Abstract
Skin aging is the most intuitive manifestation of aging. Skin aging inevitably leads to cosmetic and psychological problems, and even diseases. The present study aims to research the pathological and molecular mechanisms underlying skin aging and identify the therapeutic agents for reversing skin aging. Two available gene expression datasets (GSE55118 and GSE72264) for skin aging were downloaded from Gene Expression Omnibus, followed by bioinformatic analyses performed on the datasets. Firstly, 169 crucial mRNAs, 27 crucial miRNAs and 50 crucial lncRNAs closely related to skin aging were identified by weighted gene co-expression network analysis. Then, function Enrichment Analysis performed by Metascape database showed that skin aging involves a variety of biological functions, such as detection of stimulus, response to steroid hormone and water channel activity, regulation of muscle contraction. Next, ten hub genes including AQP4, TRPM8, TBR1, NTSR2, MPPED1, BARHL2, PAX9, CPN1, CES3, and CHGB were screened out by the protein–protein interaction analysis. Next, the “lncRNA-miRNA-mRNA” network and the “lncRNA-miRNA-hub mRNA” network were constructed to explore the competing endogenous RNAs mechanism of skin aging. Finally, ten significant potential small molecules mitigating skin aging were screened using CMAP platform, including tretinoin, pifithrin, selamectin, entinostat, bretazenil, syringic-acid, BRD-K96475865, emedastine, abacavir, and rotenone, and their reliability was verified by molecular docking experiments. The present study provided basis for revealing the molecular mechanism of skin aging and identified the potential candidate drugs for mitigating skin aging.
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Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Asselineau D, Bernard B, Bailly C, Darmon M (1989) Retinoic acid improves epidermal morphogenesis. Dev Biol 133:322–335. https://doi.org/10.1016/0012-1606(89)90037-7
Barrett T, Wilhite S, Ledoux P, Evangelista C, Kim I, Tomashevsky M, Marshall K, Phillippy K, Sherman P, Holko M, Yefanov A, Lee H, Zhang N, Robertson C, Serova N, Davis S, Soboleva A (2013) NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res 41:D991-995. https://doi.org/10.1093/nar/gks1193
Bıçakçı H, Sarsılmaz M, Ocaklı S, Uysal M, Irmak Sapmaz H, Acar T, Demirtaş İ, Açıkgöz R (2017) Investigation of the effects of aging on the expression of aquaporin 1 and aquaporin 4 protein in heart tissue. Anatol J Cardiol 17:18–23. https://doi.org/10.14744/AnatolJCardiol.2016.7033
Boismal F, Serror K, Dobos G, Zuelgaray E, Bensussan A, Michel L (2020) Skin aging: pathophysiology and innovative therapies. Med Sci 36:1163–1172. https://doi.org/10.1051/medsci/2020232
Bonté F, Girard D, Archambault J, Desmoulière A (2019) Skin changes during ageing. Sub-cellular Biochem 91:249–280. https://doi.org/10.1007/978-981-13-3681-2_10
Chang L, Zhou G, Othman S, Xia J (2020) miRNet 2.0: network-based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res. https://doi.org/10.1093/nar/gkaa467
Chen Q, Thompson J, Hu Y, Lesnefsky EJ (2022a) Reversing mitochondrial defects in aged hearts: role of mitochondrial calpain activation. Am J Physiol 322:C296
Chen Q, Zhang H, Yang Y, Zhang S, Wang J, Zhang D, Yu H (2022b) Metformin attenuates UVA-induced skin photoaging by suppressing mitophagy and the PI3K/AKT/mTOR pathway. Int J Mol Sci. https://doi.org/10.3390/ijms23136960
Choi S, Bin B, Kim W, Lee E, Lee T, Cho E (2018) Exposure of human melanocytes to UVB twice and subsequent incubation leads to cellular senescence and senescence-associated pigmentation through the prolonged p53 expression. J Dermatol Sci 90:303–312. https://doi.org/10.1016/j.jdermsci.2018.02.016
Dillon GA, Lichter ZS, Alexander LM (2022) Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome. Microvasc Res 139:104271
Eckert R, Rorke E (1989) Molecular biology of keratinocyte differentiation. Environ Health Perspect 80:109–116. https://doi.org/10.1289/ehp.8980109
Fuchs E (2007) Scratching the surface of skin development. Nature 445:834–842. https://doi.org/10.1038/nature05659
Fuchs E, Green H (1981) Regulation of terminal differentiation of cultured human keratinocytes by vitamin A. Cell 25:617–625
Huang H, Lin Y, Li J, Huang K, Shrestha S, Hong H, Tang Y, Chen Y, Jin C, Yu Y, Xu J, Li Y, Cai X, Zhou Z, Chen X, Pei Y, Hu L, Su J, Cui S, Wang F, Xie Y, Ding S, Luo M, Chou C, Chang N, Chen K, Cheng Y, Wan X, Hsu W, Lee T, Wei F, Huang H (2020) miRTarBase 2020: updates to the experimentally validated microRNA-target interaction database. Nucleic Acids Res 48:D148–D154. https://doi.org/10.1093/nar/gkz896
Ikarashi N, Kon R, Kaneko M, Mizukami N, Kusunoki Y, Sugiyama K (2017) Relationship between aging-related skin dryness and aquaporins. Int J Mol Sci. https://doi.org/10.3390/ijms18071559
Jing XH, Liu J, Hou W, Gao Y (2016) Age-related changes in renal AQP3 and AQP4 expression in Sprague Dawley rats. Genet Mol Res. https://doi.org/10.4238/gmr.15037532
Kafi R, Kwak H, Schumacher WE, Cho S, Hanft VN, Hamilton TA, King AL, Neal JD, Varani J, Fisher GJ (2007) Improvement of naturally aged skin with vitamin A (Retinol). Arch Dermatol. https://doi.org/10.1001/archderm.143.5.606
Kockaert M, Neumann M (2003) Systemic and topical drugs for aging skin. J Drugs Dermatol 2:435–441
Krutmann J, Schikowski T, Morita A, Berneburg M (2021) Environmentally-induced (extrinsic) skin aging: exposomal factors and underlying mechanisms. J Investig Dermatol 141:1096–1103. https://doi.org/10.1016/j.jid.2020.12.011
Laimer M, Kocher T, Chiocchetti A, Trost A, Lottspeich F, Richter K, Hintner H, Bauer J, Onder K (2010) Proteomic profiling reveals a catalogue of new candidate proteins for human skin aging. Exp Dermatol 19:912–918. https://doi.org/10.1111/j.1600-0625.2010.01144.x
Lamb J, Crawford E, Peck D, Modell J, Blat I, Wrobel M, Lerner J, Brunet J, Subramanian A, Ross K, Reich M, Hieronymus H, Wei G, Armstrong S, Haggarty S, Clemons P, Wei R, Carr S, Lander E, Golub T (2006) The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313:1929–1935. https://doi.org/10.1126/science.1132939
Li M, Li L, Zhang X, Zhao H, Wei M, Zhai W, Wang B, Yan Y (2019) LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts. Aging 11:5992
Mering CV, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B (2003) STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. https://doi.org/10.1093/nar/gkg034
Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Current Biol 22:R741-752. https://doi.org/10.1016/j.cub.2012.07.024
Owasil R, O’Neill R, Keable A, Nimmo J, Carare RO (2020) The pattern of AQP4 expression in the ageing human brain and in cerebral amyloid angiopathy. Int J Mol Sci 21:1225
Rossetti D, Kielmanowicz MG, Vigodman S, Hu YP, Chen N, Nkengne A, Oddos T, Fischer D, Seiberg M, Lin CB (2011) A novel anti-ageing mechanism for retinol: induction of dermal elastin synthesis and elastin fibre formation. Int J Cosmet Sci 33:62–69. https://doi.org/10.1111/j.1468-2494.2010.00588.x
Salminen A, Kaarniranta K, Kauppinen A (2022) Photoaging: UV radiation-induced inflammation and immunosuppression accelerate the aging process in the skin. Inflamm Res. https://doi.org/10.1007/s00011-022-01598-8
Thapa D, Valente J, Barrett B, Smith M, Argunhan F, Lee S, Nikitochkina S, Kodji X, Brain S (2021) Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing. eLife. https://doi.org/10.7554/eLife.70153
Wang L, Si X, Chen S, Wang X, Yang D, Yang H, He C (2021a) A comprehensive evaluation of skin aging-related circular RNA expression profiles. J Clin Lab Anal 35:e23714. https://doi.org/10.1002/jcla.23714
Wang T, Zhou Z, Luo E, Zhong J, Zhao D, Dong H, Yao B (2021b) Comprehensive RNA sequencing in primary murine keratinocytes and fibroblasts identifies novel biomarkers and provides potential therapeutic targets for skin-related diseases. Cell Mol Biol Lett 26:42. https://doi.org/10.1186/s11658-021-00285-6
Woodby B, Penta K, Pecorelli A, Lila M, Valacchi G (2020) Skin Health from the Inside Out. Annu Rev Food Sci Technol 11:235–254. https://doi.org/10.1146/annurev-food-032519-051722
Yan W, Zhang LL, Yan L, Zhang F, Yin NB, Lin HB, Huang CY, Wang L, Yu J, Wang DM, Zhao ZM (2013) Transcriptome analysis of skin photoaging in chinese females reveals the involvement of skin homeostasis and metabolic changes. PLoS ONE 8:e61946. https://doi.org/10.1371/journal.pone.0061946
Yang K, Dinasarapu A, Reis E, Deangelis R, Ricklin D, Subramaniam S, Lambris J (2013) CMAP: Complement Map Database. Bioinformatics 29:1832–1833. https://doi.org/10.1093/bioinformatics/btt269
Yao L, Mengbi L, Yufang L, Jie Z, Wei L, Qingfang X, Yue Z (2020) Predicting miRNA-lncRNA-mRNA network in ultraviolet A-induced human skin photoaging. J Cosmet Dermatol 20:1875
Yeh S, Lin J, Chen B (2021) Multiple-molecule drug design based on systems biology approaches and deep neural network to mitigate human skin aging. Molecules. https://doi.org/10.3390/molecules26113178
Zhang S, Duan E (2018) Fighting against skin aging: the way from bench to bedside. Cell Transpl 27:729–738. https://doi.org/10.1177/0963689717725755
Zhang J, Zhou B, Xu Y, Chen X, Liu J, Gozali M, Wu D, Yin Z, Luo D (2016) MiR-23a-depressed autophagy is a participant in PUVA- and UVB-induced premature senescence. Oncotarget 7:37420–37435. https://doi.org/10.18632/oncotarget.9357
Zhou J, Dong Y, Liu J, Ren J, Wu J, Zhu N (2020) AQP5 regulates the proliferation and differentiation of epidermal stem cells in skin aging. Braz J Med Biol Res 53:e10009. https://doi.org/10.1590/1414-431x202010009
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XX and HF carried out the studies, participated in collecting data, and drafted the manuscript. HT, YL and LL performed the statistical analysis and participated in its design. KL and FH participated in acquisition, analysis, or interpretation of data and draft the manuscript. All authors read and approved the final manuscript.
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Xiao, X., Feng, H., Liao, Y. et al. Identification of lncRNA-miRNA-mRNA Regulatory Network and Therapeutic Agents for Skin Aging by Bioinformatics Analysis. Biochem Genet 61, 1606–1624 (2023). https://doi.org/10.1007/s10528-023-10334-8
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DOI: https://doi.org/10.1007/s10528-023-10334-8