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Molecular Mechanisms of Skin Aging
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Molecular Mechanisms of Skin Aging

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 May 2020) | Viewed by 130343

Special Issue Editor

Prof. Dr. Genji Imokawa

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Guest Editor
Center for Bioscience Research & Education, Utsunomiya University, 350 Mine Utsunomiya, Tochigi 321-8505, Japan
Interests: photo-aging/fibroblast biology; atopic dermatitis/sphingolipid metabolism; melanogenesis/melanocyte biology; keratinization/keratinocyte biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite the fact that anti-aging products in the cosmetic field are becoming more popular, little is known about the precise molecular mechanisms involved in skin aging, including photo-aging. Thus, major targets for skin aging are: (1) age-related xerosis, (2) wrinkle formation (including the loss of skin elasticity), (3) hyperpigmentation (such as solar lentigos), and (4) other age-related processes including carcinogenesis. There are many unresolved issues, such as: (1) how and why do ceramide deficiencies occur in age-related xerosis?, (2) what are essential factor(s) that attenuate skin elasticity (e.g. fibroblast elastase or neutrophil elastase and collagenase I or other matrix-metalloproteinases)?, (3) how and why do solar lentigos emerge in sun-exposed skin?, what kinds of mutations are involved in that, or novel mechanisms of developing those? And (4) what factors are involved in the mechanisms of photo-aging following exposure of the skin to UVA? This Special Issue on “Molecular Mechanisms of Skin Aging” aims to provide a summary of those emerging fields with emphasis on novel developments of anti-aging products and novel results about different types of skin aging. This Special Issue will publish original research articles as well as mini and full reviews, including perspectives in the field on the current understanding of molecular mechanisms involved in skin aging and in photo-aging. Manuscripts on the molecular mechanisms of new or old skin anti-aging products, introduction of ideas for new skin anti-aging agents and new techniques for measuring the level of skin aging are welcome.

Prof. Dr. Genji Imokawa
Guest Editor

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Published Papers (17 papers)

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Research

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21 pages, 3783 KiB  
Article
Screening of an Epigenetic Drug Library Identifies 4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-Phenyl-Benzeneacetamide that Reduces Melanin Synthesis by Inhibiting Tyrosinase Activity Independently of Epigenetic Mechanisms
by Hyerim Song, Yun Jeong Hwang, Jae Won Ha and Yong Chool Boo
Int. J. Mol. Sci. 2020, 21(13), 4589; https://doi.org/10.3390/ijms21134589 - 28 Jun 2020
Cited by 5 | Viewed by 2804
Abstract
The aim of this study was to identify novel antimelanogenic drugs from an epigenetic screening library containing various modulators targeting DNA methyltransferases, histone deacetylases, and other related enzymes/proteins. Of 141 drugs tested, K8 (4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-phenyl-benzeneacetamide; HPOB) was found to effectively [...] Read more.
The aim of this study was to identify novel antimelanogenic drugs from an epigenetic screening library containing various modulators targeting DNA methyltransferases, histone deacetylases, and other related enzymes/proteins. Of 141 drugs tested, K8 (4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-phenyl-benzeneacetamide; HPOB) was found to effectively inhibit the α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16-F10 murine melanoma cells without accompanying cytotoxicity. Additional experiments showed that K8 did not significantly reduce the mRNA and protein level of tyrosinase (TYR) or microphthalmia-associated transcription factor (MITF) in cells, but it potently inhibited the catalytic activity TYR in vitro (IC50, 1.1–1.5 µM) as compared to β-arbutin (IC50, 500–700 µM) or kojic acid (IC50, 63 µM). K8 showed copper chelating activity similar to kojic acid. Therefore, these data suggest that K8 inhibits cellular melanin synthesis not by downregulation of TYR protein expression through an epigenetic mechanism, but by direct inhibition of TYR catalytic activity through copper chelation. Metal chelating activity of K8 is not surprising because it is known to inhibit histone deacetylase (HDAC) 6 through zinc chelation. This study identified K8 as a potent inhibitor of cellular melanin synthesis, which may be useful for the treatment of hyperpigmentation disorders Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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12 pages, 1472 KiB  
Article
6-Shogaol Protects Human Melanocytes against Oxidative Stress through Activation of the Nrf2-Antioxidant Response Element Signaling Pathway
by Lingli Yang, Fei Yang, Lanting Teng and Ichiro Katayama
Int. J. Mol. Sci. 2020, 21(10), 3537; https://doi.org/10.3390/ijms21103537 - 16 May 2020
Cited by 35 | Viewed by 3410
Abstract
Skin is a major target of oxidative stress. Increasing evidence suggests that oxidative stress is the cause of melanocyte disappearance in vitiligo, which is an acquired pigmentary skin disorder characterized by patches of skin that have lost pigmentation. New herbal extracts with antioxidant [...] Read more.
Skin is a major target of oxidative stress. Increasing evidence suggests that oxidative stress is the cause of melanocyte disappearance in vitiligo, which is an acquired pigmentary skin disorder characterized by patches of skin that have lost pigmentation. New herbal extracts with antioxidant activity are therefore being studied. 6-Shogaol (6-SG), an active compound from ginger, is capable of attenuating oxidative stress-induced ageing and neurotoxicity. Subsequently, to investigate whether 6-SG could protect melanocytes from oxidative stress, cultured human primary epidermal melanocytes (HEMn-MPs) were treated with hydrogen peroxide (H2O2) in the presence or absence of 6-SG. The 6-SG exhibited protective effects against H2O2-induced cell death by reducing oxidative stress. In addition, the 6-SG treatment activated the Nrf2-antioxidant response element signaling pathway by upregulating the mRNA expression of the antioxidant enzyme heme oxygenase 1 (HO-1), and protein expression of Nrf2, NAD(P)H: quinine oxidoreductase 1 (Nqo1), and HO-1. Furthermore, the 6-SG also displayed protective effects on melanocytes against Rhododendrol-induced oxidative stress. We concluded that 6-SG protects melanocytes against oxidative stress in vitro, and its protective effect is associated with the activation of the Nrf2-antioxidant response element signaling pathway. 6-SG, therefore, has potential for use in the prevention of melanocyte loss in the early stages of vitiligo or other pigmentary disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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13 pages, 1886 KiB  
Article
Caviar Extract and Its Constituent DHA Inhibits UVB-Irradiated Skin Aging by Inducing Adiponectin Production
by Kyung-Eun Lee, Youn-Hwa Nho, Seok Kyun Yun, Sung-Min Park, Seunghyun Kang and Hyeonju Yeo
Int. J. Mol. Sci. 2020, 21(9), 3383; https://doi.org/10.3390/ijms21093383 - 11 May 2020
Cited by 11 | Viewed by 6411
Abstract
In this study, caviar (sturgeon eggs) was used to elucidate its roles in adiponectin production and skin anti-aging. Recently, caviar has been largely used not only as a nutritional food, but also in cosmetic products. In particular, it has been reported that docosahexaenoic [...] Read more.
In this study, caviar (sturgeon eggs) was used to elucidate its roles in adiponectin production and skin anti-aging. Recently, caviar has been largely used not only as a nutritional food, but also in cosmetic products. In particular, it has been reported that docosahexaenoic acid (DHA), as one of the main phospholipid components of caviar extract, induces intracellular lipid accumulation and the expression of adiponectin in adipocytes. Although adipocytes are well known to be associated with the skin dermis by secreting various factors (e.g., adiponectin), the effects of caviar extract and DHA on the skin are not well studied. Here, we demonstrate the effects of caviar extract and DHA on adipocyte differentiation and adiponectin production, resulting in a preventive role in UV-irradiated skin aging. Caviar extract and DHA enhanced adipocyte differentiation and promoted the synthesis of transcription factors controlling adipocyte differentiation and adiponectin. In addition, the mRNA expression levels of matrix metalloproteinase-1 (MMP-1) were decreased in UVB-irradiated Hs68 fibroblasts that were cultured in conditioned medium from caviar extract or DHA-treated differentiated adipocytes. Taken together, these results indicate that caviar extract and DHA induce adipocyte differentiation and adiponectin production, thereby inhibiting UVB-induced premature skin aging via the suppression of MMP-1 production. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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13 pages, 2563 KiB  
Article
Protective Effect of the Aqueous Extract of Deschampsia antarctica (EDAFENCE®) on Skin Cells against Blue Light Emitted from Digital Devices
by Silvia Lorrio, Azahara Rodríguez-Luna, Pablo Delgado-Wicke, Marta Mascaraque, María Gallego, Azahara Pérez-Davó, Salvador González and Ángeles Juarranz
Int. J. Mol. Sci. 2020, 21(3), 988; https://doi.org/10.3390/ijms21030988 - 02 Feb 2020
Cited by 22 | Viewed by 5076
Abstract
Skin is being increasingly exposed to artificial blue light due to the extensive use of electronic devices. This, together with recent observations reporting that blue light—also known as high-energy visible light—can exert cytotoxic effects associated with oxidative stress and promote hyperpigmentation, has sparked [...] Read more.
Skin is being increasingly exposed to artificial blue light due to the extensive use of electronic devices. This, together with recent observations reporting that blue light—also known as high-energy visible light—can exert cytotoxic effects associated with oxidative stress and promote hyperpigmentation, has sparked interest in blue light and its potential harmful effects on skin. The photoprotective properties of new extracts of different botanicals with antioxidant activity are therefore being studied. Deschampsia antarctica (Edafence®, EDA), a natural aqueous extract, has shown keratinocyte and fibroblast cell protection effects against ultraviolet radiation and dioxin toxicity. In this regard, we studied the protective capacity of EDA against the deleterious effects of artificial blue light irradiation in human dermal fibroblasts (HDF) and melanocytes. We analyzed the impact of EDA on viability, cell morphology, oxidative stress, melanogenic signaling pathway activation and hyperpigmentation in HDF and melanocytes subjected to artificial blue light irradiation. Our results show that EDA protects against cell damage caused by artificial blue light, decreasing oxidative stress, melanogenic signaling pathway activation and hyperpigmentation caused by blue light irradiation. All these findings suggest that EDA might help prevent skin damage produced by artificial blue light exposure from screen of electronic devices. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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20 pages, 4367 KiB  
Article
Riboflavin Plays a Pivotal Role in the UVA-Induced Cytotoxicity of Fibroblasts as a Key Molecule in the Production of H2O2 by UVA Radiation in Collaboration with Amino Acids and Vitamins
by Satoshi Yoshimoto, Nana Kohara, Natsu Sato, Hideya Ando and Masamitsu Ichihashi
Int. J. Mol. Sci. 2020, 21(2), 554; https://doi.org/10.3390/ijms21020554 - 15 Jan 2020
Cited by 12 | Viewed by 4928
Abstract
To investigate environmental factors that contribute to ultraviolet A (UVA)-induced oxidative stress, which accelerates the senescence and toxicity of skin cells, we irradiated human fibroblasts cultured in commonly used essential media with UVA and evaluated their viability and production of reactive oxygen species. [...] Read more.
To investigate environmental factors that contribute to ultraviolet A (UVA)-induced oxidative stress, which accelerates the senescence and toxicity of skin cells, we irradiated human fibroblasts cultured in commonly used essential media with UVA and evaluated their viability and production of reactive oxygen species. The viability of fibroblasts exposed to a single dose of 3.6 J/cm2 UVA was not reduced when cultured in Hanks balanced salt solution, but it was significantly decreased when cultured in Dulbecco’s modified Eagle’s medium (DMEM), which contains various amino acids and vitamins. Furthermore, cell viability was not reduced when fibroblasts were cultured in DMEM and treated with a hydrogen peroxide (H2O2) scavenger such as glutathione or catalase added after UVA irradiation. In addition, we confirmed that the production of H2O2 was dramatically increased by UVA photosensitization when riboflavin (R) coexisted with amino acids such as tryptophan (T), and found that R with folic acid (F) produced high levels of H2O2 after UVA irradiation. Furthermore, we noticed that R and F or R and T have different photosensitization mechanisms since NaN3, which is a singlet oxygen quencher, suppressed only R and T photosensitization. Lastly, we examined the effects of antioxidants (L-ascorbic acid, trolox, L-cysteine, and L-histidine), which are singlet oxygen or superoxide or H2O2 scavengers, on R and F or on R and T photosensitization, and found that 1 mM ascorbic acid, Trolox, and L-histidine were strongly photosensitized with R, and produced significant levels of H2O2 during UVA exposure. However, 1 mM L-cysteine dramatically suppressed H2O2 production by UVA photosensitization. These data suggest that a low concentration of R-derived photosensitization is elicited by different mechanisms depending on the coexisting vitamins and amino acids, and regulates cellular oxidative stress by producing H2O2 during UVA exposure. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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12 pages, 5579 KiB  
Article
Anti-Wrinkle Benefits of Peptides Complex Stimulating Skin Basement Membrane Proteins Expression
by Sekyoo Jeong, Seokjeong Yoon, Sungwoo Kim, Juyeon Jung, Myungho Kor, Kayoung Shin, Chaejin Lim, Hyo Sun Han, Haekwang Lee, Kyeong-Yong Park, Jinwan Kim, Hwa Jee Chung and Hyun Jung Kim
Int. J. Mol. Sci. 2020, 21(1), 73; https://doi.org/10.3390/ijms21010073 - 20 Dec 2019
Cited by 29 | Viewed by 11432
Abstract
The dermal-epidermal junction (DEJ) provides a physical and biological interface between the epidermis and the dermis. In addition to providing a structural integrity, the DEJ also acts as a passageway for molecular transport. Based on the recently reported importance of the DEJ in [...] Read more.
The dermal-epidermal junction (DEJ) provides a physical and biological interface between the epidermis and the dermis. In addition to providing a structural integrity, the DEJ also acts as a passageway for molecular transport. Based on the recently reported importance of the DEJ in skin aging, novel peptide derivatives have been tested for their effects on basement membrane (BM) protein expressions in cultured human epidermal keratinocytes. As a result, protein expressions of collagen XVII, laminin and nidogen were stimulated by the test peptide and peptides complex. Further ex vivo evaluation using excised human skin, confirmed that the topical application of the peptides complex significantly increased dermal collagen expression, as well as expressions of collagen XVII and laminin. Interestingly, while the origin of the laminin protein is epidermal keratinocytes, the immunohistochemical staining of skin showed that laminin was only detected in the uppermost layer of the dermis, which suggests a tight assembly of laminin protein onto the dermal side of the DEJ. These results suggest that a peptide complex could improve the structural properties of the DEJ through its ability to stimulate BM proteins. In order to evaluate the anti-wrinkle benefits of the peptide complex in vivo, a clinical study was performed on 22 healthy Asian female volunteers older than 40 years. As a result, significant improvements in skin wrinkles for all of the five sites were observed after two weeks, as assessed by skin topographic measurements. Collectively, these results demonstrate the anti-aging efficacy of the peptides complex. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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16 pages, 2892 KiB  
Article
Discovery of a Highly Selective MC1R Agonists Pentapeptide to Be Used as a Skin Pigmentation Enhancer and with Potential Anti-Aging Properties
by Eileen Jackson, Marc Heidl, Dominik Imfeld, Laurent Meeus, Rolf Schuetz and Remo Campiche
Int. J. Mol. Sci. 2019, 20(24), 6143; https://doi.org/10.3390/ijms20246143 - 05 Dec 2019
Cited by 21 | Viewed by 5188
Abstract
One of the first lines of cutaneous defense against photoaging is (a) the synthesis of melanin and (b) the initiation of an oxidative stress response to protect skin against the harmful effects of solar radiation. Safe and selective means to stimulate epidermal pigmentation [...] Read more.
One of the first lines of cutaneous defense against photoaging is (a) the synthesis of melanin and (b) the initiation of an oxidative stress response to protect skin against the harmful effects of solar radiation. Safe and selective means to stimulate epidermal pigmentation associated with oxidative stress defense are; however, scarce. Activation of the melanocortin-1 receptor (MC1R) on epidermal melanocytes represents a key step in cutaneous pigmentation initiation and, additionally, it regulates cellular defense mechanisms like oxidative stress and DNA-repair. Thus, making the activation of MC1R an attractive strategy for modulating skin pigmentation and oxidative stress. In this context, we designed and synthesized pentapeptides that act as MC1R agonists. These peptides bound, with high potency, to MC1R and activated cAMP synthesis in CHO cells expressing human MC1R. Using one lead pentapeptide, we could show that this activation of MC1R was specific as testing the activation of other G-protein coupled receptors, including the MC-receptor family, was negative. In vitro efficacy on mouse melanoma cells showed similar potency as for the synthetic MC1R agonist alpha-melanocyte stimulating hormone (NDP-alpha-MSH). Moreover, we could reproduce this activity in human skin tissue culture. The lead pentapeptide was able to induce ex-vivo protein expression of key melanogenesis markers melanocyte inducing transcription factor (MITF), tyrosinase (TYR), and tyrosinase-related protein 1 (TYRP-1). Concerning oxidative stress response, we found that the pentapeptide enhanced the activation of Nrf2 after UVA-irradiation. Our results make this pentapeptide an ideal candidate as a skin pigmentation enhancer that mimics alpha-MSH and may also have anti-photoaging effects on the skin. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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14 pages, 2777 KiB  
Article
Anti-Aging Potential of Substance P-Based Hydrogel for Human Skin Longevity
by Da Jung Kim, Song Sun Chang and Jungsun Lee
Int. J. Mol. Sci. 2019, 20(18), 4453; https://doi.org/10.3390/ijms20184453 - 10 Sep 2019
Cited by 15 | Viewed by 5756
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. [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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9 pages, 1284 KiB  
Article
Caffeic Acid Phenethyl Ester Inhibits UV-Induced MMP-1 Expression by Targeting Histone Acetyltransferases in Human Skin
by Eun Ju Shin, Seongin Jo, Hyo-kyoung Choi, Sungbin Choi, Sanguine Byun and Tae-Gyu Lim
Int. J. Mol. Sci. 2019, 20(12), 3055; https://doi.org/10.3390/ijms20123055 - 22 Jun 2019
Cited by 24 | Viewed by 4325
Abstract
Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and [...] Read more.
Caffeic acid phenethyl ester (CAPE), a naturally occurring bioactive compound, displays anti-inflammatory, anti-carcinogenic, and anti-microbial effects. However, the effect of CAPE on skin photoaging is unknown. Herein, we investigated the inhibitory effect of CAPE against ultraviolet (UV) irradiation-mediated matrix metalloproteinase (MMP)-1 expression and its underlying molecular mechanism. CAPE treatment suppressed UV-induced MMP-1 levels in both human dermal fibroblasts (HDF) and human skin tissues. While CAPE did not display any significant effects against the upstream regulatory pathways of MMP-1, CAPE was capable of reversing UV-mediated epigenetic modifications. CAPE suppressed UV-induced acetyl-histone H3 (Lys9) as well as total lysine acetylation in HDF cells. Similarly, CAPE also attenuated UV-induced lysine acetylations in human skin tissues, suggesting that the CAPE-mediated epigenetic alterations can be recapitulated in ex vivo conditions. CAPE was found to attenuate UV-induced histone acetyltransferase (HAT) activity in HDF. Notably, CAPE was able to directly inhibit the activity of several HATs including p300, CREP-binding protein (CBP), and p300/CBP-associated factor (PCAF), further confirming that CAPE can function as an epigenetic modulator. Thus, our study suggests that CAPE maybe a promising agent for the prevention of skin photoaging via targeting HATs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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16 pages, 3593 KiB  
Article
Slc7a11 Modulated by POU2F1 is Involved in Pigmentation in Rabbit
by Yang Chen, Shuaishuai Hu, Lin Mu, Bohao Zhao, Manman Wang, Naisu Yang, Guolian Bao, Cigen Zhu and Xinsheng Wu
Int. J. Mol. Sci. 2019, 20(10), 2493; https://doi.org/10.3390/ijms20102493 - 20 May 2019
Cited by 17 | Viewed by 3609
Abstract
Solute carrier family 7 member 11 (Slc7a11) is a cystine/glutamate xCT transporter that controls the production of pheomelanin pigment to change fur and skin color in animals. Previous studies have found that skin expression levels of Slc7a11 varied significantly with fur [...] Read more.
Solute carrier family 7 member 11 (Slc7a11) is a cystine/glutamate xCT transporter that controls the production of pheomelanin pigment to change fur and skin color in animals. Previous studies have found that skin expression levels of Slc7a11 varied significantly with fur color in Rex rabbits. However, the molecular regulation mechanism of Slc7a11 in pigmentation is unknown. Here, rabbit melanocytes were first isolated and identified. The distribution and expression pattern of Slc7a11 was confirmed in skin from rabbits with different fur colors. Slc7a11 affected the expression of pigmentation related genes and thus affected melanogenesis. Meanwhile, Slc7a11 decreased melanocyte apoptosis, but inhibition of Slc7a11 enhanced apoptosis. Furthermore, the POU2F1 protein was found to bind to the −713 to −703 bp region of Slc7a11 promoter to inhibit its activity in a dual-luciferase reporter and site-directed mutagenesis assay. This study reveals the function of the Slc7a11 in melanogenesis and provides in-depth analysis of the mechanism of fur pigmentation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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14 pages, 4646 KiB  
Article
Characterization of a New Reconstructed Full Thickness Skin Model, T-Skin™, and its Application for Investigations of Anti-Aging Compounds
by Michel Bataillon, Damien Lelièvre, Adeline Chapuis, Fabienne Thillou, Jean Baptiste Autourde, Steven Durand, Nathalie Boyera, Anne-Sophie Rigaudeau, Isabelle Besné and Christian Pellevoisin
Int. J. Mol. Sci. 2019, 20(9), 2240; https://doi.org/10.3390/ijms20092240 - 07 May 2019
Cited by 31 | Viewed by 9915
Abstract
Background: We have characterized a new reconstructed full-thickness skin model, T-Skin™, compared to normal human skin (NHS) and evaluated its use in testing anti-aging compounds. Methods: The structure and layer-specific markers were compared with NHS using histological and immunohistological staining. In anti-aging experiments, [...] Read more.
Background: We have characterized a new reconstructed full-thickness skin model, T-Skin™, compared to normal human skin (NHS) and evaluated its use in testing anti-aging compounds. Methods: The structure and layer-specific markers were compared with NHS using histological and immunohistological staining. In anti-aging experiments, T-SkinTM was exposed to retinol (10 µM) or vitamin C (200 µM) for 5 days, followed by immunohistological staining evaluation. Results: T-Skin™ exhibits a well stratified, differentiated and self-renewing epidermis with a dermal compartment of functional fibroblasts. Epidermal (cytokeratin 10, transglutaminase 1), dermo–epidermal junction (DEJ) (laminin 5, collagen-IV, collagen VII) and dermally-located (fibrillin 1, procollagen I) biomarkers were similar to those in NHS. Treatment of T-Skin™ with retinol decreased the expression of differentiation markers, cytokeratin 10 and transglutaminase 1 and increased the proliferation marker, Ki67, in epidermis basal-layer cells. Vitamin C increased the expression of DEJ components, collagen IV and VII and dermal procollagen 1. Conclusions: T-Skin™ exhibits structural and biomarker location characteristics similar to NHS. Responses of T-Skin™ to retinol and vitamin C treatment were consistent with those of their known anti-aging effects. T-Skin™ is a promising model to investigate responses of epidermal, DEJ and dermal regions to new skin anti-ageing compounds. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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10 pages, 2415 KiB  
Article
Rottlerin Reduces cAMP/CREB-Mediated Melanogenesis via Regulation of Autophagy
by Nurinanda Prisky Qomaladewi, Mi-Yeon Kim and Jae Youl Cho
Int. J. Mol. Sci. 2019, 20(9), 2081; https://doi.org/10.3390/ijms20092081 - 27 Apr 2019
Cited by 16 | Viewed by 5373
Abstract
Melanogenesis is the sequential process of melanin production by melanocytes in order to protect the skin from harmful stimuli. Melanogenesis is disrupted by radiation exposure, which results in the differentiation of melanocytes into melanoma. Recently, some methods have been developed to maintain the [...] Read more.
Melanogenesis is the sequential process of melanin production by melanocytes in order to protect the skin from harmful stimuli. Melanogenesis is disrupted by radiation exposure, which results in the differentiation of melanocytes into melanoma. Recently, some methods have been developed to maintain the instability of melanogenesis in melanoma by activating cellular autophagy. However, there is still a lack of knowledge about how autophagy is involved in the regulation of melanogenesis in melanoma cells. Here, we used rottlerin as an autophagy inducer to investigate the role of the cyclic adenosine monophosphate (cAMP)/cAMP response element binding (CREB) signaling pathway in melanogenesis. We found that rottlerin can inhibit melanin production by targeting cAMP, which is initially activated by alpha-melanocyte stimulating hormone (α-MSH). Our findings suggest that rottlerin has a pivotal role as an autophagy inducer in the regulation of melanogenesis by targeting the cAMP/CREB signaling pathway. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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Review

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21 pages, 1069 KiB  
Review
Role of the Aryl Hydrocarbon Receptor in Environmentally Induced Skin Aging and Skin Carcinogenesis
by Christian Vogeley, Charlotte Esser, Thomas Tüting, Jean Krutmann and Thomas Haarmann-Stemmann
Int. J. Mol. Sci. 2019, 20(23), 6005; https://doi.org/10.3390/ijms20236005 - 28 Nov 2019
Cited by 50 | Viewed by 8864
Abstract
The skin is constantly exposed to a variety of environmental threats, including solar electromagnetic radiation, microbes, airborne particulate matter, and chemicals. Acute exposure to these environmental factors results in the activation of different signaling pathways that orchestrate adaptive stress responses to maintain cell [...] Read more.
The skin is constantly exposed to a variety of environmental threats, including solar electromagnetic radiation, microbes, airborne particulate matter, and chemicals. Acute exposure to these environmental factors results in the activation of different signaling pathways that orchestrate adaptive stress responses to maintain cell and tissue homeostasis. Chronic exposure of skin to these factors, however, may lead to the accumulation of damaged macromolecules and loss of cell and tissue integrity, which, over time, may facilitate aging processes and the development of aging-related malignancies. One transcription factor that is expressed in all cutaneous cells and activated by various environmental stressors, including dioxins, polycyclic aromatic hydrocarbons, and ultraviolet radiation, is the aryl hydrocarbon receptor (AHR). By regulating keratinocyte proliferation and differentiation, epidermal barrier function, melanogenesis, and immunity, a certain degree of AHR activity is critical to maintain skin integrity and to adapt to acute stress situations. In contrast, a chronic activation of cutaneous AHR signaling critically contributes to premature aging and the development of neoplasms by affecting metabolism, extracellular matrix remodeling, inflammation, pigmentation, DNA repair, and apoptosis. This article provides an overview of the detrimental effects associated with sustained AHR activity in chronically stressed skin and pinpoints AHR as a promising target for chemoprevention. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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12 pages, 1269 KiB  
Review
Role of HYBID (Hyaluronan Binding Protein Involved in Hyaluronan Depolymerization), Alias KIAA1199/CEMIP, in Hyaluronan Degradation in Normal and Photoaged Skin
by Hiroyuki Yoshida and Yasunori Okada
Int. J. Mol. Sci. 2019, 20(22), 5804; https://doi.org/10.3390/ijms20225804 - 19 Nov 2019
Cited by 25 | Viewed by 6367
Abstract
Photoaged skin is characterized clinically by apparent manifestations such as wrinkles and sagging, and histologically by an accumulation of abnormal elastin and a severe loss of collagen fibers in the dermis. Quantitative and qualitative alterations in elastin and collagens are considered to be [...] Read more.
Photoaged skin is characterized clinically by apparent manifestations such as wrinkles and sagging, and histologically by an accumulation of abnormal elastin and a severe loss of collagen fibers in the dermis. Quantitative and qualitative alterations in elastin and collagens are considered to be responsible for the formation of wrinkles and sagging. However, since the integrity of elastin and collagen fibers in the dermis is maintained by their interactions with hyaluronan (HA) and a proteoglycan network structure, HA degradation may be the initial process, prior to the breakdown of the fibrillary components, leading to wrinkles and sagging in photoaged skin. We have recently discovered a new HA-degrading mechanism mediated by HYBID (hyaluronan binding protein involved in hyaluronan depolymerization), alias KIAA1199/CEMIP, in human skin fibroblasts, and examined the implication of HYBID for skin photoaging. In this review, we give an overview of the characteristics of HYBID and its prospective roles in HA turnover in normal skin and excessive HA degradation in photoaged skin. In addition, we describe our data on the inhibition of HYBID activity and expression by plant extracts in skin fibroblasts; and propose novel strategies to prevent or improve photoaging symptoms, such as skin wrinkling, by inhibition of HYBID-mediated HA degradation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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16 pages, 5323 KiB  
Review
Melanocyte Activation Mechanisms and Rational Therapeutic Treatments of Solar Lentigos
by Genji Imokawa
Int. J. Mol. Sci. 2019, 20(15), 3666; https://doi.org/10.3390/ijms20153666 - 26 Jul 2019
Cited by 24 | Viewed by 6026
Abstract
To characterize the pathobiology of solar lentigos (SLs), analyses by semiquantitative RT-PCR, Western blotting, and immunohistochemistry revealed the upregulated expression of endothelin (EDN)-1/endothelin B receptors (EDNBRs), stem cell factor (SCF)/c-KIT, and tumor necrosis factor (TNF)α in the lesional epidermis, which contrasted with the [...] Read more.
To characterize the pathobiology of solar lentigos (SLs), analyses by semiquantitative RT-PCR, Western blotting, and immunohistochemistry revealed the upregulated expression of endothelin (EDN)-1/endothelin B receptors (EDNBRs), stem cell factor (SCF)/c-KIT, and tumor necrosis factor (TNF)α in the lesional epidermis, which contrasted with the downregulated expression of interleukin (IL) 1α. These findings strongly support the hypothesis that previous repeated UVB exposure triggers keratinocytes to continuously produce TNFα. TNFα then stimulates the secretion of EDNs and the production of SCF in an autocrine fashion, leading to the continuous melanogenic activation of neighboring melanocytes, which causes SLs. A clinical study of 36 patients with SLs for six months treated with an M. Chamomilla extract with a potent ability to abrogate the EDN1-induced increase in DNA synthesis and melanization of human melanocytes in culture revealed a significant improvement in pigment scores and color differences expressed as L values. Another clinical study using a tyrosinase inhibitor L-ascorbate-2-phosphate 3 Na (ASP) demonstrated that L values of test lotion (6% APS)-treated skin significantly increased in SLs and in non-lesional skin with a significantly higher ΔL value in SLs when compared with non-lesional skin. The sum of these findings strongly suggests that combined topical treatment with EDN signaling blockers and tyrosinase inhibitors is a desirable therapeutic choice for SLs. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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19 pages, 1151 KiB  
Review
Neuroendocrine Aspects of Skin Aging
by Georgeta Bocheva, Radomir M. Slominski and Andrzej T. Slominski
Int. J. Mol. Sci. 2019, 20(11), 2798; https://doi.org/10.3390/ijms20112798 - 07 Jun 2019
Cited by 84 | Viewed by 11168
Abstract
Skin aging is accompanied by a gradual loss of function, physiological integrity and the ability to cope with internal and external stressors. This is secondary to a combination of complex biological processes influenced by constitutive and environmental factors or by local and systemic [...] Read more.
Skin aging is accompanied by a gradual loss of function, physiological integrity and the ability to cope with internal and external stressors. This is secondary to a combination of complex biological processes influenced by constitutive and environmental factors or by local and systemic pathologies. Skin aging and its phenotypic presentation are dependent on constitutive (genetic) and systemic factors. It can be accelerated by environmental stressors, such as ultraviolet radiation, pollutants and microbial insults. The skin’s functions and its abilities to cope with external stressors are regulated by the cutaneous neuroendocrine systems encompassing the regulated and coordinated production of neuropeptides, neurohormones, neurotransmitters and hormones, including steroids and secosteroids. These will induce/stimulate downstream signaling through activation of corresponding receptors. These pathways and corresponding coordinated responses to the stressors decay with age or undergo pathological malfunctions. This affects the overall skin phenotype and epidermal, dermal, hypodermal and adnexal functions. We propose that skin aging can be attenuated or its phenotypic presentation reversed by the topical use of selected factors with local neurohormonal activities targeting specific receptors or enzymes. Some of our favorite factors include melatonin and its metabolites, noncalcemic secosteroids and lumisterol derivatives, because of their low toxicity and their desirable local phenotypic effects. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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16 pages, 748 KiB  
Review
Molecular Mechanisms of Dermal Aging and Antiaging Approaches
by Jung-Won Shin, Soon-Hyo Kwon, Ji-Young Choi, Jung-Im Na, Chang-Hun Huh, Hye-Ryung Choi and Kyung-Chan Park
Int. J. Mol. Sci. 2019, 20(9), 2126; https://doi.org/10.3390/ijms20092126 - 29 Apr 2019
Cited by 322 | Viewed by 27742
Abstract
The dermis is primarily composed of the extracellular matrix (ECM) and fibroblasts. During the aging process, the dermis undergoes significant changes. Collagen, which is a major component of ECM, becomes fragmented and coarsely distributed, and its total amount decreases. This is mainly due [...] Read more.
The dermis is primarily composed of the extracellular matrix (ECM) and fibroblasts. During the aging process, the dermis undergoes significant changes. Collagen, which is a major component of ECM, becomes fragmented and coarsely distributed, and its total amount decreases. This is mainly due to increased activity of matrix metalloproteinases, and impaired transforming growth factor-β signaling induced by reactive oxygen species generated during aging. The reduction in the amount of collagen hinders the mechanical interaction between fibroblasts and the ECM, and consequently leads to the deterioration of fibroblast function and further decrease in the amount of dermal collagen. Other ECM components, including elastic fibers, glycosaminglycans (GAGs), and proteoglycans (PGs), also change during aging, ultimately leading to a reduction in the amount of functional components. Elastic fibers decrease in intrinsically aged skin, but accumulate abnormally in photoaged skin. The changes in the levels of GAGs and PGs are highly diverse, and previous studies have reported conflicting results. A reduction in the levels of functional dermal components results in the emergence of clinical aging features, such as wrinkles and reduced elasticity. Various antiaging approaches, including topicals, energy-based procedures, and dermal fillers, can restore the molecular features of dermal aging with clinical efficacy. This review summarizes the current understanding of skin aging at the molecular level, and associated treatments, to put some of the new antiaging technology that has emerged in this rapidly expanding field into molecular context. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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