Inhibitory effect of oyster hydrolysate on wrinkle formation against UVB irradiation in human dermal fibroblast via MAPK/AP-1 and TGFβ/Smad pathway
Introduction
Skin is the outermost tissue that makes up the human body. It is constituted with several layers containing epidermis, dermis, and hypodermis. The human skin is structurally maintained by extracellular matrix (ECM) in the dermis. The ECM is composed of collagen fibers, elastin fibers and proteoglycans [1]. However, internal and external factors change this structural maintenance. Internal factors including aging, immunological, hormonal, and genetic changes degenerate skin structure and its physiological functions [2]. Also, due to various extrinsic stimuli such as ultraviolet radiation (UV), air pollution and chemical substances, the shape, function, and structure of skin are changed [2].
Among several external factors that cause skin aging, ultraviolet (UV) radiation is the main influential factor [3]. UV is classified with UVA (315-400 nm), UVB (280-315 nm) and UVC (100-280 nm). UV irradiation causes skin damage and continuous damage of UV radiation leads to photoaging [4]. Long term UV irradiation induces direct DNA damage and brought indirect oxidative stress by producing reactive oxygen species (ROS) like hydrogen peroxide, hydroxyl radical, and nitric oxide [[5], [6], [7]]. Elevated DNA damage and ROS increase wrinkle formation, skin thickening and degradation of skin structure [8,9]. Particularly, UVB reaches the upper part of skin dermis and weakens the cells in the dermis. Due to the accumulation of damages, wrinkle, cancer, sagging, hyperpigmentation and other symptoms occurred in photoaged skin [10].
Wrinkle is formed as a result of the collapse of ECM arisen from a reduction of ECM proteins [11]. Collagen is one of the main ECM proteins constituting various fibrous tissues such as tendons, ligament, and skin. Especially type I collagen, which is bountiful (approximately 85%) in the skin dermis, is crucial to managing the structure of connective tissue and the strength of the skin [12]. The precursor of type I collagen is type I procollagen and it is produced in human dermal fibroblasts. Collagen degradation and fragmentation are well-known features in photoaged skin and they are the main characteristics of wrinkle formation [[13], [14], [15]]. ECM proteins, including collagen, are degraded by matrix metalloproteinases (MMPs). MMPs degrade various kinds of extracellular proteins and they're also well-known as carrying out roles such as cell differentiation, proliferation, apoptosis and tissue remodeling [16,17]. Normally, their activity is low, however, MMPs are overexpressed by the chronic UV irradiation [3,18]. Increase of MMPs accelerates the degradation of ECM proteins and leads to malfunction of connective tissue remodeling [19]. It brings imbalance of collagen synthesis and degradation, resulting in collapse structure of ECM. Therefore, managing collagen levels is crucial for maintaining extracellular matrix and human skin.
Bioactive peptides with low molecular weights contain various amino acids and exhibit biological effects [20]. Further, bioactive compounds derived from marine organisms contain numerous amino acids and have the pharmaceutical potential [21]. Oyster (Crassostrea gigias) is a marine food resource abundant in Asia and Europe. Oyster contains several functional substances like vitamin A, B₁, B₂, C, calcium and zinc ion, etc. We prepared oyster hydrolysate (OH) in order to utilize the functional compounds of oyster effectively [22]. OH has been described to have an antioxidant, antiviral and anti-apoptotic effect [[23], [24], [25]]. In our previous study, we have found that the OH, hydrolyzed by commercial enzymes (Protamex and Neutrase) and yeast, an organism, inhibits wrinkle formation in UVB-induced mice [26]. In this research, we proved the wrinkle suppression effect of OH in the viewpoint of the balance of collagen degradation and collagen production and examined the signaling mechanisms focusing on mitogen-activated protein kinases (MAPK) pathway and transforming growth factor β (TGF-β)/Smad pathway in human dermal fibroblasts (HDFs).
Section snippets
Preparation of Oyster Hydrolysate
We prepared OH in the same way we previously described [26,27]. Pacific oyster (Crassostrea gigas) was gathered from the sea of Tongyeong-si in South Korea. The oyster was blanched at the boiled water and grinded three times. The minced oyster was homogenized with commercial proteases; Protamex (Ajinomoto, Chuo-ku, Tokyo, Japan), Neutrase (Biosis, Busan, Korea) and fermented by food grade yeast (Societe Industrielle Lesaffre, Marcq-en-Baroeul, France). Then, the oyster was centrifuged at 3000g
Effects of OH on Type I Procollagen and MMP-1 Production in UVB Damaged HDFs
Before investigating the anti-wrinkle effect of OH in HDFs, we measured OH cell viability in HDFs. Diverse concentrations (50, 100, 200, 400, 600, 800 and 1000 μg/ml) of OH were treated to the cells without or with UVB radiation. Without UVB radiation, OH didn't induce cell cytotoxicity up to 200 μg/ml. However, 400 μg/ml of OH decreased cell viability (Supplementary Fig. S1A). When UVB was irradiated, the cell viability was reduced to 70% and cell viability was increased until 200 μg/ml of OH
Discussion
Skin is a part of the human body that is largely affected by external factors. Due to various stimuli, wrinkles and irregular pigmentation are formed and abnormal skin aging is accelerated [33,34]. Among many external stimuli, UV radiation leads to DNA damage and ROS which cause apoptosis, inflammation and skin damage [35]. Gene expression levels of various factors are changed, the amount of ECM protein is decreased, the skin structure is collapsed, and then, skin wrinkles are generated by UV
Conclusion
This study demonstrated that OH restores type I procollagen level which was reduced by UVB radiation in HDFs. OH decreased MMPs expression by regulating the MAPK phosphorylation and expression of transcription factor AP-1. In addition, OH activated the synthesis of type I procollagen by stimulating TGFβ receptor II expression and Smad3 phosphorylation and by reducing expression of Smad-7. These multiple actions of OH on the type I collagen production will help to suppress wrinkle formation and
Author statement
Joon Sok Bang conducted the research and performed experiments. Joon Sok Bang and Se Young Choung wrote the original draft. Se Young Choung supervised this study. All authors are participated with the reviewing and editing the manuscript.
Declaration of Competing Interest
There are no conflicts of interest to declare.
Acknowledgments
The study was supported by Development and Industrialization of Natural Functional Foods from Marine Invertebrate Program (Project No. 20140442) from the Ministry of Oceans and Fisheries (Republic of Korea).
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