Background: Exposure of human skin to solar ultraviolet A (UVA) irradiation causes severe oxidative stress with damage to various cellular components and concomitant inflammation and carcinogenesis. Objective: The aim of this study is to investigate the protective effect of acetyl-11-keto-β-boswellic acid (AKBA) against UVA radiation on human skin keratinocytes. Methods: HaCaT cells were pretreated with AKBA followed by UVA irradiation. Radiation effects on cell morphology, cell viability, intracellular reactive oxygen species (ROS) levels, and antioxidant enzymes were examined. Results: AKBA reduces UVA irradiation-induced cell viability loss, accompanied by a decreased production of UVA-induced ROS, decreased malondialdehyde, and increased superoxide dismutase expression. In addition, AKBA increased basal and UVA-induced levels of Nrf2 (NF-E2-related factor 2), the redox-sensitive factor, and its target genes NQO1 and heme oxygenase-1 (HO-1), whereas expression of the transcriptional repressor Bach1 (BTB and CNC homology 1) was reduced. Furthermore, the cytoprotective effects of AKBA against UVA-derived oxidative damage were accompanied by modulating expression of inflammatory mediators (i.e., cyclooxygenase-2 and nuclear factor-κB) and NOX1. Conclusions: AKBA protects skin cells from UVA-induced damage by modulating inflammatory mediators and/or ROS production. Therefore, AKBA has potential in the development of skin care products.

1.
Watson RE, Gibbs NK, Griffiths CE, Sherratt MJ: Damage to skin extracellular matrix induced by UV exposure. Antioxid Redox Signal 2014;21:1063-1077.
2.
Kostyuk V, Potapovich A, Stancato A, De Luca C, Lulli D, Pastore S, Korkina L: Photo-oxidation products of skin surface squalene mediate metabolic and inflammatory responses to solar UV in human keratinocytes. PLoS One 2012;7:e44472.
3.
George KS, Elyassaki W, Wu Q, Wu S: The role of cholesterol in UV light B-induced apoptosis. Photochem Photobiol 2012;88:1191-1197.
4.
Ikehata H, Kumagai J, Ono T, Morita A: Solar-UV-signature mutation prefers TCG to CCG: extrapolative consideration from UVA1-induced mutation spectra in mouse skin. Photochem Photobiol Sci 2013;12:1319-1327.
5.
Weinkauf B, Rukwied R, Quiding H, Dahllund L, Johansson P, Schmelz M: Local gene expression changes after UV-irradiation of human skin. PLoS One 2012;7:e39411.
6.
Sage E, Tyrrell R: Introduction to the themed issue on the biology of UVA. Photochem Photobiol Sci 2012;11:28-29.
7.
Vile GF, Tanew-Ilitschew A, Tyrrell RM: Activation of NF-kappa B in human skin fibroblasts by the oxidative stress generated by UVA radiation. Photochem Photobiol 1995;62:463-468.
8.
Liu HP, Gao ZH, Cui SX, Wang Y, Li BY, Lou HX, Qu XJ: Chemoprevention of intestinal adenomatous polyposis by acetyl-11-keto-beta-boswellic acid in APC(Min/+) mice. Int J Cancer 2013;132:2667-2681.
9.
Valencia A, Kochevar IE: Nox1-based NADPH oxidase is the major source of UVA-induced reactive oxygen species in human keratinocytes. J Invest Dermatol 2008;128:214-222.
10.
Ding Y, Chen M, Wang M, Wang MM, Zhang T, Park J, Zhu Y, Guo C, Jia Y, Li Y, Wen A: Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway. Sci Rep 2014;4:7002.
11.
Kim DW, Hwang IK, Kim DW, Yoo KY, Won CK, Moon WK, Won MH: Coenzyme Q_{10} effects on manganese superoxide dismutase and glutathione peroxidase in the hairless mouse skin induced by ultraviolet B irradiation. Biofactors 2007;30:139-147.
12.
Aroun A, Zhong JL, Tyrrell RM, Pourzand C: Iron, oxidative stress and the example of solar ultraviolet A radiation. Photochem Photobiol Sci 2012;11:118-134.
13.
Tyrrell RM: Modulation of gene expression by the oxidative stress generated in human skin cells by UVA radiation and the restoration of redox homeostasis. Photochem Photobiol Sci 2012;11:135-147.
14.
Yan SX, Hong XY, Hu Y, Liao KH: Tempol, one of nitroxides, is a novel ultraviolet-A1 radiation protector for human dermal fibroblasts. J Dermatol Sci 2005;37:137-143.
15.
Tan AS, Berridge MV: Evidence for NAD(P)H: quinone oxidoreductase 1 (NQO1)-mediated quinone-dependent redox cycling via plasma membrane electron transport: a sensitive cellular assay for NQO1. Free Radic Biol Med 2010;48:421-429.
16.
Itoh K, Mimura J, Yamamoto M: Discovery of the negative regulator of Nrf2, Keap1: a historical overview. Antioxid Redox Signal 2010;13:1665-1678.
17.
Zhao CR, Gao ZH, Qu XJ: Nrf2-ARE signaling pathway and natural products for cancer chemoprevention. Cancer Epidemiol 2010;34:523-533.
18.
Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal AK: Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H: quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 2005;280:16891-16900.
19.
Zhong JL, Raval C, Edwards GP, Tyrrell RM: A role for Bach1 and HO-2 in suppression of basal and UVA-induced HO-1 expression in human keratinocytes. Free Radic Biol Med 2010;48:196-206.
20.
Tyrrell RM, Reeve VE: Potential protection of skin by acute UVA irradiation - from cellular to animal models. Prog Biophys Mol Biol 2006;92:86-91.
21.
Tian FF, Zhang FF, Lai XD, Wang LJ, Yang L, Wang X, Singh G, Zhong JL: Nrf2-mediated protection against UVA radiation in human skin keratinocytes. Biosci Trends 2011;5:23-29.
22.
Hirota A, Kawachi Y, Itoh K, Nakamura Y, Xu X, Banno T, Takahashi T, Yamamoto M, Otsuka F: Ultraviolet a irradiation induces NF-E2-related factor 2 activation in dermal fibroblasts: protective role in UVA-induced apoptosis. J Invest Dermatol 2005;124:825-832.
23.
Wagner AE, Ernst I, Iori R, Desel C, Rimbach G: Sulforaphane but not ascorbigen, indole-3-carbinole and ascorbic acid activates the transcription factor Nrf2 and induces phase-2 and antioxidant enzymes in human keratinocytes in culture. Exp Dermatol 2010;19:137-144.
24.
Zhang Y, Ma WY, Kaji A, Bode AM, Dong Z: Requirement of ATM in UVA-induced signaling and apoptosis. J Biol Chem 2002;277:3124-3131.
25.
Zhong JL, Yang L, Lu F, Xiao H, Xu R, Wang L, Zhu F, Zhang Y: UVA, UVB and UVC induce differential response signaling pathways converged on the eIF2α phosphorylation. Photochem Photobiol 2011;87:1092-1104.
26.
Quyen BT, Choi HK, Kang KW: Pin1 is required for ultraviolet A-stimulated cyclooxygenase-2 induction in mouse epidermal cells. Cancer Lett 2013;335:31-40.
27.
Applegate LA, Noel A, Vile G, Frenk E, Tyrrell RM: Two genes contribute to different extents to the heme oxygenase enzyme activity measured in cultured human skin fibroblasts and keratinocytes: implications for protection against oxidant stress. Photochem Photobiol 1995;61:285-291.
28.
Mekkawy IA, Mahmoud UM, Osman AG, Sayed Ael D: Effects of ultraviolet A on the activity of two metabolic enzymes, DNA damage and lipid peroxidation during early developmental stages of the African catfish, Clarias gariepinus (Burchell, 1822). Fish Physiol Biochem 2010;36:605-626.
29.
Liu Y, Chan F, Sun H, Yan J, Fan D, Zhao D, An J, Zhou D: Resveratrol protects human keratinocytes HaCaT cells from UVA-induced oxidative stress damage by downregulating keap1 expression. Eur J Pharmacol 2011;650:130-137.
30.
Yasui H, Sakurai H: Age-dependent generation of reactive oxygen species in the skin of live hairless rats exposed to UVA light. Exp Dermatol 2003;12:655-661.
31.
Choi JY, Choi DI, Lee JB, Yun SJ, Lee DH, Eun JB, Lee SC: Ethanol extract of peanut sprout induces Nrf2 activation and expression of antioxidant and detoxifying enzymes in human dermal fibroblasts: implication for its protection against UVB-irradiated oxidative stress. Photochem Photobiol 2013;89:453-460.
32.
Shin SW, Jung E, Kim S, Kim JH, Kim EG, Lee J, Park D: Antagonizing effects and mechanisms of afzelin against UVB-induced cell damage. PLoS One 2013;8:e61971.
33.
Liu JJ, Huang B, Hooi SC: Acetyl-keto-beta-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells. Br J Pharmacol 2006;148:1099-1107.
34.
Monsalves MT, Amenabar MJ, Ollivet-Besson GP, Blamey JM: Effect of UV radiation on a thermostable superoxide dismutase purified from a thermophilic bacterium isolated from a sterilization drying oven. Protein Pept Lett 2013;20:749-754.
35.
Elassiuty YE, Klarquist J, Speiser J, Yousef RM, El Refaee AA, Hunter NS, Shaker OG, Gundeti M, Nieuweboer-Krobotova L, Le Poole IC: Heme oxygenase-1 expression protects melanocytes from stress-induced cell death: Implications for vitiligo. Exp Dermatol 2011;20:496-501.
36.
Jian Z, Li K, Liu L, Zhang Y, Zhou Z, Li C, Gao T: Heme oxygenase-1 protects human melanocytes from H2O2-induced oxidative stress via the Nrf2-ARE pathway. J Invest Dermatol 2011;131:1420-1427.
37.
Zhong JL, Edwards GP, Raval C, Li H, Tyrrell RM: The role of Nrf2 in ultraviolet A mediated heme oxygenase 1 induction in human skin fibroblasts. Photochem Photobiol Sci 2010;9:18-24.
38.
Zhong JL, Raval CM, Nisar MF, Bian C, Zhang J, Yang L, Tyrrell RM: Development of refractoriness of HO-1 induction to a second treatment with UVA radiation and the involvement of Nrf2 in human skin fibroblasts. Photochem Photobiol 2014;90:1340-1348.
39.
Zhu J, Wang H, Chen F, Fu J, Xu Y, Hou Y, Kou HH, Zhai C, Nelson MB, Zhang Q, Andersen ME, Pi J: An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy. Free Radic Biol Med 2016;99:544-556.
40.
Hseu YC, Chou CW, Senthil Kumar KJ, Fu KT, Wang HM, Hsu LS, Kuo YH, Wu CR, Chen SC, Yang HL: Ellagic acid protects human keratinocyte (HaCaT) cells against UVA-induced oxidative stress and apoptosis through the upregulation of the HO-1 and Nrf-2 antioxidant genes. Food Chem Toxicol 2012;50:1245-1255.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.