N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway

Wang, Chengfen; Chen, Kan; Xia, Yujing; Dai, Weiqi; Wang, Fan; Miao, Song; Cheng, Ping; Wang, Junshan; Lü, Jie; Zhang, Yan; Yang, Jing; Zhu, Rong; Zhang, Huawei; Li, Jingjing; Zheng, Yuanyuan; Zhou, Yingqun; Guo, Chuanyong

doi:10.1371/journal.pone.0108855

Cited by 88 publications

(74 citation statements)

References 41 publications

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“…[71][72][73][74] Recently, NAC was reported to attenuate ischemia-reperfusion-induced autophagy via ROS/JNK/bcl-2 pathway. 75 Therefore, we speculated that ROS-mediated MAPK/Bcl-2 may be a novel mechanism in the protective effects of NAC on SiNPs-induced autophagy in endothelial cells. Studies revealed that mTOR inhibition could lead to and even promote apoptosis, 76,77 suggesting that the detected downregulation of mTOR may also be responsible for SiNPs-induced apoptosis.…”

mentioning

confidence: 99%

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Guo¹,

Yang²,

Li³

et al. 2016

IJN

196

111

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Environmental exposure to silica nanoparticles (SiNPs) is inevitable due to their widespread application in industrial, commercial, and biomedical fields. In recent years, most investigators focus on the evaluation of cardiovascular effects of SiNPs in vivo and in vitro. Endothelial injury and dysfunction is now hypothesized to be a dominant mechanism in the development of cardiovascular diseases. This study aimed to explore interaction of SiNPs with endothelial cells, and extensively investigate the exact effects of reactive oxygen species (ROS) on the signaling molecules and cytotoxicity involved in SiNPs-induced endothelial injury. Significant induction of cytotoxicity as well as oxidative stress, apoptosis, and autophagy was observed in human umbilical vein endothelial cells following the SiNPs exposure ( P <0.05). The oxidative stress was induced by ROS generation, leading to redox imbalance and lipid peroxidation. SiNPs induced mitochondrial dysfunction, characterized by membrane potential collapse, and elevated Bax and declined bcl-2 expression, ultimately leading to apoptosis, and also increased number of autophagosomes and autophagy marker proteins, such as LC3 and p62. Phosphorylated ERK, PI3K, Akt, and mTOR were significantly decreased, but phosphorylated JNK and p38 MAPK were increased in SiNPs-exposed endothelial cells. In contrast, all of these stimulation phenomena were effectively inhibited by N -acetylcysteine. The N -acetylcysteine supplement attenuated SiNPs-induced endothelial toxicity through inhibition of apoptosis and autophagy via MAPK/Bcl-2 and PI3K/Akt/mTOR signaling, as well as suppression of intracellular ROS property via activating antioxidant enzyme and Nrf2 signaling. In summary, the results demonstrated that SiNPs triggered autophagy and apoptosis via ROS-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling in endothelial cells, and subsequently disturbed the endothelial homeostasis and impaired endothelium. Our findings may provide experimental evidence and explanation for cardiovascular diseases triggered by SiNPs. Furthermore, results hint that the application of antioxidant may provide a novel way for safer use of nanomaterials.

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mentioning

confidence: 99%

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Guo¹,

Yang²,

Li³

et al. 2016

IJN

196

111

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“…17,18 A previous study by Wang and associates showed that NAC can prevent hepatic IRI-induced autophagy and apoptosis by influencing the Janus kinase signaling pathway. 19 The effect of NAC on suppressing the TLR4/IRF5 axis and its downstream proinflammatory cytokines suggests another possible mechanism of action for preventing hepatic IRI. Findings from our present study show that activation of the TLR4/IRF5 signaling axis may have an essential role in the early inflammatory phase of hepatic IRI.…”

Section: Discussionmentioning

confidence: 99%

Evaluating mRNA Expression Levels of the TLR4/IRF5 Signaling Axis During Hepatic Ischemia-Reperfusion Injuries

Nasiri

Saadat²,

Karimi³

et al. 2017

Exp Clin Transplant

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Objectives: Hepatic ischemia and reperfusion during liver transplant surgery result in hepatocellular damage. Toll-like receptors, especially TLR4, have a fundamental basic role in the inflammatory phase of ischemia-reperfusion injuries. The effect of the TRIFdependent signaling pathway downstream of TLR4 in hepatic ischemia-reperfusion injury has been well established. However, the role of TLR4-MyD88-dependent signal transduction in hepatic ischemiareperfusion injury has not yet been clarified. The interferon regulatory factor 5 was introduced as the main regulator of the TLR4-MyD88 signaling pathway for activating proinflammatory cytokines. The present study was carried out to investigate the functional impact of the TLR4/IRF5 signaling axis in hepatic ischemia-reperfusion injury. Materials and Methods: mRNA expression levels of TLR4, IRF5, tumor necrosis factor α, interleukin 1β, and interleukin 6 were measured using real-time polymerase chain reaction after short (3 h) and long (168 h) reperfusion periods in a hepatic mouse model of ischemia-reperfusion injury in the presence and absence of N-acetylcysteine. Liver damage was evaluated by plasma levels of alanine aminotransferase and histopathology. Results: Our results show that mRNA levels of TLR4/IRF5 and its downstream cytokines were significantly elevated 3 hours after reperfusion and had drastically fallen to baseline levels 168 hours after reperfusion. Plasma levels of alanine aminotransferase showed the same pattern. Histopathologic study of the samples revealed significant hepatic cell infiltration and necrosis 168 hours after reperfusion. Pretreatment with N-acetylcysteine significantly decreased the mRNA levels of TLR4/IRF5 and its downstream cytokines 3 hours after reperfusion and subsequently improved the previously mentioned hepatic damages 168 hours after reperfusion. Conclusions: This study suggests a possible role for the TLR4/IRF5 signaling pathway in hepatic ischemiareperfusion injury. Furthermore, it reveals that Nacetylcysteine may suppress this inflammatory axis and consequently improve hepatic injuries.

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“…However, the mechanism still remains unclear. Mounting evidence indicates that apoptosis results in post-ischemic cardiomyocyte death [26] . In a previous study, SFN could protect cardiomyocytes against oxidative damage [27] .…”

Section: Discussionmentioning

confidence: 99%

Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress

et al. 2016

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Aim: Sulforaphane (SFN), a natural dietary isothiocyanate, is found to exert beneficial effects for cardiovascular diseases. This study aimed to investigate the mechanisms underlying the protective effects of SFN in a model of myocardial hypoxia/reoxygenation (H/R) injury in vitro. Methods: Cultured neonatal rat cardiomyocytes pretreated with SFN were subjected to 3-h hypoxia followed by 3-h reoxygenation. Cell viability and apoptosis were detected. Caspase-3 activity and mitochondrial membrane potential (ΔΨm) was measured. The expression of ER stress-related apoptotic proteins were analyzed with Western blot analyses. Silent information regulator 1 (SIRT1) activity was determined with SIRT1 deacetylase fluorometric assay kit. Results: SFN (0.1-5 μmol/L) dose-dependently improved the viability of cardiomyocytes, diminished apoptotic cells and suppressed caspase-3 activity. Meanwhile, SFN significantly alleviated the damage of ΔΨm and decreased the expression of ER stress-related apoptosis proteins (GRP78, CHOP and caspase-12), elevating the expression of SIRT1 and Bcl-2/Bax ratio in the cardiomyocytes. Co-treatment of the cardiomyocytes with the SIRT1-specific inhibitor Ex-527 (1 μmol/L) blocked the SFN-induced cardioprotective effects. Conclusion: SFN prevents cardiomyocytes from H/R injury in vitro most likely via activating SIRT1 pathway and subsequently inhibiting the ER stress-dependent apoptosis.

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N-Acetylcysteine Attenuates Ischemia-Reperfusion-Induced Apoptosis and Autophagy in Mouse Liver via Regulation of the ROS/JNK/Bcl-2 Pathway

Cited by 88 publications

References 41 publications

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Evaluating mRNA Expression Levels of the TLR4/IRF5 Signaling Axis During Hepatic Ischemia-Reperfusion Injuries

Sulforaphane prevents rat cardiomyocytes from hypoxia/reoxygenation injury in vitro via activating SIRT1 and subsequently inhibiting ER stress

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