Aminoglycoside-Induced Oxidative Stress: Pathways and Protection

Rybak, Leonard P.; Brenner, Michael

doi:10.1007/978-3-319-13473-4_10

Cited by 3 publications

(1 citation statement)

References 136 publications

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“…A similar distribution was observed after KI04 ( Figure 3 b, KI04). Aminoglycosides can induce oxidative stress [ 40 ], and our group has demonstrated that Cx46 hemichannels are sensitive to changes in redox potential [ 14 ], where oxidations in the extracellular cysteines seem to induce Cx46 hemichannel closure [ 13 ]. Therefore, we then explored the possibility that the inhibitory effect of KI04 could be reversed by a cysteine-reducing agent.…”

Section: Resultsmentioning

confidence: 99%

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

et al. 2023

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Background: Connexins (Cxs) are proteins that help cells to communicate with the extracellular media and with the cytoplasm of neighboring cells. Despite their importance in several human physiological and pathological conditions, their pharmacology is very poor. In the last decade, some molecules derived from aminoglycosides have been developed as inhibitors of Cxs hemichannels. However, these studies have been performed in E. coli, which is a very simple model. Therefore, our main goal is to test whether these molecules have similar effects in mammalian cells. Methods: We transfected HeLa cells with the human Cx46tGFP and characterized the effect of a kanamycin-derived molecule (KI04) on Cx46 hemichannel activity by time-lapse recordings, changes in phosphorylation by Western blot, localization by epifluorescence, and possible binding sites by molecular dynamics (MD). Results: We observed that kanamycin and KI04 were the most potent inhibitors of Cx46 hemichannels among several aminoglycosides, presenting an IC50 close to 10 μM. The inhibitory effect was not associated with changes in Cx46 electrophoretic mobility or its intracellular localization. Interestingly, 5 mM DTT did not reverse KI04 inhibition, but the KI04 effect completely disappeared after washing out KI04 from the recording media. MD analysis revealed two putative binding sites of KI04 in the Cx46 hemichannel. Results: These results demonstrate that KI04 could be used as a Cx46 inhibitor and could help to develop future selective Cx46 inhibitors.

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Section: Resultsmentioning

confidence: 99%

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

et al. 2023

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Current Issues in Clinical and Translational Research in the Hearing Sciences, Audiology, and Otolaryngology

Prell

2016

Translational Research in Audiology, Neurotology, and the Hearing Sciences

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Drug-Induced Ototoxicity: Diagnosis and Monitoring

Campbell

Prell

2018

Drug Saf

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Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.

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Aminoglycoside-Induced Oxidative Stress: Pathways and Protection

Cited by 3 publications

References 136 publications

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

KI04 an Aminoglycosides-Derived Molecule Acts as an Inhibitor of Human Connexin46 Hemichannels Expressed in HeLa Cells

Current Issues in Clinical and Translational Research in the Hearing Sciences, Audiology, and Otolaryngology

Drug-Induced Ototoxicity: Diagnosis and Monitoring

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