Autophagy is a protective response to ethanol neurotoxicity

Chen, Gang; Zhang, Ke; Xu, Mei; Liao, Mingjun; Wang, Xin; Qi, Yuanlin; Zhang, Tao; Frank, Jacqueline A.; Bower, Kimberly A.; Shi, Xianglin; Luo, Jia

doi:10.4161/auto.21376

Cited by 145 publications

(135 citation statements)

References 37 publications

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“…However, Prof Daniel revealed an apparently contradictory result that bafilomycin A1 did not block the fusion of autophagosomes with lysosomes [92] . Data from the relatively recent literature also show that bafilomycin A1 and rapamycin potentiate ethanol-increased LC3 lipidation, whereas wortmannin and a BECN1-specific shRNA inhibit ethanol-promoted LC3 lipidation [93] . Furthermore, concanamycin A, another selective V-ATPase inhibitor, also increased the accumulation of autophagosomes [94] .…”

Section: Vacuolar-type H (+)-Atpase Inhibitorsmentioning

confidence: 86%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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Autophagy is the major intracellular degradation system, by which cytoplasmic materials are delivered to and degraded in the lysosome. As a quality control mechanism for cytoplasmic proteins and organelles, autophagy plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases. The discovery of ATG genes and the dissection of the signaling pathways involved in regulating autophagy have greatly enriched our knowledge on the occurrence and development of this lysosomal degradation pathway. In addition to its role in degradation, autophagy may also promote a type of programmed cell death that is different from apoptosis, termed type II programmed cell death. Owing to the dual roles of autophagy in cell death and the specificity of diseases, the exact mechanisms of autophagy in various diseases require more investigation. The application of autophagy inhibitors and activators will help us understand the regulation of autophagy in human diseases, and provide insight into the use of autophagy-targeted drugs. In this review, we summarize the latest research on autophagy inhibitors and activators and discuss the possibility of their application in human disease therapy.

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Section: Vacuolar-type H (+)-Atpase Inhibitorsmentioning

confidence: 86%

Application and interpretation of current autophagy inhibitors and activators

et al. 2013

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“…Chen et al . have shown that increased autophagic flux protects the ethanol‐induced death of SH‐SY5Y neuronal cells 12. To elucidate the roles of activated autophagy in neurotoxicity of LAs in this study, we examined the effects of autophagy inhibition on LAs‐provoked cell injury.…”

Section: Discussionmentioning

confidence: 99%

“…Autophagy is a double‐edged sword in the regulation of cell survival 12, 31, 33. In some cases, autophagy may promote cell death.…”

Section: Discussionmentioning

confidence: 99%

“…In some cases, autophagy may promote cell death. The term ‘autophagic cell death’ or ‘type II cell death’ was coined to differentiate it from apoptotic (type I cell death) or necrotic (type III cell death) 12, 31. As an example, we reported recently that autophagy activation mediates the transition of cardiac hypertrophy to heart failure 33.…”

Section: Discussionmentioning

confidence: 99%

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Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Xiong

Kong

Dai

et al. 2016

J Cellular Molecular Medi

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The local anaesthetics (LAs) are widely used for peripheral nerve blocks, epidural anaesthesia, spinal anaesthesia and pain management. However, exposure to LAs for long duration or at high dosage can provoke potential neuronal damages. Autophagy is an intracellular bulk degradation process for proteins and organelles. However, both the effects of LAs on autophagy in neuronal cells and the effects of autophagy on LAs neurotoxicity are not clear. To answer these questions, both lipid LAs (procaine and tetracaine) and amide LAs (bupivacaine, lidocaine and ropivacaine) were administrated to human neuroblastoma SH‐SY5Y cells. Neurotoxicity was evaluated by MTT assay, morphological alterations and median death dosage. Autophagic flux was estimated by autolysosome formation (dual fluorescence LC3 assay), LC3‐II generation and p62 protein degradation (immunoblotting). Signalling alterations were examined by immunoblotting analysis. Inhibition of autophagy was achieved by transfection with beclin‐1 siRNA. We observed that LAs decreased cell viability in a dose‐dependent manner. The neurotoxicity of LAs was tetracaine > bupivacaine > ropivacaine > procaine > lidocaine. LAs increased autophagic flux, as reflected by increases in autolysosome formation and LC3‐II generation, and decrease in p62 levels. Moreover, LAs inhibited tuberin/mTOR/p70S6K signalling, a negative regulator of autophagy activation. Most importantly, autophagy inhibition by beclin‐1 knockdown exacerbated the LAs‐provoked cell damage. Our data suggest that autophagic flux was up‐regulated by LAs through inhibition of tuberin/mTOR/p70S6K signalling, and autophagy activation served as a protective mechanism against LAs neurotoxicity. Therefore, autophagy manipulation could be an alternative therapeutic intervention to prevent LAs‐induced neuronal damage.

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“…However, these results should be carefully interpreted since inhibition of autophagy was carried out by using chloroquine and bafilomycin A1 (a specific inhibitor of the V‐ATPase), both of which lack specificity and are believed to inhibit lysosomal acidification and thereby subsequent fusion of the autophagosome with lysosomes rather than the assembly of the autophagosome,274 which results in impaired autophagosome maturation and accumulation of autophagosomes. In the case of bafilomycin A1, the actual inhibitory potential with regard to blocking autophagosome‐lysosome fusion has been doubted previously and bafilomycin A1 increases LC3 lipidation to a similar degree as autophagy‐inducer rapamycin 275, 276. Conversely, others have confirmed increased A β generation associated with preceding autophagosome accumulation in different mammalian cell types 277, 278, 279…”

Section: Degenerative Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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Autophagy is a protective response to ethanol neurotoxicity

Cited by 145 publications

References 37 publications

Application and interpretation of current autophagy inhibitors and activators

Application and interpretation of current autophagy inhibitors and activators

Autophagy activated by tuberin/mTOR/p70S6K suppression is a protective mechanism against local anaesthetics neurotoxicity

Immune and myodegenerative pathomechanisms in inclusion body myositis

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