Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy

Shi, Jing; Yin, Ning; Xuan, Lingling; Yao, Chun‐Suo; Meng, Aimin; Hou, Qi

doi:10.1038/aps.2012.73

Cited by 42 publications

(37 citation statements)

References 37 publications

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“…This supports our finding that autophagy induction can control CSinduced emphysema in subjects with COPD. The sequential investigation of the role of autophagy in CS-induced COPD-emphysema in this study clarifies that CS in fact impairs autophagy, in contrast to the findings of a previous report (44,76). Moreover, a recent study demonstrated the efficacy of CBZ in controlling hepatic fibrosis caused by ATZ mutation (45), which is also known to develop emphysema in a small population (5%) of subjects with COPD, suggesting its potential to also control ATZ-related emphysema.…”

Section: Copdemphysema Pathogenesissupporting

confidence: 77%

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Tran

et al. 2015

Am J Respir Cell Mol Biol

103

121

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Cigarette smoke (CS) exposure is known to induce proteostasis imbalance that can initiate accumulation of ubiquitinated proteins. Therefore, the primary goal of this study was to determine if first-and secondhand CS induces localization of ubiquitinated proteins in perinuclear spaces as aggresome bodies. Furthermore, we sought to determine the mechanism by which smoke-induced aggresome formation contributes to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Hence, Beas2b cells were treated with CS extract (CSE) for in vitro experimental analysis of CSinduced aggresome formation by immunoblotting, microscopy, and reporter assays, whereas chronic CS-exposed murine model and human COPD-emphysema lung tissues were used for validation. In preliminary analysis, we observed a significant (P , 0.01) increase in ubiquitinated protein aggregation in the insoluble protein fraction of CSE-treated Beas2b cells. We verified that CS-induced ubiquitin aggregrates are localized in the perinuclear spaces as aggresome bodies. These CS-induced aggresomes (P , 0.001) colocalize with autophagy protein microtubule-associated protein 1 light chain-3B 1 autophagy bodies, whereas U.S. Food and Drug Administration-approved autophagy-inducing drug (carbamazepine) significantly (P , 0.01) decreases their colocalization and expression, suggesting CS-impaired autophagy. Moreover, CSE treatment significantly increases valosin-containing protein-p62 protein-protein interaction (P , 0.0005) and p62 expression (aberrant autophagy marker; P , 0.0001), verifying CSimpaired autophagy as an aggresome formation mechanism. We also found that inhibiting protein synthesis by cycloheximide does not deplete CS-induced ubiquitinated protein aggregates, suggesting the role of CS-induced protein synthesis in aggresome formation. Next, we used an emphysema murine model to verify that chronic CS significantly (P , 0.0005) induces aggresome formation. Moreover, we observed that autophagy induction by carbamazepine inhibits CS-induced aggresome formation and alveolar space enlargement (P , 0.001), confirming involvement of aggresome bodies in COPD-emphysema pathogenesis. Finally, significantly higher p62 accumulation in smokers and severe COPD-emphysema lungs (Global Initiative for Chronic Obstructive Lung Disease Stage III/IV) as compared with normal nonsmokers (Global Initiative for Chronic Obstructive Lung Disease Stage 0) substantiates the pathogenic role of autophagy impairment in aggresome formation and COPD-emphysema progression. In conclusion, CS-induced aggresome formation is a novel mechanism involved in COPD-emphysema pathogenesis.Keywords: cigarette smoke; chronic obstructive pulmonary disease; ubiquitin; aggresomes; autophagy Clinical RelevanceWe anticipate that these research findings will have a great impact on development of novel therapeutics for treatment of chronic obstructive pulmonary disease-emphysema and other diseases involving impaired proteostasis or autophagy. In addition to the therapeutic application, thes...

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Section: Copdemphysema Pathogenesissupporting

confidence: 77%

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Tran

et al. 2015

Am J Respir Cell Mol Biol

103

121

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“…SIRT1 and FoxO proteins may work synergistically to protect cells. Increased FoxO3a and SIRT1 activity with a reduction in autophagy limits oxidative stress in human bronchial epithelial cells exposed to cigarette smoke condensates (247). Loss of the forkhead transcription factors FoxO1 and FoxO3 in combination with decreased SIRT1 activity during oxidative stress leads to a reduction in autophagy and subsequent chondrocyte cell death, suggesting that SIRT1 with FoxO proteins may be required for cellular protection during oxidative stress (248).…”

Section: Signaling Pathways Of Erythropoietinmentioning

confidence: 99%

Regeneration in the nervous system with erythropoietin

Maiese¹

2016

Front Biosci

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Globally, greater than 30 million individuals are afflicted with disorders of the nervous system accompanied by tens of thousands of new cases annually with limited, if any, treatment options. Erythropoietin (EPO) offers an exciting and novel therapeutic strategy to address both acute and chronic neurodegenerative disorders. EPO governs a number of critical protective and regenerative mechanisms that can impact apoptotic and autophagic programmed cell death pathways through protein kinase B (Akt), sirtuins, mammalian forkhead transcription factors, and wingless signaling. Translation of the cytoprotective pathways of EPO into clinically effective treatments for some neurodegenerative disorders has been promising, but additional work is necessary. In particular, development of new treatments with erythropoiesis-stimulating agents such as EPO brings several important challenges that involve detrimental vascular outcomes and tumorigenesis. Future work that can effectively and safely harness the complexity of the signaling pathways of EPO will be vital for the fruitful treatment of disorders of the nervous system.

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“…Yet, FoxO cell protection may not always be directly tied to the induction of autophagy. Up-regulation of FoxO3 and SIRT1 with a reduction in autophagy occurs in human bronchial epithelial cells exposed to cigarette smoke condensates in the presence of the anti-oxidant Amurensis H (Vam3), a dimeric derivative of resveratrol, that can reduce oxidative stress (184). …”

Section: Foxo Proteins Oxidative Stress Apoptosis and Autophagymentioning

confidence: 99%

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

Maiese¹

2015

CNR

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Mammalian forkhead transcription factors of the O class (FoxO) are exciting targets under consideration for the development of new clinical entities to treat metabolic disorders and diabetes mellitus (DM). DM, a disorder that currently affects greater than 350 million individuals globally, can become a devastating disease that leads to cellular injury through oxidative stress pathways and affects multiple systems of the body. FoxO proteins can regulate insulin signaling, gluconeogenesis, insulin resistance, immune cell migration, and cell senescence. FoxO proteins also control cell fate through oxidative stress and pathways of autophagy and apoptosis that either lead to tissue regeneration or cell demise. Furthermore, FoxO signaling can be dependent upon signal transduction pathways that include silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), Wnt, and Wnt1 inducible signaling pathway protein 1 (WISP1). Cellular metabolic pathways driven by FoxO proteins are complex, can lead to variable clinical outcomes, and require in-depth analysis of the epigenetic and post-translation protein modifications that drive FoxO protein activation and degradation.

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Vam3, a derivative of resveratrol, attenuates cigarette smoke-induced autophagy

Cited by 42 publications

References 37 publications

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Role of Cigarette Smoke–Induced Aggresome Formation in Chronic Obstructive Pulmonary Disease–Emphysema Pathogenesis

Regeneration in the nervous system with erythropoietin

FoxO Transcription Factors and Regenerative Pathways in Diabetes Mellitus

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