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Wu 2022 Antioxidants (Basel)

From Bioblast
Publications in the MiPMap
Wu YL, Chang JC, Chao YC, Chan H, Hsieh M, Liu CS (2022) In vitro efficacy and molecular mechanism of curcumin analog in pathological regulation of spinocerebellar ataxia type 3.

ยป Antioxidants (Basel) 11:1389. PMID: 35883884 Open Access

Wu Yu-Ling, Chang Jui-Chih, Chao Yi-Chun, Chan Hardy, Hsieh Mingli, Liu Chin-San (2022) Antioxidants (Basel)

Abstract: 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 ฮผM, 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 ฮผM) 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. โ€ข Keywords: Anti-oxidative enzymes, Curcumin analog, Mitochondrial function, Nuclear factor erythroid-2 related factor 2, Spinocerebellar ataxia type 3 โ€ข Bioblast editor: Plangger M

Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Neurodegenerative 

Organism: Human  Tissue;cell: Neuroblastoma  Preparation: Intact cells 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k