PUBLICATION
Modulation of NAD+ biosynthesis activates SIRT1 and resist cisplatin-induced ototoxicity
- Authors
- Zhan, T., Xiong, H., Pang, J., Zhang, W., Ye, Y., Liang, Z., Huang, X., He, F., Jian, B., He, W., Gao, Y., Min, X., Zheng, Y., Yang, H.
- ID
- ZDB-PUB-210606-4
- Date
- 2021
- Source
- Toxicology letters 349: 115-123 (Journal)
- Registered Authors
- Keywords
- ACMSD, Cisplatin, NAD(+), Ototoxicity, SIRT1
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Carboxy-Lyases/antagonists & inhibitors
- Carboxy-Lyases/metabolism
- Cisplatin
- Disease Models, Animal
- Enzyme Activation
- Enzyme Inhibitors/pharmacology*
- Hair Cells, Auditory/drug effects*
- Hair Cells, Auditory/enzymology
- Hair Cells, Auditory/pathology
- Hearing/drug effects*
- Hearing Loss/chemically induced
- Hearing Loss/enzymology
- Hearing Loss/physiopathology
- Hearing Loss/prevention & control*
- Lateral Line System/drug effects
- Lateral Line System/enzymology
- Mice, Inbred C57BL
- Mitochondria/drug effects
- Mitochondria/enzymology
- Mitochondria/pathology
- NAD/biosynthesis*
- Ototoxicity/enzymology
- Ototoxicity/etiology
- Ototoxicity/physiopathology
- Ototoxicity/prevention & control*
- Sirtuin 1/metabolism*
- Zebrafish
- PubMed
- 34089817 Full text @ Toxicol. Lett.
- CTD
- 34089817
Citation
Zhan, T., Xiong, H., Pang, J., Zhang, W., Ye, Y., Liang, Z., Huang, X., He, F., Jian, B., He, W., Gao, Y., Min, X., Zheng, Y., Yang, H. (2021) Modulation of NAD+ biosynthesis activates SIRT1 and resist cisplatin-induced ototoxicity. Toxicology letters. 349:115-123.
Abstract
Cisplatin often induces progressive sensorineural hearing loss in patients. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. Nicotinamide adenine dinucleotide (NAD+), a co-substrate for the sirtuin family and PARPs, has emerged as a potent therapeutic molecular target in various diseases. In our investigates, we observed that NAD+ level was changed in the cochlear explants of mice treated with cisplatin. Supplementation of a specific inhibitor (TES-1025) of α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), a rate-limiting enzyme of NAD+de novo synthesis pathway, promoted SIRT1 activity, increased mtDNA contents and enhanced AMPK expression, thus significantly reduced hair cells loss and deformation. The protection was blocked by EX527, a specific SIRT1 inhibitor. Meanwhile, the use of NMN, a precursor of NAD+ salvage synthesis pathway, had shown beneficial effect to hair cell under cisplatin administration, effectively suppressing PARP1. In vivo experiments confirmed the hair cell protection of NAD+ modulators in cisplatin treated mice and zebrafish. In conclusion, we demonstrated that modulation of NAD+ biosynthesis via the de novo synthesis pathway and the salvage synthesis pathway could both prevent ototoxicity of cisplatin. These results suggested that direct modulation of cellular NAD+ levels could be a promising therapeutic approach for protection of hearing from cisplatin-induced ototoxicity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping