Reduced
            DNA
            methylation patterning and transcriptional connectivity define human skin aging

Abstract Skin aging is a complicated physiological process and epigenetic feature, including microRNA-mediated regulation and DNA methylation, have been shown to contribute to this process. DNA methylation is regulated by DNA methyltransferase, of which DNA methyltransferase 1 (DNMT1) is the most abundantly known. But evidence supporting its role in skin aging remains scarce, and no report regards its specifical upstream-regulating molecules in the process of skin aging so far. Here, we found that DNMT1 expression was markedly higher in young human skin fibroblasts (HSFs) than that in passage-aged HSFs, and DNMT1 knockdown significantly induced the senescence phenotype in young HSFs. We predicted the upstream miRNAs which could regulate DNMT1 with miRNA databases and found miR-377 had high homology with a sequence in the 3′-UTR of human DNMT1 mRNA. We confirmed that miR-377 was a potential regulator of DNMT1 by luciferase reporter assays. miR-377 expression in passage-aged HSFs was markedly higher than that in the young HSFs. miR-377 overexpression promoted senescence in young HSFs, and inhibition of miR-377 reduced senescence in passage-aged HSFs. Moreover, these functions were mediated by targeting DNMT1. Microfluidic PCR and next-generation bisulfite sequencing of 24 senescent-associated genes’ promoters revealed alterations of the promoter methylation levels of FoxD3, p53, and UTF1 in HSFs treated with miR-377 mimics or inhibitors. We also verified that the miR-377-mediated changes in p53 expression could be reversed by regulation of DNMT1 in HSFs. Similarly, there was a negative correlation between miR-377 and DNMT1 expression in young and photoaged HSFs, HSFs, or skin tissues from UV-unexposed areas of different aged donors. Our results highlight a novel role for miR-377-DNMT1-p53 axis in HSF senescence. These findings shed new light on the mechanisms of skin aging and identify future opportunities for its therapeutic prevention.

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Multiple-Molecule Drug Design Based on Systems Biology Approaches and Deep Neural Network to Mitigate Human Skin Aging

Molecules ◽

10.3390/molecules26113178 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3178

Author(s):

Shan-Ju Yeh ◽

Jin-Fu Lin ◽

Bor-Sen Chen

Keyword(s):

Neural Network ◽

Systems Biology ◽

Signaling Pathways ◽

Human Skin ◽

Deep Neural Network ◽

Middle Age ◽

Skin Aging ◽

Identification System ◽

Potential Candidate ◽

Systems Medicine

Human skin aging is affected by various biological signaling pathways, microenvironment factors and epigenetic regulations. With the increasing demand for cosmetics and pharmaceuticals to prevent or reverse skin aging year by year, designing multiple-molecule drugs for mitigating skin aging is indispensable. In this study, we developed strategies for systems medicine design based on systems biology methods and deep neural networks. We constructed the candidate genomewide genetic and epigenetic network (GWGEN) via big database mining. After doing systems modeling and applying system identification, system order detection and principle network projection methods with real time-profile microarray data, we could obtain core signaling pathways and identify essential biomarkers based on the skin aging molecular progression mechanisms. Afterwards, we trained a deep neural network of drug–target interaction in advance and applied it to predict the potential candidate drugs based on our identified biomarkers. To narrow down the candidate drugs, we designed two filters considering drug regulation ability and drug sensitivity. With the proposed systems medicine design procedure, we not only shed the light on the skin aging molecular progression mechanisms but also suggested two multiple-molecule drugs for mitigating human skin aging from young adulthood to middle age and middle age to old age, respectively.

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Exploring Human Skin Aging at the Single-Cell Level

Developmental Cell ◽

10.1016/j.devcel.2021.01.006 ◽

2021 ◽

Vol 56 (3) ◽

pp. 253-254

Author(s):

Mary Mohrin ◽

Heinrich Jasper

Keyword(s):

Single Cell ◽

Human Skin ◽

Skin Aging ◽

Single Cell Level ◽

Cell Level

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Neuropeptides and skin aging

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0062 ◽

2013 ◽

Vol 16 (1) ◽

Cited By ~ 1

Author(s):

Rana Elewa ◽

Evgenia Makrantonaki ◽

Christos C. Zouboulis

Keyword(s):

Human Skin ◽

Inflammatory Cytokines ◽

Vasoactive Intestinal Polypeptide ◽

Skin Aging ◽

Target Cells ◽

Hormone Metabolism ◽

Skin Cells ◽

Calcitonin Gene ◽

Aged Skin ◽

Human Skin Cells

AbstractNeuropeptides (NP) are peptides that are released as chemical messengers from nerve cells. They act either in an endocrine manner, where they reach their target cells via the bloodstream or a paracrine manner, as co-transmitters modulating the function of neurotransmitters. To date approximately 100 different NP have been described in the literature. In recent years, several studies have documented that human skin expresses several functional receptors for NP, such as corticotropin-releasing hormone, melanocortins, β-endorphin, vasoactive intestinal polypeptide, neuropeptide Y and calcitonin gene-related peptide. These receptors modulate the production of inflammatory cytokines, proliferation, differentiation, lipogenesis and hormone metabolism in human skin cells. In addition, several NP are directly produced by human skin cells, indicating the complexity of understanding the real functions of NPs in human skin. In this review we address the possible effects of neuropeptides on the pathogenesis of aged skin.

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Assessment of Human Skin Gene Expression by Different Blends of Plant Extracts with Implications to Periorbital Skin Aging

International Journal of Molecular Sciences ◽

10.3390/ijms19113349 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3349 ◽

Cited By ~ 3

Author(s):

Jin Namkoong ◽

Dale Kern ◽

Helen Knaggs

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Human Skin ◽

Barrier Function ◽

Skin Barrier ◽

Skin Aging ◽

Skin Barrier Function ◽

Oxidative Stress Biomarkers ◽

Stress Biomarkers ◽

And Oxidative Stress

Since the skin is the major protective barrier of the body, it is affected by intrinsic and extrinsic factors. Environmental influences such as ultraviolet (UV) irradiation, pollution or dry/cold air are involved in the generation of radical oxygen species (ROS) and impact skin aging and dermal health. Assessment of human skin gene expression and other biomarkers including epigenetic factors are used to evaluate the biological/molecular activities of key compounds in cosmetic formulas. The objective of this study was to quantify human gene expression when epidermal full-thickness skin equivalents were exposed to: (a) a mixture of betaine, pentylene glycol, Saccharomyces cerevisiae and Rhodiola rosea root extract (BlendE) for antioxidant, skin barrier function and oxidative stress (with hydrogen peroxide challenge); and (b) a mixture of Narcissus tazetta bulb extract and Schisandra chinensis fruit extract (BlendIP) for various biomarkers and microRNA analysis. For BlendE, several antioxidants, protective oxidative stress biomarkers and many skin barrier function parameters were significantly increased. When BlendE was evaluated, the negative impact of the hydrogen peroxide was significantly reduced for the matrix metalloproteinases (MMP 3 and MMP 12), the skin aging and oxidative stress biomarkers, namely FBN2, ANXA1 and HGF. When BlendIP was tested for cell proliferation and dermal structural components to enhance the integrity of the skin around the eyes: 8 growth factors, 7 signaling, 7 structural/barrier function and 7 oxidative stress biomarkers were significantly increased. Finally, when BlendIP was tested via real-time RT-PCR for microRNA expression: miR-146a, miR-22, miR155, miR16 and miR21 were all significantly increased over control levels. Therefore, human skin gene expression studies are important tools to assess active ingredient compounds such as plant extract blends to advance dermal hypotheses toward validating cosmetic formulations with botanical molecules.

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