In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3
Unlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by...
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MDPI AG
2022-07-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/7/1389 |
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| author | Yu-Ling Wu Jui-Chih Chang Yi-Chun Chao Hardy Chan Mingli Hsieh Chin-San Liu |
| author_facet | Yu-Ling Wu Jui-Chih Chang Yi-Chun Chao Hardy Chan Mingli Hsieh Chin-San Liu |
| author_sort | Yu-Ling Wu |
| collection | DOAJ |
| description | Unlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by polyglutamine neurotoxicity and oxidative stress. Presently, we compared actions of JM17 with those of known Nrf2 activators, omaveloxolone (RTA-408) and dimethyl fumarate (DMF), using human neuroblastoma SK-N-SH cells with stable transfection of full-length ataxin-3 protein with 78 CAG repeats (MJD78) to clarify the resulting pathological mechanism by assaying mitochondrial function, mutant ataxin-3 protein toxicity, and oxidative stress. JM17, 1 μM, comprehensively restored mitochondrial function, decreased mutant protein aggregates, and attenuated intracellular/mitochondrial reactive oxygen species (ROS) levels. Although JM17 induced dose-dependent Nrf2 activation, a low dose of JM17 (less than 5 μM) still had a better antioxidant ability compared to the other Nrf2 activators and specifically increased mitochondrial superoxide dismutase 2 in an Nrf2-dependent manner as shown by knockdown experiments with siRNA. It showed that activation of Nrf2 in response to ROS generated in mitochondria could play an import role in the benefit of JM17. This study presents the diversified regulation of JM17 in a pathological process and helped develop more effective therapeutic strategies for SCA3. |
| first_indexed | 2024-03-09T03:45:20Z |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T03:45:20Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
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| series | Antioxidants |
| spelling | doaj.art-5f9d9f3ac7fc4fb090f4d1a86ce5b1c82023-12-03T14:34:25ZengMDPI AGAntioxidants2076-39212022-07-01117138910.3390/antiox11071389In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3Yu-Ling Wu0Jui-Chih Chang1Yi-Chun Chao2Hardy Chan3Mingli Hsieh4Chin-San Liu5Vascular and Genomic Center, Institute of ATP, Changhua Christian Hospital, Changhua 50091, TaiwanCenter of Regenerative Medicine and Tissue Repair, Changhua Christian Hospital, Changhua 50091, TaiwanInflammation Research & Drug Development Center, Changhua Christian Hospital, Changhua 50091, TaiwanAllianz Pharmascience Limited, Taipei 10682, TaiwanDepartment of Life Science, Life Science Research Center, Tunghai University, Taichung 40704, TaiwanVascular and Genomic Center, Institute of ATP, Changhua Christian Hospital, Changhua 50091, TaiwanUnlike other nuclear factor erythroid-2-related factor 2 (Nrf2) activators, the mechanism of action of curcumin analog, ASC-JM17 (JM17), in regulating oxidative homeostasis remains unknown. Spinocerebellar ataxia type 3 (SCA3) is an inherited polyglutamine neurodegenerative disease caused mainly by polyglutamine neurotoxicity and oxidative stress. Presently, we compared actions of JM17 with those of known Nrf2 activators, omaveloxolone (RTA-408) and dimethyl fumarate (DMF), using human neuroblastoma SK-N-SH cells with stable transfection of full-length ataxin-3 protein with 78 CAG repeats (MJD78) to clarify the resulting pathological mechanism by assaying mitochondrial function, mutant ataxin-3 protein toxicity, and oxidative stress. JM17, 1 μM, comprehensively restored mitochondrial function, decreased mutant protein aggregates, and attenuated intracellular/mitochondrial reactive oxygen species (ROS) levels. Although JM17 induced dose-dependent Nrf2 activation, a low dose of JM17 (less than 5 μM) still had a better antioxidant ability compared to the other Nrf2 activators and specifically increased mitochondrial superoxide dismutase 2 in an Nrf2-dependent manner as shown by knockdown experiments with siRNA. It showed that activation of Nrf2 in response to ROS generated in mitochondria could play an import role in the benefit of JM17. This study presents the diversified regulation of JM17 in a pathological process and helped develop more effective therapeutic strategies for SCA3.https://www.mdpi.com/2076-3921/11/7/1389spinocerebellar ataxia type 3curcumin analognuclear factor erythroid-2 related factor 2anti-oxidative enzymesmitochondrial function |
| spellingShingle | Yu-Ling Wu Jui-Chih Chang Yi-Chun Chao Hardy Chan Mingli Hsieh Chin-San Liu In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3 Antioxidants spinocerebellar ataxia type 3 curcumin analog nuclear factor erythroid-2 related factor 2 anti-oxidative enzymes mitochondrial function |
| title | In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3 |
| title_full | In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3 |
| title_fullStr | In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3 |
| title_full_unstemmed | In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3 |
| title_short | In Vitro Efficacy and Molecular Mechanism of Curcumin Analog in Pathological Regulation of Spinocerebellar Ataxia Type 3 |
| title_sort | in vitro efficacy and molecular mechanism of curcumin analog in pathological regulation of spinocerebellar ataxia type 3 |
| topic | spinocerebellar ataxia type 3 curcumin analog nuclear factor erythroid-2 related factor 2 anti-oxidative enzymes mitochondrial function |
| url | https://www.mdpi.com/2076-3921/11/7/1389 |
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