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      Mechanisms of Aminoglycoside Ototoxicity and Targets of Hair Cell Protection

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          Abstract

          Aminoglycosides are commonly prescribed antibiotics with deleterious side effects to the inner ear. Due to their popular application as a result of their potent antimicrobial activities, many efforts have been undertaken to prevent aminoglycoside ototoxicity. Over the years, understanding of the antimicrobial as well as ototoxic mechanisms of aminoglycosides has increased. These mechanisms are reviewed in regard to established and potential future targets of hair cell protection.

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          Most cited references306

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          Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.

          Bcl-2 protein is able to repress a number of apoptotic death programs. To investigate the mechanism of Bcl-2's effect, we examined whether Bcl-2 interacted with other proteins. We identified an associated 21 kd protein partner, Bax, that has extensive amino acid homology with Bcl-2, focused within highly conserved domains I and II. Bax is encoded by six exons and demonstrates a complex pattern of alternative RNA splicing that predicts a 21 kd membrane (alpha) and two forms of cytosolic protein (beta and gamma). Bax homodimerizes and forms heterodimers with Bcl-2 in vivo. Overexpressed Bax accelerates apoptotic death induced by cytokine deprivation in an IL-3-dependent cell line. Overexpressed Bax also counters the death repressor activity of Bcl-2. These data suggest a model in which the ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus.
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            Mitochondrial dynamics and apoptosis.

            In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.
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              Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE.

              Recent studies suggest that proteases of the interleukin 1-beta-converting enzyme (ICE)/ced-3 family are involved in initiating the active phase of apoptosis. Here we identify a novel protease resembling ICE (prICE) that is active in a cell-free system that reproduces the morphological and biochemical events of apoptosis. prICE cleaves the nuclear enzyme poly(ADP-ribose) polymerase (PARP) at a tetrapeptide sequence identical to one of two ICE sites in pro-interleukin-1-beta. However, prICE does not cleave purified pro-interleukin-1-beta, and purified ICE does not cleave PARP, indicating that the two activities are distinct. Inhibition of prICE abolishes all manifestations of apoptosis in the extracts including morphological changes, cleavage of PARP and production of an oligonucleosomal ladder. These studies suggest that prICE might be pivotal in initiating the active phase of apoptosis in vitro and in intact cells.
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                Author and article information

                Journal
                Int J Otolaryngol
                IJOL
                International Journal of Otolaryngology
                Hindawi Publishing Corporation
                1687-9201
                1687-921X
                2011
                25 October 2011
                : 2011
                Affiliations
                1Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, 801 Welch Road, Stanford, CA 94305-5739, USA
                2Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland
                3Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA
                Author notes

                Academic Editor: Jeffrey P. Pearson

                Article
                10.1155/2011/937861
                3202092
                22121370
                e7b9850c-413a-4f92-b8f3-d447c240e8d3
                Copyright © 2011 M. E. Huth et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Review Article

                Otolaryngology
                Otolaryngology

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