Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System
Geranylgeranylacetone (GGA) exerts cytoprotective activity against various toxic stressors via the thioredoxin (TRX) redox system; however, its effect on skin inflammation and molecular mechanism on inducing the TRX of GGA is still unknown. We investigated the effects of GGA in a murine irritant con...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/9/1701 |
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| author | Tiancheng Jin Yitong You Wenjie Fan Junyang Wang Yuhao Chen Shujing Li Siyuan Hong Yaxuan Wang Ruijie Cao Junji Yodoi Hai Tian |
| author_facet | Tiancheng Jin Yitong You Wenjie Fan Junyang Wang Yuhao Chen Shujing Li Siyuan Hong Yaxuan Wang Ruijie Cao Junji Yodoi Hai Tian |
| author_sort | Tiancheng Jin |
| collection | DOAJ |
| description | Geranylgeranylacetone (GGA) exerts cytoprotective activity against various toxic stressors via the thioredoxin (TRX) redox system; however, its effect on skin inflammation and molecular mechanism on inducing the TRX of GGA is still unknown. We investigated the effects of GGA in a murine irritant contact dermatitis (ICD) model induced by croton oil. Both a topical application and oral administration of GGA induced TRX production and Nrf2 activation. GGA ameliorated ear swelling, neutrophil infiltration, and inhibited the expression of TNF-α, IL-1β, GM-CSF, and 8-OHdG. GGA’s cytoprotective effect was stronger orally than topically in mice. In vitro studies also showed that GGA suppressed the expression of NLRP3, TNF-α, IL-1β, and GM-CSF and scavenged ROS in PAM212 cells after phorbol myristate acetate stimulation. Moreover, GGA induced endogenous TRX production and Nrf2 nuclear translocation in PAM212 cells (dependent on the presence of ROS) and activated the PI3K-Akt signaling pathway. GGA significantly downregulated thioredoxin-interacting protein (TXNIP) levels in PAM212 cells treated with or without Nrf2 siRNA. After knocking down Nrf2 in PAM212 cells, the effect of GGA on TRX induction was significantly inhibited. This suggests that GGA suppress ICD by inducing endogenous TRX, which may be regulated by PI3K/Akt/Nrf2 mediation of the TRX redox system. |
| first_indexed | 2024-03-10T23:06:58Z |
| format | Article |
| id | doaj.art-f30ac04d8257451e9876d4949c4b4f7b |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T23:06:58Z |
| publishDate | 2023-08-01 |
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| series | Antioxidants |
| spelling | doaj.art-f30ac04d8257451e9876d4949c4b4f7b2023-11-19T09:19:13ZengMDPI AGAntioxidants2076-39212023-08-01129170110.3390/antiox12091701Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox SystemTiancheng Jin0Yitong You1Wenjie Fan2Junyang Wang3Yuhao Chen4Shujing Li5Siyuan Hong6Yaxuan Wang7Ruijie Cao8Junji Yodoi9Hai Tian10Department of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaLaboratory of Infection and Prevention, Department of Biological Response, Institute for Virus Research, Kyoto University, Kyoto 606-8507, JapanDepartment of Basic Medicine, Medical College, Shaoxing University, Shaoxing 312000, ChinaGeranylgeranylacetone (GGA) exerts cytoprotective activity against various toxic stressors via the thioredoxin (TRX) redox system; however, its effect on skin inflammation and molecular mechanism on inducing the TRX of GGA is still unknown. We investigated the effects of GGA in a murine irritant contact dermatitis (ICD) model induced by croton oil. Both a topical application and oral administration of GGA induced TRX production and Nrf2 activation. GGA ameliorated ear swelling, neutrophil infiltration, and inhibited the expression of TNF-α, IL-1β, GM-CSF, and 8-OHdG. GGA’s cytoprotective effect was stronger orally than topically in mice. In vitro studies also showed that GGA suppressed the expression of NLRP3, TNF-α, IL-1β, and GM-CSF and scavenged ROS in PAM212 cells after phorbol myristate acetate stimulation. Moreover, GGA induced endogenous TRX production and Nrf2 nuclear translocation in PAM212 cells (dependent on the presence of ROS) and activated the PI3K-Akt signaling pathway. GGA significantly downregulated thioredoxin-interacting protein (TXNIP) levels in PAM212 cells treated with or without Nrf2 siRNA. After knocking down Nrf2 in PAM212 cells, the effect of GGA on TRX induction was significantly inhibited. This suggests that GGA suppress ICD by inducing endogenous TRX, which may be regulated by PI3K/Akt/Nrf2 mediation of the TRX redox system.https://www.mdpi.com/2076-3921/12/9/1701geranylgeranylacetoneirritant contact dermatitisthioredoxin redox systemPI3K/Akt/Nrf2 signaling pathwayanti-inflammatory effect and mechanism |
| spellingShingle | Tiancheng Jin Yitong You Wenjie Fan Junyang Wang Yuhao Chen Shujing Li Siyuan Hong Yaxuan Wang Ruijie Cao Junji Yodoi Hai Tian Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System Antioxidants geranylgeranylacetone irritant contact dermatitis thioredoxin redox system PI3K/Akt/Nrf2 signaling pathway anti-inflammatory effect and mechanism |
| title | Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System |
| title_full | Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System |
| title_fullStr | Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System |
| title_full_unstemmed | Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System |
| title_short | Geranylgeranylacetone Ameliorates Skin Inflammation by Regulating and Inducing Thioredoxin via the Thioredoxin Redox System |
| title_sort | geranylgeranylacetone ameliorates skin inflammation by regulating and inducing thioredoxin via the thioredoxin redox system |
| topic | geranylgeranylacetone irritant contact dermatitis thioredoxin redox system PI3K/Akt/Nrf2 signaling pathway anti-inflammatory effect and mechanism |
| url | https://www.mdpi.com/2076-3921/12/9/1701 |
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