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  1. 1. Journal of Cosmetic Dermatology, 0, 1--13 Fifty years of research and development of cosmeceuticals: a contemporary review Chun-Man Lee, MB BS, MRCP (UK) Department of Dermatology, Frimley Park Hospital NHS Foundation Trust, Frimley, UK Summary Facial rejuvenation can be categorized into skincare and facial contouring. Research and development of cosmeceuticals is aimed at addressing the major signs of photoaging: wrinkles, dyschromia, and sallowness. Assessment of photoaging comes in clinical and photographic forms; a photonumeric scale developed by Griffiths et al. has been assured of its validity and reliability for the assessment of severity of photoaging in qualitative studies. Treatment of photoaging comes in two categories: preventive and reversal of signs; whilst sunfactors are the most efficient and essential in preventing photodamage, research and development of cosmeceuticals for facial rejuvenation has been robust, thanks to several landmark studies in the last fifty years, funded by some of the forerunners in contemporary cosmetic industry. Stem cell research remains the current forerunner in research concerning cosmeceuticals. Nevertheless, high-quality, randomized control trials remain scarce within the contemporary literature, and more research and trials without funding by the industry are required to give rise to impartial comparisons between various cosmeceutical products. The “perfect cream” for facial rejuvenation remains elusive. Keywords: cosmeceutical, sunscreens, antioxidant, photoaging of the skin, facial rejuvenation, alpha hydroxy acids Introduction: facial aging and rejuvenation A strong correlation exists between physical attrac- tiveness and social status, where a youthful appear- ance confers economic and social advantages.1 Facial rejuvenation can be broadly categorized into alteration of skin’s structure and functionality and facial con- touring; within the literature, there is evidence for the superiority of youthful-looking skin over facial symme- try and proportions.2 Facial soft tissue changes associ- ated with aging are well known for their effects on facial morphology – from skeletal atrophy giving rise to less anchoring support to overlying tissues, to the loss of facial fat pad volume leading to the downward migration of esthetic units that results in folds in between two vertically adjacent units – the sequelae of facial aging include deep wrinkles and folds, a gaunt appearance with protrusion of infraorbital fat pads, thinning of the lips as well as jowls; a triangular facial shape gives the impression of an aging face, in contrast to an “inverted triangle” that represents youthfulness.3 Whilst facial contouring can be addressed by means of surgical and such nonsurgical procedures as injectables (of neurotoxins and synthetic volumizing and/or stimulatory fillers) and thread-lift, topical therapies have been developed to enhance the effects of ablative procedures such as chemical peels, microneedling, and CO2 ablative laser resurfacing: to Correspondence: Chun-Man Lee, Speciality Doctor in Dermatology, Department of Dermatology, Frimley Park Hospital NHS Foundation Trust, Dermatology, Portsmouth Road, Frimley, GU16 7UJ, UK. E-mail: benjam- Accepted for publication July 8, 2016 © 2016 Wiley Periodicals, Inc. 1 Review Article
  2. 2. improve the appearance of skin under the main pillars of photoaging – wrinkles, dyschromia, and sallowness – unlike nonsurgical procedures, the onset of action, effectiveness, and tolerance for the latter are slow and certainly not immediately observable, care has to be taken when analyzing data purporting efficacy of cosmetic products – data must be obtained from a reliable assessment of photoaging when comparing products. Assessment of photoaging Photoaging accounts for the largest proportion of cases of extrinsic skin aging; it is characterized by its preco- cious onset and such exaggerated characteristics as coarse wrinkling, dyschromia, and sallowness that form the basis of a descriptive grading scale used in the assessment of cutaneous photodamage (Fig. 1).4 The earliest validated photonumeric scale described in the literature was the Leeds scoring system for assess- ing acne severity.5 Griffiths photonumeric scale appears to be derived from a pre-existing facial acne scale, with five high-quality, paired photographic stan- dards (profile and oblique views) to which a photoaged facial skin is graded against.6 It appears to be compre- hensive and superior in consistency of getting the same results amongst assessors/graders, and repeatability, when compared against a basic descriptive scale – it has been utilized in numerous studies aimed at com- paring efficacies of “antiaging” cosmetic products are available in the literature, in addition to the famous Leiden Longevity Study that explored a link between facial appearance and familial longevity.7 (Fig. 2) Prevention and reversal of photoaging Clinical signs of skin aging solely by the passage of time rarely manifest prior to the seventh decade – pre- mature skin aging result from the accumulative expo- sure to environmental factors, amongst which terrestrial UV radiation and sunlight has to be the most important owing to it being the most ubiquitous of all.8 Signs of photoaging can be categorized and matched against histological changes of skin, in addi- tion to examples of ingredients that have been researched and developed to prevent, alleviate, or even reverse these changes (Table 1) – this article will look at these ingredients in greater details. The scope of this article focuses on the prevention and reversal of the process by the above-mentioned cosmeceutical ingredients. The term “cosmeceutical” is used to refer to skincare products formulated with biologically active ingredients in the discussion. A timeline of “land-mark” ingredients is illustrated below (Fig. 3). Much of the available evidence comes from the literature research – from manufacturers’ claims with traceable references, to landmark studies refer- enced by contemporary academic resources such as textbooks.11 From the outset, the most direct approach of photoprotection is sun avoidance (long-sleeves, sun- hat, and avoidance of outdoor activities at peak UV hours) and application of sunscreen. Figure 1 Descriptive scale used in the assesment of cutaneous photodamage*. 2 © 2016 Wiley Periodicals, Inc. A contemporary review of cosmeceuticals .C-M Lee
  3. 3. Prevention Sunscreens can be broadly categorized functionally into absorbers and reflectors, which are comprised of organic chemical compounds (benzophenones, avoben- zone, ecamsule, methyl antranilate, salicylates, cinna- mates, etc.) and the inorganic metal particles, respectively. A summary of categories of some common sunscreen ingredients used in cosmeceuticals is illus- trated as follows11 : (Fig. 4) Organic compounds absorb solar UV radiation and dissipate it by means of a series of exothermic reactions or high wavelength (therefore low energy) irradiation into the surrounds: Benzophenones (benzophenone-3, oxybenzophe- none) are predominant UVB absorbers (peak absorption at 290 nm) with weak absorption of UVA that are added as a secondary sunscreen ingredient in combina- tion with other ingredients for several reasons: • Benzophenones have the highest bioavailability out of all sunscreen ingredients due to their being lipid soluble and are readily absorbed systemically into skin; there are reports of these compounds being found in blood and urine samples of human sub- jects following topical applications.17,18 • Because of its lipophilicity, high concentrations may render the end product sticky and esthetically unpleasant. • They accounted for the highest incidence of photo- dermatitis in the literature of the last decade.19 Avobenzone (also known as Parsol 1789) is a highly effective UVA absorber with UVB coverage (290-400 nm). It has the best safety profile amongst all sunscreen ingredients but its photo-instability and incompatibility with metal oxide sunscreen ingredients renders it an unpopular choice until the issues are negotiated by the combination with benzophenones that confer photo-stability; such a formulation has been marketed under the patent name of HelioplexTM : Neutrogena division of Johnson & Johnson, New Brunswick, NJ, USA (SPF70) by Neutrogenaâ (Neutro- gena, Los Angeles, CA, USA).20 Ecamsule was another organic compound patented by L’Orealâ (^Ile-de-France, France) (1982) under the trade name MexorylTM (L’Orealâ ) to stabilize avoben- zone. Figure 2 CEM Griffiths et al. ©1992 “A photonumeric Scale for the Assessment of Cutaneous Photodamage from Archives of Der- matology”.4 Each of the five photographic standards (frontal and oblique) is assigned a grade (even numbers) to indicate an inter- val degree of photodamage. A nine-point scale is completed with intermediate grades to fill in gaps (odd numbers) where 0 indi- cates no photodamage and 8 being most severe. In this article, a high degree of intergrader agreement illustrates reliability of the scale upon comparison with a descriptive grading scale (see below). © 2016 Wiley Periodicals, Inc. 3 A contemporary review of cosmeceuticals .C-M Lee
  4. 4. Methyl anthranilate is safe and effective organic sunscreen ingredient frequently found in formulations that confer photoprotection against UVA. Its stickiness renders it esthetically unpleasant in higher concentra- tions.21 Titanium dioxide and zinc oxide are metal oxides. In the form of microparticles, these inorganic com- pounds deflect and protect the skin beneath from solar UV radiation. Nanoparticles have been developed in an attempt to mitigate white streaks in cosmetically sensi- tive areas on skin and/or clothing; for years, there remained fear for possible systemic absorption through the skin.20 Reversal of photoaging All-trans retinoic acid acts as a hormone that is taken up by cells to reach the nucleus, where it interacts with the corresponding receptors, retinoic acid recep- tors (RAR), and retinoid x receptors (RXR), to activate or inhibit the transcription process of elements that modulate keratinization of epidermis, synthesis of colla- gen, and production of matrix metalloproteinases (MMPs) – the antiwrinkle effect is therefore attributed to the combined effect of stimulated pro-collagen I synthesis, through a cell signaling pathway, and the inhibition of UV-induced production of MMPs.12,22 Immunohistochemical evidence exists for the increase in collagen content and thickening in epidermis in sec- tions biopsied from all-trans RA-treated skin. In addi- tion, for a mechanism not completely understood, retinoic acid and derivatives seem to promote a rela- tively minor lightening effect by suppressing expression of the key enzyme tyrosinase in melanin (pigment) synthesis.23,24 The current data available for molecular mechanisms of all-trans RA’s effects on skin rejuvena- tion have been summarized in a British journal article, published in 2010 (extract, in Table 2). Tretinoin has been the prescription only form of topi- cal vitamin A since the beginning; it has been well studied over the centuries, and its profile of side effects has been predominately by irritability to skin – CEM Griffiths (1992) illustrated the better of the two most studied concentrations promoting similar effects on photoaged skin. Based on an abundance of clinical evi- dence, over-the-counter retinoids are developed from such intermediate forms as retinol and retinyl esters (the least irritating of two) that may produce the same effects and side effects but to a lesser degree26 ; these chemicals are unstable upon exposure to sunlight and Table 1 A summary of main characteristics of photoaged skin with their histological correlates on which cosmeceutical products are researched and developed Characteristics of photoaging and underlying mechanisms Additional information Examples of topical therapies/cosmeceutical ingredients Sallowness and uneven texture due to accumulation of elastotic material. Poor quality of keratinization due to slowing of differentiation process and subsequently shedding of squamocytes lead to enlarged and clogged pores. UVR induces reactive hyperproliferation of keratinocytes at some sites and apoptosis in others.9 An abundance of dystrophic elastotic materials in place of healthy elastic fibers that are now degraded and damaged either directly by photochemical reaction or indirectly via generation of reactive oxygen molecules (RoS) and metalloproteinases (MMP) 8 – in a process known as solar elastosis. Sunscreens (benzophenone, avobenzone, ecamsule, methyl anthranilate, metal oxides) to block skin interaction with UVR; hydroxyl acids (AHAs, PHAs, bionic acids) to exfoliate in low concentrations and induce renewal of keratinization by epidermolysis in high concentrations; vitamin B3 and its derivatives to regulate keratinization whilst conferring antioxidative effects. Coarse wrinkles secondary to loss of major extracellular matrix (ECM) components and as a consequence the loss of firmness. Dehydrated skin is marked with finer wrinkles. Photoaging is predominantly characterized by wrinkling in Fitzpatrick skin types I-III. Reduced density of dermal collagen as a result of UVR induced breakdown either directly or indirectly via generation of MMP; thinning of epidermis and impaired barrier function of skin results in profound dehydration Sunscreens as above. Retinoids (retinaldehyde, retinol, retinyl propionate) to promote thickening of epidermis, stimulate synthesis of procollagen I and thence dermal collagen; peptides (pal-KTTKS) stimulate collagen synthesis and improve barrier function.10 Polyhydroxy/bionic acids are large molecule hydroxyl acids that are strong humectants. Dyschromia is the uneven skin tone found in photoaged skin; it is predominant in aging skin amongst darker skin types. Such is the result of clumping of melanocytes induced by UVR exposure. Lentigines result from a fundamental increase in melanocytes in basal epidermis; ephilides (freckles) due to accumulation of melanin (pigment) in the more superficial layers, more common in summer months and in younger, fairer skin types. Sunscreens as above. Antioxidants to enhance photo-protective effects of sunscreens. Sugar amines such as N-acetyle glucosamine (NAG) and botanicals such as kojic acid, liquorice extract, and arbutin are effective lightening agents to skin tone. 4 © 2016 Wiley Periodicals, Inc. A contemporary review of cosmeceuticals .C-M Lee
  5. 5. atmospheric oxygen; therefore, extra caution must be taken with storage. (Fig. 5) Topical antioxidants Antioxidants confer ability of the skin to ameliorate oxidative stress in addition to the various molecular components of skin with intrinsic antioxidant proper- ties.29 Humans lack the ability to synthesize vitamin C due to a mutated gene present in most mammals 29,30 and therefore are reliant on dietary source. Only a small proportion of what is absorbed will end up in the skin – topical vitamin C needs to be in high concentration (15% L-ascorbic acid) in order to achieve efficacy; it has an in vivo half-life of 4 days when applied on skin, and any exposure to oxidative stress would deplete its content in a neutralizing reac- tion – the ideal pH for the stabilization of a solution of pure vitamin C is acidic, at pH 3.5.31 Either vitamin C or vitamin E alone is ineffective in preventing UV radiation-induced skin damage, as manifested in skin erythema (sun burn); Halperin, et al. (1993) demonstrated the lack of effect of topical 15% L-ascorbic acid alone on radiation dermatitis – topical 15% vitamin C (L-ascorbic acid) in combi- nation with 1% vitamin E (alpha-tocopherol) Figure 3 The popular use of the term cosmeceutical originates from the discovery of the antiaging effect of topical retinoic acid and derivatives on skin by Dr Albert Kligman PhD in 1984.12 In 1989, two researchers Dr Eugene Van Scott and Dr Ruey Yu PhD presented alpha hydroxyl acids as chemical compounds with cosmetic properties, 10 years after their discovery of their molecular effects on skin.13 This was followed by the development of topical antioxidants formulated with vitamins C and E.14 In 2009, a double-blind, randomized controlled trial 15 that illustrated efficacy in some contemporary cosmeceutical created a shopping frenzy for that product, which was hailed by the media as “the miracle ingredient”. The cosmetic companies behind these studies with or without historical affiliations with the researchers have thrived in brand management in the name of science for the decades to come. Figure 4 Representation of the ultraviolet (UV) component of the electromagnetic spectrum, copyright © 1997.16 Each organic com- pound tends to have a specific target range of UV radiation for photochemical reaction/absorption, whilst inorganic compounds which are largely tiny particles of minerals or metals would deflect UV beams indiscriminately – cosmeceuticals in today’s market are largely formulated with not one but several ingredients to achieve broad spectrum photoprotection. © 2016 Wiley Periodicals, Inc. 5 A contemporary review of cosmeceuticals .C-M Lee
  6. 6. provide synergistic protection against oxidative stress in skin32 ; 2 years later, the same authors suggested that adding ferulic acid (a botanical chemical, a potent phenolic antioxidant found in plants) to vita- mins C+E results in a fourfold increase in protection against UV-induced photodamage.33 In this study, higher minimal erythematous doses (MED) are required to activation of caspases that are markers of cell death response to the exposure of UV radiation, concluding that skin saturated in a solution of ferulic acid added into a solution of vitamins C+E has reduced clinical erythematous and immunological response to UV-induced damage. Vitamin B3, or niacin, is interconvertible with niaci- namide. It is a precursor molecule to a vast number of coenzymes that play a role in neutralizing oxidative stress in over 40 cellular biochemical reactions.34 Studies are largely randomized controlled trials looking at the in vivo effects of topical niacinamide (2-5%) of using sophisticated specialized skin analysis imaging systems that capture high-quality, standardized facial images.35–37 The antiaging effects an overall improve- ment of skin barrier (reduced TEWL and facial red blotchiness) and skin tone (with reduced sallowness), a reduction of fine wrinkles, and reduction of hyperpig- mentation.38 Like most other antioxidants, niaci- namide is chemically unstable when exposed to the atmosphere. One author who is the leading figure in research and development of topical niacinamide has suggested formulating products in the pH range of 4–7 to avoid hydrolysis (it converts niacinamide to nico- tinic acid that is irritant to skin);38 nicotinate esters such as tocopheryl nicotinate and methyl nicotinate have been developed to address skin irritability but evidence for efficacy is meager. Hydroxy acids Alpha hydroxyl acids (AHAs) are amongst the first to be discovered (Table 1) and developed for skin rejuve- nation in two formulations13 : In high concentrations (e.g., glycolic acid 35% and above), these promote epi- dermolysis exfoliation and effectively producing a chemical peel; in low concentrations, they normalize epidermal layers by thinning stratum corneum whilst promoting thickening of granular layer. Polyhydoxy (PHA)/bionic acids were subsequently developed that would rectify the irritating effect of alpha hydroxy acids on skin, whilst retaining their skin rejuvenation effects. One in vitro study used simulated solar radia- tion (SSR) on cultured murine fibroblasts, treated with gluconolactone (a PHA) in various concentrations, to demonstrate some activity in suppressing solar elasto- sis, via downregulating the gene responsible for the UV-induced production of dystrophic elastic fibers.39 In addition, antioxidative properties of gluconolactone and lactobionic acid have been demonstrated with the inhibition of oxidative discoloration of banana peels to the atmosphere.11 (Table 3) Peptide cellular messengers Peptides are long-chain molecules made up of build- ing blocks of protein, the amino acid molecules. In Table 2 A schematic representation of retinoid effects on skin, courtesy of Medscape ©201025 Molecular mechanisms Histological/ultrastructural features Clinical effects Increased collagen synthesis: o Inhibition of the UV-induced c-Jun o Alteration in the TGF-beta expression Inhibition of collagen degradation: o AP-1 mediated MMP inhibition Collagen rich “repair zone” in upper papillary dermis Increased collagen I, III and VII (anchor fibrils) Reorganization of dermal collagen into woven bundles of fibers Normalization of elastic tissue organization Increased angiogenesis Improvement of coarse wrinkling Initiation of increased epidermal proliferation o EGF receptor activation via specific induction of its ligands heparin-biding EGF and amphiregulin Increased epidermal differentiation Stimulated transglutaminase, involucrin, and fillagrin expression Epidermal hyperplasia Compaction of the stratum corneum Thickening of the granular layer Increased epidermal and dermal intercellular mucin deposition Increased skin smoothness and decreased roughness Inhibition of tyrosinase activity Inhibition of melanosome transfer Physicochemical UV photoabsorption Decreased melanin content Enhanced keratinocyte shedding Reduced size of melanocytes’ Golgi complex and endoplasmic reticulum Improvement of skin discoloration/dyschromia 6 © 2016 Wiley Periodicals, Inc. A contemporary review of cosmeceuticals .C-M Lee
  7. 7. cosmetics, peptides’ long-chain structures rendered the molecules lipophilic: able to absorb water content and confer hydration to the corneal layer of skin as a strong humectant. However, in recent years, new scientific interests have evolved into the use of pep- tides as cellular messengers – cells communicate and modulate activities by means of protein molecules (peptides) being secreted from one cell and inserted Figure 5 In this diagram, sourced from Bickers Athar ©2006, reactive oxygen species, ROS (O2 À and H2O2), and reactive nitrogen species, RNS (NO), are generated to promote oxidative stress by lipid peroxidation.27 The cascades of reactions that promote the conver- sion of these reactive species to the even more highly reactive groups of molecules are initiated by the exposure of skin cells to solar radi- ation (UVA and UVB, bottom left) and chemicals (termed xenobiotics in this representation, top left) from the environment. Antioxidants in skin include the soluble glutathione and ascorbic acid (vitamin C), in addition to the lipophilic alpha-tocopherol (vitamin E).28 Within each skin cell enzymes, such as glutathione (GSH), GSH reductase, superoxide dismutases (SOD), GSH peroxidase, catalase, and quinone reductases (QR, top left), act to neutralize reactive species by converting them to less reactive and/or nontoxic particles. Table 3 Antiaging effects of hydroxyl acids Hydroxy acids Histological effects Clinical effects Evidence Alpha hydroxy acids (glycolic, citric, lactic, mandelic acids) Epidermal: low concentration ↓melanin clumping, normalizing proliferation of keratinocytes Dermal: ↑ collagen, ↑ GAGs ↓mottled pigmentation and sallowness, ↓fine wrinkles, ↑skin firmness 40–43 Polyhydroxy acids (gluconolactone) Epidermal: ↑ thickness with normalized stratum corneum Dermal: ↑GAGs (HA) Antioxidative activity; minimizing solar elastosis; A large molecule with slower absorption and therefore ↓irritation and a humectant; ↓TEWL and irritant erythema with ↑protective barrier 39 Polyhydroxy bionic acids (lactobionic, maltobionic acids) As above Also a strong humectant, nonirritant; same action as alpha hydroxyl acids at epidermal and dermal levels. 44 Alpha hydroxyl acids have been shown in in vivo studies to rebuild dermal extracellular matrix components, by stimulating syntheses of procollagen I and glycoasminoglycans (GAGs) of which hyaluronic acid (HA) are predominant,40 and normalize cellular layers in the epidermis,13 in addition to a reduction in uneven pigmentation illustrated in various in vivo studies that was illustrated by a dose-depen- dent decrease in melanin deposition in vitro by mouse and human melanoma cells42 ; they are nonetheless highly irritating to skin. Poly- hydroxy/bionic acids are referred to as the second- and third-generation hydroxyl acids, respectively. These acids have acquired a larger molecular structure and thence properties of a strong humectant. Human studies performed with patch testing with 0.1% sodium lauryl sulfate (SLS) solution demonstrated an anti-irritant property 11 on a par with an improvement of barrier protection by the skin. Evidence is provided by selected randomized controlled studies utilizing clinical (digital imaging) and histological methods.45 © 2016 Wiley Periodicals, Inc. 7 A contemporary review of cosmeceuticals .C-M Lee
  8. 8. into another – amongst many peptides that have been developed to reduce wrinkles by targeting fibroblasts and stimulating collagenesis, one of the best known palmitoyl peptides has been developed by French manufacturer Sedermaâ (Sederma, Croda International Group, Le Perray-en-Yvelines, France), made up of palmitoyl-lysine, threonine, threonine, lysine, and serine (hence the abbreviated name pal- KTTKS).46 At a molecular level, this peptapeptide is a fragment of procollagen I; as long-chain polypep- tides are poorly penetrated into skin, the more lipo- philic compound has been developed by palmitoylation; such is rooted in an in vivo study demonstrating an enhanced absorption of a peptide drug.47 In one in vitro experiment, KTTKS has demonstrated efficacy in stimulating production of collagen in cultured fibroblasts.10 In a double-blind, randomized, placebo-controlled trial setup by researchers in the United States, digital facial imag- ing offered the best objective evidence of significant improvement in skin texture with reductions in wrin- kles at 8 weeks,48 without a report of skin intoler- ance. Growth factors and cytokines These are naturally occurring signal protein molecules involved in an inflammatory response in wound heal- ing; such has triggered research and development of applying physiologically balanced ingredients into topi- cally applied products – cosmeceuticals.49 Such mini- mally invasive procedures as dermabrasion and microneedling are based upon the idea of simulating wound healing to achieve skin rejuvenation; growth factors and cytokines are secreted by various skin cells to activate fibroblasts, stimulate collagenesis and colla- gen remodeling, in order to aid tissue regeneration and wound healing.50 Topical transforming growth factor (TGF)-beta 1 has been extracted from neonatal dermal fibroblasts in an in vivo study to develop a novel skin cream containing a mixture of human growth factors and cytokines.52 Histology and ultrastructural analysis have demon- strated evidence of skin rejuvenation with thickening of epidermis, and reduced solar elastosis and neocolla- genesis (Fig. 6), which correlates well with the improved appearance of skin texture and wrinkles after 6 months of twice daily topical application of study cream (PSPTM – processed skin cell proteins; Neocutis, Inc., San Francisco, CA, USA). The authors have pur- ported a positive correlation between an increased pro- duction of thinner collagen fibers and fibroblast density.49 However, whether the findings of an increase in collagen III fibers being represented by the appearance of thinner fibers in the papillary dermis, and such an increase being truly representative of neo- collagenesis, remains debatable. (Fig. 7) In addition, TGF-beta 1 appears to mediate lighten- ing effects effected by adipose tissue stem cells (ASC- CM), through an increased degradation of such important copper-containing enzymes for melanin production as tyrosinase and tyrosinase-related pro- tein 1.53 On that note, stem cells derived from Swiss Uttwiler Spatlauber apple trees have been extensively Figure 6 Extract, all rights reserved S Werner, R Grose. 2003 © Physiological Reviews 51 “Multiple functions of TFG-b during wound heal- ing”. TFG-b is produced by skin cells including fibroblasts and keratinocytes during wound healing to stimulate formation of new blood vessels, collagen fibers, and remodeling of ECM. TFG-b also regulates epithelial thickness by an inhibitory process. 8 © 2016 Wiley Periodicals, Inc. A contemporary review of cosmeceuticals .C-M Lee
  9. 9. studied in vitro for their potential effects of skin reju- venation.54 Whilst cosmeceutical products that con- tain Swizz apple stem cell extract have been developed with purported antiwrinkle effects evident in as little as 2 weeks,55 insufficient data are avail- able as evidence of a plausible mechanism of action and further research is needed. Skin-lightening agents For more than half a century, hydroquinone in low concentrations (2%) had been the gold standard over- the-counter (OTC) treatment for dyspigmentation; it binds onto the pigment-producing enzyme tyrosinase to inhibit its activity, thereby inhibiting melanosome production. Due to controversies over the safety of hydroquinone in cosmeceutical products – the most fearsome of which was a possible association with malignancies – numerous isolated reports have been gathered from the literature, dated to the first decade of this century.56 The need for an alternative skin- lightening agent has led to enhanced research and development of some of the currently widely available ingredients in cosmeceuticals, such as topical retinoids, vitamins C and B3, in addition to several others as out- lined below: (Table 4) Discussion Photoaging remains the biggest contributing factor for facial aging; three major signs of photoaging are wrinkles, dyschromia, and sallowness. Whilst this is only additional to the changes in facial contours with aging, which would require surgical and Figure 7 Courtesy of Dr Mussarrat Hussain, MD 52 # 2008 Informa UK Ltd. (Informa Healthcare, Taylor Francis AS); (top) electron microscopy demonstrating a slight decrease in coarse type I collagen fibers (60 nm) and a 58.4% increase in finer type III fibers were evidence 6 months after treatment (b). (bottom) under light microscopy, an increased density of fibroblasts in the dermis beneath a thickened epidermis is evident after treatment (b). © 2016 Wiley Periodicals, Inc. 9 A contemporary review of cosmeceuticals .C-M Lee
  10. 10. nonsurgical procedures to achieve a reversal of signs, research and development into finding the “perfect cream” has been robust, thanks to the major break- throughs in the discovery of numerous botanical ingredients that have subsequently led to develop- ment of cosmeceutical products accumulated in the market today. In addition, the methodology in assess- ing severity of photoaging has evolved over the years, from being descriptive and rather subjective, to becoming reliably reproducible and objective, with the help of digital imaging. The prevention and reversal of photoaging come in as part of a package in facial rejuvenation. Prevention is achieved by sun avoidance and application of sun- screen in regular intervals. Active ingredients of sun- screens can be categorized into reflectors and absorbers, with each of absorbers having a specific tar- get range of UV radiation for photochemical reaction/ absorption and therefore would require combination when formulating a broad spectrum, fit-for-all sun- screen, whilst the largely broad spectrum inorganic reflectors come with leaving the white streaks of metal oxide particulates that remain much undesired. Cases of photo-dermatitis, oily formulations, and the funda- mental necessity for regular application may render it unpopular for some. Reversal of photoaging has unfortunately been used excessively by the marketing in cosmetic indus- try – much of the scientific basis and research back- ing for most of cosmetic products remain meager, with only a handful remain worthy of literature research where materials are available – from ran- domized controlled experiments illustrating in vitro effects of a botanical ingredient, to the large-scaled trials demonstrating in vivo efficacies with modifica- tions to skin evident at the histological level. Herein, I have listed and described the most promising ingre- dients found in cosmeceuticals, with the backing of a plausible mechanism of action, a valid in vivo research evidence for efficacy at treatment the major signs of facial photoaging: wrinkles, dyschromia, and sallowness, whilst leaving room for imagination with the potential of research in stem cell therapy for facial rejuvenation. Whilst there is no such “perfect cream” in one single formulation for both the prevention and treatment of photoaging available to date, research and develop- ment for novel ingredients may lead to a change of culture of the modern cosmetics industry to one that is more scientific research, and less commercial market- ing, driven. High-powered, good quality clinical studies to look at efficacies and side effects of cosmeceutical Table 4 A summary of the most common pigment-lightening cosmeceutical ingredients with mechanisms of action supported by in vitro studies and available evidence of efficacy found in the literature Cosmeceutical ingredients Mechanism of action Evidence N-acetyl glucosamine (NAG), a precursor molecule to hyaluronic acid, which is an ECM component known collectively as glycoaminoglycans (GAGs) Inhibition of the activation of melanin-producing enzyme tyrosinase, also a strong humectant due to its hydrophilic molecular structure Mechanism of action is rooted in an in vitro study.57 Topical use of 2% NAG results in reduction in facial hyperpigmentation 58 and more so when combined with 4% niacinamide.59 Kojic acid, found as a by-product in malting rice, derived from fungi (Aspergillus and Peniciliium species) during fermentation process. Chelation of copper (an important cofactor constituent of the enzyme) and thereby inhibits the production of melanin by tyrosinase. A comparative study looking at combinations of glycolic acid + kojic acid versus glycolic acid + hydroquinone indicates equivocal efficacies in the treatment of melasma,60 but skin irritability remains an issue; cases of contact dermatitis exist for the topical use of kojic acid 61 Liquorice extract contains a number of active pigment-lightening agents known as flavonoids that act to inhibit melanogenesis at various levels of the pathway. Liquirtin contained in the extract disperses melanin; glabridin acts on tyrosinase and inhibits melanogensis 62 other chemicals within it confers an anti-inflammatory effect and therefore render it nonirritating to skin 61 In vivo studies indicate some therapeutic value in treating postinflammatory hyperpigmentation 63 but efficacy appears minimal in comparative studies 64 Arbutin is a botanical ingredient extracted from the bearberry plant and is used in a variety of products manufactured in Japan and is a common pigment-lightening ingredient in many cosmeceutical formulations marketed in the United States.65 It is glycosylated hydroquinone.66 It inhibits activity of tyrosinase as well as melanosome maturation via extracellular signal-related protein kinase (ERK) activation67 ; tyrosinase activity is inhibited without altering intracellular RNA expression. Efficacy is concentration-dependent, with 3% being commonly used in common cosmeceuticals, beyond which concentration there are reports of postinflammatory hyperpigmentation.61 10 © 2016 Wiley Periodicals, Inc. A contemporary review of cosmeceuticals .C-M Lee
  11. 11. products as one formulation of a mix of ingredients remain an area to explore. References 1 Heilman M, Stopeck M. Being attractive, advantage or disadvantage? Performance-based evaluations and recom- mended personnel acions as a unction of appearance, sex, and job type. Organ Behav Hum Decis Process 1985; 35: 202–15. 2 Roberts S, Little AC, Morris Gosling L et al. MHC-Hetero- zygosity and human facial attractiveness. Evol Hum Behav 2005; 26: 213–26. 3 Rohrich R, Pessa J, Ristow B. The youthful cheek and the deep medial fat compartment. Plast Reconstr Surg 2008; 121: 2107–12. 4 Griffiths CE, Wang TS, Hamilton TA et al. A photonu- meric scale for the assessment of cutaneous photodam- age. Arch Dermatol 1992; 128: 347–51. 5 Tan J, Fung JTK, Gupta A et al. Development and valida- tion of a comprehensive acne severity scale. J Cutan Med Surg 2007; 11: 211–6. 6 Griffiths C. 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