Antioxidant, anti-inflammatory and anti-aging effects of urolithin A on UVB-induced HaCaT cells

Year 2026, Volume: 30 Issue: 2, 681 - 692, 15.03.2026

Mehmet Berköz , Güneş Açıkgöz

https://doi.org/10.12991/jrespharm.1701142

https://izlik.org/JA98UG87RR

Abstract

This study investigated the photoprotective, antioxidant, anti-inflammatory and anti-aging effects of urolithin A on HaCaT cells irradiated with ultraviolet B (UVB) light. Urolithin A showed no toxic effects on HaCaT cells at concentrations of 10, 20 and 30 μM, and the survival rate of UVB-damaged HaCaT cells increased in a concentration-dependent manner when pre-treated with urolithin A. The test results confirmed that urolithin A conferred protective effects on HaCaT cells. The cellular activity of urolithin A in UVB-irradiated HaCaT cells was investigated using reactive oxygen species (ROS) scavenging assay, antioxidant, pro-inflammatory and anti-aging gene expression. Urolithin A pre-treatment scavenged ROS in a concentration-dependent manner and suppressed UVB-induced cellular senescence. Gene expression analysis also showed that urolithin A increased antioxidant and anti-aging gene expressions and decreased pro-inflammatory gene expressions, suggesting that urolithin A protects HaCaT cells against UVB-induced oxidative stress. Therefore, our results support the antioxidant properties of urolithin A as observed in UVB-irradiated HaCaT cells and also confirm the photoprotective, antioxidant, anti-inflammatory, and anti-aging effects of urolithin A. Urolithin A, as a natural phytochemical, can be used as a cosmetic ingredient due to its anti-aging and protective properties.

Keywords

HaCaT cells , urolithin A , ultraviolet B , anti-oxidant , anti-inflammatory , anti-aging

Ethical Statement

Not applicable for this study.

Project Number

TLO-2023-10610

Thanks

This research was financially supported in part by the Office of Scientific Research Projects of Van Yuzuncu Yil University under Grant number (TLO-2023-10610).

References

• [1] Negre-Salvayre A, Salvayre R. Post-Translational Modifications Evoked by Reactive Carbonyl Species in Ultraviolet-A-Exposed Skin: Implication in Fibroblast Senescence and Skin Photoaging. Antioxidants (Basel). 2022; 11(11): 2281. https://doi.org/10.3390/antiox11112281.
• [2] Munshi A, Ramesh R. Mitogen-activated protein kinases and their role in radiation response. Genes Cancer. 2013; 4(9-10): 401-408. https://doi.org/10.1177/1947601913485414.
• [3] Chen YY, Yan XJ, Jiang XH, Lu FL, Yang XR, Li DP. Vicenin 3 ameliorates ECM degradation by regulating the MAPK pathway in SW1353 chondrocytes. Exp Ther Med. 2021; 22(6): 1461. https://doi.org/10.3892/etm.2021.10896.
• [4] Malta MD, Cerqueira MT, Marques AP. Extracellular matrix in skin diseases: The road to new therapies. J Adv Res. 2023; 51: 149-160. https://doi.org/10.1016/j.jare.2022.11.008.
• [5] Zorina A, Zorin V, Isaev A, Kudlay D, Vasileva M, Kopnin P. Dermal Fibroblasts as the Main Target for Skin Anti-Age Correction Using a Combination of Regenerative Medicine Methods. Curr Issues Mol Biol. 2023; 45(5): 3829-3847. https://doi.org/10.3390/cimb45050247.
• [6] Weihermann AC, Lorencini M, Brohem CA, de Carvalho CM. Elastin structure and its involvement in skin photoageing. Int J Cosmet Sci. 2017; 39(3): 241-7. https://doi.org/10.1111/ics.12372.
• [7] Gutiérrez-Del-Río I, López-Ibáñez S, Magadán-Corpas P, et al. Terpenoids and Polyphenols as Natural Antioxidant Agents in Food Preservation. Antioxidants (Basel). 2021; 10(8): 1264. https://doi.org/10.3390/antiox10081264.
• [8] Meléndez-Martínez AJ, Stinco CM, Mapelli-Brahm P. Skin Carotenoids in Public Health and Nutricosmetics: The Emerging Roles and Applications of the UV Radiation-Absorbing Colourless Carotenoids Phytoene and Phytofluene. Nutrients. 2019; 11(5): 1093. https://doi.org/10.3390/nu11051093.
• [9] Fabbrini M, D'Amico F, Barone M, et al. Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties. Biomolecules. 2022; 12(7): 875. https://doi.org/10.3390/biom12070875.
• [10] Bae JY, Choi JS, Kang SW, Lee YJ, Park J, Kang YH. Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation. Exp Dermatol. 2010; 19(8): 182-190. https://doi.org/10.1111/j.1600-0625.2009.01044.x.
• [11] Afaq F, Zaid MA, Khan N, Dreher M, Mukhtar H. Protective effect of pomegranate-derived products on UVB-mediated damage in human reconstituted skin. Exp Dermatol. 2009;18(6):553-561. https://doi.org/10.1111/j.1600-0625.2008.00829.x.
• [12] Liu C, Guo H, DaSilva NA, et al. Pomegranate (Punica granatum) Phenolics Ameliorate Hydrogen Peroxide-Induced Oxidative Stress and Cytotoxicity in Human Keratinocytes. J Funct Foods. 2019; 54: 559-567. https://doi.org/10.1016/j.jff.2019.02.015.
• [13] Seeram NP, Lee R, Heber D. Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta. 2004; 348(1-2): 63-68. https://doi.org/10.1016/j.cccn.2004.04.029.
• [14] Espín JC, Larrosa M, García-Conesa MT, Tomás-Barberán F. Biological significance of urolithins, the gut microbial ellagic Acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med. 2013; 2013: 270418. https://doi.org/10.1155/2013/270418.
• [15] Kang I, Kim Y, Tomás-Barberán FA, Espín JC, Chung S. Urolithin A, C, and D, but not iso-urolithin A and urolithin B, attenuate triglyceride accumulation in human cultures of adipocytes and hepatocytes. Mol Nutr Food Res. 2016; 60(5): 1129-1138. https://doi.org/10.1002/mnfr.201500796.
• [16] Chen P, Wang Y, Xie J, Lei J, Zhou B. Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice. Neuropharmacology. 2024;252:109950. https://doi.org/10.1016/j.neuropharm.2024.109950.
• [17] Liu W, Yan F, Xu Z, et al. Urolithin A protects human dermal fibroblasts from UVA-induced photoaging through NRF2 activation and mitophagy. J Photochem Photobiol B. 2022; 232: 112462. https://doi.org/10.1016/j.jphotobiol.2022.112462.
• [18] Papaccio F, D Arino A, Caputo S, Bellei B. Focus on the Contribution of Oxidative Stress in Skin Aging. Antioxidants (Basel). 2022; 11(6): 1121. https://doi.org/10.3390/antiox11061121.
• [19] Masaki H. Role of antioxidants in the skin: anti-aging effects. J Dermatol Sci. 2010; 58(2): 85-90. https://doi.org/10.1016/j.jdermsci.2010.03.003.
• [20] Bartosz G, Pieńkowska N, Sadowska-Bartosz I. Effect of Selected Antioxidants on the In Vitro Aging of Human Fibroblasts. Int J Mol Sci. 2024; 25(3): 1529. https://doi.org/10.3390/ijms25031529.
• [21] Lei D, Liu D, Zhang J, Zhang L, Man MQ. Benefits of topical natural ingredients in epidermal permeability barrier. Front Physiol. 2024; 14: 1275506. https://doi.org/10.3389/fphys.2023.1275506.
• [22] Hwang D, Goo TW, Lee SH, Yun EY. Skin Anti-Aging Potential through Whitening and Wrinkle Improvement Using Fermented Oil Derived from Hermetia illucens Larvae. Int J Mol Sci. 2024; 25(5): 2736. https://doi.org/10.3390/ijms25052736.
• [23] Bose VBSC, Balaganesan V, Govindaraj G, Veerichetty V. Cellular antioxidant and cytotoxic activity of astaxanthin and ellagic acid on UV irradiated skin melanoma cells and gel formulation, Mater Today. 2023. https://doi.org/10.1016/j.matpr.2023.08.209.
• [24] Kang SJ, Choi BR, Kim SH, et al. Beneficial effects of dried pomegranate juice concentrated powder on ultraviolet B-induced skin photoaging in hairless mice. Exp Ther Med. 2017; 14(2): 1023-1036. https://doi.org/10.3892/etm.2017.4626.
• [25] Baek B, Lee SH, Kim K, Lim HW, Lim CJ. Ellagic acid plays a protective role against UV-B-induced oxidative stress by up-regulating antioxidant components in human dermal fibroblasts. Korean J Physiol Pharmacol. 2016; 20(3): 269-277. https://doi.org/10.4196/kjpp.2016.20.3.269.
• [26] Bae JY, Choi JS, Kang SW, Lee YJ, Park J, Kang YH. Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation. Exp Dermatol. 2010; 19(8): 182-190. https://doi.org/10.1111/j.1600-0625.2009.01044.x.
• [27] Yang Y, Lee PK, Wong HC, Zhao D. Oral supplementation of Gordonibacter urolithinfaciens promotes ellagic acid metabolism and urolithin bioavailability in mice. Food Chem. 2024; 437(Pt 2): 137953. https://doi.org/10.1016/j.foodchem.2023.137953.
• [28] Park C, Park J, Kim WJ, Kim W, Cheong H, Kim SJ. Malonic Acid Isolated from Pinus densiflora Inhibits UVB-Induced Oxidative Stress and Inflammation in HaCaT Keratinocytes. Polymers (Basel). 2021; 13(5): 816. https://doi.org/10.3390/polym13050816.
• [29] Huang WC, Liou CJ, Shen SC, et al. Urolithin A Inactivation of TLR3/TRIF Signaling to Block the NF-κB/STAT1 Axis Reduces Inflammation and Enhances Antioxidant Defense in Poly(I:C)-Induced RAW264.7 Cells. Int J Mol Sci. 2022; 23(9): 4697. https://doi.org/10.3390/ijms23094697.
• [30] Deshpande KC, Kulkarni MM, Rajput DV. Evaluation of glutathione peroxidase in the blood and tumor tissue of oral squamous cell carcinoma patients. J Oral Maxillofac Pathol. 2018; 22(3): 447. https://doi.org/10.4103/jomfp.JOMFP_140_17.
• [31] Shields HJ, Traa A, Van Raamsdonk JM. Beneficial and Detrimental Effects of Reactive Oxygen Species on Lifespan: A Comprehensive Review of Comparative and Experimental Studies. Front Cell Dev Biol. 2021; 9: 628157. https://doi.org/10.3389/fcell.2021.628157.
• [32] Cásedas G, Les F, Choya-Foces C, Hugo M, López V. The Metabolite Urolithin-A Ameliorates Oxidative Stress in Neuro-2a Cells, Becoming a Potential Neuroprotective Agent. Antioxidants (Basel). 2020; 9(2): 177. https://doi.org/10.3390/antiox9020177.
• [33] Hwang YP, Oh KN, Yun HJ, Jeong HG. The flavonoids apigenin and luteolin suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and AP-1-dependent signaling in HaCaT cells. J Dermatol Sci. 2011; 61(1): 23-31. https://doi.10.1016/j.jdermsci.2010.10.016
• [34] Deng H, Wan M, Li H, et al. Curcumin protection against ultraviolet-induced photo-damage in Hacat cells by regulating nuclear factor erythroid 2-related factor 2. Bioengineered. 2021; 12(2): 9993-10006. https://doi.10.1080/21655979.2021.1994720
• [35] Fu C, Chen J, Lu J, et al. Roles of inflammation factors in melanogenesis (Review). Mol Med Rep. 2020; 21(3): 1421-1430. https://doi.org/10.3892/mmr.2020.10950.
• [36] Ansary TM, Hossain MR, Kamiya K, Komine M, Ohtsuki M. Inflammatory Molecules Associated with Ultraviolet Radiation-Mediated Skin Aging. Int J Mol Sci. 2021; 22(8): 3974. https://doi.org/10.3390/ijms22083974.
• [37] Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011; 31(5): 986-1000. https://doi.org/10.1161/ATVBAHA.110.207449.
• [38] Pyrillou K, Burzynski LC, Clarke MCH. Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease. Front Immunol. 2020; 11: 613170. https://doi.org/10.3389/fimmu.2020.613170.
• [39] Cui B, Wang Y, Jin J, et al. Resveratrol Treats UVB-Induced Photoaging by Anti-MMP Expression, through Anti-Inflammatory, Antioxidant, and Antiapoptotic Properties, and Treats Photoaging by Upregulating VEGF-B Expression. Oxid Med Cell Longev. 2022; 2022: 6037303. https://doi.10.1155/2022/6037303
• [40] Desai SJ, Prickril B, Rasooly A. Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer. Nutr Cancer. 2018; 70(3): 350-375. https://doi.org/10.1080/01635581.2018.1446091.
• [41] Mohd Zawawi Z, Kalyanasundram J, Mohd Zain R, Thayan R, Basri DF, Yap WB. Prospective Roles of Tumor Necrosis Factor-Alpha (TNF-α) in COVID-19: Prognosis, Therapeutic and Management. Int J Mol Sci. 2023; 24(7): 6142. https://doi.org/10.3390/ijms24076142.
• [42] Chen P, Lei J, Chen F, Zhou B. Ameliorative effect of urolithin A on d-gal-induced liver and kidney damage in aging mice via its antioxidative, anti-inflammatory and antiapoptotic properties. RSC Adv. 2020; 10(14): 8027-8038. https://doi.org/10.1039/d0ra00774a.
• [43] Russell-Goldman E, Murphy GF. The Pathobiology of Skin Aging: New Insights into an Old Dilemma. Am J Pathol. 2020; 190(7): 1356-1369. https://doi.org/10.1016/j.ajpath.2020.03.007.
• [44] Lee SY. Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides. Biomedicines. 2021; 9(2): 198. https://doi.org/10.3390/biomedicines9020198.
• [45] Pfisterer K, Shaw LE, Symmank D, Weninger W. The Extracellular Matrix in Skin Inflammation and Infection. Front Cell Dev Biol. 2021; 9: 682414. https://doi.org/10.3389/fcell.2021.682414.
• [46] Sun J, Jiang Y, Fu J, et al. Beneficial Effects of Epigallocatechin Gallate in Preventing Skin Photoaging: A Review. Molecules. 2024; 29(22): 5226. https://doi.10.3390/molecules29225226
• [47] Matsuoka K, Bakiri L, Bilban M, et al. Metabolic rewiring controlled by c-Fos governs cartilage integrity in osteoarthritis. Ann Rheum Dis. 2023; 82(9): 1227-1239. https://doi.org/10.1136/ard-2023-224002.
• [48] Liu CF, Li XL, Zhang ZL, et al. Antiaging Effects of Urolithin A on Replicative Senescent Human Skin Fibroblasts. Rejuvenation Res. 2019; 22(3): 191-200. https://doi.org/10.1089/rej.2018.2066.
• [49] Chen P, Zhuang CN, Cui JJ, et al. Effects of Combination of 1,25(OH) 2D 3 and TLR-4 Inhibitor on the Damage to HaCaT Cells Caused by UVB Irradiation. Biomed Environ Sci. 2022; 35(11): 1051-1062. https://doi.org/10.3967/bes2022.133.
• [50] Joo KM, Kim S, Koo YJ, et al. Development and validation of UPLC method for WST-1 cell viability assay and its application to MCTT HCE™ eye irritation test for colorful substances. Toxicol In Vitro. 2019; 60: 412-419. https://doi.org/10.1016/j.tiv.2019.06.017.
• [51] Choi MK, Kim J, Park HM, et al. The DPA-derivative 11S, 17S-dihydroxy 7,9,13,15,19 (Z,E,Z,E,Z)-docosapentaenoic acid inhibits IL-6 production by inhibiting ROS production and ERK/NF-κB pathway in keratinocytes HaCaT stimulated with a fine dust PM10. Ecotoxicol Environ Saf. 2022; 232: 113252. https://doi.org/10.1016/j.ecoenv.2022.113252.
• [52] Ritchey LE, Su Z, Tang Y, Tack DC, Assmann SM, Bevilacqua PC. Structure-seq2: sensitive and accurate genome-wide profiling of RNA structure in vivo. Nucleic Acids Res. 2017; 45(14): e135. https://doi.org/10.1093/nar/gkx533.
• [53] Ryu JY, Na EJ. MMP expression alteration and MMP-1 production control by syringic acid via AP-1 mechanism. Biomedical Dermatology.2018; 2(1): 15. https://doi.org/10.1186/s41702-018-0023-x.
• [54] Park K, Lee JH, Cho HC, Cho SY, Cho JW. Down-regulation of IL-6, IL-8, TNF-α and IL-1β by glucosamine in HaCaT cells, but not in the presence of TNF-α. Oncol Lett. 2010; 1(2): 289-292. https://doi.org/10.3892/ol_00000051.
• [55] Yin J, Kim HH, Hwang IH, Kim DH, Lee MW. Anti-Inflammatory Effects of Phenolic Compounds Isolated from Quercus Mongolica Fisch. ex Ledeb. on UVB-Irradiated Human Skin Cells. Molecules. 2019; 24(17): 3094. https://doi.org/10.3390/molecules24173094.