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Journal of Cosmetics, Dermatological Sciences and Applications, 2020, 10, 59-75

https://www.scirp.org/journal/jcdsa

ISSN Online: 2161-4512

ISSN Print: 2161-4105

DOI:

10.4236/jcdsa.2020.102007 Jun. 1, 2020 59 J. Cosmetics, Dermatological Sciences and Applications

Safe Retinol-Like Skin Biological Effect by

a New Complex, Enriched with

Retinol Precursors

Ze’evi Ma’or

1,2

, Dror Cohen

1,2

, Ya’ara La’or-Costa

1,2

, Meital Portugal-Cohen

1,2

Ahava Dead Sea Laboratories, Lod, Israel

The Skin Research Institute, the Dead-Sea and Arava Science Center, Masada, Israel

Abstract

Background:

Retinol (RE) is deeply involved in skin processes, therefore it is

widely formulated in cosmetics, primarily as an anti-aging in

gredient. Despite

its efficacy, the safety profile of RE is controversial.

Objectives:

Pretinol (PRE)

complex was formulated with two RE precursors,

-Carotene and Niacinamide,

in order to deliver retinol-like skin benefits with healthier characteristics, as-

suming that skin enzymes will enable safe RE supply on spot.

Methods:

The ex-

pression levels of hyaluronic acid, Tumor Necrosis Factor alpha (TNF

) and In-

terleukin 1 alpha (IL-1

), were measured using various skin models before and

after exposure to PRE and RE. Full genome microarray was performed and the

affected genes and pathways were analyzed.

Results:

Following fibroblasts ex-

posure to PRE, the natural synthesis of hyaluronic acid is significantly elevated.

Skin safety, demonstrated via cytokines expression on

ex-vivo

skin, results with

TNF

and IL-1

elevation by RE application. In contrary PRE significantly re-

duces TNF

while IL-1

is not affected. These results establish skin safety ad-

vantage of PRE

RE. Microarray results examined on skin equivalents reveal

the involvement of PRE in inflammatory attenuation.

Conclusions:

Formulat-

ing RE precursors as a safe source for RE is partially supported. PRE presents

a skin benefit in parallel to RE, while PRE

characteristics are suggested to be

safer to skin.

Keywords

Retinol, Hyaluronic Acid,

-Carotene, Skin, Inflammaging, Irritation

1. Introduction

Vitamin A, the most multifunctional vitamin in the human body, constitutes a

How to cite this paper:

Ma’or, Z.,

Cohen,

., La’or-Costa, Y. and Portugal-Cohen, M.

(20

20) Safe Retinol-Like Skin Biological Effect

by a New Complex, Enriched with Retinol

Precursors

Journal of Cosmetics

Dermat

logical

Sciences and Applications

, 59-75.

https://doi.org/10.4236/jcdsa.2020.102007

Received:

April 19, 2020

Accepted:

May 28, 2020

Published:

June 1, 2020

20 by author(s) and

Scientific

Research Publishing Inc.

This work is licensed under the Creative

Commons Attribution International

License (CC BY

4.0).

http://creativecommons.org/licenses/by/4.0/

Open Access

Z. Ma’or et al.

DOI:

10.4236/jcdsa.2020.102007 60 J. Cosmetics, Dermatological Sciences and Applications

group of organic lipid-soluble compounds comprising retinol (RE) and its de-

rivatives, mainly the RE esters, retinyl palmitate and retinyl acetate [1] [2] [3].

RE is deeply involved in growth and maintenance due to its cellular contribution

to cell proliferation and differentiation from early embryogenesis to adulthood

[4]. RE participates in many skin biological processes in epidermis and dermis

and hence is formulated in a lot of cosmetic preparations, mainly as anti-aging

and skin brightening agent [5] [6]. Its contribution to alleviating acne symp-

toms was proven and as a result it is widely formulated in dermo-cosmetic prod-

ucts aiming to treat acne-prone and oily to problematic skin conditions [7] [8].

Despite its proven efficacy, the safety assessment of RE is still controversial [9].

According to some reports, the topical applications of RE containing skin prep-

arations might trigger severe side effects, such as dryness and irritation, skin

color changes and sensitivity to sunlight [10]. This fragile safety status affects RE

acceptance in cosmetics. Chemists all over the world are searching for new ways

to develop safe RE cosmetics,

i.e.

formulating skin preparations with proven RE

skin benefits, that are free off RE related side effects. Sophisticated delivery sys-

tems for RE, such as liposomes, nano and micro encapsulations were proposed

and clinically tested [11], but these technologies did not solve the fragile status

related to RE containing formulae. In some cases, the situation was even wor-

sened, especially if enhanced RE percutaneous penetration was measured [12].

In order to achieve a desired safe retinol-like skin activity, the idea to formulate

its precursors was raised, assuming that the natural skin enzymatic activity will

effectively convert these precursors, and will enable the skin tissue a safe level of

RE supply “on the spot”.

-Carotene was chosen to serve as a successful RE pre-

cursor and a bio-available RE source [13], as it is a safe compound, that when

processed by epidermal enzymes, is converted into retinyl esters to supply skin

with RE [14]. Combined with Niacinamide, known as Niacin and Vitamin B3, as

it is also involved in the final stage of the skin’s natural process of retinol biosyn-

thesis, mediated by RE dehydrogenase enzyme with Nicotinamide adenine di-

nucleotide Coenzyme A (NAD Co-A) [15] [16]. The natural skin process of RE

biosynthesis from

-Carotene and Niacinamide as precursors is described in

Figure 1 below.

A new complex named “pRETINOL

” (PRE) was designed containing

carotene and Niacinamide as RE precursors, with the addition of two Dead Sea

natural actives, Dead Sea mineral rich water and an extract of

Dunaliella Salina

Dead Sea alga. Dead Sea water skin benefits are well established and are widely

formulated in cosmetics, mainly as a moisturizing humectant and an anti-aging

active ingredient [17] [18].

Dunaliella Salina

, a key micro-flora microorganism

of The Dead Sea, was first discovered by Volcani in the Dead Sea saturated saline

water in 1940 [19]. Following

Dunaliella Salina

exposure to sun the alga accu-

mulates large quantities of

-carotene at its cell periphery [20]. The

-carotene

accumulated level depends on water salinity, temperature and light intensity and

could accomplish up to 10% of alga dry weight [19].

Z. Ma’or et al.

DOI:

10.4236/jcdsa.2020.102007 62 J. Cosmetics, Dermatological Sciences and Applications

2.1.2. Retinol

Retinol (RE) (BASF, Retinol 50C), contains 46.6% all-trans retinol, 49% poly-

sorbate 20, 1.0% of Butylhydroxyanisole, and 3.4% of Butylhydroxytoluene. RE

was diluted with ethanol according to test protocols. On HSOC skin test, 3 µl of

1% (w/w) RE in ethanol, was topically applied. On dermal Fibroblasts test, 1.0

µM of RE were added to fibroblast culture medium.

2.2. Ex-Vivo Human Skin Organ Culture Preparation Protocols

Ex-vivo

human skin organ culture (HSOC) was prepared as described in Por-

tugal

et al.

[22]. Human skin cultures were obtained from healthy females, aged

37 - 60, undergoing abdominal plastic surgery in accordance with Hospital Eth-

ics Committee approval. 0.64 cm

fixed-size of explant skin pieces were cut from

donated skin tissue, placed with dermal side down in culture medium Dulbec-

co’s Modified Eagle’s High D glucose medium (DMEM), supplemented with 100

U/ml penicillin and 100 μg/ml streptomycin), and incubated overnight at 37˚C

with 5% CO

for 24 h of recovery. Following incubation

ex-vivo

HSOC pieces

were treated topically with tested materials.

2.3. Human Primary Fibroblast Cell Culture Protocols

In-vitro

human primary dermal fibroblast cell culture was obtained based on the

protocol described by Limat

et al.

[23]. Human primary fibroblast cells were

grown in cultures to 80% confluency with DMEM culture medium, enriched

with 10% fetal bovine serum 100 U/ml penicillin, and 100 U/ml streptomycin.

The cells were cultivated in 6 wells plates. Tested materials were diluted before

application as follows: PRE complex was diluted × 2.5 with culture medium

DMEM. RE was added to the culture medium at a final concentration of 1.0 µM.

Fibroblast cells were incubated at 37˚C, 5% CO

for 48 h. After incubation, the

cells were extracted using RIPA Lysis Buffer System (Santa Cruz Biotechnology)

collected to a blending Eppendorf and ground using stain steal beads and a bul-

let blender tissue homogenizer (Bullet blender blue, Next Advance) at maximum

speed for 5 min. The samples were centrifuged at 4˚C for 15 min at 5000 rpm,

and the supernatant was collected. Protein content on epidermis lysate was de-

termined using BCA Protein assay [24]. The protein level for all samples was di-

luted with PBS to reach a final concentration of 0.1 ng/ml. Samples were tested

for Hyaluronic Acid (HA) using ELISA assay kit (R&D Systems). Results are pre-

sented as ng/ml of HA per 1.0 µg of protein.

2.4. Reconstructed Skin Model

Full Thickness reconstructed skin tissues (MatTek EFT-400 full-thickness skin

tissues) was used as described in Portugal

et al.

[25]. Skin pieces were placed into

a 6-well plate containing 2.5 ml of assay medium and incubated overnight at 37˚C

and 5% CO

. Then, the assay medium was replaced with 5 ml of fresh medium

and the tissues were treated topically with tested materials for 48 h. At the end of

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