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Anti-Aging Potential of Substance P-Based Hydrogel for Human Skin Longevity

substance p anti-aging effect anti-inflammatory effect skin absorption 3d human skin model cosmetic ingredient

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#1 Engadin

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Posted 25 September 2019 - 12:46 PM


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F U L L   T E X T   S O U R C E :    International Journal of Molecular Sciences

 

 

 

 

 

Abstract

 

Skin aging is generally caused by a decline in the components of the extracellular matrix (e.g., collagen and elastin) and due to inflammatory phenomena. Many growth factors and peptides with cell-growth and collagen-synthesis activities have shown promise in their application in anti-aging materials. However, the effect of collagen production, without anti-inflammatory effect, and skin penetration may not be enough for their use in anti-aging agents. Previously, we reported a substance P (SP)-based hydrogel (SP gel) that had potential wound-healing activities via induction of skin cell regeneration and collagen synthesis. Here, we analyzed the anti-aging activities and skin absorption effects of SP gel to extend its characterization. Toxicity tests, performed on human dermal fibroblasts (HDFs) and on a reconstructed 3D human skin model, indicated SP gel to be safe for long-term use, without causing irritation, even at high concentrations. In-vitro analysis revealed that SP gel elicited stronger collagen production activities than SP alone, and promoted anti-inflammatory effects with increased skin absorption properties. Moreover, SP gel did not induce melanin synthesis in a keratinocyte-melanocyte co-culture system. Together, the results suggest that SP gel has potential cosmetic effects and applicability as a novel ingredient in anti-aging products.

 

 

1. Introduction
 
Aging of skin occurs due to various processes, including internal (cellular metabolism, hormonal changes, and genetic mutation) and external factors (toxins, chemicals, and ultraviolet (UV) radiation) [1,2,3]. Aged skin is biologically characterized by a general decline of the components of extracellular matrix (ECM), with disorganized and reduced collagen and elastin [4,5]. Additionally, an inflammatory phenomenon is usually induced in aging skin, causing wrinkling and thickening of the dermis and epidermis. Pro-inflammatory mediators released from inflammatory cells can enhance the activation of collagenases, named matrix metalloproteinases (MMPs), thus leading to collagen degradation [6,7,8].
 
Many anti-aging materials, possessing the ability to enhance collagen synthesis, have been suggested in recent days. One of the well-known materials is the growth factor. Growth factors have been studied extensively for skin wound healing [9]. Many of them, such as platelet-derived growth factor (VEGF), epidermal growth factor (EGF), and keratinocyte growth factor, directly affect collagen synthesis via a network of inter and intracellular signaling pathways [9,10]. However, topically applied growth factors have not been very helpful as anti-aging agents due to their large molecular size, which limits their ability to penetrate the tight stratum corneum [11]. In addition to growth factors, many anti-aging peptides of low molecular weight have also been developed. For example, palmitoyl tripeptides prevent collagen degradation by interfering with collagen reduction by collagenases, such as MMP1 and 3 [12]. Moreover, copper tripeptides, the most well-examined peptides, have been shown to stimulate procollagen synthesis [13].
 
Although several studies have indicated the promotion of collagen synthesis by topically applied growth factors and peptides, the single effect of collagen synthesis, without anti-inflammatory effect, may not be enough to clinically improve anti-aging performance. For more obvious effects, the compound needs to be delivered into the deep layers of the skin. Therefore, there is a strong need for the development of new materials, which possess the dual function of collagen synthesis and anti-inflammatory effects, along with increased skin absorption.
Substance P (SP), a small-sized peptide consisting of 11 amino acids, exhibits potential wound healing activity, exerted via induction of cell proliferation, collagen synthesis, and anti-inflammatory effects [14,15,16]. However, the therapeutic application of SP has been limited by its low stability, which can delay its healing properties [17,18,19]. In our previous study, we developed a novel formulation of SP, known as SP gel, which increases the stability of SP under various storage conditions [20]. In addition to its stability, SP gel has shown more effective wound healing than SP alone by enhancing keratinocyte and fibroblast proliferation.
 
In the current work, we have extended the characterization of SP gel and demonstrated its promotion of collagen synthesis and anti-inflammatory effects for anti-aging performance. Skin absorption and pigmentation by SP gel were also examined further. Our findings demonstrate higher anti-aging potential of SP gel over that of SP alone, with increased skin absorption effect, and hence, broader cosmetic applicability.
 
 
2. Results
 
2.1. In-Vitro Toxicity of SP Gel
 
For the SP gel to be of anti-aging application, high activities combined with low toxicity against human skin would be desirable. Therefore, in-vitro toxicity of SP gel was evaluated using human dermal fibroblasts (HDFs) and a reconstructed 3D human skin, keraskin®-FT.
 
First, we assessed the damaging effects of SP gel on cell membrane, with respect to that of SP alone, by lactate dehydrogenase (LDH) assay using HDFs (Figure 1A). The LDH assay was further used, in addition to the previous 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay [20], for more accurate toxicity measurement of SP gel. Results showed that neither SP gel nor SP alone showed any cell membrane damage against HDFs at all tested concentrations. Moreover, treatment with a vehicle lacking SP had no effect on the cell membrane relative to medium containing PBS only. To further test the potential irritation on human skin due to the SP gel, we applied the latter, at different concentrations, on the full thickness skin model, keraskin®-FT (Figure 1B,C) for a total of 24 h. To compare the effects on tissue viability, 5% sodium dodecyl sulfate (SDS), a known irritant, was used as a positive control. SP gel (1–10 μg/mL) was non-toxic to keraskin®-FT, as demonstrated by the MTT assay (Figure 1B), indicating no potential skin irritation compared to control (PBS treatment). In addition, histological examination revealed the keraskin®-FT to have suffered no damage at all by SP gel (Figure 1C). The same results were obtained in the group treated with SP alone (Figure S1). Based on these results, even a high concentration of SP gel (10 μg/mL of SP) was concluded to be non-toxic, causing no skin irritation.
 
 
ijms-20-04453-g001.png
 
Figure 1. Effect of substance P (SP) gel on the viability of HDFs and in-vitro reconstructed 3D human skin, keraskin®-FT. (A) For damaging effects of SP gel formulation on cell membrane, HDFs were treated with PBS (Con; control), SP alone, or SP gel (1–10 μg/mL) for 24 h, and cell viability was determined by LDH assay. (B,C) Skin irritability was tested using SP gel (1–10 μg/mL) on in-vitro reconstructed 3D human skin, keraskin®-FT. Tissue viability in the SP gel-treated group was analyzed by MTT assay (B) and histological examination ©, PBS was used as a control. Values represent mean ± SD from three independent experiments. Each value was compared with the control using Student’s t-test (** p < 0.01). Scale bar = 500 μm. HDF, human dermal fibroblast; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PBS, phosphate-buttered saline; SDS, sodium dodecyl sulfate.
 
 
 
 
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F O R   T H E   R E S T   O F   T H E  S T U D Y ,   P L E A S E   V I S I T   T H E   S O U R C E .
 
 
 
 
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#2 adamh

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Posted 04 October 2019 - 08:53 PM

Another thread about a miraculous new thing that of course no one can get. 


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