{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T10:25:50Z","timestamp":1787221550278,"version":"build-2736575974"},"reference-count":38,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T00:00:00Z","timestamp":1786838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010731","name":"Faculty of Medicine, Chiang Mai University","doi-asserted-by":"crossref","award":["167\/2568"],"award-info":[{"award-number":["167\/2568"]}],"id":[{"id":"10.13039\/501100010731","id-type":"DOI","asserted-by":"crossref"}]},{"award":["167\/2568"],"award-info":[{"award-number":["167\/2568"]}],"id":[{"id":"https:\/\/ror.org\/05m2fqn25","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Ultraviolet B (UVB) irradiation is a major environmental factor contributing to skin photoaging by inducing oxidative stress, apoptosis, inflammation, and extracellular matrix degradation in dermal fibroblasts. This study investigated the photoprotective effects of Thua Nao, a Thai fermented soybean, against UVB-induced human dermal fibroblast damage, and explored its underlying mechanisms. The dichloromethane fraction of Thua Nao (TN-DC) most effectively mitigated UVB-induced cell death. HPLC analysis identified daidzein and glycitein as the major constituent isoflavones in TN-DC that protect fibroblasts against UVB-induced cellular damage. Mechanistically, they reduced apoptosis by suppressing caspase-9 and poly (ADP-ribose) polymerase activation and preserving mitochondrial membrane potential. Additionally, they suppressed inflammatory mediators including interleukin-6, interleukin-8, inducible nitric oxide synthase, and cyclooxygenase-2 and prevented collagen loss. These protective outcomes correlated with decreased intracellular reactive oxygen species and upregulated endogenous antioxidant enzymes including superoxide dismutase 1 and heme oxygenase. Signaling pathway analysis revealed that TN-DC activated the pro-survival extracellular-signal-regulated kinase and Akt pathways in UVB-exposed cells. Conversely, daidzein and glycitein selectively attenuated c-Jun N-terminal kinase activation, downregulating downstream pro-inflammatory cytokines and mediators. Collectively, these findings demonstrate that TN-DC protects human dermal fibroblasts against UVB-induced photoaging primarily by enhancing endogenous antioxidant defense, thereby preserving cellular homeostasis through coordinated regulation of oxidative stress-responsive signaling pathways.<\/jats:p>","DOI":"10.3390\/ijms27167303","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7303","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Isoflavone-Rich Fraction of Traditional Thai Fermented Soybean (Thua Nao) Protects Dermal Fibroblasts from Photoaging by Modulating MAPK and Akt Signaling Pathways"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5560-4309","authenticated-orcid":false,"given":"Natsinee","family":"U-on","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thitikan","family":"Jaiwong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aitsaraphorn","family":"Prongjit","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2264-5313","authenticated-orcid":false,"given":"Tistaya","family":"Semangoen","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jittasak","family":"Khowsathit","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8732-8911","authenticated-orcid":false,"given":"Pornngarm","family":"Dejkriengkraikul","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9023-2283","authenticated-orcid":false,"given":"Supachai","family":"Yodkeeree","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Anticarcinogenesis and Apoptosis Research Cluster, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1097\/JD9.0000000000000068","article-title":"Pathogenesis of Photoaging in Human Dermal Fibroblasts","volume":"3","author":"Lee","year":"2022","journal-title":"Int. J. Dermatol. Venereol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.exger.2017.01.009","article-title":"Molecular mechanisms of UVB-induced senescence of dermal fibroblasts and its relevance for photoaging of the human skin","volume":"94","author":"Cavinato","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S1011-1344(01)00201-9","article-title":"Solar UV irradiation and dermal photoaging","volume":"63","author":"Wlaschek","year":"2001","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.mrgentox.2017.06.002","article-title":"Apigenin prevents ultraviolet-B radiation induced cyclobutane pyrimidine dimers formation in human dermal fibroblasts","volume":"821","author":"Britto","year":"2017","journal-title":"Mutat. Res. Genet. Toxicol. Environ. Mutagen."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1562\/0031-8655(2000)072<0788:KOULIC>2.0.CO;2","article-title":"Kinetics of UV Light\u2013induced Cyclobutane Pyrimidine Dimers in Human Skin In Vivo: An Immunohistochemical Analysis of both Epidermis and Dermis","volume":"72","author":"Katiyar","year":"2000","journal-title":"Photochem. Photobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1046\/j.1523-1747.2003.12414.x","article-title":"Proteins of the extracellular matrix are sensitizers of photo-oxidative stress in human skin cells","volume":"121","author":"Wondrak","year":"2003","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tong, T., Park, J., Moon, Y., Kang, W., and Park, T. (2019). \u03b1-ionone protects against UVB-induced photoaging in human dermal fibroblasts. Molecules, 24, Erratum in Molecules\u00a02020, 25, 3517.","DOI":"10.3390\/molecules25153517"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1111\/j.1600-0625.2008.00747.x","article-title":"UV-induced DNA damage initiates release of MMP-1 in human skin","volume":"17","author":"Dong","year":"2008","journal-title":"Exp. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e13580","DOI":"10.1016\/j.heliyon.2023.e13580","article-title":"Molecular basis of skin photoaging and therapeutic interventions by plant-derived natural product ingredients: A comprehensive review","volume":"9","author":"Tanveer","year":"2023","journal-title":"Heliyon"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e70114","DOI":"10.1111\/exd.70114","article-title":"Role of Mitochondrial Dysfunction in UV-Induced Photoaging and Skin Cancers","volume":"34","author":"Yuan","year":"2025","journal-title":"Exp. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13008-024-00107-z","article-title":"Role of reactive oxygen species in ultraviolet-induced photodamage of the skin","volume":"19","author":"Wei","year":"2024","journal-title":"Cell Div."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wongkarn, S., Chewonarin, T., Ruangsuriya, J., Taya, S., Dejkriengkraikul, P., and Yodkeeree, S. (2025). Biochemical Mechanism of Thai Fermented Soybean Extract on UVB-Induced Skin Keratinocyte Damage and Inflammation. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073418"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e14422","DOI":"10.1111\/acel.14422","article-title":"A subset of human dermal fibroblasts overexpressing Cockayne syndrome group B protein resist UVB radiation-mediated premature senescence","volume":"24","author":"Fotopoulou","year":"2024","journal-title":"Aging Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"213","DOI":"10.5021\/ad.2020.32.3.213","article-title":"Ultraviolet b downregulated aquaporin 1 expression via the MEK\/ERK pathway in the dermal fibroblasts","volume":"32","author":"Kim","year":"2020","journal-title":"Ann. Dermatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3321","DOI":"10.1021\/jf405570u","article-title":"Substituent effects on in vitro antioxidizing properties, stability, and solubility in flavonoids","volume":"62","author":"Plaza","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1002\/fft2.494","article-title":"Structural insights and biological activities of flavonoids: Implications for novel applications","volume":"6","author":"Tang","year":"2025","journal-title":"Food Front."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/S0891-5849(03)00472-6","article-title":"Radical scavenging properties of genistein","volume":"35","author":"Zielonka","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"692846","DOI":"10.1155\/2011\/692846","article-title":"Synergic effect of genistein and daidzein on UVB-induced DNA damage: An effective photoprotective combination","volume":"2011","author":"Bevilacqua","year":"2011","journal-title":"BioMed Res. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1078\/0944-7113-00060","article-title":"Synergy and other interactions in phytomedicines","volume":"8","author":"Williamson","year":"2001","journal-title":"Phytomedicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1039\/C9NP00011A","article-title":"Synergy and antagonism in natural product extracts: When 1 + 1 does not equal 2","volume":"36","author":"Caesar","year":"2019","journal-title":"Nat. Prod. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Agrawal, R., Hu, A., and Bollag, W.B. (2023). The Skin and Inflamm-Aging. Biology, 12.","DOI":"10.3390\/biology12111396"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e16688","DOI":"10.1111\/jocd.16688","article-title":"Influences on Skin and Intrinsic Aging: Biological, Environmental, and Therapeutic Insights","volume":"24","author":"Hussein","year":"2025","journal-title":"J. Cosmet. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e12931","DOI":"10.1111\/phpp.12931","article-title":"Collagen study advances for photoaging skin","volume":"40","author":"Liu","year":"2024","journal-title":"Photodermatol. Photoimmunol. Photomed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1046\/j.1468-3083.2003.00751.x","article-title":"Antioxidant activity, lipid peroxidation and skin diseases. What\u2019s new","volume":"17","author":"Briganti","year":"2003","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Calvo, M.J., Navarro, C., Dur\u00e1n, P., Galan-Freyle, N.J., Hern\u00e1ndez, L.A.P., Pacheco-Londo\u00f1o, L.C., Castelanich, D., Berm\u00fadez, V., and Chacin, M. (2024). Antioxidants in Photoaging: From Molecular Insights to Clinical Applications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25042403"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4290","DOI":"10.1021\/jf0502698","article-title":"Standardized methods for the determination of antioxidant capacity and phenolics in foods and dietary supplements","volume":"53","author":"Prior","year":"2005","journal-title":"J. Agric. Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.freeradbiomed.2013.05.045","article-title":"How do nutritional antioxidants really work: Nucleophilic tone and para-hormesis versus free radical scavenging in vivo","volume":"66","author":"Forman","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1089\/rej.2017.1971","article-title":"Prunella vulgaris L. Exerts a Protective Effect Against Extrinsic Aging Through NF-\u03baB, MAPKs, AP-1, and TGF-\u03b2\/Smad Signaling Pathways in UVB-Aged Normal Human Dermal Fibroblasts","volume":"21","author":"Zhang","year":"2018","journal-title":"Rejuvenation Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/s41419-022-05106-y","article-title":"Activation of the JNKs\/ATM-p53 axis is indispensable for the cytoprotection of dermal fibroblasts exposed to UVB radiation","volume":"13","author":"Mavrogonatou","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18946","DOI":"10.1038\/s41598-020-75873-1","article-title":"Apoptosis, the only cell death pathway that can be measured in human diploid dermal fibroblasts following lethal UVB irradiation","volume":"10","author":"Gary","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113034","DOI":"10.1016\/j.biopha.2022.113034","article-title":"Inhibition of matrix metalloproteinase expression by selective clearing of senescent dermal fibroblasts attenuates ultraviolet-induced photoaging","volume":"150","author":"Kim","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/j.1600-0625.2012.01517.x","article-title":"Anti-ageing effects of alpha-naphthoflavone on normal and UVB-irradiated human skin fibroblasts","volume":"21","author":"Liao","year":"2012","journal-title":"Exp. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4","DOI":"10.48048\/tis.2025.9395","article-title":"Protective Effects of Syringaresinol against UVB-Induced Human Dermal Fibroblast Senescence and Apoptosis","volume":"22","author":"Wisidsri","year":"2025","journal-title":"Trends Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ding, Y., Jiratchayamaethasakul, C., and Lee, S.H. (2020). Protocatechuic aldehyde attenuates uva-induced photoaging in human dermal fibroblast cells by suppressing mapks\/ap-1 and nf-\u03bab signaling pathways. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134619"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"84","DOI":"10.4062\/biomolther.2023.179","article-title":"Rosmarinic Acid Inhibits Ultraviolet B-Mediated Oxidative Damage via the AKT\/ERK-NRF2-GSH Pathway In Vitro and In Vivo","volume":"32","author":"Piao","year":"2024","journal-title":"Biomol. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S0891-5849(98)00315-3","article-title":"Antioxidant activity applying an improved ABTS radical cation decolorization assay","volume":"26","author":"Re","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_37","first-page":"1215","article-title":"Determination of Tocopherols (Vitamin E) by Reduction of Cupric Ion","volume":"65","author":"Strong","year":"1982","journal-title":"J. Assoc. Off. Anal. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mapoung, S., Umsumarng, S., Semmarath, W., Arjsri, P., Srisawad, K., Thippraphan, P., Yodkeeree, S., and Dejkriengkraikul, P. (2021). Photoprotective effects of a hyperoside-enriched fraction prepared from houttuynia cordata thunb. On ultraviolet B-induced skin aging in human fibroblasts through the MAPK signaling pathway. Plants, 10.","DOI":"10.3390\/plants10122628"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7303\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:49:41Z","timestamp":1787219381000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,16]]},"references-count":38,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167303"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167303","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,16]]}}}