Modulation of NAD+ biosynthesis activates SIRT1 and resists cisplatin-induced ototoxicity.

Cisplatin, the most widely used platinum-based anticancer drug, often causes progressive and irreversible sensorineural hearing loss in cancer 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-ß-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 reducing 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 on 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.

Histone deacetylase activity is required for embryonic posterior lateral line development.

OBJECTIVES: The posterior lateral line (PLL) system in zebrafish has recently become a model for investigating tissue morphogenesis. PLL primordium periodically deposits neuromasts as it migrates along the horizontal myoseptum from head to tail of the embryonic fish, and this migration requires activity of various molecular mechanisms. Histone deacetylases (HDACs) have been implicated in numerous biological processes of development, by regulating gene transcription, but their roles in regulating PLL during embryonic development have up to now remained unexplored. MATERIAL AND METHODS: In this study, we used HDAC inhibitors to investigate the role of HDACs in early development of the zebrafish PLL sensory system. We further investigated development of the PLL by cell-specific immunostaining and in situ hybridization. RESULTS: Our analysis showed that HDACs were involved in zebrafish PLL development as pharmacological inhibition of HDACs resulted in its defective formation. We observed that migration of PLL primordium was altered and accompanied by disrupted development of PLL neuromasts in HDAC inhibitor-treated embryos. In these, positions of PLL neuromasts were affected. In particular, the first PLL neuromast was displaced posteriorly in a treatment dose-dependent manner. Primordium cell proliferation was reduced upon HDAC inhibition. Finally, we showed that inhibition of HDAC function reduced numbers of hair cells in PLL neuromasts of HDAC inhibitor-treated embryos. CONCLUSION: Here, we have revealed a novel role for HDACs in orchestrating PLL morphogenesis. Our results suggest that HDAC activity is necessary for control of cell proliferation and migration of PLL primordium and hair cell differentiation during early stages of PLL development in zebrafish.

Epizootic neoplasia of the lateral line system of lake trout (Salvelinus namaycush) in New York's Finger Lakes.

This article documents an epizootic of inflammation and neoplasia selectively affecting the lateral line system of lake trout (Salvelinus namaycush) in 4 Finger Lakes in New York from 1985 to 1994. We studied more than 100 cases of this disease. Tumors occurred in 8% (5/64) of mature and 21% (3/14) of immature lake trout in the most severely affected lake. Lesions consisted of 1 or more neoplasm(s) in association with lymphocytic inflammation, multifocal erosions, and ulcerations of the epidermis along the lateral line. Lesions progressed from inflammatory to neoplastic, with 2-year-old lake trout showing locally extensive, intense lymphocytic infiltrates; 2- to 3-year-old fish having multiple, variably sized white masses up to 3 mm in diameter; and fish over 5 years old exhibiting 1 or more white, cerebriform masses greater than 1 cm in diameter. Histologic diagnoses of the tumors were predominantly spindle cell sarcomas or benign or malignant peripheral nerve sheath neoplasms, with fewer epitheliomas and carcinomas. Prevalence estimates did not vary significantly between sexes or season. The cause of this epizootic remains unclear. Tumor transmission trials, virus isolation procedures, and ultrastructural study of lesions failed to reveal evidence of a viral etiology. The Finger Lakes in which the disease occurred did not receive substantially more chemical pollution than unaffected lakes in the same chain during the epizootic, making an environmental carcinogen an unlikely primary cause of the epizootic. A hereditary component, however, may have contributed to this syndrome since only fish of the Seneca Lake strain were affected.