32 FORMULATING FOR MILDNESS
lines and wrinkles by acting through well- documented biological pathways. Inside the cell, retinoids can bind to specific nuclear receptors and modulate expression of genes involved in cellular proliferation and differentiation.4 In the first analysis, the treatments with
retinyl linoleate compared with a vehicle only control) are analyzed to see what responses these treatments have in common. In theory, this analysis may reveal molecular responses that are associated with the retinol half of the treatment compounds. In the skin model treated with 0.2% retinyl
linoleate, 1,650 genes were up-regulated at least twofold and 35 genes at least fivefold versus the vehicle control. The subset of genes with known function and up-regulated more than fivefold by the retinyl linoleate treatment (and general function of the protein) is listed in Table 1, along with the fold-induction observed after a 24-hour treatment with the retinyl ester. Many of the gene products up-regulated
more than fivefold by R-LIN included proteins associated with cell proliferation, a known target pathway for retinoids in skin. In contrast to the R-LIN treatment, the Retinyl palmitate treatment induced many fewer genes and these genes are generally not up-regulated as abundantly. These comparative results suggested that R-LIN was more effectively absorbed or metabolized by the cultured skin cells than retinyl palmitate.
General function
Proliferation Proliferation Proliferation Proliferation Proliferation Proliferation Cell adhesion Cell adhesion Receptor
Protein synthesis Protease inhibitor Transcription factor Stress response Anti-inflammatory
Protein name
ABO transferase CDK cyclin kinase MAGEA5 frizzled OR10H LYNX1
MEGF11L EPH
DAOA
Ribosomal RNA WFIKKN1 ZEC
crystallin IL188P
ANTI-AGEING FORMULATION - WITH EASTMAN GEM™ RETINYL LINOLEATE Phase Ingredients A Water
INCI –
Kolliphor* CS A Zemea*
Genencare* OSMS BA
B
2-Ethylhexyl palmitate
Eastman GEM* retinyl linoleate
C KerrPoly GA D Spectrastat™
Cetearyl alcohol (and) sodium cetearyl sulfate Propanediol
Betaine Ethylhexyl palmitate Retinyl linoleate Acacia senegal gum Caprylhdroxamic acid (and) caprylyl glycol (and) glycerin
4 5
6
SPLR w/w (%) 60.9 6.0
1
2 3
10.0 1.0
20.0
0.1 1.0
1.0
Procedure: heat and mix part A until uniform and fully melted/dispersed. Remove heat, and propeller stir at medium speed. Add part B with medium stirring when part A reaches 45°C or below. Add part C with propeller stirring. Add part D with propeller stirring.
Suppliers: 1. BASF 2. Dupont Tate & Lyle 3. Dupont 4. Eastman 5. Kerry Figure 1: Formulation for clinical testing (from CC PC 14452)
Expression of retinoid marker genes The regulation of specific retinol-related genes by retinyl linoleate can be extracted from the global data set. Retinoic acid binding proteins and collagen synthesis and degradation proteins are of particular interest. Treatment with retinyl linoleate and the vehicle only are compared. A number greater than 1 indicates induction while a number less than one indicates repression by the topical retinoid treatment.
Fold Induction vs Vehicle only
Retinyl linoleate 16.7 7.5 6.2 5.5 5.1 5.1
5.6 6.0 7.0 6.9 8.9 6.0 6.3 8.5
Retinyl palmitate 9.9 –
3.7 –
8.6 7.7
6.4 – – – – – – –
Table 1: Select gene products of known function up-regulated > fivefold in a cultured skin model treated topically with 0.2% retinoid in vehicle. (- means the gene was up-regulated less than twofold)
General function
CRBP1 CRBP2 CRBP3 CRBP4
CRBP1 CRBP2
Retinoic acid receptor Protein name
RBP1 RBP2 RBP5 RBP7
RBP51 RBP61
RARA Signal
Vehicle 16.7 7.5
6.2 5.5
200
23807 430
R-LIN 9.9 –
3.7 –
252
21364 1250
Table 2: Differential signal intensities for retinol and retinoic acid binding proteins PERSONAL CARE April 2023
Fold Induction or repression
1.61 1.12
2.94 1.33
1.26
0.90 2.91
6. Inolex
Signal intensities for retinol and retinoic
acid binding protein genes were extracted from the data sets using keyword searches (Table 2). Known retinoid binding proteins genes were well-represented on the microarray.
Retinol binding proteins Cellular retinol binding proteins (CRBP) have been shown to bind retinol specifically and can be induced in vivo by treatment with both retinol and retinoic acid.5
At least four human
genes have been characterized. CRBP1 is important in retinol metabolism
in the liver but is widely expressed in human tissues, while CRBP4 is common in muscle and connective tissue. In our results, CRBP1 and CRBP4 expression are both detected at moderate levels in the experimental tissue and are modestly up-regulated by the retinyl Linoleate treatment. CRBP2 is reported as abundant in the small
intestinal epithelium but is expressed only at low levels in the experimental cultured skin tissue we used. CRBP3 (RBP5) is expressed in various human tissues, including the experimental cultured skin tissue, and appears to be up- regulated almost threefold by topical treatment with 0.2% R-LIN. Since the first product from the hydrolysis of a retinyl ester in the skin will be retinol, it makes sense that some retinol binding proteins are up-regulated by the treatment.
Retinoic acid binding proteins While there are two cellular retinoic acid binding proteins (CRABP) in humans, CRABP2 is the predominant protein in human skin, both in vivo and in in vitro cultured cells. The reported use of CRABP2 as a marker
for retinoic acid activity in vivo and in cultured human skin fibroblasts in the literature is mixed. In our experiment, the expression of CRABP2 is high in the control tissue and does not appear to be further induced by the R-LIN treatment. The high signal intensity for CRABP2 mRNA
in both data sets may reflect the tissue origin. The skin model used in our studies is derived from neonatal foreskin tissue, and CRABP levels
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