SEARCH

SEARCH BY CITATION

Keywords:

  • cosmetics;
  • elderly;
  • peptides;
  • percutaneous penetration;
  • proteins

Synopsis

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

Ageing, a basic biological process seen in all living creatures, is not preventable. Surgical and topical modalities have been invented and substances were applied topically to alter the ageing process. Peptides and proteins, frequently used for this purpose, were categorized into four groups: signal peptides, enzyme-inhibitor peptides, neurotransmitter-inhibitor peptides and carrier peptides. We comprehensively review eligible studies -including controlled ex vivo or in vivo efficacy studies on any topical peptide or protein that has been administered to treat signs and symptoms of ageing.

Résumé

Le vieillissement, processus biologique concernant toutes les créatures vivantes est inévitable. Divers moyens chirurgicaux et topiques ont été inventés et plusieurs substances ont été appliquées pour modifier ce processus. Les peptides et les protéines fréquemment utilisés dans ce but sont regroupés en 4 catégories : les peptides signaux, les peptides inhibiteurs enzymatiques, les peptides inhibiteurs de neurotransmetteurs et les peptides transporteurs. Nous passons en revue les études recevables – y compris les études d’efficacitéex vivo ou in vivo– concernant les peptides ou les protéines mis en œuvre pour traiter les symptômes et les signes du vieillissement.


Introduction

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

In the year 2000, individuals over the age of 65 represented 13% of the United States population; this is expected to increase to 20% by 2030. This preponderance of older individuals over younger ones will transform the shape of the age distribution graph into a rectangle rather than the current pyramid observed [1].

This demographic shift calls for increased efforts to prevent the ageing process and develop safe and effective drugs for the elderly. In cosmetic dermatology, experts are exploring better anti-solar, anti-ageing, anti-wrinkle and firming products. Pharmaceutical companies frequently use peptides as active ingredients in their creams. Peptides have different effects on the skin especially for cosmetics purposes, but one important hurdle to use them topically is their permeability to penetrate skin.

Generally, permeation ability depends on different factors: physicochemical properties of the substance (acid dissociation constant [pKa], molecular size, stability, binding affinity, solubility and partition coefficient); the time-scale of permeation; integrity, thickness and components of the skin, cutaneous metabolism; site, area and duration of application; properties of the transdermal device and the creation of a local depot at the site of application [2, 3]. In summary, it is ideal to have a topical drug with parameters within the below-mentioned listed range:

  • 1
     Molecular weight less than 500 Da;
  • 2
     Moderate log of partition coefficient octanol/water between 1 and 3;
  • 3
     Melting point less than 200°C;
  • 4
     Reasonable aqueous solubility (>1 mg mL1);
  • 5
    No or few polar centres [4, 5].

Diffusivity of the molecules in stratum corneum is related to the size and number of hydrogen bonding groups on a molecule, being maximal for small non-hydrogen bonding molecules and reaching a minimum with about four hydrogen bonding groups [6].

As peptides and proteins contain many amide bonds, (as hydrogen bond donor and acceptor groups), and because of their large molecular size, they have low diffusivity in skin. Furthermore, as they often charged at physiological pH, they are intrinsically hydrophilic. Hence, the lipophilic stratum corneum is a significant barrier to penetration [7].

Overall, topical peptides and proteins have been successfully and widely used. Patch test of purified protein derivatives tuberculin protein and more specific derivatives like MPB64 have been effectively addressed for active tuberculosis diagnosis [8, 9]. Tacrolimus and with lower permeability, pimecrolimus can penetrate through the skin to treat atopic dermatitis patients [10, 11].

Frech et al. [12] found a safe and protective vaccine patch containing heat-labile protein enterotoxin to prevent diarrhoea in travellers to Mexico and Guatemala. Even topical cyclosporine A with molecular weight of more than 1200 Da could be delivered into the skin with delivery enhancing methods [13].

The main barrier for topical drugs is stratum corneum, the outermost layer of epidermis. Several techniques overcome such a barricade. For example, chemical penetration enhancers might be useful for peptide dermal delivery [14].

One study [15] addressed usefulness of iontophoresis for topical insulin application. Other mechanisms like sonophoresis in liposomal peptides [16] and colloidal carrier systems [17] are considered helpful in this regard. Carrier peptides can increase and accelerate the permeation process. Chen et al. [18] reported that a short synthetic peptide (ACSSSPSKHCG) identified by in vivo phage display assay, facilitated efficient transdermal insulin delivery through intact skin. Although topical use of a peptide has potential to be effective, delivery across skin can be difficult because of the ionic nature of such materials. An approach to improving delivery is the use of fatty acid derivatives to increase the lipophilic property of the peptide. For example, the palmitoyl derivative of the polypeptide interferon α penetrates across human skin five- to six-fold greater than the simple peptide [19] and also, facial skin improvement has been reported after topical pal-KTTKS (palmitoyl pentapeptide-4) therapy [20].

Many peptides and proteins used for cosmetic indications; glycyl-histidyl-lysine (GHK)-Cu is one of the most widely utilized for wound healing and anti-ageing indications. Abdulghani et al. [21] revealed its enhanced but insignificant anti-ageing effects when compared with tretinoin, Vitamin C and melatonin.

Palmitoyl KTTKS, the other frequently used peptide, was shown to have more significant results than placebo and an active comparator [20, 22]. Acetyl hexapeptide-3 (Argireline®; Centerchem, Barcelona, Spain) had promising results. The depth of wrinkles was reduced more than 30% for Argireline® vs. 10% for placebo after 30 days [23].

All aforementioned peptides as examples can suggest that these agents may be effective. Note that in the only published systematic review [24] on interventions for ageing skin; no peptide therapy was included. Here, published peptides and proteins categorized in four categories, their characteristics, in vitro studies and in vivo efficacy data are presented.

Material and methods

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

Pubmed, embase and Scopus were systematically searched from 1974 to June 15, 2008 (Appendix I). Different words have been used to locate any known peptides or proteins; find all possible topical therapies; locate all cosmeceutical-related papers and rule out irrelevant papers. The irrelevant studies were mainly on topical peptide application for skin cancers, inflammatory diseases, infectious diseases or blistering diseases. They also considered irrelevant if they used peptides as vaccines. We screened all references of relevant articles to find other eligible resources. In addition, some in vitro and in vivo data were collected from pharmaceutical companies’ websites. The main purpose of this study was to evaluate available evidence on efficacy data of topical peptides and proteins for ageing skin and only controlled trials were included in this regard.

Results and discussion

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

Surprisingly, there were scarce data about permeation abilities of these topical peptides. Only permeation coefficients for three widely used topical cosmeceutical peptides (GHK and γ-L-glutamyl-L-cysteinyl-glycine (GSH); [25]) and Melanocyte stimulating hormone (MSH) ([26, 27]) and some amino acids [28, 29] as well as some of their Cu complexes were reported (Table I).

Table I.    Permeation coefficients (Kp) of available relevant peptides
PeptidePermeation coefficient (cm s−1)PeptidePermeation coefficient (cm s−1)
  1. GHK, glycyl-histidyl-lysine; GSH, γ-L-glutamyl-L-cysteinyl-glycine; MSH, Melanocyte stimulating hormone.

  2. *Liposome model membranes were used.

  3. †Hairless mouse skins were used.

  4. ‡Human skin was used.

GHK*[1]1.36 × 10−9Serine†[2]1.00 × 10−8, pH = 5.6
GHK-Cu*[1]1.35 × 10−98.33 × 10−9, pH = 7.4
GSH*[1]8.63 × 10−10Threonine†[2]3.27 × 10−8, pH = 6.2
GSH-Cu*[1]1.5 × 10−93.61 × 10−9, pH = 7.4
Histidine†[2]4.44 × 10−9, pH = 7.6Isoleucine†[2]1.44 × 10−8, pH = 6.0
5.55 × 10−9, pH = 7.43.61 × 10−9, pH = 7.4
Histidine-Cu*[3]2.72 × 10−6 ± 0.05 × 10−6Leucine†[2]4.44 × 10−9, pH = 6.0
Alanine†[2]1.03 × 10−8, pH = 6.08.05 × 10−9, pH = 7.4
1.53 × 10−8, pH = 7.4Asparagine†[2]1.14 × 10−8, pH = 5.4
Alanine-Cu*[3]1.90 × 10−6 ± 0.16 × 10−69.72 × 10−9, pH = 7.4
Lysine†[2]1.08 × 10−7, pH = 9.8Asparatic acid†[2]2.38 × 10−8, pH = 2.8
5.83 × 10−9, pH = 7.42.22 × 10−9, pH = 7.4
Lysine-Cu*[3]1.66 × 10−6 ± 0.07 × 10−6Glutamine†[2]8.88 × 10−9, pH = 5.6
Glycine†[2]3.30 × 10−8, pH = 6.01.39 × 10−8, pH = 7.4
1.05 × 10−8, pH = 7.4Glutamic acid†[2]1.36 × 10−8, pH = 7.4
Glycine-Cu*[3]1.62 × 10−6 ± 0.06 × 10−62.78 × 10−9, pH = 7.4
Valine†[2]1.25 × 10−8, pH = 6.0Phenylalanine†[2]6.78 × 10−8, pH = 5.4
3.61 × 10−9, pH = 7.48.33 × 10−9, pH = 7.4
Valine-Cu*[3]1.59 × 10−6 ± 0.07 × 10−6Arginine†[2]9.05 × 10−8, pH = 10.8
α-MSH (hisetal)†[4]1.55 × 10−82.77 × 10−8, pH = 7.4
α-MSH (hisetal)‡[5] 2.58 × 10−9Tyrosine†[2]7.22 × 10−9, pH = 5.6
Methionine†[2]4.72 × 10−9, pH = 5.64.44 × 10−9, pH = 7.4
8.61 × 10−9, pH = 7.4Tryptophan†[2]5.28 × 10−9, pH = 5.7
Proline†[2] 9.16 × 10−9, pH = 6.34.17 × 10−9, pH = 7.4
7.50 × 10−9, pH = 7.4Cysteine†[2]9.44 × 10−9, pH = 5.2
 5.28 × 10−9, pH = 7.4

Braun et al. [30] reported relative superoxide dismutase content that has been absorbed in the epidermis and dermis after an 8-h penetration. The ratios of total concentration for epidermis and dermis were 0.009% and 0.010% after 4 h and 0.031% and 0.010% after 8 h respectively. The characteristics of included substances are shown in Table II. Eligible in vivo efficacy studies are shown in Table III.

Table II.    General characteristics of peptides and proteins
Peptides and proteinsAlternate/generic namesSourcePeptide typeMechanism of actionCosmeceutical applications
  1. GHK, glycyl-histidyl-lysine; IGF, insulin growth factor; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor.

Copper tripeptide complexCopper tripeptide-1 or GHK-Cu or Iamin®SyntheticSignal and carrier peptidePromotes ‘extra large’ collagen aggregates degradation, more regularly collagen synthesis, elastin, proteoglycans, glycosaminoglycans production and anti-inflammatory and antioxidant responsesAnti-ageing, anti-wrinkle, After-sun products, after skin resurfacing, skin moisturizer, hair growth stimulator
Biopeptide-CLPal-GHKSyntheticSignal peptideStimulates collagen and gylcosaminoglycans synthesisAnti-ageing, anti-wrinkle, antisolar, firming, skin moisturizer
Syn®-CollPalmitoyl tripeptide-3/5SyntheticSignal peptideMimics thrombospondin I tripeptide sequence and promotes collagen formationImproves stretch marks, anti-wrinkle, skin moisturizer, improves skin’s firmness and tone
Peptamide-6FVAPFP or phe-val-ala-pro-phe-proBiotechnological (Saccharomyces yeast fermentation)Signal peptideIncreases collagen synthesis, upregulates growth factors, transmembrane, matrix and cell shock proteinsFirming peptide ideal for all face/body/eye creams, anti-ageing
Acetyl tetrapeptide-9AcTP1SyntheticSignal peptideStimulates collagen I and lumican synthesisAnti-ageing, Anti-wrinkle, firming peptide
Acetyl tetrapeptide-11AcTP2SyntheticSignal peptideStimulates keratinocyte cell growth and syndecan-1 synthesisAnti-ageing, Anti-wrinkle, firming peptide
Acetyl hexapeptide-3Argireline® or acetyl hexapeptide-8SyntheticNeurotransmitter inhibitor peptideInhibits SNARE complex formation and catecholamine releaseAnti-wrinkle especially periorbital, skin moisturizer, improves skin’s firmness and tone
Pentapeptide-18Leuphasyl®SyntheticNeurotransmitter inhibitor peptideMimics the natural mechanism of enkephalins and inhibits neuronal activity and catecholamine releaseAnti-wrinkle (periorbital), skin moisturizer, improves skin’s firmness and tone
Pentapeptide-3Vialox®SyntheticNeurotransmitter inhibitor peptideCompetitive antagonist at the acetylcholine receptorsAlternative to Botox®, anti-wrinkle (against expression wrinkles), anti-ageing
Pal-KTTKSPalmitoyl pentapeptide-4 or palmitoyl pentapeptide-3 or palmitoyl oligopeptide or Matrixyl®Synthetic (Pro-collage n I fragment)Signal peptideStimulates collagen I, III and VI, fibronectin, elastin and glucosamnoglycans productionAnti-ageing, anti-wrinkle
Tripeptide-10 CitrullineDecorin-like tetrapeptide (Decorinyl™)SyntheticSignal peptideRegulates collagen fibrillogenesis and influences diameter and placement of collagen fibresAnti-ageing, firming agent
Human growth hormonehGHBiotechnological (recombinant)Signal peptideIncreased IGF-1 production, fibroblast and keratinocyte activity, and sebum productionAnti-ageing, anti-wrinkle, after skin resurfacing
Transforming growth factorsTGF-α and TGF-βBiotechnological (recombinant)Signal peptideReversibly inhibits keratinocytes and leucocytes growth, promotes keratinocyte migration, chemotactic for marcrophages and fibroblastsAnti-photoageing, anti-wrinkle, post-laser uses
Interferon AlphaIFN-αBiotechnological (recombinant)Signal peptideIncreases the concentration of dendritic cells and CD1a and HLA-DR-positive cellsAnti-ageing, anti-wrinkle
Heat shock protein (70)Hsp70Biotechnological (recombinant)Signal peptideProtects the cells against apoptosis, ageing and UV damageAnti-ageing, anti-wrinkle
Syn®-AkeTripeptide-3 or dipep tide diaminobutyroyl benzylamide diacetateSyntheticNeurotransmitter inhibitor peptideMimics the effect of Waglerin 1, a peptide that is found in the venom of the Temple Viper, Tropidolaemus wagleriAnti-ageing, intensive anti-wrinkles
Soybean protein/amino acidsGlycine Soja Protein or Preregen®Natural (Soybean seed)Enzyme inhibitor peptideInhibits the formation of proteinases, increases trichoblast and atrichoblast numbers, increases the number and length of the root hairsAnti-ageing, skin moisturizer, used in cleansing detergents, sensitive skin care, anti-solar, regenerating effect. Hair-promoting agent
Keratin proteins/amino acidsKeramino 25®Natural (human hair and sheep’s wool)Structural peptideImproves hydration and elasticity of the skin and hairSkin and hair moisturizer, firming agent, hair shiner
Decorinyl™Tipeptide-10 CitrullineSyntheticSignal peptideMimics the sequences of decorinand regulates fibrillogenesis and control fibril growth and their uniformityAnti-wrinkle, increases skin suppleness and tone
Silk proteinSericinNatural (moddle silk gland of the silkworm Bombyx Mori)Antioxidant, enzyme inhibitor protein, copper chelator proteinChelates with copper, inhibits lipid peroxidation and tyrosinase activity and keratinocyte apoptosisAnti-ageing, anti-wrinkle, skin moisturizer
AquaporinAQPNatural (extracted from Ajuga turkestanica)Signal proteinIncreases epidermal proliferation and differentiation. Makes stratum corneum thickerAnti-ageing, anti-wrinkle, skin moisturizer
Table III.   Efficacy data
PeptidesStudy IDIndication of topical useStudy designCharacteristics of subjectsTreatment arm(s)Treatment protocolEfficacy
  1. AB, assessor-blind; AC, active-controlled; b.i.d., twice daily; BA, before-after study; BSA, bovine serum albumin; COX-2, cyclooxygenase 2; CRS, cell rejuvenation serum; DB, double-blind; IWL, internal wool lipid; OL, open-label; O/W, oil-in-water; PB, patient-blind; PG, parallel-group; PC, placebo-controlled; PSP, processed skin cell proteins; PUVA, Psoralen + UVA; Sig., significant; R, randomized; TEWL, transepidermal water loss; TNS, tissue nutrient solution recovery complex; UC, untreated-controlled; UV, ultraviolet; WP, within-patient; HR, xxxxxx; TGF, transforming growth factor; GHK, glycyl-histidyl-lysine.

Biotinyl-GHKLintner K [38]Skin conditioning (anti-ageing)Controlled ex vivo studyEx vivo cell culture model containing dermal and epidermal cellsBiotinyl-GHK vs. control groupThe solutions were applied to the cell cultureBiotinyl-GHK but not control solution stimulates collagen IV and laminin production and keratinocyte mitosis
GHK-CuAppa et al. [85]Skin conditioning (anti-ageing)Non-R, ACVolunteer femalesGHK-Cu containing liquid foundation and GHK-Cu containing cream concealerFormulations were applied for 8 weeksSig. improvements in all evaluations were found for both products
Leyden et al. [86]Anti-ageingDB, PC71 Female volunteers with mild to advanced photodamageGHK-Cu vs. placebo creamsThe creams were applied on the faces b.i.d. for 12 weeks Sig. improvements for GHK-Cu than placebo for all measurements by week 4
Leyden et al. [88]Anti-ageing (periorbital)DB, PC41 Female volunteers with mild to advanced photodamageGHK-Cu vs. Vitamin K creamsThe creams were applied around the eyes b.i.d. for 12 weeks Sig. improvements for GHK-Cu than placebo for all measurements by week 4
Finkey et al. [87]Anti-ageingR, DB, PG, PC67 Female volunteers aged 50–59 with mild to advanced photodamageGHK-Cu vs. placebo creamsCreams were applied on the face b.i.d. for 12 weeksGHK-Cu improved skin laxity, clarity and appearance, reduced wrinkles and increased density and thickness
Finkey et al. [87]Anti-ageingNon-R, UC5 Female volunteers aged 50–59 with mild-advanced photodamageGHK-Cu vs. no treatmentThe cream was applied on face b.i.d. for 12 weeksGHK-Cu stimulated dermal keratinocyte proliferation
Abdulghani et al. [21]Anti-ageingNon-R, AC, PG, WP20 Healthy volunteersTopical tretinoin, topical Vitamin C, Topical GHK-Cu, topical melatonin20 Subjects received creams to the extensor surface of thighs for 1 monthIn terms of increase of pro-collagen synthesis, 4/10, 5/10, 5/10 and 7/10 of patients showed response to tretinoin, Vitamin C, melatonin, and GHK-Cu respectively
Tripeptide-10Puig et al. [40]Anti-ageingAB, PC, PG43 Female volunteers aged 40–580.01% Liposomal tripeptide-10 citrulline cream vs. placebo creamThe creams were applied on the face (temple) daily for 28 daysTripeptide-10 induced a sig. increase in skin suppleness. No sig. increase in placebo group
Leuphasyl® vs. Argireline®Centerchem fact sheetAnti-ageingAC, PG43 Healthy female volunteers aged 39–64Cream containing 5% Leuphasyl® solution (0.05%) vs. cream containing 5% Argireline® solution (0.05%) vs. combinationEach cream was applied b.i.d. around the eyes of 14 volunteers for 28 daysMean wrinkle reduction was 11.64% vs. 16.26% vs. 24.62% for Leuphasyl®, Argireline® and combination, respectively
lipopentapeptideWatson et al. [54]Anti-ageingR, ACNine healthy photoaged volunteers (2 men 7 women; aged 42–79)6% vs. 2% total active complex cream (lipopentapeptide, white lupin peptide, antioxidants) vs. Retin-ASubstances were patch tested separately to the extensor aspect of forearm on days 1, 4 and 8. Patch tests were removed on day 12.6% Formula significantly increased fibrillin-1 and procollagen I deposition. Retin-A and 6% complex was the best triggers for fibrillin-1 and procollagen I deposition respectively
Peptamide®6Arch personal care products technical sheetAnti-ageing (periorbital)PC, WP25 healthy volunteers2.80% Peptamide® 6 firming toner vs. control tonerEach cream was applied to half-face (periorbital and cheek) b.i.d. for 4  weeksInitial skin elasticity and deformation response were improved at week 4
Pal-KTTKSRobinson et al. [20]Anti-ageingR, DB, PC, WP93 Caucasian female volunteers aged 35–55Pal-KTTKS O/W moisturizer vs. placebo oil-in-water moisturizerEach formulation was applied to the half-face skin b.i.d. for 12 weeks Sig. better scores for expert grader assessment and subject self-assessment in age spots
Osborne et al. [22]Anti-ageingR, DB, AC, PC, WP180 female volunteers aged 35–65Pal-KTTKS facial moisturizer vs. Boswellia Serrata extract vs. moisturizer base (vehicle)Each formulation was applied to the randomly selected half-face skin b.i.d. for 8 weeks Pal-KTTKS made sig. reduction in bumpy texture and fine lines/wrinkles compared with other comparators and baseline
Acetyl tetrapeptide-9 (AcTP1)Pauly et al. [42]Anti-ageingPC17 healthy female volunteers aged 45–55 with loss of elasticity on the forearms3% Cream containing AcTP1 vs. Cream containing placeboThe creams were applied b.i.d. for 112 daysSig. increase in skin thickness and firmness for active cream. AcTP1 was more effective than placebo too
Acetyl tetrapeptide-11 (AcTP2)Blanes-Mira et al. [23]Anti-ageingPC19 healthy female volunteers aged 60–70 with loss of elasticity on the forearms3% Cream containing AcTP2 vs. Cream containing placeboThe creams were applied b.i.d. for 112 daysSig. increase in biomechanical parameters of the superficial layers of epidermis was observed for active cream. AcTP2 had 5–10% better effect than placebo
Acetyl hexapeptide-3 (Argireline®)Blanes-Mira et al. [23]Anti-ageingPC, OL10 healthy women volunteersO/W emulsion containing 10% Argireline® solutionSolution was applied b.i.d. around the eyes during 30 daysSig. more reduction in the depth of wrinkles for Argireline® group
Syn®- Ake vs. Argireline®Pentapharm fact sheetAnti-ageingPC45 Healthy volunteers4% Syn®-Ake vs. 10% acetyl hexapeptide-3 (Argireline®) vs. placeboEach cream was applied to the skin of forehead b.i.d. for 28 daysBefore-after measurements were sig. for Syn®-Ake only
Syn®-CollPentapharm fact sheetAnti-ageingAC, PC60 Healthy volunteers2.5% Syn®-Coll vs. 10% Argireline® vs. placebo creamsCreams were applied to facial skin b.i.d. for 84 daysSyn®-Coll showed better sig. results for all parameters than the controls
Fibronectin-like peptidedal Farra et al. [71]Anti-ageingR, DB, PC, PG24 Healthy volunteers1% Fibronectin-like peptide vs. placebo creamsCreams were applied to lips once and evaluations occurred 1 and 3 h afterSig. improve in hydration, and smoothness in active group
dal Farra et al. [71]Anti-ageingR, DB, PC, WP12 Healthy volunteers1% Fibronectin-like peptide vs. placebo creamsEach cream was applied to back of hands b.i.d. for 7 daysActive cream increased smoothness and lightening effects, and skin appearance
Soy extractSüdel et al. [72]Anti-ageingR, DB, PC, WP21 Healthy females (55 ± 6 years) with skin types of II and III2% Soy extract vs. placebo creamsEach cream was applied to volar forearm b.i.d. for 2 weeksPapillae Index was more increased by soy extract than placebo
Andre-frei et al. [73]Anti-ageingPseudo-R, PB, PC, WP10 Healthy Caucasian females aged between 42 and 672% Soya biopeptide vs. placebo emulsionsControl emulsion was applied to left side of the face and soya emulsion to right side b.i.d. for 4 weeksCollagen and glycosaminoglycan contents were significantly stimulated by soya extract
Silk protein vs. BSAZhaorigetu et al. [78]Anti-ageing and anti-tumourR, AC, PC30 Four-week-old female Hos: HR-1 UVB-exposed hairless mice (three groups of five mice)Single doses of 5 mg silk protein in 0.2 mL ethanol vs. 5 mg BSA in 0.2 mL ethanol vs. 0.2 mL ethanol Each treatment group received its solution after single application of 180 mJ cm−2 UVB treatmentSilk protein significantly inhibited skin lesion formation and elevated expression of COX-2 protein more than BSA and vehicle
Zhaorigetu et al. [78]Anti-ageing and anti-tumourR, AC, PC30 Four-week-old female Hos: HR-1 UVB-exposed hairless mice (three groups of five mice)5 mg Silk protein in 0.2 mL ethanol vs. 5 mg BSA in 0.2 mL ethanol vs. 0.2 mL ethanol Each treatment group received its solution after 180 mJ cm−2 of UVB treatment daily for 7 daysSilk protein significantly inhibited skin lesion formation and elevated expression of COX-2 protein more than BSA and vehicle
Silk proteinPadamwar et al. [75]Skin moisturizerUC, WPSix healthy human volunteers of both sexes (aged 22–25)0.2 g sericin gel vs. no treatmentSericin vs. control gel was applied on the skin of forearmNo sig. difference in all measurements
Daithankar et al. [76]Skin moisturizerAC, UC, WPSix healthy volunteers1% Fibrion vs. 3% fibroin vs. 5% fibroin vs. 5% silk-Pro-100 solutions1 mL of each solution was applied to inner upper portion of the forearm for 15 min and lower portion was left untreated as control For TEWL, 5% fibroin solution, Silk-pro-100 >1% and 3% fibroin solutions. Sig. drop in impedance observed for both 5% solutions
Keratin peptideBarba et al. [70]Skin moisturizerR, AC, PC, WPSix healthy Caucasian female volunteers phototype III–IV, aged 24–36Keratin peptide aqueous solution vs. keratin peptide liposome solution vs. IWL liposomes vs. water vs. 0.9% NaCl solutionEach cream were applied onto marked areas of 9 cm2 once a day for 4 daysSig. differences of skin capacitance and elasticity parameters in keratin samples. IWL liposomal keratin showed a sig. beneficial effect
  R, PC, UC, WP16 Healthy female volunteers aged 24–50 with skin types of III to V 3% Keratin peptide vs. 3% deionized water in base cream vs. untreatmentEach cream was applied to a 9 cm2 area of hand once a day for 12 days.Insignificant difference between topical therapies; elasticity results were significantly better for keratin
Barba et al. [69]Skin moisturizerR, PC, UC, WP9 Healthy females aged 24–50 with dry skin types of III to V3% Keratin peptide vs. 3% deionized water in cream vs. untreatmentThe treated areas were exposed to 2% sodium lauryl sulphate after 12-day daily application of creams on the handSignificantly lower results for skin capacitance and TEWL in keratin group.
Aquaporins (protein)Dumas et al. [41]Skin moisturizerUC, WP15 Healthy female volunteers aged 22–56Ajuga turkestanica extract formulated in a complex oil–water emulsionThe emulsion was applied to forearm skin b.i.d. for 21 daysSig. TEWL decrease in treated site vs. untreated site (4.8 ± 0.4 vs. 5.4 ± 0.3)
CRSEhrlich et al. [52]Anti-ageingR, PC, WP, AB12 Females with facial wrinkles (aged 42–74)CRS cream vs. same cream without TGF-β1 component (Vitamin C base)Each cream was applied b.i.d. for 3 monthsSig. improvement in wrinkle scores for CRS and non-sig. for Vitamin C
CRS vs. TNSEhrlich et al. [52]Anti-ageingR, AC, WP, AB20 Healthy females with facial wrinkles (aged 29–74)CRS cream vs. TNS creamEach cream was applied b.i.d. for 3 monthsSig. improvement in wrinkle score for CRS and non-sig. for Vitamin C
PSPGold et al. [53]Anti-ageingR, DB, PC, WP20 Females with demonstrable facial wrinkles (aged 35–65)PSP cream vs. its physically identical placebo creamEach cream was applied to the half-face skin b.i.d. for 2 months Roughness parameters were significantly better in PSP group. No difference between the two groups
Alpha-interferonGhersetich and Lotti [48]Anti-ageingBA with three inclusion protocols15 volunteers who experienced a periauricular area surgery (5 aged 18–21, 5 aged 57–75, and 5 underwent cycles of PUVA therapy over a year and aged 30–45)Alpha-interferon cream (2 000 000 IU per day) in carboxymethylcellulose and glycerinThe cream was applied on periauricular area three times a day for 4 weeks Expressed CD-1 and HLA-DR cell counts were sig. compared with baseline for aged and PUVA-exposed volunteers.
Hsp70Cucumel et al. [57]Anti-ageingBA with two inclusion protocols10 healthy volunteers aged 50–70, 5 healthy volunteers aged 31–40Artemia extractArtemia extract was applied to half of subjects before UV exposureSig. effect of Artemia extract on Hsp70 expression of aged skin

We categorized topical peptides and proteins into four groups:

  • 1
     Signal peptides,
  • 2
     enzyme inhibitor peptides,
  • 3
     neurotransmitter-inhibitor peptides and
  • 4
     carrier peptides.

Signal peptides

Signal peptides stimulate matrix protein production in general and collagen synthesis in specific. They may be accomplished by stimulation and growth of different skin cells like human skin fibroblasts. Signal peptides can also increase elastin, proteoglycan, glycosaminoglycans and fibronectin proliferation. By increasing matrix cell activities and consequently collagen production, the skin looks firmer and younger.

The tripeptide-1 (glycyl-l-histidyl-l-lysine or GHK) is primarily known as carrier peptides. It mainly helps to stabilize and deliver Cu. Carrier peptides are discussed later. However, GHK was originally isolated from human plasma in 1973 by Pickart and Thaler [31] and its wound repair properties were observed in 1985 by Maquart et al. [32] In 1999, Maquart et al. concluded that GHK or its Cu complex functioned as an activator of tissue remodelling [32]. It is also a signal peptide that promotes extra large collagen aggregates degradation in scars, regular collagen synthesis in normal skin, elastin, proteoglycans and glycosaminoglycans production, growth rate and migration of different cell types and anti-inflammatory and antioxidant responses [33–37]. In a controlled ex vivo study [38], biotinyl-GHK and vehicle were investigated. Biotinyl-GHK but not vehicle solution showed stimulation of collagen IV, laminin production and keratinocyte mitosis.

Tripeptide-1 can be also conjugated with palmitic acid and form pal-tripeptide-1 (Biopeptide-CL). In vitro and in vivo studies approved that Biopeptide-CL stimulates collagen and gylcosaminoglycans synthesis [39].

Palmitoyl tripeptide-3/5 (Syn®-Coll; Pentapharm, Basel, Switzerland) is a synthetic signal peptide. Thrombospondin I is a protein that binds to tissue growth factor beta (TGF-β) and makes it biologically inactive. Syn®-Coll mimics thrombospondin I tripeptide sequence to activate TGF-β. Therefore, it promotes collagen formation via TGF-β (Pentapharm). In a controlled trial, 60 healthy volunteers received 2.5% Syn®-Coll cream vs. 10% palmitoyl pentapeptide-3 cream vs. placebo cream twice daily for 84 days. Syn®-Coll significantly decreased average and maximum relief by −22 and −36 μm respectively; when compared with pal-pentapeptide-3, it showed better significant results for Ra, Rz and Rt parameters (Pentapharm).

Tripeptide-10 Citrulline (Decorinyl™; Centerchem) is a peptide with firming effects and mimics the sequences of decorin that binds to collagen fibrils. It also regulates fibrillogenesis and controls fibril growth and their uniformity (Centerchem). Puig et al. [40] presented a single-blind parallel group controlled trial comparing 0.01% liposomal Decorinyl™ and placebo creams. Tripeptide-10 induced a 54% increase in skin suppleness (P < 0.001). No significant changes were seen in placebo group.

Peptamide-6 (FVAPFP), a firming peptide that is biotechnologically derived from saccharomyces yeast fermentation, increases collagen synthesis and upregulates growth factors, transmembrane, matrix and heat shock proteins. This peptide was applied onto half-face (periorbital and cheek) of 25 healthy subjects twice daily for 4 weeks. Initial skin elasticity and deformation response were improved at week 4.

Pal-KTTKS (palmitoyl pentapeptide-4), a synthetic signal peptide from pro-collagen I fragment, stimulates collagen I, III and VI and also fibronectin, elastin and glycosaminoglycan production [38] and has been frequently used as topical anti-ageing or anti-wrinkle agents. In a study [20] on 93 Caucasian female volunteers, Pal-KTTKS had significantly better scores than placebo for expert grader assessment and subject self-assessment of age hyperpigmented spots. Osborne et al. [22] showed a robust result for this peptide in reducing bumpy texture and fine wrinkles compared with other baseline and comparators.

Aquaporin is an epidermal water channel peptide that is upregulated by the extract of Ajuga turkestanica. One study [41] showed a significant transepidermal water loss (TEWL) decrease in aquaporin-treated forearms vs. untreated forearms (4.8 ± 0.4 g m−2 h−1 vs. 5.4 ± 0.3 g m−2 h−1).

Pauly et al. [42] evaluated two new synthetic peptides: acetyl tetrapeptide-9 and -11 ((AcTP1, AcTP2, respectively). In vitro study revealed an increase in collagen I and lumican synthesis for AcTP1 and stimulation of keratinocyte cell growth and syndecan-1 synthesis for AcTP2. In vivo study showed significant increase in skin thickness (5.0%) and skin firmness (Ur/Uf = 7.5%) for AcTP1 cream. AcTP1 was also more effective than placebo. AcTP2 had significant effect on biomechanical parameters of the superficial layers of epidermis and 5–10% better effect than placebo [42].

Growth factors play an important role in reversing the ageing process on skin caused by extrinsic and intrinsic factors, although main use of growth factors is in wound healing. Recombinant human growth hormone has mitogenic effect on keratinocytes and fibroblasts [43] and increases insulin growth factor-1 and sebum production [44]. Cutaneous wound healing properties were confirmed by two trials on acute wounds [45, 46].

Interferon alpha increases the concentration of dendritic cells and CD1a and HLA-DR positive cells [47, 48]. Ghersetich and Lotti [48] conducted a before-after study with three different inclusion protocols: five individuals aged 18–21 years, five aged 57–75 years, and five underwent cycles of Psoralen + UVA (PUVA) therapy over a year and aged 30–45 years. Alpha-interferon cream (2 000 000 IU per day) in carboxymethylcellulose and glycerin was applied on periauricular area three times a day for 4 weeks. Counts for cells that expressed CD-1 and HLA-DR were significant compared with baseline only for aged and PUVA-exposed volunteers (5 ± 1.75 vs. 10 ± 4.47 and 6 ± 3.18 vs. 16 ± 2.15 for aged group and 4 ± 3.47 vs. 10 ± 3.53 and 3 ± 3.12 vs. 14 ± 1.75 for PUVA group respectively).

Transforming growth factor α and β are growth factors that reversibly inhibit keratinocytes and leucocytes growth, promote keratinocyte migration, chemotactic for marcrophages and fibroblasts [49–51]. Among major growth factors, transforming growth factor (TGF)α has the highest human keratinocyte pro-motility activity, reaching nearly 80% of the activity in serum [50].

Several growth factors and cytokines have been applied to treat ageing skin problems. Cell rejuvenation serum (CRS) contains liposome-encapsulated TGF-β1, ascorbic acid and Cimicifuga racemosa extract in a silicone base. In a trial [52], topical CRS was compared with placebo without TGF-β1 component to define the additive effect of TGF-β. TGF-β1 containing arm had 21.7% significant mean improvement in physician-rated wrinkle score and the other arm had 6.2% improvement (P > 0.05) compared with baseline. This trial [52] continued to compare topical CRS to another cream named tissue nutrient solution (TNS) in 20 patients. TNS contains growth factors and cytokines including vascular endothelial growth factor, platelet-derived growth factor alpha polypeptide (PDGF-A), granulocyte-colony stimulating factor, hepatyte growth factor (HGF), interleukin (IL)-6, IL-8 and TGF-β1 without Vitamin C. The results revealed that both creams produced significant improvement in wrinkle score.

Bio-restorative skin cream contains processed skin-cell proteins (PSP), a proprietary growth factor and cytokine mixture extracted from cultured first trimester foetal human dermal fibroblasts in a moisturizing cream. In a randomized placebo-controlled trial, Gold et al. [53] concluded that some skin roughness parameters were significantly improved in PSP group compared with the baseline but no statistical difference between the two groups was detected.

Lipopentapeptide, in combination with white lupin peptide and antioxidants had significant effect on increasing fibrillin-1 and procollagen I deposition in its 6% concentration. It was also the best trigger for procollagen I deposition when compared with 2% concentration, Retin-A and untreated areas [54].

Heat shock proteins involve in one of the principal mechanisms of cell defence and protection from stress. Among its family, Hsp70 has protective effects against UV, apoptosis and ischaemia and recommended for wound healing and anti-ageing uses [55]. Hsp70 can effectively inhibit aggregation and assist in the refolding of denatured proteins. It can reduce cellular damage by retaining the damaged proteins in soluble form, as well as by binding to unfolded or misfolded proteins to assist in their proper refolding [55]. Hsp70 can be biotechnologically synthesized from yeasts [56]. Studies on both cultured human epidermal cells and ex vivo skin showed that induction or administration of Hsp70 prior to stress significantly diminished UV-related morphological changes and sunburn cell number [56–58]. It can also modulate inflammatory cytokine synthesis and reduce UV-induced inflammatory responses [59]. Hsp70 was proved to be able to block apoptosis by inhibiting signalling events upstream of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase. activation [60, 61]. Ageing alters the ability of cells to express Hsp70 in response to stress and any Hsp70 induction or application can reverse the process [61–67].

Generally, studies [62–68] showed that although aged skin exhibits a normal level of Hsp70 under non-stressful conditions, it fails to produce the typical protective Hsp70 increase, comparing with younger skin when exposed by UV. To sum up, Hsp70 can act against UV exposure especially in aged skin.

Keratin is a major protein in the structure of hair and skin that can be extracted from human hair or sheep’s wool. Keratin’s topical application can improve hydration and elasticity of the skin and hair. It is commonly used in skin and hair moisturizers, firming agents and hair shiners. Barba et al. [69] conducted a randomized trial comparing 3% keratin peptides with deionized water and untreated control in 16 healthy females. Keratin peptides were effective on disturbed but not undisturbed skin. In another recent trial [70], significant differences were achieved for skin capacitance (especially) and elasticity parameters with application of the keratin samples. Among all keratin containing creams, a combination of keratin peptide with the internal wool lipid liposomes had a significant beneficial effect compared with aqueous solution [70].

In two consecutive double-blind studies, dal Farra et al. [71] investigated the potential anti-ageing effects of a synthetic fibronectine-like peptide at 0.5% together with a booster molecule at 1%. Twelve volunteers applied the cream formula containing the active ingredient twice a day on the back of one hand and the placebo on the other hand. Evaluations were performed after 1 and 3 h, and after 7 days. Increased smoothness of skin surface and also lightening effect on the skin were noticed by volunteers at all time points. Volunteers estimated a 40% improvement on the peptide-treated side 1 h after application. A second study was performed on the lips and included two groups of 12 volunteers each. One group applied the cream formula with the active ingredient, and the other group applied the placebo. Evaluations were made at 1 and 3 h. Significant increase in smoothness, hydration and repulping effect were mentioned.

Enzyme inhibitor peptides

Enzyme inhibitor peptides directly or indirectly inhibit an enzyme. Soybean protein (Soja protein) or peptides, enzyme inhibitor peptides naturally extracted from soybean seeds, inhibit the formation of proteinases (Centerchem). Soy protein is frequently used as anti-ageing, skin moisturizer, anti-solar, cleansing detergent and hair-promoting agent. In a randomized, double-blind, placebo-controlled study [72], soy extract and placebo creams were applied to volar forearm of 21 healthy women. Papillae index was increased more by soy extract than placebo (3.76 vs. 4.56 in arbitrary units, P < 0.05). Another study with pseudo-randomized design in 10 Caucasian females [73], concluded the superiority of 2% soya biopeptide emulsion to placebo, in terms of collagen and stimulation of glycosaminoglycan contents.

Rice peptides/amino acids (Colhibin®) is another natural protein that inhibits matrix metalloproteinase activity and induces expression of hyaluronan synthase 2 gene in keratinocytes. Anti-ageing, film-forming and hair conditioning products may contain this protein [74].

Another enzyme inhibitor protein (silk protein, sericin), naturally extracted from Moddle silk gland of the silkworm Bombyx Mori, has antioxidant properties with high affinity to chelate with Cu. In addition, it inhibits lipid peroxidation and tyrosinase activity and keratinocyte apoptosis. In a within-patient untreated-controlled study [75], 0.2 g sericin gel was compared with untreated site with hydroxyproline assay and TEWL measurement to evaluate its hydrating effect. For hydroxyproline assay, Sericin gel was applied on the dried skin of the forearm at the test site. For TEWL, the upper portion of forearm was used as the application site of sericin gel and lower portion of forearm for control. Although hydroxyproline content was slightly promising in all related parameters for sericin, no significant differences in hydroxyproline content, skin impedance and TEWL contents were seen when compared with no treatment. In another trial by Daithankar et al. [76], silk-protein 100 and different fibroin concentrations were tested. Five per cent firoin solution had similar TEWL content to 5% silk-protein-100 solution but more than 1% and 3% fibroin solutions. Significant drop in impedance was observed for both 5% sericin and 5% fibroin solutions within 1 h. Silk protein was compared with bovin serum albumin and vehicle and the results confirmed its superiority to both serum albumin and vehicle in reducing UV-B induced symptoms in short-term and long-term treatment courses [77].

Neurotransmitter inhibitor peptide

Neurotransmitter inhibitor peptides inhibit acetylcholine release at the neuromuscular junction and have curare-like effect. Seven types (A–G) of botulinum toxin target peripheral cholinergic neurons where they selectively proteolyse synaptosome-associated protein of 25 000 Da (SNAP-25), syntaxin 1 and synaptobrevin, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins responsible for transmitter release, to cause neuromuscular paralysis but of different durations. Type A toxin proteolytically degrades the SNAP-25 protein, a type of SNARE protein. The SNAP-25 protein is required for the release of neurotransmitters from the axon endings. Botulinum toxin specifically cleaves these SNAREs, and so prevents neurosecretory vesicles from docking and or fusing with the nerve synapse plasma membrane and releasing their neurotransmitters. botulinum toxin type A (BXT-A) paralysis lasts longer (4–6 months) among botulinum toxin subtypes, make it a good choice for anti-wrinkle uses.

Researchers have found less invasive topical equivalents of these toxins [78]. Acetyl hexapeptide-3 (Argireline®) is a synthetic peptide that is especially marketed as a component of eye care products and patterned from the N-terminal end of the protein SNAP-25 that inhibits SNARE complex formation and catecholamine release. Inhibition of noradrenaline and adrenaline release was also demonstrated. This small peptide exhibits the great advantage of its insignificant acute toxicity (2000 mg kg−1) as compared with BTX-A (20 ng kg−1) [23]. Argireline® (Centerchem) inhibits vesicle docking by preventing the ternary SNARE complex formation, which is involved in synaptic vesicle exocytosis [79, 80].

Another open label vehicle-controlled trial, 10% acetyl hexapeptide-3 and placebo creams were applied twice daily on 10 women and demonstrated a nearly 30% vs. 10% improvement in periorbital rhytids after 30 days as measured by silicone replica analysis respectively [23].

Pentapeptide-18 (Leuphasyl®) mimics the natural mechanism of enkephalins and as a result inhibits neuronal activity and catecholamine release. An active-controlled trial, compared cream containing 5% leuphasyl® solution (0.05%), cream containing 5% Argireline® solution (0.05%) and combination. Mean wrinkle reductions were 11.64% vs. 16.26% vs. 24.62% for Leuphasyl®, Argireline® and combination respectively. This study suggested a synergistic effect between Leuphasyl® and Argireline® (Centerchem).

Pentapeptide-3 (Vialox®), a synthetic peptide that is a competitive antagonist at the acetylcholine receptors, safely blocks the sodium ion release at the synaptic membrane on muscles so they cannot contract as frequently. In vitro tests showed muscle contractions reduced by 71% within 1 min after treatment and 58% 2 h later. Less frequent muscle contractions result in shallower lines. After 28 days of twice-daily use, wrinkle depth was reduced 49% (Centerchem).

Tripeptide-3 (Syn®-Ake) is used as an intensive anti-wrinkle agent and mimics the effect of Waglerin 1, a peptide that is found in the venom of the Temple Viper, Tropidolaemus wagleri. Syn®-Ake (at a concentration of 0.5 mmol L−1) was able to reduce the frequency of innervated muscle cell contractions by 82% (P < 0.05) after 2 h of treatment.

In a study on 45 healthy subjects, Syn®-Ake, Argireline® and placebo were compared. Syn®-Ake clearly showed a remarkable higher efficacy for all tested parameters. Before-after measurements were significant for Syn®-Ake only and not for Argireline®. Best results were seen on forehead skin by up to 52% (parameter Rt) (Lipotec, Barcelona, Spain). A high quality randomized controlled trial is needed to confirm these robust results for Syn®-Ake.

Carrier peptide

Carrier peptides belong to a general category that acts as a facilitator of an important substance’ transportation, but their major application is to deliver important trace elements (like Cu and Mn) necessary for wound healing and enzymatic processes. Recently, several peptides and proteins have been developed to accelerate and facilitate the delivery of bioactive molecules into the skin. These peptides and proteins are known as penetrating peptides or membrane transduction peptides and have basic transduction domains in their structure [81]. A study [82], demonstrated that short arginine-rich intracellular delivery peptides facilitate the transport of various proteins into living cells. Hou et al. [82] also investigate whether arginine-rich peptide could serve as carriers for topical and/or transdermal drug delivery and concluded that protein penetration can be stimulated by such peptides even without fusion between carrier peptide and the protein. Another example of membrane transduction peptides is PEP-1 that can facilitate the skin penetration of an anti-ageing protein, ribosomal protein S3 (rpS3) [83, 84].

Abdulghani et al. [21] conducted a non-randomized four-arm active-controlled trial on 20 participants to compare GHK-Cu with topical tretinoin, Vitamin C and melatonin. Ten subjects received tretinoin and Vitamin C creams on the extensor surface of their right and left thighs respectively and the other ten subjects received GHK-Cu and melatonin creams to the extensor surface of their right and left thighs respectively, for 1 month. Tretinoin, Vitamin C, melatonin and GHK-Cu increased pro-collagen synthesis in 4/10, 5/10, 5/10 and 7/10 of patients respectively. Appa et al. [85] evaluated the efficacy of two cosmetic GHK-Cu containing formulations for skin conditioning. The skin treatment benefits of a GHK-Cu containing liquid foundation and cream concealer were evaluated over an 8-week period. Significant improvement in all visual evaluations of skin condition was found within first 2 weeks for both products. Skin viscoelastic properties significantly improved.

GHK-Cu was tested in a 12-week placebo-controlled study [86] on facial skin of 71 women with mild to advanced photodamage. By week 1, the active cream delivered significant improvement in skin laxity, clarity and overall appearance when compared with placebo. Significant improvement in fine lines was noted at week 2 and in wrinkles at week 4 over placebo. Significantly improved viscoelastic properties were consistent with ultrasound increase in overall skin density and thickness. Subjects indicated strong cream’s performance acceptability. There were no adverse objective or subjective irritation findings.

In a randomized, double blind placebo-controlled study [87] that included 67 volunteers, GHK-Cu vs. placebo were applied twice daily for 12 weeks on facial skin. GHK-Cu Improved skin laxity, clarity and appearance, reduced fine lines, coarse wrinkles and mottled hyperpigmentation and increased skin density and thickness. Five included women also applied the cream to one forearm and leave the other forearm as untreated control. GHK-Cu Strongly induced dermal keratinocyte proliferation.

The efficacy and safety of GHK-Cu have been investigated in periorbital area of 41 female volunteers with mild to advanced photodamage. Within 4 weeks of this blind and controlled study with Vitamin K containing cream as the comparator group, there was significant improvement in all parameters, including fine lines, wrinkles and overall appearance of eyelids. The viscoelastic properties of periorbital skin – which was determined by ballistometer – exhibited statistically significant improvement by week 1. Increase in overall skin density and thickness was demonstrated with ultrasound and digital images captured noticeable improvement in appearance of periorbital skin [88].

Conclusions

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

Taken together, some peptides have notable effects on chronologically aged and/or photo-damaged skin. There is a large gap for permeability coefficient of major cosmeceutical peptides and proteins and researchers should focus on this ambiguity to find more efficient substances with better permeability. Although topical peptides are frequently used in anti-ageing products, some do not have any well designed in vivo studies with adequate sample size. High quality randomized double-blind active-controlled large trials are needed to calculate exact effect sizes of main topical peptides or proteins to reach to these conclusions (i) whether they are effective enough to be approved, (ii) whether they can be utilized as an equivalent to current recommended treatments for ageing skin and (iii) at what doses they have maximum efficacy with acceptable safety profile.

Acknowledgements

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

There are no conflicts of interest or funding received for this article.

References

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix
  • 1
    Kosmadaki, M.G. and Gilchrest, B.A. The demographics of aging in the United States: implications for dermatology. Arch. Dermatol. 138, 14271428 (2002).
  • 2
    Ranade, V.V. Drug delivery systems. 6. Transdermal drug delivery. J. Clin. Pharmacol. 31, 401418 (1991).
  • 3
    Buri, P., Puisieux, F., Doelker, E. and Benoit, J.P. Formes pharmaceutiques nouvelles. Technique et Documentation, Paris (1985).
  • 4
    Vecchia, B.E. and Bunge, A.L. Evaluating the transdermal permeability of chemicals. In: Transdermal Drug Delivery (electronic resource). (Guy, R.H. and Hadgraft, J. eds), pp. 2526. Dekker, New York (2003).
  • 5
    Guy, R.H. Current status and future prospects of transdermal drug delivery. Pharm. Res. 13, 17651769 (1996).
  • 6
    Roberts, M.S., Cross, S.E. and Pellett, M.A. Skin transport. In: Dermatological and Transdermal Formulations. (Walters, A.W., ed.), p. 121. Dekker, New York (2002).
  • 7
    Cullander, C. and Guy, R.H. Routes of delivery: case studies (6). Trasdermal delivery of peptides and proteins. Adv. Drug Deliv. Rev. 8, 291329 (1992).
  • 8
    Nakamura, R.M., Einck, L., Velmonte, M.A., Kawajiri, K., Ang, C.F., Delasllagas, C.E., Nacy, C.A. Detection of active tuberculosis by an MPB-64 transdermal patch: a field study. Scand. J. Infect. Dis. 33, 405407 (2001).
  • 9
    Pai, M., Kalantari, S. and Dheda, K. New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance. Expert Rev. Mol. Diagn. 6, 423432 (2006).
  • 10
    Billich, A., Aschauer, H., Aszodi, A. and Stuetz, A. Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus. Int. J. Pharm. 269, 2935 (2004).
  • 11
    Weiss, M., Fresneau, M., Monius, T., Stutz, A. and Billich, A. Binding of pimecrolimus and tacrolimus to skin and plasma proteins: Implications for systemic exposure after topical application. Drug Metab. Dispos. 36, 18121818 (2008).
  • 12
    Frech, S.A., Dupont, H.L., Bourgeois, A.L., McKenzie, R., Belkind-Gerson, J., Figueroa, J.F. et al. Use of a patch containing heat-labile toxin from Escherichia coli against travellers’ diarrhoea: a phase II, randomised, double-blind, placebo-controlled field trial. Lancet 371, 20192025 (2008).
  • 13
    Billich, A., Vyplel, H., Grassberger, M., Schmook, F.P., Steck, A. and Stuetz, A. Novel cyclosporin derivatives featuring enhanced skin penetration despite increased molecular weight. Bioorg. Med. Chem. 13, 31573167 (2005).
  • 14
    Smith, E.W. and Maibach, H.I. Percutaneous Penetration Enhancers, 2nd edn. Taylor and Francis Group, New York (2006).
  • 15
    Pillai, O. and Panchagnula, R. Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers. J. Control Release 89, 127140 (2003).
  • 16
    Silva, R., Little, C., Ferreira, H. and Cavaco-Paulo, A. Incorporation of peptides in phospholipid aggregates using ultrasound. Ultrason. Sonochem. 15, 10261032 (2008).
  • 17
    Goebel, A. and Neubert, R.H. Dermal peptide delivery using colloidal carrier systems. Skin Pharmacol. Physiol. 21, 39 (2008).
  • 18
    Chen, Y., Shen, Y., Guo, X., Zhang, C., Yang, W., Ma, M. et al. Transdermal protein delivery by a coadministered peptide identified via phage display. Nat. Biotechnol. 24, 455460 (2006).
  • 19
    Foldvari, M., Attah-Poku, S., Hu, J., Li, Q., Hughes, H., Babiuk, L.A. et al. Palmitoyl derivatives of interferon alpha: potential for cutaneous delivery. J. Pharm. Sci. 87, 12031208 (1998).
  • 20
    Robinson, L.R., Fitzgerald, N.C., Doughty, D.G., Dawes, N.C., Berge, C.A. and Bissett, D.L. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int. J. Cosmet. Sci. 27, 155160 (2005).
  • 21
    Abdulghani, A.A., Sherr, A., Shirin, S., Solodkina, G., Morales Tapia, E., Wolf, B. et al. Effects of topical creams containing vitamin C, a copper-binding peptide cream and melatonin compared with tretinoin on the ultrastructure of normal skin. Dis. Manag. Clin. Outcomes 1, 136141 (1998).
  • 22
    Osborne, R., Robinson, L.R., Mullins, L. and Raleigh, P. Use of a facial moisturizer containing palmitoyl pentapeptide improves the appreance of aging skin J. Am. Acad. Dermatol. 52(3 Suppl 1):96 (2005).
  • 23
    Blanes-Mira, C., Clemente, J., Jodas, G., Gil, A., Fernandez-Ballester, G., Ponsati, B. et al. A synthetic hexapeptide (Argireline) with antiwrinkle activity. Int. J. Cosmet. Sci. 24, 303310 (2002).
  • 24
    Samuel, M., Brooke, R.C., Hollis, S. and Griffiths, C.E. Interventions for photodamaged skin. Cochrane Database Syst. Rev. CD001782 (2005).
  • 25
    Mazurowska, L. and Mojski, M. Biological activities of selected peptides: skin penetration ability of copper complexes with peptides. J. Cosmet. Sci. 59, 5969 (2008).
  • 26
    Ruland, A., Kreuter, J. and Rytting, J.H. Transdermal delivery of the tetrapeptide hisetal (melanotropin (6-9)): II. Effect of various penetration enhancers. In vitro study across human skin. Int. J. Pharm. 103, 7780 (1994).
  • 27
    Ruland, A., Kreuter, J. and Rytting, J.H. Transdermal delivery of the tetrapeptide hisetal (melanotropin (6-9)). I. Effect of various penetration enhancers: In vitro study across hairless mouse skin. Int. J. Pharm. 101, 5761 (1994).
  • 28
    Mazurowska, L., Nowak-Buciak, K. and Mojski, M. ESI-MS method for in vitro investigation of skin penetration by copper-amino acid complexes: from an emulsion through a model membrane. Anal. Bioanal. Chem. 388, 11571163 (2007).
  • 29
    Ruland, A. and Kreuter, J. Transdermal permeability and skin accumulation of amino acids. Int. J. Pharm. 72, 149155 (1991).
  • 30
    Braun, E., Wagner, A., Furnschlief, E., Katinger, H. and Vorauer-Uhl, K. Experimental design for in vitro skin penetration study of liposomal superoxide dismutase. J. Pharm. Biomed. Anal. 40, 11871197 (2006).
  • 31
    Pickart, L. and Thaler, M.M. Tripeptide in human serum which prolongs survival of normal liver cells and stimulates growth in neoplastic liver. Nat. New Biol. 243, 8587 (1973).
  • 32
    Maquart, F.X., Siméon, A., Pasco, S. and Monboisse, J.C. Regulation of cell activity by the extracellular matrix: the concept of matrikines. J. Soc. Biol. 193, 423428 (1999).
  • 33
    Simeon, A., Wegrowski, Y., Bontemps, Y. and Maquart, F.X. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J. Invest. Dermatol. 115, 962968 (2000).
  • 34
    Simeon, A., Emonard, H., Hornebeck, W. and Maquart, F.X. The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures. Life Sci. 67, 22572265 (2000).
  • 35
    Buffoni, F., Pino, R. and Dal Pozzo, A. Effect of tripeptide-copper complexes on the process of skin wound healing and on cultured fibroblasts. Arch. Int. Pharmacodyn. Ther. 330, 345360 (1995).
  • 36
    Wegrowski, Y., Maquart, F.X. and Borel, J.P. Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. Life Sci. 51, 10491056 (1992).
  • 37
    Maquart, F.X., Pickart, L., Laurent, M., Gillery, P., Monboisse, J.C. and Borel, J.P. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+. FEBS Lett. 238, 343346 (1988).
  • 38
    Lintner, K. Promoting production in the extracellular matrix without compromising barrier. Cutis 70(6 Suppl):1316; discussion 21–3 (2002).
  • 39
    Croda USA. News and News Releases. Croda, Edison, NJ (1998).
  • 40
    Puig, A., Anton, J.M.G. and Mangues, M. A new decorin-like tetrapeptide for optimal organization of collagen fibres. Int. J. Cosmet. Sci. 30, 97104 (2008).
  • 41
    Dumas, M., Sadick, N.S., Noblesse, E., Juan, M., Lachmann-Weber, N., Boury-Jamot, M. et al. Hydrating skin by stimulating biosynthesis of aquaporins. J. Drugs Dermatol. 6(6 Suppl):s20s24 (2007).
  • 42
    Pauly, G., Contet-Audonneau, J., Moussou, P., Danoux, L., Bardey, V., Freis, O. et al. Small proteoglycans in the skin: New targets in the fight against aging. IFSCC 11, 2129 (2008).
  • 43
    Marikovsky, M., Breuing, K., Liu, P.Y., Eriksson, E., Higashiyama, S., Farber, P. et al. Appearance of heparin-binding EGF-like growth factor in wound fluid as a response to injury. Proc. Natl Acad. Sci. USA 90, 38893893 (1993).
  • 44
    Deplewski, D. and Rosenfield, R.L. Growth hormone and insulin-like growth factors have different effects on sebaceous cell growth and differentiation. Endocrinology 140, 40894094 (1999).
  • 45
    Cohen, I.K., Crossland, M.C., Garrett, A. and Diegelmann, R.F. Topical application of epidermal growth factor onto partial-thickness wounds in human volunteers does not enhance reepithelialization. Plast. Reconstr. Surg. 96, 251254 (1995).
  • 46
    Brown, G.L., Nanney, L.B., Griffen, J., Cramer, A.B., Yancey, J.M., Curtsinger Iii, L.J. et al. Enhancement of wound healing by topical treatment with epidermal growth factor. N. Engl. J. Med. 321, 7679 (1989).
  • 47
    Ghersetich, I., Comacchi, C. and Lotti, T. Immunohistochemical and ultrastructural investigation of multiple common warts before and after therapy with alpha-interferon. G. Ital. Dermatol. Venereol. 127, 207210 (1992).
  • 48
    Ghersetich, I. and Lotti, T. Alpha-interferon cream restores decreased levels of Langerhans/indeterminate (CD1a+) cells in aged and PUVA-treated skin. Skin Pharmacol. 7, 118120 (1994).
  • 49
    Frank, S., Madlener, M. and Werner, S. Transforming growth factors beta1, beta2, and beta3 and their receptors are differentially regulated during normal and impaired wound healing. J. Biol. Chem. 271, 1018810193 (1996).
  • 50
    Li, Y., Fan, J., Chen, M., Li, W. and Woodley, D.T. Transforming growth factor-alpha: A major human serum factor that promotes human keratinocyte migration. J. Invest. Dermatol. 126, 20962105 (2006).
  • 51
    Govinden, R. and Bhoola, K.D. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol. Ther. 98, 257265 (2003).
  • 52
    Ehrlich, M., Rao, J., Pabby, A. and Goldman, M.P. Improvement in the appearance of wrinkles with topical transforming growth factor beta (1) and l-ascorbic acid. Dermatol. Surg. 32, 618625 (2006).
  • 53
    Gold, M.H., Goldman, M.P. and Biron, J. Human growth factor and cytokine skin cream for facial skin rejuvenation as assessed by 3D in vivo optical skin imaging. J. Drugs Dermatol. 6, 10181023 (2007).
  • 54
    Watson, R.E., Long, S.P., Bowden, J.J., Bastrilles, J.Y., Barton, S.P. and Griffiths, C.E. Repair of photoaged dermal matrix by topical application of a cosmetic ‘antiageing’ product. Br. J. Dermatol. 158, 472477 (2008).
  • 55
    Dal Farra, C., Bauza, E. and Domloge, N. Heat shock proteins for cosmeceuticals. In: Cosmeceuticals and Active Cosmetics. (Elsner, P. and Maibach, H.I., eds), pp. 523536. Marcel Dekker, New York, NY (2005).
  • 56
    Botto, J., Cucumel, K., Dal Farra, C. and Domloge, N. Treatment of human cells with Hsp-70-rich yeast extract enhances cell thermotolerance and resistance to stress. J. Invest. Dermatol. 117, 452 (2001).
  • 57
    Cucumel, K., Botto, J., Bauza, E., Dal Farra, C., Roetto, R. and Domloge, N. Artemia Extract Induces Hsp70 in Human Cells and Enhances Cell Protection from Stress. J. Invest. Dermatol. 117, 454 (2001).
  • 58
    Domloge, N., Bauza, E., Cucumel, K., Peyronel, D. and Dal Farra, C. Artemia extract toward more extensive sun protection. Cosmet. Toiletries 2002, 6978 (2002).
  • 59
    Bauza, E., Dal Farra, C. and Domloge, N. Hsp70 induction by Artemia extract exhibits anti-inflammatory effect and down-regulates IL-1 and IL-8 synthesis in human HaCaT cells. J. Invest. Dermatol. 117, 415 (2001).
  • 60
    Mosser, D.D., Caron, A.W., Bourget, L., Denis-Larose, C. and Massie, B. Role of the human heat shock protein hsp70 in protection against stress- induced apoptosis. Mol. Cell. Biol. 17, 53175327 (1997).
  • 61
    Gabai, V.L., Meriin, A.B., Mosser, D.D., Caron, A.W., Rits, S., Shifrin, V.I. et al. Hsp70 prevents activation of stress kinases: A novel pathway of cellular thermotolerance. J. Biol. Chem. 272, 1803318037 (1997).
  • 62
    Gutsmann-Conrad, A., Heydari, A.R., You, S. and Richardson, A. The expression of heat shock protein 70 decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp. Cell Res. 241, 404413 (1998).
  • 63
    Wu, B., Gu, M.J., Heydari, A.R. and Richardson, A. The effect of age on the synthesis of two heat shock proteins in the HSP70 family. J. Gerontol. 48, B50B56 (1993).
  • 64
    Blake, M.J., Fargnoli, J., Gershon, D. and Holbrook, N.J. Concomitant decline in heat-induced hyperthermia and HSP70 mRNA expression in aged rats. Am. J. Physiol: Regul. Integr. Compar. Physiol. 260, R663R667 (1991).
  • 65
    Pardue, S., Groshan, K., Raese, J.D. and Morrison-Bogorad, M. Hsp70 mRNA induction is reduced in neurons of aged rat hippocampus after thermal stress. Neurobiol. Aging 13, 661672 (1992).
  • 66
    Fargnoli, J., Kunisada, T., Fornace Jr, A.J., Schneider, E.L. and Holbrook, N.J. Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats. Proc. Natl Acad. Sci. USA 87, 846850 (1990).
  • 67
    Muramatsu, T., Hataoko, M., Tada, H., Shirai, T. and Ohnishi, T. Age-related decrease in the inductability of heat shock protein 72 in normal human skin. Br. J. Dermatol. 134, 10351038 (1996).
  • 68
    Cucumel, K., Dal Farra, C. and Domloge, N. Artemia extract “compensates” for age-related decrease of Hsp70 in skin. J. Invest. Dermatol. 119, 257 (2002).
  • 69
    Barba, C., Mendez, S., Roddick-Lanzilotta, A., Kelly, R., Parra, J.L. and Coderch, L. Wool peptide derivatives for hand care. J. Cosmet. Sci. 58, 99107 (2007).
  • 70
    Barba, C., Mendez, S., Roddick-Lanzilotta, A., Kelly, R., Parra, J.L. and Coderch, L. Cosmetic effectiveness of topically applied hydrolysed keratin peptides and lipids derived from wool. Skin Res. Technol. 14, 243248 (2008).
  • 71
    Dal Farra, C., Oberto, G., Berghi, A. and Domloge, N. An anti-aging effect on the lips and skin observed in in vivo studies on a new fibronectin-like peptide. J. Am. Acad. Dermatol. 56(2Suppl2):AB88 (2007).
  • 72
    Sudel, K.M., Venzke, K., Mielke, H., Breitenbach, U., Mundt, C., Jaspers, S. et al. Novel aspects of intrinsic and extrinsic aging of human skin: beneficial effects of soy extract. Photochem. Photobiol. 81, 581587 (2005).
  • 73
    Andre-Frei, V., Perrier, E., Augustin, C., Damour, O., Bordat, P., Schumann, K. et al. A comparison of biological activities of a new soya biopeptide studied in an in vitro skin equivalent model and human volunteers. Int. J. Cosmet. Sci. 21, 299311 (1999).
  • 74
    Sim, G.S., Lee, D.H., Kim, J.H., An, S.K., Choe, T.B., Kwon, T.J. et al. Black rice (Oryza sativa L. var. japonica) hydrolyzed peptides induce expression of hyaluronan synthase 2 gene in HaCaT keratinocytes. J. Microbiol. Biotechnol. 17, 271279 (2007).
  • 75
    Padamwar, M.N., Pawar, A.P., Daithankar, A.V. and Mahadik, K.R. Silk sericin as a moisturizer: an in vivo study. J. Cosmet. Dermatol. 4, 250257 (2005).
  • 76
    Daithankar, A.V., Padamwar, M.N., Pisal, S.S., Paradkar, A.R. and Mahadik, K.R. Moisturizing efficiency of silk protein hydrolysate: Silk fibroin. Indian J. Biotechnol. 4, 115121 (2005).
  • 77
    Zhaorigetu, S., Yanaka, N., Sasaki, M., Watanabe, H. and Kato, N. Inhibitory effects of silk protein, sericin on UVB-induced acute damage and tumor promotion by reducing oxidative stress in the skin of hairless mouse. J. Photochem. Photobiol. B Biol. 71, 1117 (2003).
  • 78
    Foran, P.G., Mohammed, N., Lisk, G.O., Nagwaney, S., Lawrence, G.W., Johnson, E. et al. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A: Basis for distinct durations of inhibition of exocytosis in central neurons. J. Biol. Chem. 278, 13631371 (2003).
  • 79
    Gutierrez, L.M., Viniegra, S., Rueda, J., Ferrer-Montiel, A.V., Canaves, J.M. and Montal, M. A peptide that mimics the C-terminal sequence of SNAP-25 inhibits secretory vesicle docking in chromaffin cells. J. Biol. Chem. 272, 26342639 (1997).
  • 80
    Gutierrez, L.M., Canaves, J.M., Ferrer-Montiel, A.V., Reig, J.A., Montal, M. and Viniegra, S. A peptide that mimics the carboxy-terminal domain of SNAP-25 blocks Ca2+-dependent exocytosis in chromaffin cells. FEBS Lett. 372, 3943 (1995).
  • 81
    Snyder, E.L. and Dowdy, S.F. Recent advances in the use of protein transduction domains for the delivery of peptides, proteins and nucleic acids in vivo. Expert Opin. Drug Deliv. 2, 4351 (2005).
  • 82
    Hou, Y.W., Chan, M.H., Hsu, H.R., Liu, B.R., Chen, C.P., Chen, H.H. et al. Transdermal delivery of proteins mediated by non-covalently associated arginine-rich intracellular delivery peptides. Exp. Dermatol. 16, 9991006 (2007).
  • 83
    Choi, S.H., Kim, S.Y., An, J.J., Lee, S.H., Kim, D.W., Ryu, H.J. et al. Human PEP-1-ribosomal protein S3 protects against UV-induced skin cell death. FEBS Lett. 580, 67556762 (2006).
  • 84
    Morris, M.C., Depollier, J., Mery, J., Heitz, F. and Divita, G. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat. Biotechnol. 19, 11731176 (2001).
  • 85
    Appa, Y., Stephens, T., Barkovic, S. and Finkey, M.B. A clinical evaluation of a copper-peptide-containing liquid foundation and cream concealer designed for improving skin condition. In: American Academy of Dermatology 60th Annual Meeting (Gaspan, A.A., Goldberg, L.H., Gupta, A.K. et al. , ed.), p. 28. American Academy of Dermatology, New Orleans, LA, USA (2002).
  • 86
    Leyden, J.J., Stevens, T., Finkey, M.B. and Barkovic, S. Skin care benefits of copper peptide containing facial cream. In: American Academy of Dermatology 60th Annual Meeting (Gaspari, A.A., Goldberg, L.H., Gupta, A.K. et al. , ed.), pp. 29, American Academy of Dermatology, New Orleans, LA, USA (2002).
  • 87
    Finkey, M.B., Appa, Y. and Bhandarkar, S. Copper peptide and skin. In: Cosmeceuticals and Active Cosmetics, 2nd edn (Elsner, P. and Maibach, H.I., eds), pp. 549564. Marcel Dekker, New York, NY (2005).
  • 88
    Leyden, J.J., Stevens, T., Finkey, M.B. and Barkovic, S. Skin care benefits of copper peptide containing eye creams. In: American Academy of Dermatology 60th Annual Meeting (Gaspari, A.A., Goldberg, L.H., Gupta, A.K. et al. , ed.), pp. 29, American Academy of Dermatology, New Orleans, LA, USA (2002).

Appendix

  1. Top of page
  2. SynopsisRésumé
  3. Introduction
  4. Material and methods
  5. Results and discussion
  6. Conclusions
  7. Acknowledgements
  8. References
  9. Appendix

Search strategy

Target of searchSearch strategy
To locate all potentially used topical peptides for this indication(‘peptide’/exp OR ‘decapeptide’ OR ‘tripeptide’/exp OR ‘octapeptide’/exp OR ‘oligopeptide’/exp OR ‘pentapeptide’/exp OR ‘ghk’ OR ‘ghk cu’ OR ‘iamin’ OR ‘ghl’ OR ‘gsh’/exp OR ‘gsh cu’ OR ‘neova’ OR ‘complex cu3’ OR ‘biopeptide’ OR ‘collagen pentapeptide’ OR ‘manganese tripeptide’ OR ‘egf’ OR ‘igf 1’ OR ‘fgf’ OR ‘growth factor’/exp OR ‘thiorexidin’ OR ‘growth hormone’/exp OR ‘hgh’/exp OR ‘vegf’/exp OR ‘kgf’ OR ‘tgf’ OR ‘ahk’ OR ‘argireline’ OR ‘hexapeptide’/exp OR ‘pal kttks’ OR ‘matrixyl’ OR ‘lipospondin’ OR ‘elaidyl kfk’ OR ‘syn coll’ OR ‘syn ake’ OR ‘syn tacks’ OR ‘tetrapeptide’/exp OR ‘vialox’ OR ‘fvapfp’ OR ‘vgvapg’ OR ‘leuphasyl’ OR ‘dipeptide’/exp OR ‘serilesine’ OR ‘decorinyl’ OR ‘eyeseryl’ OR ‘saccharomyces lysate extract’ OR ‘oxy 229-bt’ OR ‘pepha timp’ OR ‘placentol’ OR ‘kinetin’/exp OR ‘neuropeptide’/exp OR ‘algae extract’/exp OR ‘amaranth protein’ OR ‘fnk protein’ OR ‘gelatin protein’ OR ‘keratin protein’ OR ‘elastin protein’ OR ‘collagen protein’ OR ‘rh sod’ OR ‘superoxide dismutase’/exp OR ‘bovine albumin’/exp OR ‘pep-1 ribosomal protein’ OR ‘pl 14736’ OR ‘skin respiratory factor’ OR ‘becaplermin’/exp OR ‘psp’/exp OR ‘etaf’ OR ‘tns’ OR ‘glutathione’/exp OR ‘secma’ OR ‘ctp complex’ OR ‘soy protein’/exp OR ‘wheat protein’ OR ‘oat protein’ OR ‘rice protein’ OR ‘corn protein’ OR ‘vegetable protein’/exp OR ‘milk protein’/exp OR ‘silk protein’ OR ‘yeast extract’/exp OR ‘honey protein’ OR ‘revitalin’ OR ‘immucell’ OR ‘sericin’/exp OR ‘lipeptide’ OR ‘elhibin’ OR ‘colhibin’ OR Hsp70 OR ‘heat shock protein’ OR melatonin OR MSH OR ‘aquaporin’ OR ‘pyratine 6’ OR ‘AcTP’ OR ‘pal kt’ OR ‘snap 8’)
To locate all topical therapiesAND (‘topical’/exp OR ‘skin’/exp OR cutaneous)
To locate all cosmeceutical indicationsAND (cosmetic* OR cosmeceutical* OR hydrat* OR (‘hair growth’/exp OR ‘hair growth’) OR (‘hair loss’/exp OR ‘hair loss’) OR moistur* OR (‘aged’/exp OR ‘aged’) OR (‘aging’/exp OR ‘aging’) OR (‘elderly’/exp OR ‘elderly’) OR senile OR photoaged OR photodamaged OR firm* OR lift* OR ‘conditioner’ OR ‘hair conditioning’ OR ‘skin repair’ OR (‘rejuvenation’/exp OR ‘rejuvenation’) OR ‘anti-wrinkle’ OR ‘hair remover’ OR tightening OR ‘hair care’ OR ‘scalp care’ OR lightening)
Alternative search strategy obtained from embase emtreeOR ((‘skin’/exp OR ‘skin’) OR (‘skin care’/exp OR ‘skin care’) OR (‘cutaneous parameters’/exp OR ‘cutaneous parameters’) OR (‘cosmetic’/exp OR ‘cosmetic’) AND ((‘proteomics’/exp OR ‘proteomics’) OR (‘peptide’/exp OR ‘peptide’)))
To rule out all irrelevant articlesNOT (melanoma*:ti,ab OR cancer*:ti,ab OR carcino*:ti,ab OR malignan*:ti,ab OR onco*:ti,ab OR neoplas*:ti,ab OR tumor*:ti,ab OR tumour*:ti,ab OR sarcoma*:ti,ab OR lymphoma*:ti,ab OR ‘c-reactive’:ti,ab OR vaccine:ti,ab OR vaccines:ti,ab OR infectio*:ti,ab OR antimicrobial:ti,ab OR psoria*:ti,ab OR pemphig*:ti,ab OR *menopaus*:ti,ab OR replacement:ti,ab OR asthma*:ti,ab OR allerg*:ti OR sclerosis:ti,ab OR vasculitis:ti,ab OR arthritis:ti,ab OR obesity:ti,ab OR tuberculosis:ti,ab OR aortic:ti,ab OR lupus:ti,ab OR scleroderma:ti,ab OR alzheimer*:ti,ab OR ‘sezary syndrome’:ti,ab OR ‘mycosis fungoides’:ti,ab OR hypertens*:ti,ab OR bullous:ti OR onchocerc*:ti,ab OR polyneuropath*:ti,ab OR dialysis:ti,ab OR renal:ti OR kidney:ti OR apoptosis:ti,ab OR orthop*:ti,ab)