RoyalEpigen P5 Rejuvenation through epigenetic science – A Royal Jelly-like Peptide for Skin Regeneration

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A Royal Jelly-like Peptide for Skin Regeneration

RoyalEpigen P5 is a new and biologically-active peptide that activates skin regeneration and glow. Inspired by epigenetic science, this peptide mimics royal jelly to maximize its positive effects on the skin.

Honeybee workers and queens greatly differ in appear- ance, longevity and behavior despite the fact that they share exactly the same DNA. In 2011, Japanese scientists discovered that honeybees modify their genetic code by consuming royal jelly. Indeed, a protein of this peculiar juice was shown to be able to modify gene expression in honeybees without changing the DNA sequence, a bio- logical process called epigenetics. This protein was named royalactin (“queenmaker”) as it determined the fate of the honeybee.

Due to the fact that royalactin is unstable and too large to penetrate the skin, Mibelle Biochemistry has deve- loped a peptide that copies its active sequence. For improved skin uptake, the peptide was incorporated into a soft sphere carrier system based on shea butter.

In vitro assays performed on skin cells showed the capacity of RoyalEpigen P5 to:

  • improve tissue regeneration by stimulating cell proliferation and migration
  • maintain the regenerative potential of skin cells in an aging environment
  • activate protein turnover through proteasome stimulation.

In clinical studies, RoyalEpigen P5 stimulated the skin renewal, which led to a rapid increase in skin smooth- ness. In addition to this, when applied on the face of women presenting uneven skin tones, this royalactin-like peptide improved the uniformity of their complexions within just 28 days.

RoyalEpigen P5

A new and biomimetic peptide based on Royalactin

Design of a Royalactin-like Peptide

Royalactin protein is unstable as it degrades very quickly. In addition, this molecule is too large to penetrate the skin. Therefore Mibelle Biochemistry developed a peptide that copies its active sequence.

This sequence, which consists of five amino acids corresponds to a highly conserved domain based on arginine that is shared by different ligands to the EGF receptor such as the EGF and TGF-α human growth factors.


Encapsulation to Become Biologically-Active

The stratum corneum is poorly permeable to hydro- philic and high molecular weight compounds such as peptides. Consequently, the pentapeptide (TRSEL) was incorporated into a soft sphere carrier system based on shea butter in order to:

• increase its penetration into the skin
• enhance its uptake by keratinocytes
• enable a controlled-release delivery
• protect the peptide molecules in the formulation against degradation.

RoyalEpigen P5 -Study results

Acceleration of Tissue Regeneration

The capacity of RoyalEpigen P5 to speed up tissue regeneration was analyzed by creating an artificial wound in a skin cell culture.

Normal human epidermal keratinocytes (NHEK) were seeded in 96-well microplates in which a stopper is placed in the center of the well in order to create a cell- free area (artificial wound). Once cell adhesion is com- plete the stopper is removed and the test compounds (different concentrations of RoyalEpigen P5) are either added or not added to the culture medium.

Keratinocytes were labeled using a dye in order to follow their migration to the artificial wound, their proliferation and therefore the reduction of the wound surface.

Results showed that keratinocytes treated with Royal- Epigen P5 were able to close the wound much more quickly than the control ones. In addition, this effect was dose-dependent.

Compared to the control, following 24 hours
of incubation:
• 0.011% RoyalEpigen P5 accelerated wound healing

by half a day
• 0.033 % RoyalEpigen P5 accelerated wound healing

by one and a half days.

Furthermore, the effect of 0.033 % RoyalEpigen P5 was comparable to that of the positive reference (EGF 10 ng / mL).

Therefore, by stimulating cell migration and proliferation after tissue injury, RoyalEpigen P5 makes the skin recover its integrity more quickly.

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Acceleration of Skin Cell Regeneration in Aging Conditions

The regenerative capacity of RoyalEpigen P5

during aging was analyzed by using a special pro-aging medium. Skin cells grown in this pro-aging environment exhibit a reduced proliferation and a shorter lifespan whilst remaining vital and maintaining a normal mor- phology.

Primary human keratinocytes were cultured in this medium either with or without 0.008 % RoyalEpigen P5 for a period of three weeks. Keratinocytes grown in a classic medium served as a control. On a weekly basis, the population doublings were analyzed.

The results show that the treatment with RoyalEpigen P5 was able to clearly improve the proliferation capacity of keratinocytes compared to the control (pro-aging medium).

RoyalEpigen P5 can therefore maintain an active cellular proliferation despite the aging process.

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Activation of Protein Turnover

Normal human epidermal keratinocytes (NHEK) were cultured either with or without Royal- Epigen P5. From there, the expression of the SKP1 gene was analyzed by quantitative PCR. SKP1 codes for a protein (ubiquitin ligase component) that is required for the proteasome’s activation.

The proteasome is the cell’s own cleaning system.
Its role consists of degrading damaged and oxidized proteins and recycling them. The proteasome’s activity declines with age and with the increase in oxidative stress factors. This leads to an accumulation of oxidized proteins that favor a dull complexion.
SKP1 tags damaged proteins to make them recognizable by the proteasome.

Results showed that keratinocytes treated with Royal- Epigen P5 expressed much more SKP1 and this occurred in a dose-dependent way.
Therefore, RoyalEpigen P5 activates the protein turnover by stimulating the proteasome.

Epigenetic Mechanism: RoyalEpigen P5 Influences miRNA Expression

One epigenetic mechanism to influence the expression of genes without interfering with the genetic code are microRNAs (miRNAs).

miRNAs are short RNA pieces that are complementary to a part of a messenger RNA (mRNA) encoding for a protein. By binding to the mRNA, miRNAs can block protein production and even lead to degradation of the mRNA (1, graph below). Conversely, down regulation of miRNAs would lead to upregulation of protein production (2).

To investigate whether RoyalEpigen P5 is able to induce epigenetic changes in human skin cells, expression
of > 1000 miRNAs was analyzed in aged fibroblasts (passage 18) either untreated or treated with 0.1 % RoyalEpigen P5 for 24 h. The seven most downregulated miRNAs were analyzed for their target mRNAs.

Interestingly, these miRNAs target collagen, two types of keratins and a proliferation factor, which are important for youthful skin:

• COL1A1: Encodes the major component of type I collagen, found in most connective tissues

• KRT6B: Keratin 6B, component of keratin filament, decreases with age. Involved in wound healing

• KRT77: Epithelial keratin that is expressed in the skin and eccrine sweat glands

• E2F1-3: Transcription factor which is essential for cellular proliferation.

Therefore, treatment with RoyalEpigen P5 enables skin cells to again produce more of those skin firming and cell proliferation proteins. It thus leads to rejuvenation of fibroblasts through an epigenetic mechanism.

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Increase of the Skin Renewal

The effect of RoyalEpigen P5 on the renewal time of the epidermis was measured by using a fluorescent dye (dansyl chloride) that irreversibly stains the stratum corneum cells. And it is only following a complete renewal of the stratum corneum that the dansyl chloride is entirely removed.

Twenty women aged between 40 and 60 (average age: 48.9 years) and presenting an uneven skin tone applied the test products (2 % RoyalEpigen P5 cream and the corresponding placebo) twice daily for a period of

56 days to the inner side of their forearms. At day 28,
a 5 % dansyl chloride suspension was applied to the test areas under occlusive patches for 24 hours. Following this, the level of fluorescence was assessed visually under UV light from day 43 onwards until the skin was no longer fluorescent.

Results showed that RoyalEpigen P5 increased the turn- over of the epidermis as it led to a reduction of the skin renewal time of almost 12 % (which corresponds to a 3 day reduction) compared to untreated and almost 6% compared to the placebo.


Smoothing Effect

Twenty women aged between 40 and 60 (aver-age age: 48.9 years) and presenting an uneven skin tone applied either a cream with 2 % RoyalEpigen P5 or the corresponding placebo twice daily for a period of 28 days to the inner side of their forearms. The smoothness of their skin was determined by using the PRIMOS system.

As a result of the increased skin renewal, RoyalEpigen P5 smooths the skin and this occurs after just 14 days of application. With 2% RoyalEpigen P5, the skin smoothness was increased by:

• more than 10 % compared to initial conditions after 14 days

• 16 % compared to initial conditions after 28 days.

The increase in skin smoothness was observed on 100 % of the volunteers.

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Improvement of Skin Tone Evenness

Twenty women aged between 40 and 60 (average age: 48.9 years) and presenting an uneven skin tone applied a 2 % RoyalEpigen P5 cream onto their faces twice daily for a period of 28 days.

The heterogeneity of their complexion was analyzed by measuring the skin lightness (L*) on six selected locations across the face (the forehead, temples and cheeks) using a chromameter. From there, the standard deviation of these six measurements was calculated. The higher the standard deviation, the higher was the heterogeneity of the complexion.

Results showed that RoyalEpigen P5 led to a rapid de- crease in standard deviation of the L* values measured on the six points in the face.

RoyalEpigen P5 therefore increased the homogeneity of the skin:

• +6 % compared to initial conditions after 14 days
• +12.6 % compared to initial conditions after 28 days. Thus, by improving the uniformity of the complexion, RoyalEpigen P5 makes the skin more radiant.

The increase in skin clarity was observed on 80 % of the volunteers.

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