, the most
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21. common isoflavone incorporated into cosmeceuticals are daidzein and genistein, derived from soybeans. Other
sourees of flavonoids include curcumin, silyrnarin. pycnogenol, and gingko.
5.7 Soy
The soybean-derived isoflavones genistein and daidzein function as
phytoestrogens when orally consumed, and have been credited with the
decrease in cardiovascular disease and breast cancer seen in Asian women.
These isoflavones are present when the soy is fermented. Some of the
cutaneous effects of soy have been linked to its estrogenic effect in
postmenopausal wornen. Topical estrogens have been shown to increase skin
thickness and promote collagen synthesis [35]. It is interesting to note that gemsrein increases collagen gene
excressicn in cell culture, out there are no published reports of this collagen-stimulating effect in topical human
trials. Genistein has also been reported to function as a potent antioxidant, scavenging peroxyl radicals and
protecting against lipid peroxidation in vivo.
5.8 Curcumin
Curcumin is a popular natural yellow food coloring used in everything from
prepackaged snack foods to rneats. It is sometimes used in skin-care products as
a natural yellow coloring in products that claim to be tree of artificial ingredients.
Curcumin comes from the rhizome of the turmeric plant and is consumed orally
as an Asian spice, frequently found in rice dishes to color the otherwise white
rice yellow. However, this yellow color is undesirable in cosmetic preparations.
Since yellowing of products is typically associated with oxidative spoilage. Tetrahydrocurcumin, a hydrogenated
form of curcumin, is off-white in color and can be added to skincare products not only to function as a skin
antioxidant but also to prevent the lipids in the moisturizer from becoming rancid, the antioxidant effect of
tetrahydrocurcumin is said to be greater than vita min E by cosmetic chemists. It is said to provide antioxidant
skin benefits by quenching oxye-gen radicals and inhibiting nuclear factor-KB.
5.9 Silymarin
Silymarin is an extract of the milk thistle (Silybum marianums, which belongs to the
aster family of plants including diasies, thistles. and artichokes. The plant is named
milk thistle because the oldest recorded use of the extract was to enhance human
lactation, and because the plant produces a white milky sap. The extract consists of
three flavonoids derived from the fruit, seeds, and leaves of the plant. These
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22. flavonoids are silybin, silydianin, and silychristin. Homeopathically, silymarin is used
to treat liver discase. But it is a strong antioxidant, preventing lipid peroxidation by
scavenging free radical species. Its antioxidant effect have been Cosmeceuticals
demonstrated topically in hairless mice by a 92% reduction in skin tumors Icllowing
UVB exposure. The mechanism for this decrease in tumor production is unknown but
topical silymarin has been shown to decrease the formation of pyrimicline dimers in a
mouse model. It has also been found to improve the healing ofburns in albino rats,
which is the rationale for its incorporation into some wound-healing and postresurfacing preparations. Silymarin
is found in a number of high-end moisturizers for benign photoaging to prevent cutaneous oxidative damage and
to re duce facial redness. A double-blind placebo-controlled study in 46 subjects with stage I-UI rosacea found
improvement in skin redness, papules, itching, hydration and skin color. This was felt to be due to its direct
activity on modulating cytokines and angiokines.
5.10 Pycnogenol
Pycnogenol is an extract of French marine pine bark iPinus pinasters. The extract is a
water-soluble liquid containing several phenolic constituents, inelucling taxifolin,
catechin, procyanidins. It also contains several phenolic acids inelucling phydroxybenzoic. Protocatechuic, gallic, vanillic, p-couric, caffeic, and ferulic. It is a
trademarked ingredient, a potent tree radical scavenger that can reduce the vita min C
radical returning the vitamin C to its active form (VI, C). The active vita min C in turn
regenerates vitamin E to its active Iorrn, maintainlng the natural oxygen-scavenging
mechanisms of the skin intact. Pycnogenol is the ideal anti-aging additive since it demonstrates no chronic toxicity
no mutagenicity, no teratogenicity, and no allergenicity. In B16 melanoma cells. It was shown to inhibit tyrosinase
activity and melanin biosynthesis. Many discussions of antioxidant flavonoids include a mention of pycnogenol,
but few high-quality data are presented.
5.11 Ginkgo
Ginkgo biloba, also named the maidenhair tree, is the last member of Ginkgoaceae
family which grew on earth some 200-250 million years ago. For this reason,
ginkgo contains flavonoids not found in other botanieals. In possesses bilobalide
(a sequiterpene), ginkgolides (diterpenes with 20 carbon atoms), and other
aromatic substances such as ginkgol, bilobdol, and ginkgolic acid. It is a plant with
numerous purported benefits and has been a common part of homeopathic
medicine in East Asia for 4000 years. The plant leaves are said to contain unique polyphenols such as terpenoids
19 | P a g e

23. (ginkgolides. bilobalides) flavinoids and flavonol glycosides that have antlinflammatory effects. These antiinflammatory effects have been linked to anti-radical and anti-lipoperoxidant effects in experimental fibroblast
models. Ginkgo flavonoid fractions containing quercetin, kaempferol, sciadopitysin, ginlegetin, and isoginkgetin
have been demonstrated to induce human skin fibroblast proliferation in vitro. Increased collagen and
extracellular fibronectin were also demonstrated by radioisotope assay. Ginkgo extracts are therefore added to
many cosmeceuticals to function as antioxidants and promoters of collagen synthesis following resurfacing, based
on non-human mode Is of oxidative damage. Polyphenols Polyphenols are a subset of flavonoids used in many
cosmeceuticals. Two main sourees of polyphenols are teas and fruits. This section presents green tea and
pomegranate as examples of the evidence available to support polyphenol biologie activity.
5.12 Green tea
Tea (Camellia sinensis) is botanical popular in East Asia for 5000 years. Used both
topically and orally. There are several different types of teas: green, black, oolong
and white. The different teas come from the same plant, but different processing
imparts different properties. Green tea is made from unfermented tea leaves and
contains the highest concentration of polyphenol antioxidants. Green tea can be
easily added to topical creams and lotions designed to combat the signs of
photoaging but it must be stabilized itself with an antioxidant, such as butylated hydroxytoluene. A topically
applied green tea Cosmeceuticals extract containing GTP ((-)-epigallocatechin- 3-gallate) was found to reduce
UVB-induced inflammation as measured by double skin-Iold swelling. They also found proteetion against UVinduced edema, erythema, and antioxidant depletion in the epidermis. This was further investigated by applying
GTP 10 the back of humans 30 minutes prior 10 UV irradiation, which resulted in decreased myeloperoxidase
activity and decreased infiltration of leukocytes as compared to untreated skin. The application of topical green
tea polyphenols prior to UV exposure has also been shown to decrease the formation of cyclobutane pyrimidine
dimers. These dimers are critical in initiating UV-induced mutagenesis and carcinogenesis which represent the
end stage of the aging process. Thus green tea polyphenols can function topically as antioxidants,
antiinflammatories, and anti-carcinogens, making them a popular cosmeceutical additive.
5.13 Pomegranate
Pomegranate iPunica granatum) is a deciduous tree bearing a red fruit native to
Afghanistan, Pakistan, Iran, and northern India. It was brought to California by the
Spanish settlers in 1769 and is commercially cultivated for its juice. Pomegranate
juice commonly consurned in the Middle East, provides about 16% of the adult
requirement of vitamin C per 100 mg serving. It also contains pantothenic acid,
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24. also known as vita min B5, potassium. And antioxidant polyphenols. These substances have been demonstrated
to proteet against UVA- and UVB-induced cell damage in SKU-1064 human skin fibroblasts. Pomegranate juice
has also been purposed to reduce oxidative stress and to affect low-density lipoprotein (LDL) and platelet
aggregation in humans and apolipoprotein E-deficient mice. It has also been studied for improving hyperlipidemia
in diabetic patients. It is found in some wound-healing preparations to promote healing, but its value has never
been demonstrated.
6. Other antioxidants used in post-resurfacing
Other antioxidants are commonly found in commercial preparations for use after resurfacing procedures. These
ingredients are used to promo te healing, and they include aloe vera and ubiquinone.
6.1 Aloevera
Probably the most widely used cutaneous botanical anti-inflarnmatory is aloe vera.
The mucilage is released from the plant leaves as a colorless gel containing 99.5%
water and a complex mixture of mucopolysaccharides, amino acids hydroxy
quinone glycosides and minerals. Compounds isolated from aloe vera juice inelude
aloin, aloe emodin, aletinic acid, choline, and choline salicylate. Reponed cutaneous
effects of aloe vera inelude increased blood flow, reduced inflammation, decreased skin bacterial colonization,
and enhanced wound healing. The anti-inflarnrnatory effects of aloe vera may result from its ability to inhibit
cyclooxygenase as part of the arachidonic acid pathway. Studies have evaluated the effect of aloe vera on burn
wounds and acne. Aloe vera cream was found to show no tanning or sunburn proteetion and no efficacy in sunburn
treatment as compared to placebo. Rueter and colleagues studied a 97.5% concentration of aloe vera for its antiinflammatory effect and demonstrated positive results in a sunburn cell assay as compared to 1% hydrocortisone.
These data provide evidence for the anti-inflammatory effect of pure aloe vera gel. However, most products sold
over the counter for under $10 do not contain a high enough percentage of aloe vera to induce clinically relevant
inflammation reduction.
6.2 Ubiquinone
An endogenous antioxidant that has been incorporated into antiaging moisturizers is ubiquinone, also known as Coenzyme Q10 or
CoQ10. For a topical I antioxidant to be clinically effective, it must
penetrate into the skin. Hoppe and colleagues from Beiersdorf
demonstrated the topical penetration of ubiquinone into the viable
epidermis and a reduction in oxidation as measured by weak photon emission. They were also able to show a
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25. significant decrease in the expression of collagenase in human dermal fibroblasts following UVA radiation and
improvement in orbital wrinkling. However, oral supplementation had no effect on the main antioxidant defenses
or pro-oxidant generation in tissues in mice. It also did not affect the life span in mice, according to Shoal and
colleagues. In a .human study, Passi et al. administered 50 mg vitamin E, 50 mg Coenzyme Q10, and 50 mg
selenium. An increase in stratum corneum Coenzyme QI0 was noted after 15 and 30 days of ingestion, but the
significance of this finding was not evaluated. Other evidence suggests that topical Coenzyme QI0 may provide
additive antioxidant benefits when combined with the colorless carotenoids phytoene and phytofluene. This effect
was demonstrated in fibroblast cultures.
7. DEPIGMENTATION AGENTS
Since the introduction of hydroquinone as a skin lightening agent in 1961,
several products with bleaching properties have been used for the
treatment of pigmentary disorders of the skin. The most important medical
indications for the use of these agents are melasma and postinflammatory
hyperpigmentation, although they have also been used as alternative
options for the treatment of ephelides, solar lentigenes, nevi, and lentigo
maligna. This article reviews the most commonly used bleaching agents, discusses their mechanism of action,
and focuses on their efficacy and safety in treating unwanted skin pigmentation. Based on our current knowledge,
the ideal bleaching agent has to fulfill certain pharmacologic criteria. It should have a potent bleaching effect with
a rapid time of onset (less than 2 to 3 months), carry no short- or long-term side effects, and lead to a permanent
removal of undesired pigment. Most of the currently available bleaching or depigmenting agents cause a
temporary removal of hyperpigmentation, which usually recurs after discontinuation of therapy. Presently, there
are three categories of bleaching agents, phenolic compounds, nonphenolic compounds, and combination
formulas.
7.1 Phenolic Compounds
These chemical compounds contain a phenol group. The most important agent of this group is hydroquinone
(HQ), which is considered the most commonly prescribed bleaching agent today. HQ derivatives are the
monobenzyl ether of hydroquinone, the 4-methoxyphenol, the 4-isopropylcatechol, the 4-hydroxyanisol, and the
N-acetyl-4-S-cystaminylphenol. Hydroquinone HQ, a hydroxyphenolic chemical compound, inhibits the
conversion of dopa to melanin by inhibiting the tyrosinase enzyme. These cytotoxic compounds are responsible
for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting
themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the
enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the
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26. conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by
buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these
two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of alltrans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic
skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more
susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown
to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA
to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the
impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.
7.2 B Nonphenolic Compounds
7.2.1 Azelaic Acid
Azelaic acid (AZA) is a naturally occurring 9-carbon dicarboxylic acid that was
isolated recently from cultures of Pityrosporum ovale and was associated with
the hypomelanosis seen in tinea versicolor. It has been shown to have beneficial
therapeutic effects in acne vulgaris and certain pigmentary disorders, such as
melasma and lentigo maligna. AZA interferes with the function of tyrosinase in
vitro and may also inhibit DNA synthesis and mitochondrial oxidoreductase. It does not appear to affect normal
melanocytes, and treatment of constitutively pigmented normal skin, freckles, lentigenes, and nevi with AZA did
not produce a significant therapeutic result. The drug, however, appears to exert an antiproliferative and cytoxic
effect on hyperactive and abnormal melanocytes and may halt the progression of lentigo maligna to lentigo
maligna melanoma. AZA has been used at concentrations of 15–20% for the treatment of melasma and
postinflammatory hyperpigmentation. In double-blind comparative studies, topical AZA achieved a good-toexcellent response in 60–70% of melasma patients, and was found to be more effective than 2% HQ and of
equivalent efficacy to 4% HQ. A combination regimen of AZA with topical tretinoin 0.05% for the treatment of
melasma produced similar results after 6 months compared with AZA monotherapy (approximately 73% of goodto-excellent improvement), although the addition of tretinoin was associated with an earlier and more pronounced
lightening of melasma pigmentation and a greater percentage reduction of lesion size during the early phase of
treatment. These results suggest that tretinoin augments the efficacy of AZA. In another clinical study, the
addition of 15–20% glycolic acid lotion to AZA cream 20% was as effective as 4% HQ cream for the treatment
of facial hyperpigmentation in darker-skinned individuals. At the usual concentrations, AZA is well tolerated in
humans. Adverse reactions such as pruritus, transient erythema, scaling, and irritation are usually mild and subside
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27. within 2 to 4 weeks. Allergic sensitization and phototoxic reactions can occur, but are rare. No systemic toxicity
has been reported.
7.2.2 Tretinoin
The use of tretinoin for the treatment of cutaneous hyperpigmentation was
introduced by Kligman in 1975, stemming from his observation that acne
patients receiving tretinoin developed lighter skin after months of treatment.
Tretinoin has been shown in vitro to inhibit both constitutive and induced
melanin formation in melanoma cell lines. In vivo, tretinoin enhances the
epidermal cell turnover, decreasing the contact time between keratinocytes
and melanocytes and promoting the rapid loss of pigment through epidermopoesis. Tretinoin has been used in
concentrations from 0.025–0.1% to treat a variety of pigmentary disorders. The bleaching action is usually very
protracted and occurs anywhere within 12 to 44 weeks of continuous daily application. Comparative studies in
melasma patients have shown a 68–73% degree of improvement by tretinoin at 40 weeks of treatment compared
with a control group. Moderate cutaneous side effects, such as erythema and desquamation, are observed in the
majority of patients, and in some cases a more severe dermatitis as well as distressing hyperpigmentation have
been reported. When prescribing tretinoin, the use of sunscreen is rather important to counteract the possibility of
sunburn and photo damage.
7.2.3 L-ascorbic Acid
Vitamin C, or L-ascorbic acid (AsA), interferes with pigment production at
various oxidative steps of melanin synthesis, for example 5, 6 dihydroxyindole
oxidation. AsA has a reducing effect on o-quinones and oxidized melanin and
it can alter melanin from jet black to light tan. A disadvantage of AsA is its
chemical instability in aqueous solution where it becomes quickly oxidized and denatures. AsA esters have been
tested in an effort to overcome this problem. A stable derivative of AsA, magnesium L-ascorbyl-2-phosphate
(VC-PMG), was used in a 10% cream base and produced a significant lightening effect in 19 of 34 patients with
melasma after 3 months of twice daily application.
7.2.4 Kojic Acid
Kojic acid (5-hydroxy-2-hydroxymethyl-4-H-pyran-4- one) is a fungal metabolic product that is structurally
related to maltol. It is a potent tyrosinase inhibitor and functions by chelating copper at the active site of the
enzyme. It also acts as an antioxidant and prevents the conversion of the o-quinones of DL-DOPA,
norepinephrine, and dopamine to their corresponding melanin. Kojic acid is used in a 1–4% cream base, alone or
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28. in combination with tretinoin, hydroquinone, and/or a corticosteroid. It appears to act synergistically with glycolic
acid. The addition of 2% kojic acid in a gel containing 10% glycolic acid and 2% HQ was superior to the same
gel without kojic acid in improving the epidermal melasma of 40 women after 12 weeks of treatment. Compared
with 2% HQ, kojic acid alone appears to be less effective. There are scant data from the literature with regard to
its long-term side effects, al-though some investigators have reported a high frequency of contact sensitivity to
this product.
7.2.5 Arbutin
Tyrosinase is the enzyme for conversion of the substrate tyrosine to melanin in melanocytes, providing
pigmentation to skin. Various compounds that bind to the active site of tyrosinase to inhibit its activity have been
developed as agents to lighten skin and ameliorate unwanted pigmentation. These agents include hydroquinone,
kojic
acid,
and
arbutin,
amongst
others.
Arbutin
is
derived
from
the
leaves
of bearberry, cranberry, mulberry or blueberry shrubs, and also is present in most types of pears. It can
have melanin-inhibiting properties. Arbutin and other plant extracts are considered safe alternatives to commonly
used depigmenting agents to make the skin fairer. Medical studies have shown the efficiency of Arbutin for skin
lightening. There are patents controlling its use for skin lightening. Arbutin actually exists in two conformations,
alpha and beta. The alpha conformation offers higher stability over the beta conformation and is the preferred
form for skin lightening indications.
8. Hydroxy Acids
Hydroxy acids are organic carboxylic acids classified into alphahydroxy acids (AHA), beta‐hydroxy acids (BHA),
polyhydroxy acids, and bionic acids on the basis of their molecular structure. Hydroxy acids are found in most of
the marketed cosmetic preparation but are used in very low concentration.
8.1 α-Hydroxyacids
The AHAs are organic carboxylic acids with one hydroxyl group attached to the αposition of the carboxyl group. The hydroxyl and carboxyl groups are both directly
attached to an aliphatic or alicyclic carbon atom. The hydroxyl group in the AHA is
neutral, and only the carboxyl group provides an acidic property. Many AHAs are
present in foods and fruits and, therefore, are called fruit acids. Glycolic acid, the
smallest AHA, occurs in sugar cane and is the most widely used HA in skin care.
Lactic acid, the next smallest AHA, is also widely used in topical formulations to exfoliate and provide antiaging
effects. Some AHAs contain a phenyl group as a side-chain substituent. This changes the solubility profile of the
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29. AHA, providing increased lipophilicity over conventional water-soluble AHAs and can be used to target oily and
acne-prone skin. Examples include mandelic acid (phenyl glycolic acid) and benzilic acid (diphenyl glycolic
acid).
8.2 β-Hydroxyacids
The BHAs are organic carboxylic acids having one hydroxyl group attached to the
β-position of the carboxyl group. The hydroxyl group in the BHA is neutral in
nature and the carboxyl group provides the acidic property. Some BHAs, such as
β-hydroxybutanoic acid, are present in body tissues as metabolic intermediates and
energy sources; however, they have not yet been commercialized in dermatologic
formulations. Some molecules are both an AHA and BHA because they contain a hydroxyl group in the α-position
to one carboxyl group and in the β-position to another carboxyl group. Malic acid (apple acid), for example,
contains one hydroxyl and two carboxyl groups, and citric acid contains one hydroxyl and three carboxyl groups,
making both molecules an AHA and a BHA. Citric acid is widely used in topical formulations as an antioxidant
and pH adjustor, and its antiaging benefits are well established.5 Although some have termed salicylic acid a
BHA, we do not consider it to be a BHA; for that reason, it is not included in this discussion. Salicylic acid
behaves differently on skin than other HAs, presumably due to its phenolic hydroxyl attachment that renders the
hydroxyl acidic rather than neutral.
8.3 Polyhydroxy acids
The PHAs are organic carboxylic acids with two or more hydroxyl groups in the
molecule attached to carbon atoms of an aliphatic or alicyclic chain. All the hydroxyl
groups in the PHA are neutral, and only the carboxyl group provides its acidity. To
be both an AHA and PHA, also known as a polyhydroxy AHA, it is essential that at
least one hydroxyl group be attached to the α-position. Many PHAs are naturally
occurring, endogenous metabolites, or intermediate products from carbohydrate
metabolism in body tissues. For example, gluconic acid and gluconolactone are
important metabolites formed in the pentose phosphate pathway from glucose during the biosynthesis of ribose
for ribonucleic acid. Gluconolactone is the most commercialized PHA in skin care products, because it is readily
available and delivers the antiaging benefits of HAs, in addition to strengthening skin barrier function and being
a gentle, moisturizing, antioxidant/ chelating substance. For example, an in vitro cutaneous model of photoaging
demonstrated that gluconolactone protects against ultraviolet (UV) radiation. These findings were attributed to
the ability of gluconolactone to chelate oxidation-promoting metals and trap free radicals. In addition,
pretreatment of skin with gluconolactone does not lead to an increase in sunburn cells after UVB irradiation, as
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30. has been shown to occur with glycolic acid; this is thought to be due to its antioxidant effects. Gluconolactone
can also be formulated with oxidative drugs, such as benzoyl peroxide, to help reduce irritation potential and
erythema caused by the oxidative drug.
8.4 Bionic acids
The BAs are chemically classified as aldobionic acids. They consist of one
carbohydrate monomer chemically linked to an aldonic acid PHA; examples
are lactobionic acid, maltobionic acid, and cellobionic acid. BAs are
commonly obtained from their disaccharide through chemical or enzymatic
oxidation; for example, lactobionic acid is obtained from lactose, maltobionic
acid from maltose, and cellobionic acid from cellobiose. Although the BAs
are larger molecules than traditional AHAs, they are small enough to penetrate
skin at approximately 358 daltons, and their pKa is roughly equivalent to
smaller AHA molecules; for example, the pKa of lactobionic acid is 3.8, which matches that of glycolic acid.
BAs are hygroscopic materials that readily attract and retain water, forming a gel matrix when their aqueous
solution is evaporated at room temperature. The transparent gel contains certain amounts of water, forming a clear
gel matrix. Formation of a gel matrix may add protective and soothing effects for inflamed skin. Indeed,
formulations containing BA are well tolerated and help calm skin when applied after cosmetic procedures that
weaken the skin’s barrier, including superficial HA peels and microdermabrasion. One notable protective use of
lactobionic acid, a BA used in some commercial skin care formulations, is as an antioxidant chelator in organ
transplantation preservation solutions. Lactobionic acid reportedly inhibits hydroxyl radical production by
forming a complex with the oxidationpromoting metal Fe (II). Furthermore, gluconolactone (a PHA) and
lactobionic acid and maltobionic acid (BAs) inhibit oxidative degradation of hydroquinone and banana peel.
Lactobionic acid also functions as an inhibitor of the matrix metalloproteinase (MMP) enzymes. Excessive
activity of MMPs occurs with age and sun exposure, contributing to wrinkle formation, skin laxity, and visible
telangiectasia. The use of BAs to inhibit MMPs may provide a significant benefit in the prevention of
photodamage.
9. RETINOIDS
Vitamin A and its derivatives, both natural and synthetic, have been popular additives in topical for years and are
recognized as the gold standard for the prevention and treatment of photoaging. The following topical retinoids
are recognized as being useful:
Natural retinoids
• Retinol (vitamin A alcohol)
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31. • Retinyl-palmitate (vitamin A ester)
• Retinyl-acetate (vitamin A ester)
• Retinaldehyde (vitamin A aldehyde)
• Tretinoin (all-trans-retinoic acid)
• Isotretinoin (13-cis-retinoic acid)
• Alitretinoin (9-cis-retinoic acid)
Synthetic retinoids
• Tazarotene
• Adapalene
Tretinoin, isotretinoin, alitretinoin, tazarotene, and adapalene are registered as drugs; the others are
cosmeceuticals (medicinally active cosmetics). Vitamin A and its derivatives exert their action by binding to
specific nuclear receptors. The ligand-receptor complex modulates the expression of the genes involved in cellular
differentiation and proliferation, normalizing cell keratinization. Retinoids might also act independently from the
binding to nuclear receptors. Each of them exerts its own activity, offering a further choice to the dermatologists
who deal with topical retinoids. Although there are several studies proving the efficacy of tretinoin as topical
treatment of photoaging, few studies are available for the other retinoids.
9.1 Tretinoin
Kligman and Willis1 first introduced retinoids for use as photoaging agents. After
its application, the author noticed improvement of skin depigmentation and
rejuvenation. When used on photodamaged skin, tretinoin's clinical effects
include improvement of wrinkles, roughness, mottled pigmentation, and skin
appearance as a whole. The histologic changes observed are decreased corneocyte
adhesion (loss of desmosomes, decreased tonofilaments, increased autolysis of
keratinocytes, intracellular glycogen deposition), epidermal hyperplasia,
increased number of Langerhans cells, increased synthesis of collagen and elastin, and angiogenesis. Tretinoin
enhances epidermal cell turnover, decreasing contact time between keratinocytes and melanocytes and promoting
a rapid loss of pigment through epidermopoesis. Tretinoin is available in different concentrations (0.01%, 0.25%,
0.5%, and 0.1%) and as different formulations (cream, gel, solution). Creams are generally prescribed for sensitive
skins, whereas gels are prescribed for oily skins. Continuous once-daily application is mandatory to achieve
maximum results, in any case not occurring before a 3-month period. The only clinical improvement that appears
after only 1 month is skin smoothness. To maintain the results, long-term treatment is necessary. There are no
limits to the duration of tretinoin topical use. Moderate cutaneous side effects, especially erythema and
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32. desquamation, are observed in most patients even if after 2 to 4 weeks these side effects decrease without
discontinuing the treatment. It may be necessary to interrupt the treatment for 2 to 3 days, to apply a calming and
moisturizing cream, and then to restart treatment once every 2 days. Whenever tretinoin is prescribed, the use of
sunscreen is very important to avoid sunburns (the treated skin is thinner) and worsening of photodamage (UV
radiations decrease the expression of retinoid receptors in skin cells, thus limiting the effects of retinoids).
9.2 Retinol
There are no studies comparing its effectiveness with that of tretinoin, although retinol
does not appear to be as effective. In photoaging, it is used as a cream in different
concentrations, ranging from 0.075% to 1%. It can be considered a “light” alternative to
tretinoin in case of sensitive skins.
9.3 Retinyl-palmitate and retinyl-acetate
Esters are not considered effective against photoaging if used alone. Most of the products available are, in fact, a
combination of esters and hydroxy acids.
9.4 Retinaldehyde
Retinaldehyde is formulated as cream or gel and in concentrations varying from 0.015% to 0.1%.
Its efficacy is similar to that of tretinoin, but it is much less irritating.
9.5 Isotretinoin
Topical isotretinoin is available as a 0.05% cream or gel. It appears to be less irritating, yet
less effective, than tretinoin.
9.6 Alitretinoin
The theoretic benefit of alitretinoin 0.1% gel in the treatment of photoaging
originates from the binding and activation of all nuclear retinoid receptors,
but larger, blind, and controlled trials are necessary to better investigate its
role.
9.7 Tazarotene
Tazarotene is an analogue of tretinoin that belongs to the family of acetylenic
retinoids. It has a specific binding profile for beta and gamma retinoid receptors.
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33. Tazarotene improves skin roughness, fine wrinkling, and epidermal atrophy. It is available at 0.05% and 0.1%
gel and cream.
9.8 Adapalene
Even if usually indicated for acne, adapalene has also been tested for the
treatment of photoaging. Once-daily application of adapalene 0.1% gel for 4
weeks, followed by a twice-daily application for up to 9 months, significantly
reduced actinic keratoses and lentigines.
10. PEPTIDES
10.1 ANTIMICROBIAL PEPTIDES (AMPS)
Cathelicidins and defensins are the two major groups of epidermal AMPs that possess inherent antimicrobial
activity. Like most AMPs they are positively charged, with the positively charged amino acids localised to one
side of the molecule and opposite to the most hydrophobic groups. Granulysin is also an AMP but whilst it has
action in the skin it is not synthesised in the skin. Other peptides and proteins that exert antimicrobial activity
within the skin are psoriasin, RNase 7, adrenomedullin (AM), antileukoprotease and DCD. Cathelicidins The
expression of cathelicidins and mouse cathelicidin- related antimicrobial peptide (CRAMP) in skin keratinocytes
varies with infection and/or injury. Only one cathelicidin, human cationic antibacterial protein has been identified
in humans, although about 30 cathelicidin members are present in mammalian species. hCAP expression has been
detected in human skin keratinocytes at sites of inflammation in the skin and in specialised keratinocytes of the
nail, neonatal skin and in eccrine glands Cathelicidin peptide (human cathelicidin; LL-37) is produced by the
neutrophils, mast cells and keratinocytes in response to inflammatory processes. LL-37 also acts as a
chemoattractant for neutrophils, monocytes, T cells andmast cells. Mast cells can produce LL-37 thereby leading
to a positive feedback cycle. Elevated levels of LL-37 have been reported in psoriatic skin (_304 mM) and
wounded skin. LL-37 plays an important role in the repair of damaged tissue and wound closure by promoting
wound vascularisation and reepithelisation. It also induces IL-8, IL-18 and IL-20 production by human
keratinocytes through MAP kinase pathway. IL-18, an interferon (IFN)-g inducer, is a proinflammatory cytokine
intracellularly produced from a biologically inactive precursor, pro-IL-18. It is produced by keratinocytes and its
expression is highly enhanced in skin diseases, like psoriasis in which human b-defensins (hbD) and LL-37 are
highly expressed.
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34. 10.2 Defensins
Defensins are cationic peptides (MW 3–5 kDa), characterised by six cysteine residues that form characteristic
disulphide bridges. They are divided into alpha, beta and theta subfamilies based on the alignment of the
disulphide bonds. AMPs of the defensin family exhibit broad activity against gram-negative bacteria, fungi,
mycobacteria and enveloped viruses and have been isolated from neutrophil granules, macrophages and some
specialised epithelial cells of the small intestine. a-Defensins Six alpha defensins have been identified, of which
four are known as human neutrophil peptides (HNP)-1, 2, 3 and 4, as they are associated with human neutrophils.
The other two are called human defensins (HD)-5 and 6. They are expressed in the paneth cells of the intestine
and in the epithelial cells of the female genitourinary tract.21 Alpha defensins exert their action on both microbes
and the host. They have potent antiviral activity and HNPs 1–3 have been shown to increase the expression of
tumour necrosis factor (TNF) a and interleukin-1 in human monocytes activated by Staphylococcus aureus. The
expression of alpha defensins has been studied in squamous cell carcinomas of the human tongue and compared
with autogenous nontumour tissue. HPLC-MS and amino acid sequencing was utilized for separation, structural
identification and quantitation of the HNPs. MALDI-MS analysis of HPLC fractions from both tumour and
nontumour tissue detected peptide masses for HNP-1, HNP-2 and HNP-3 which were confirmed by amino acid
sequencing. When analysis of paired tumour and nontumour tissue samples was performed, the concentration of
defensins in the tumour tissue was about 2– 12 times higher than in the nontumour tissue. b-Defensins Beta
defensins have been identified in many cell types including epithelial cells and neutrophils. HbD 1–4 have been
identified in humans. HbD-1 (MW 3.9 kDa) is constitutively produced by various epithelial tissues including the
urogenital and respiratory tracts. u-Defensins This is a novel class of defensins isolated from rhesus monkey
neutrophils and named u-defensins for their circular molecular structure.
10.3 Psoriasin
Another peptide discovered in psoriatic skin lesions is psoriasin. Psoriasin is an
AMP (MW 11 kDa) which is constitutively expressed in healthy skin
keratinocytes and is a member of the S100 gene family. Although the
physiological function of S100 proteins is not fully understood, a few studies have
indicated involvement of S100 proteins in innate host defence. Over-expression
of psoriasin may be linked to inflammation which is common in psoriasis. Glaser
et al. also identified psoriasin as the principal Escherichia coli-killing AMP in
healthy human skin, which is present on the skin surface and focally expressed in healthy skin keratinocytes.
Psoriasin was induced in vitro and in vivo in keratinocytes by E. coli, indicating that its focal expression in skin
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35. may be derived from local microbial induction. Zn2þ-saturated psoriasin showed diminished antimicrobial
activity, suggesting that Zn2þ sequestration could be a possible antimicrobial mechanism.
10.4 RNase 7
RNase 7 (MW 14.5 kDa) is a basic protein that is abundant in healthy skin and is believed to be one of the
principal cationic proteins of healthy human skin.40 The RNase A superfamily has been extensively researched
over the last few decades and among the better characterised RNases are RNase 1 and RNase 5. Others include
eosinophil cationic protein (ECP) or RNase 3, and RNases 4, 6, 7 and 8. These were identified by Harder and
Schro¨der40 who showed that crude extracts from stratum corneumcontained antimicrobial activity against E.
coli and S. aureus. RNase 7 may be an inducible peptide since the levels are high in psoriatic skin and gene
expression is increased on contact of keratinocytes with bacteria. Adrenomedullin AM (MW 6 kDa) is a 52 amino
acid peptide which is expressed in keratinocytes of the epidermis and hair follicles, cells of the eccrine, apocrine
sweat glands and secretory ducts of normal skin, and in skin tumours of different histologies. AM is reported to
have numerous physiological roles including vasodilation, renal homeostasis, hormone regulation,
neurotransmission and growth modulation. It is also thought to be involved in the wound repair process. Martinez
et al. characterised adrenomedullin receptor (AM and AM-R) expression in human skin in order to understand its
potential functions in the skin. The presence of AM and its receptor in normal and neoplastic skin were confirmed
by RT-PCR and Western blot analysis performed on cell extracts from human skin cell lines. Immunoreactivity
for AM and in situ hybridization signal for AM-R was found in all epithelial components of the skin. Many
specimens corresponding to the major histological types of skin cancer showed a positive staining for AM and
AM-R. Antileukoprotease Antileukoprotease (ALP), also called mucous protease inhibitor or secretory
leukoprotease inhibitor, is present in human callus and detected in supernatants of cultured human primary
keratinocytes and in various human body fluids. It is a very potent human serine protease able to inhibit the
neutrophil derived serine proteases polymorph nuclear leukocyte elastase (HLE) and Cathepsin G (CG). Wiedow
et al. described the constitutive production and release of ALP by human keratinocytes and epithelial carcinoma
cell lines (KB grown in Dulbecco’s Modified Eagle and A431 grown in minimum essential medium). When the
antimicrobial activity of ALP was compared with HbD-2, ALP was seen to be constitutively produced and
expressed by the keratinocytes whereas HbD-2 is only expressed after stimulation of keratinocytes with bacteria.
Recombinant ALP exhibited microbiocidal activity in a dose-dependent manner.
10.5 Dermicidin 1L
DCD-1L is a novel AMP family with a broad spectrum of activity and no similarities to other known peptides. It
is constitutively expressed in eccrine sweat glands and transported to the epidermal surface. DCD expression was
not observed in epidermal keratinocytes of healthy human skin. Immunohistochemistry and RTPCR studies
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36. showed that DCD-1L expression was not induced in keratinocytes in inflammatory conditions such as psoriasis,
AD and lichen planus. DCD-1L thus functions by modulating the colonisation of the skin rather than responding
to inflammation. Lai et al. further expressed DCD-1L in E. coli as a fusion protein to understand its mechanism
and investigate its antimicrobial spectrum. DCD-1L displayed antimicrobicidal activity against nosocomial
pathogens, but no haemolytic activity against human erythrocytes. The antimicrobial activity of DCD was not
affected by the low pH and high salt concentrations of human sweat. This finding suggests that sweat glands may
have a function in the innate immune responses of the skin by secreting these antimicrobial agents.
11. PEPTIDES INVOLVED IN WOUND HEALING
Wound healing is a localised process which involves a series of specific and coordinated events such as
inflammation, wound cell migration and mitosis, neovascularisation, and regeneration of the extracellular matrix
(ECM).
11.1 RGD Peptides
Most cells are attached to the ECM through integrins that link the intracellular cytoskeleton with the ECM. Many
of the integrins recognise a tripeptide (arginine-glycine-aspartate) or RGD in target proteins of the ECM. Vigor
et al hypothesised that during the proteolytic remodelling of the ECM, small soluble RGD-containing peptides
were released into the matrix. Soluble RGD-peptides have previously been found to be internalized into a cell in
an integrin-independent manner and are able to directly bind to and activate caspase-3, thus inducing apoptosis.
To investigate this hypothesis dermal fibroblasts were embedded into collagen type I or fibrin matrices and
viability was assessed by in situ haematoxylin staining. Results indicate that apoptosis was induced specifically
in response to collagen matrix remodelling. Small soluble RGD containing peptides were produced by enzymatic
cleavage of collagen, which induces apoptosis of dermal fibroblasts through specific caspase-3 cleavage.
11.2 Copper Peptides
Copper peptides have been used in skin care in a similar way to vitamin C, alpha lipoic acid and green tree
extracts. Copper functions as a part of cytochrome c oxidase and superoxide dismutase which are used in energy
production and as antioxidants. It is also essential to the normal growth, development and function of the human
body. Copper is bound to glycine, histadine and lysine which are used to synthesize a copper based peptide.
Copper peptide has a positive influence on the growth and regulation of hair follicles and when used on wounds
increases collagen disposition, tensile strength and angiogenesis in healing tissues. A method for stimulating hairgrowth by topically administering or injecting an effective amount of a peptide copper complex has been
described and patented. Buffoni et al. examined the effects of Gly-His-Lys-Cu and of three synthetic analogues
(I, II and III) on wound healing of guinea-pig dorsal skin and on cultured fibroblasts. Hydroxyproline, proteins,
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37. DNA and semicarbazide-sensitive amine oxidase were measured and it was found that both the peptides caused
a decrease in the activity of semicarbazidesensitive amine oxidase but there was no significant difference between
the two peptides .The main effects of these peptide-copper complexes were slower reorganization of the skin and
a delayed activation of fibroblasts.
11.3 Interleukins (IL)
Interleukins are a class of cytokines identified for their role in mediating immunological functions. IL-1 is
produced by keratinocytes in two forms: IL-la and IL-lb. IL-6 (MW 26 kDa) is secreted from the cells in multiple
glycosylated forms. Like TGF-a, the levels of IL-6 are elevated in psoriasis, cultured keratinocytes and skin
tumour cell lines. IL-8, also known as neutrophil activating protein (NAP), mediates both growth stimulatory and
inflammatory processes. It is produced by cultured human dermal fibroblasts and keratinocytes in response to IL1 or TNF-a. Rennekampff et al. hypothesised that IL-8 was released from an intracellular preformed pool in
keratinocytes in the presence of psoriasis. Sticherling et al. showed that IL-8 is produced de novo by wound cells
leading to increased reepithelialisation in vitro and in vivo by stimulating keratinocyte proliferation and migration.
They investigated in vitro whether IL-8 upregulates the underlying phenotype of keratinocytes with respect to the
expression of integrin subunits a2, a3, a5 and a6. An inverse relationship between IL-8 immunoreactivity and
expression of the a6 integrin was found and loss of intracellular IL-8 immunoreactivity was accompanied by an
increase in a6 expression. Flow cytometry analysis revealed strong expression of integrin subunits a2 and a3 and
weaker expression of a5 and a6 on cultured, unstimulated keratinocytes. IL-8 was shown to be the major bioactive
chemoattractant for PMNs in human blister and skin graft donor site wound fluids. In vitro experiments on the
effect of recombinant human (rh) IL-8 on keratinocytes proliferation revealed a rise in cell number accompanied
by an increase in cells in S phase and over-expression of the integrin. Topical application of IL-8 on human skin
grafts in a chimeric mouse model showed enhanced reepithelialisation in IL-8 treated animals over controls.
12. Growth Factors
Growth factors act as regulators in wound healing and on exogenous application can modify the process. Two
peptide growth factors which play a pivotal role in normal wound healing in tissues such as skin, cornea and the
gastrointestinal (GI) tract are the structurally related peptides epidermal growth factor (EGF) and transforming
growth factor alpha (TGF-a). Other peptides such as basic and acidic fibroblast growth factors (bFGF and aFGF),
platelet derived growth factors (PDGF-AA, -AB and -BB) and insulin-like growth factor (IGF-I) have been
identified as potential wound-healing agents. EGF/TGF-a receptors are expressed by many types of cells
including skin keratinocytes, fibroblasts, vascular endothelial cells and epithelial cells of the GI tract. Healing of
a variety of wounds in animals and patients has been enhanced by treatment with EGF or TGF-a. EGF also
increased the tensile strength of skin incisions in rats and corneal incisions in rabbits, cats and primates. Sorensen
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38. et al. demonstrated that two of the important growth factors in wound healing, IGF-I and TGF-a, induce the
expression of the AMPs/polypeptides hCAP-18, hbD-3, NGAL and SLPI in human keratinocytes.
Growth hormone (GH) and prolactin (PRL) are produced in the anterior pituitary gland and skin is one of the
target organs for GH and prolactin bioregulation. Dermal fibroblasts in cell culture have been shown to produce
PRL and GH mRNA. Slominski et al.64 investigated whether the epidermis expresses the genes for GHand PRL.
Detectable levels of GH and PRL were not found in human immortalized keratinocytes or in malignant
melanocytes (basal cell carcinoma) but IGF-1 was expressed in malignant specimens. GHmRNA was detected in
normal human skin but not in cultured human epidermal keratinocytes. Transforming Growth Factor-b
Transforming growth factor-b (TGF-b) can act as a multi-functional regulator of both cell growth and
differentiation. Three isotypes of TGF-bs namely TGF-b1, TGF-b2 and TGF-b3, have been found in human
tissues. TGF-b2 is usually expressed in the intercellular space of all the layers of the epidermis and TGF-b3 is
present in the subepidermal area of the dermis. Falanga et al. could not detect TGF-b1 or TGF-b2 in the epidermis
or epithelial structures of forearm skin from healthy human volunteers. The dermal matrix contained minimally
detectable amounts of the two isoforms. In all cases, the dermal matrix and cells contained greater amounts of
TGF-b1 than TGF-b2.
13. CONCLUSION
The usage of cosmeceuticals has drastically hiked in recent years, which in turn has increased the spectrum of the
physician to broaden their range of products to enhance the comeliness of the patients associated with dermal
problems. However, at times, where generations are keenly worried for their beauty, lots of manufacturing
companies are competing and working hard to provide convincing results to meet requirements of the patients.
Claims of effectiveness lack convincing evidence, thus the industry is challenged to provide evidence on the
effectiveness of these compounds. Cosmeceuticals like vitamins, sunscreens, hydroxyl acids & many more have
diseases thus enhancing the skin texture. Clinical trials of cosmeceuticals are important to know the interaction
skin and cosmeceuticals which could even be influenced by environmental fact.
14. REFERENCES
1. Asian Journal of Pharmaceutical and Clinical Research: COSMECEUTICALS FOR THE SKIN:
OVERVIEW Vol. 4, Issue 2, 2011 ISSN - 0974-2441
AN
2. Tropical Journal of Pharmaceutical Research June 2011; 10 (3): 351-360 Herbal Cosmeceuticals for
Photoprotection from Ultraviolet B Radiation: A Review AK Mishra1, A Mishra, and P Chattopadhyay
3. Dermatologic Therapy, Vol. 19, 2006, 289 –296 Printed in the United States ISSN 1396-0296 Retinoids in
cosmeceuticals
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39. 4. Thomas C. Tsai, BS and Basil M. Hantash, Cosmeceutical Agents: A Comprehensive Review of the Literature
5. H. Dureja, D. Kaushik, M. Gupta, V. Kumar, V. Cosmeceuticals: An emerging concept Lather Indian J
Pharmacol | June 2005 | Vol 37 | Issue 3 | 155-159
6. International journal of pharmaceutical sciences and researches, SAHA IJPSR 2012, vol: 3(1):59-65 ISSN:
0975-8232, Cosmeceuticals and herbal drugs: Practical uses.
7. Skin Peptides: Biological Activity and Therapeutic Opportunities SARIKA NAMJOSHI, RIMA CACCETTA,
HEATHER A.E. BENSON School of Pharmacy, Curtin University of Technology, Perth, Western Australia,
Australia
8. Riccarda Serri, MD, Matilde Iorizzo, MD , Cosmeceuticals: focus on topical retinoids in photoaging .
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