Biomaterial Database

Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway. 2024

Rui Hu, and Fan Wu, and Yi-Qing Zheng

Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei, People's Republic of China.

Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

UI	MeSH Term	Description	Entries
D011788	Quality of Life	A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral, social environment as well as health and disease.	HRQOL,Health-Related Quality Of Life,Life Quality,Health Related Quality Of Life
D005839	Gentamicins	A complex of closely related aminoglycosides obtained from MICROMONOSPORA purpurea and related species. They are broad-spectrum antibiotics, but may cause ear and kidney damage. They act to inhibit PROTEIN BIOSYNTHESIS.	Gentamicin Sulfate (USP),Gentamycin,G-Myticin,Garamycin,Gentacycol,Gentamicin,Gentamicin Sulfate,Gentamycins,Gentavet,Genticin,G Myticin,GMyticin,Sulfate, Gentamicin
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000081015	Ototoxicity	Damage to the EAR or its function secondary to exposure to toxic substances such as drugs used in CHEMOTHERAPY; IMMUNOTHERAPY; or RADIATION.	Auditory Toxicity,Drug-Induced Cochlear Toxicity,Drug-Induced Cochleotoxicity,Drug-Induced Otological Toxicity,Drug-Induced Ototoxicity,Drug-Induced Vestibular Toxicity,Drug-Induced Vestibulotoxicity,Drug-Related Cochlear Toxicity,Drug-Related Cochleotoxicity,Drug-Related Otological Toxicity,Drug-Related Ototoxicity,Otological Toxicity,Radiation-Induced Ototoxicity,Cochlear Toxicities, Drug-Induced,Cochlear Toxicities, Drug-Related,Cochlear Toxicity, Drug-Induced,Cochlear Toxicity, Drug-Related,Cochleotoxicities, Drug-Induced,Cochleotoxicities, Drug-Related,Cochleotoxicity, Drug-Induced,Cochleotoxicity, Drug-Related,Drug Induced Cochlear Toxicity,Drug Induced Cochleotoxicity,Drug Induced Otological Toxicity,Drug Induced Ototoxicity,Drug Induced Vestibular Toxicity,Drug Induced Vestibulotoxicity,Drug Related Cochlear Toxicity,Drug Related Cochleotoxicity,Drug Related Otological Toxicity,Drug Related Ototoxicity,Drug-Induced Cochlear Toxicities,Drug-Induced Cochleotoxicities,Drug-Induced Otological Toxicities,Drug-Induced Ototoxicities,Drug-Induced Vestibular Toxicities,Drug-Induced Vestibulotoxicities,Drug-Related Cochlear Toxicities,Drug-Related Cochleotoxicities,Drug-Related Otological Toxicities,Drug-Related Ototoxicities,Otological Toxicities, Drug-Induced,Otological Toxicities, Drug-Related,Otological Toxicity, Drug-Induced,Otological Toxicity, Drug-Related,Ototoxicities,Ototoxicities, Drug-Induced,Ototoxicities, Drug-Related,Ototoxicities, Radiation-Induced,Ototoxicity, Drug-Induced,Ototoxicity, Drug-Related,Ototoxicity, Radiation-Induced,Radiation Induced Ototoxicity,Radiation-Induced Ototoxicities,Toxicity, Otological,Vestibular Toxicities, Drug-Induced,Vestibular Toxicity, Drug-Induced,Vestibulotoxicities, Drug-Induced,Vestibulotoxicity, Drug-Induced
D000627	Aminophenols	Phenols substituted in any position by an amino group.	Hydroxyanilines
D015363	Quinolones	A group of derivatives of naphthyridine carboxylic acid, quinoline carboxylic acid, or NALIDIXIC ACID.	Ketoquinoline,Ketoquinolines,Oxoquinoline,Oxoquinolines,Quinolinone,Quinolinones,Quinolone
D016660	NAD(P)H Dehydrogenase (Quinone)	A flavoprotein that reversibly catalyzes the oxidation of NADH or NADPH by various quinones and oxidation-reduction dyes. The enzyme is inhibited by dicoumarol, capsaicin, and caffeine.	DT Diaphorase,Menadione Reductase,Phylloquinone Reductase,Quinone Reductase,Vitamin K Reductase,Diaphorase, DT,Reductase, Menadione,Reductase, Phylloquinone,Reductase, Quinone,Reductase, Vitamin K
D017209	Apoptosis	A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.	Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D017382	Reactive Oxygen Species	Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of SIGNAL TRANSDUCTION and GENE EXPRESSION, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.	Active Oxygen Species,Oxygen Radical,Oxygen Radicals,Pro-Oxidant,Reactive Oxygen Intermediates,Active Oxygen,Oxygen Species, Reactive,Pro-Oxidants,Oxygen, Active,Pro Oxidant,Pro Oxidants,Radical, Oxygen
D051267	NF-E2-Related Factor 2	A basic-leucine zipper transcription factor that was originally described as a transcriptional regulator controlling expression of the BETA-GLOBIN gene. It may regulate the expression of a wide variety of genes that play a role in protecting cells from oxidative damage.	Nfe2l2 Protein,Nuclear Factor (Erythroid-Derived 2)-Like 2 Protein,Nuclear Factor E2-Related Factor 2,NF E2 Related Factor 2,Nuclear Factor E2 Related Factor 2