Ginsenoside Rg1 attenuates ultraviolet B-induced glucocortisides resistance in keratinocytes via Nrf2/HDAC2 signalling
Open accessAbstract
Oxidative stress, which occurs after ultraviolet (UV) radiation, usually results in Glucocorticoid (GC) resistance and the subsequent development of skin inflammation. One approach to protecting the skin against UV radiation is the use of antioxidants. The ginsenoside Rg1 is a novel natural antioxidant isolated from the medicinal plant Panax ginseng C.A. Mey. We demonstrated that UVB exposure exacerbated inflammation and reduced both the level of the glucocorticoid receptor (GR) and the efficacy of dexamethasone (Dex) in human keratinocytes (HaCaT cells). Pretreatment with Rg1 increased the expression of GR and restored Dex responsiveness to inflammation in UVB-irradiated HaCaT cells. Mechanistically, Rg1 rescued UVB-induced HDAC2 degradation. HDAC2 knockdown partially abolished the Rg1-induced up-regulation of GR and the enhancement of GC sensitivity. In addition, Rg1 reduced the production of reactive oxygen species (ROS), which preceded the up-regulation of HDAC2, and consequent sensitization of cells to Dex. Moreover, Rg1 treatment promoted the translocation and activation of Nrf2. Nrf2 knockdown partially abolished the Rg1-induced decrease of ROS production and increase of HDAC2. Rg1 also potentiated the anti-inflammatory effects of Dex in UVB-irradiated mouse skin. In conclusion, we demonstrated that Rg1 attenuated UVB-induced GC insensitivity. Notably, these effects were partially mediated by the Nrf2/HDAC2 pathway.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Ginsenoside Rg2 (1) and ginsenoside Rg1 (4) have exhibited anti-aging effects in Hs68 and HaCaT cells, respectively, related to a reduction in MMP-1 expression and ROS.
“In previous studies, ginsenoside Rg2 (1) and ginsenoside Rg1 (4) have exhibited anti-aging effects in Hs68 and HaCaT cells, respectively. These were related to a reduction in MMP-1 expression and ROS [17,31].”
From Anti-Aging and Anti-Inflammatory Effects of Compounds from Fresh Panax ginseng Roots: A Study on TNF-α/IFN-γ-Induced Skin Cell Damage (2024) · cites this paper as [31]
The Results section, “Rg1 restored HDAC2 levels through ROS inhibition” (page unavailable), reports that Rg1 reduced UVB-induced ROS production in HaCaT keratinocytes. The paper investigates glucocorticoid resistance and skin inflammation, not an anti-aging effect in those cells; it does not report reduced MMP-1 expression. The Rg2/Hs68 finding is not attributed specifically to this source in the multiply cited sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Annexin A1 and glucocorticoids as effectors of the resolution of inflammation
Perretti, M., & D'Acquisto, F. (2009) · Nature Reviews Immunology · doi:10.1038/nri2470 · Cited by 915 · see citing works
DNA binding site sequence directs glucocorticoid receptor structure and activity
Meijsing, S. H., Pufall, M. A., So, A. Y., Bates, D. L., Chen, L., & Yamamoto, K. R. (2009) · Science · doi:10.1126/science.1164265 · Cited by 673 · see citing works
Key role of CRF in the skin stress response system
Slominski, A. T., Zmijewski, M. A., Zbytek, B., Tobin, D. J., Theoharides, T. C., & Rivier, J. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1092 · Cited by 400 · see citing works
Mechanisms and resistance in glucocorticoid control of inflammation
Barnes, P. J. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.02.018 · Cited by 317 · see citing works
Solito, E., Mulla, A., Morris, J. F., Christian, H. C., Flower, R. J., & Buckingham, J. C. (2003) · Endocrinology · doi:10.1210/en.2002-220592 · Cited by 184 · see citing works
Marrot, L., Jones, C., Perez, P., & Meunier, J. (2008) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2007.00424.x · Cited by 164 · see citing works
Protective Effect of Garlic on Cellular Senescence in UVB-Exposed HaCaT Human Keratinocytes
Kim, H. (2016) · Nutrients · doi:10.3390/nu8080464 · Cited by 67 · see citing works
Flagged first, then by citations
Research works printed but not linked: 49
- Maubec E.. Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin. The Journal of investigative dermatology 135, 1781– 1789, doi: 10.1038/jid.2015.44 (2015). 25668238 · DOI
- Ingawale D. K., Mandlik S. K. & Patel S. S. An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance. Journal of complementary & integrative medicine 12, 1– 13, doi: 10.1515/jcim-2014-0051 (2015). 25503867 · DOI
- Yang N., Ray D. W. & Matthews L. C. Current concepts in glucocorticoid resistance. Steroids 77, 1041– 1049, doi: 10.1016/j.steroids.2012.05.007 (2012). 22728894 · DOI
- Ichihashi M.. UV-induced skin damage. Toxicology 189, 21– 39 (2003). 12821280
- Wu Z., Uchi H., Morino-Koga S., Shi W. & Furue M. Z-ligustilide ameliorated ultraviolet B-induced oxidative stress and inflammatory cytokine production in human keratinocytes through upregulation of Nrf2/HO-1 and suppression of NF-kappaB pathway. Experimental dermatology 24, 703– 708, doi: 10.1111/exd.12758 (2015). 25977183 · DOI
- Janjetovic Z.. Melatonin and its metabolites ameliorate ultraviolet B-induced damage in human epidermal keratinocytes. J Pineal Res 57, 90– 102, doi: 10.1111/jpi.12146 (2014). 24867336 PMC4106994 · DOI · Paper page
- Slominski A. T.. Local melatoninergic system as the protector of skin integrity. Int J Mol Sci 15, 17705– 17732, doi: 10.3390/ijms151017705 (2014). 25272227 PMC4227185 · DOI
- de Gruijl F. R. Photocarcinogenesis: UVA vs. UVB radiation. Skin pharmacology and applied skin physiology 15, 316– 320, doi: 64535 (2002). 12239425
- Slominski A. T., Manna P. R. & Tuckey R. C. On the role of skin in the regulation of local and systemic steroidogenic activities. Steroids 103, 72– 88, doi: 10.1016/j.steroids.2015.04.006 (2015). 25988614 PMC4631694 · DOI
- Slominski A. T.. Cytochromes p450 and skin cancer: role of local endocrine pathways. Anti-cancer agents in medicinal chemistry 14, 77– 96 (2014). 23869782 PMC3740756
- Skobowiat C., Sayre R. M., Dowdy J. C. & Slominski A. T. Ultraviolet radiation regulates cortisol activity in a waveband-dependent manner in human skin ex vivo. The British journal of dermatology 168, 595– 601, doi: 10.1111/bjd.12096 (2013). 23363016 PMC3586986 · DOI · Paper page
- Barnes P. J., Ito K. & Adcock I. M. Corticosteroid resistance in chronic obstructive pulmonary disease: inactivation of histone deacetylase. Lancet 363, 731– 733, doi: 10.1016/S0140-6736(04)15650-X (2004). 15001333 · DOI
- Hew M.. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. American journal of respiratory and critical care medicine 174, 134– 141, doi: 10.1164/rccm.200512-1930OC (2006). 16614347 PMC2662905 · DOI
- Shakespear M. R., Halili M. A., Irvine K. M., Fairlie D. P. & Sweet M. J. Histone deacetylases as regulators of inflammation and immunity. Trends in immunology 32, 335– 343, doi: 10.1016/j.it.2011.04.001 (2011). 21570914 · DOI · Paper page
- Barnes P. J. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 71, 451– 464, doi: 10.1146/annurev.physiol.010908.163257 (2009). 18817512 · DOI
- Ito K.. Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappaB suppression. The Journal of experimental medicine 203, 7– 13, doi: 10.1084/jem.20050466 (2006). 16380507 PMC2118081 · DOI · Paper page
- Adenuga D.. Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction. Biochem Biophys Res Commun 403, 452– 456, doi: 10.1016/j.bbrc.2010.11.054 (2010). 21094147 PMC3031165 · DOI
- Rangasamy T.. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. The Journal of clinical investigation 114, 1248– 1259, doi: 10.1172/JCI21146 (2004). 15520857 PMC524225 · DOI
- Malhotra D.. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. American journal of respiratory and critical care medicine 178, 592– 604, doi: 10.1164/rccm.200803-380OC (2008). 18556627 PMC2542433 · DOI
- Singh A.. Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs. Free radical biology & medicine 46, 376– 386, doi: 10.1016/j.freeradbiomed.2008.10.026 (2009). 19027064 PMC2828157 · DOI
- Sussan T. E.. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proceedings of the National Academy of Sciences of the United States of America 106, 250– 255, doi: 10.1073/pnas.0804333106 (2009). 19104057 PMC2629210 · DOI · Paper page
- Harvey C. J.. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Science translational medicine 3, 78ra32, doi: 10.1126/scitranslmed.3002042 (2011). PMC4927975 21490276 · DOI
- Kensler T. W., Wakabayashi N. & Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47, 89– 116, doi: 10.1146/annurev.pharmtox.46.120604.141046 (2007). 16968214 · DOI · Paper page
- Kleszczynski K., Zillikens D. & Fischer T. W. Melatonin enhances mitochondrial ATP synthesis, reduces reactive oxygen species formation, and mediates translocation of the nuclear erythroid 2-related factor 2 resulting in activation of phase-2 antioxidant enzymes (gamma-GCS, HO-1, NQO1) in ultraviolet radiation-treated normal human epidermal keratinocytes (NHEK). J Pineal Res 61, 187– 197, doi: 10.1111/jpi.12338 (2016). 27117941 · DOI
- Saw C. L.. Nrf2 null enhances UVB-induced skin inflammation and extracellular matrix damages. Cell & bioscience 4, 39, doi: 10.1186/2045-3701-4-39 (2014). 25228981 PMC4164960 · DOI
- Jia L., Wang W. Y., Zhou L. M., Mo F. F. & Li M. Antimotion sickness effects of ginsenosides combined with dexamethasone in rats. Zhong xi yi jie he xue bao=Journal of Chinese integrative medicine 8, 358– 362, doi: 10.3736/jcim201090410 (2010). 20388477 · DOI
- Ru W.. Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.). Drug Discov Ther 9, 23– 32, doi: 10.5582/ddt.2015.01004 (2015). 25788049 · DOI
- You Y. L.. Efficacy of ginsenosides combined with prednisone in patients with systemic lupus erythematosus: a prospective, randomized, double-blind, placebo-controlled trial. Zhong xi yi jie he xue bao=Journal of Chinese integrative medicine 8, 762– 766 (2010). 20727331
- Hu W.. The positive effects of Ginsenoside Rg1 upon the hematopoietic microenvironment in a D-Galactose-induced aged rat model. BMC Complement Altern Med 15, 119, doi: 10.1186/s12906-015-0642-3 (2015). 25881060 PMC4417299 · DOI
- Oh S. J., Oh Y., Ryu I. W., Kim K. & Lim C. J. Protective properties of ginsenoside Rb3 against UV-B radiation-induced oxidative stress in HaCaT keratinocytes. Biosci Biotechnol Biochem 80, 95– 103, doi: 10.1080/09168451.2015.1075862 (2015). 26287932 · DOI
- Li J.. Protective Effect of Ginsenoside Rg1 on Hematopoietic Stem/Progenitor Cells through Attenuating Oxidative Stress and the Wnt/beta-Catenin Signaling Pathway in a Mouse Model of d-Galactose-induced Aging. Int J Mol Sci 17, doi: 10.3390/ijms17060849 (2016). PMC4926383 27294914 · DOI
- Oh S. J., Kim K. & Lim C. J. Protective properties of ginsenoside Rb1 against UV-B radiation-induced oxidative stress in human dermal keratinocytes. Pharmazie 70, 381– 387 (2015). 26189299
- Binbin C., Yinglu F., Juan D. & Changquan L. Upregulation effect of ginsenosides on glucocorticoid receptor in rat liver. Hormone and metabolic research=Hormon- und Stoffwechselforschung=Hormones et metabolisme 41, 531– 536, doi: 10.1055/s-0029-1216373 (2009). 19418418 · DOI
- Radad K., Gille G., Moldzio R., Saito H. & Rausch W. D. Ginsenosides Rb1 and Rg1 effects on mesencephalic dopaminergic cells stressed with glutamate. Brain research 1021, 41– 53, doi: 10.1016/j.brainres.2004.06.030 (2004). 15328030 · DOI
- Lu J. M., Yao Q. & Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol 7, 293– 302 (2009). 19601854 PMC2928028
- Kirkham P. & Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacology & therapeutics 111, 476– 494, doi: 10.1016/j.pharmthera.2005.10.015 (2006). 16458359 · DOI
- Lee C. W.. Effect of Artocarpus communis Extract on UVB Irradiation-Induced Oxidative Stress and Inflammation in Hairless Mice. Int J Mol Sci 14, 3860– 3873, doi: 10.3390/ijms14023860 (2013). 23403620 PMC3588075 · DOI
- Salem S.. Transforming growth factor-beta impairs glucocorticoid activity in the A549 lung adenocarcinoma cell line. Br J Pharmacol 166, 2036– 2048, doi: 10.1111/j.1476-5381.2012.01885.x (2012). 22300324 PMC3402769 · DOI
- Kim H. K. Adenophora remotiflora protects human skin keratinocytes against UVB-induced photo-damage by regulating antioxidative activity and MMP-1 expression. Nutrition research and practice 10, 371– 376, doi: 10.4162/nrp.2016.10.4.371 (2016). 27478542 PMC4958638 · DOI
- Du J., Cheng B., Zhu X. & Ling C. Ginsenoside Rg1, a novel glucocorticoid receptor agonist of plant origin, maintains glucocorticoid efficacy with reduced side effects. J Immunol 187, 942– 950, doi: 10.4049/jimmunol.1002579 (2011). 21666059 · DOI
- Vedeckis W. V., Ali M. & Allen H. R. Regulation of glucocorticoid receptor protein and mRNA levels. Cancer Res 49, 2295s– 2302s (1989). 2702670
- Lonard D. M. & O’Malley B. W. Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Molecular cell 27, 691– 700, doi: 10.1016/j.molcel.2007.08.012 (2007). 17803935 · DOI
- Malhotra D.. Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38, 5718– 5734, doi: 10.1093/nar/gkq212 (2010). 20460467 PMC2943601 · DOI
- Loboda A., Damulewicz M., Pyza E., Jozkowicz A. & Dulak J. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cellular and molecular life sciences: CMLS 73, 3221– 3247, doi: 10.1007/s00018-016-2223-0 (2016). 27100828 PMC4967105 · DOI
- To Y.. Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine 182, 897– 904, doi: 10.1164/rccm.200906-0937OC (2010). 20224070 PMC2970861 · DOI
- Song H. Y., Zhang L., Pan J. L., Yang L. L. & Ji G. Bioactivity of five components of Chinese herbal formula Jiangzhi granules against hepatocellular steatosis. Journal of integrative medicine 11, 262– 268, doi: 10.3736/jintegrmed2013034 (2013). 23867244 · DOI
- Ding D. F.. Mechanism of resveratrol on the promotion of induced pluripotent stem cells. Journal of integrative medicine 11, 389– 396, doi: 10.3736/jintegrmed2013039 (2013). 24125057 · DOI
- Ohkawa H., Ohishi N. & Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical biochemistry 95, 351– 358 (1979). 36810
- Ebaid H., Salem A., Sayed A. & Metwalli A. Whey protein enhances normal inflammatory responses during cutaneous wound healing in diabetic rats. Lipids in health and disease 10, 235, doi: 10.1186/1476-511X-10-235 (2011). 22168406 PMC3254143 · DOI
Cited by
Sorted by citations
Natural Nrf2 Modulators for Skin Protection
Boo, Y. C. (2020) · Antioxidants · doi:10.3390/antiox9090812 · Cited by 69 · see citing works
Myung, D.-B., Han, H.-S., Shin, J.-S., Park, J. Y., Hwang, H. J., Kim, H. J., Ahn, H. S., Lee, S. H., & Lee, K.-T. (2019) · Nutrients · doi:10.3390/nu11102354 · Cited by 56 · see citing works
Kang, M., Park, S., Son, S.-R., Noh, Y., Jang, D. S., & Lee, S. (2024) · Molecules · doi:10.3390/molecules29225479 · Cited by 23 · see citing works
- Authors
- Li, J., Liu, D., Wu, J., Zhang, D., Cheng, B., Zhang, Y., Yin, Z., Wang, Y., Du, J., & Ling, C.
- Affiliations
- Second Military Medical University (CN)
- Fudan University (CN)
- University of Florida Health (US)
- Corresponding author
- Du, Juan
- Ling, Changquan
- Venue
- Scientific Reports
- Published
- 2016-12-16
- Volume
- 6
- Issue
- 1
- Pages
- 39336-39336
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5159887
- OpenAlex
- W2562433766
- Cited by
- 41
- References
- 7
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 2 · 2020: 9 · 2019: 6 · 2017: 1
- FWCI
- 1.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Shanghai Municipal Education Commission (E03008)
- E-Institutes of Shanghai Municipal Education Commission (E 03008, No E 03008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ginseng Biological Effects and Applications
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Keywords
- ginsenoside Rg1, UV-B radiation, glucocorticoid resistance, keratinocytes, Nrf2, HDAC2, glucocorticoid receptor, dexamethasone, oxidative stress, reactive oxygen species, skin inflammation, Panax ginseng, anti-inflammatory activity
- MeSH terms
- Antioxidants, Cells, Cultured, Dexamethasone, Glucocorticoids, Humans, Ultraviolet Rays, Signal Transduction, Keratinocytes, Reactive Oxygen Species, Oxidative Stress, Ginsenosides, NF-E2-Related Factor 2, Histone Deacetylase 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review