N-acetylcysteine alleviates post-resuscitation myocardial dysfunction and improves survival outcomes via partly inhibiting NLRP3 inflammasome induced-pyroptosis

He, Fan; Zheng, Guanghui; Hou, Jinlin; Hu, Qiaohua; Ling, Qin; Wu, Gongfa; Zhao, Hui; Yang, Jin Ming; Wang, Yue; Jiang, Longyuan; Tang, Wanchun; Yang, Zhengfei

doi:10.1186/s12950-020-00255-3

Cited by 22 publications

(41 citation statements)

References 48 publications

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“…Pyroptosis is another cellular pathway that has also been implicated in a variety of pathologies such as colitis, myocardial dysfunction, and neuronal damage [48][49][50]. In brief, pyroptosis is a form of inflammatory programmed cell death characterized by inflammasome activation, membrane pore-formation, swelling, rupture, and ultimate dissolution and release of intracellular contents [51].…”

Section: Discussionmentioning

confidence: 99%

Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway

Wu¹,

Chen²,

Zhuang³

et al. 2021

Int. J. Biol. Sci.

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Spinal cord injury (SCI) results in a wide range of disabilities. Its complex pathophysiological process limits the effectiveness of many clinical treatments. Betulinic acid (BA) has been shown to be an effective treatment for some neurological diseases, but it has not been studied in SCI. In this study, we assessed the role of BA in SCI and investigated its underlying mechanism. We used a mouse model of SCI, and functional outcomes following injury were assessed. Western blotting, ELISA, and immunofluorescence techniques were employed to analyze levels of autophagy, mitophagy, pyroptosis, and AMPK-related signaling pathways were also examined. Our results showed that BA significantly improved functional recovery following SCI. Furthermore, autophagy, mitophagy, ROS level and pyroptosis were implicated in the mechanism of BA in the treatment of SCI. Specifically, our results suggest that BA restored autophagy flux following injury, which induced mitophagy to eliminate the accumulation of ROS and inhibits pyroptosis. Further mechanistic studies revealed that BA likely regulates autophagy and mitophagy via the AMPK-mTOR-TFEB signaling pathway. Those results showed that BA can significantly promote the recovery following SCI and that it may be a promising therapy for SCI.

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Section: Discussionmentioning

confidence: 99%

Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway

Wu¹,

Chen²,

Zhuang³

et al. 2021

Int. J. Biol. Sci.

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“…In our study, we evaluated the level of oxidative stress, including increased MDA and decreased SOD after reperfusion (26). Up-regulation of miR-194-5p led to the decrease of SOD activity, the increase of MDA activity, and the inhibition of ROS production.…”

Section: Discussionmentioning

confidence: 98%

miR-194-5p protects against myocardial ischemia/reperfusion injury via MAPK1/PTEN/AKT pathway

Zhang¹,

Wu²,

Yang³

2021

Ann Transl Med

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Background: MicroRNA (miRNA), which participates in various physiological and pathological processes, is a highly conserved small RNA sequence. This study aimed to investigate the role of miR-194-5p in hypoxia/reoxygenation (H/R)-induced cardiomyocyte apoptosis and myocardial ischemia/reperfusion (I/R) injury. Methods: We set up an H/R H9c2 cell model in vitro and an I/R mouse model in vivo. Then, cell vitality, apoptosis, and histopathological evaluation were conducted. Reactive oxygen species (ROS) generation and the activity of superoxide dismutase (SOD) and malondialdehyde (MDA) were examined by 2',7'-Dichloro dihydrofluorescein diacetate (H2DCFDA), and enzyme-linked immunosorbent assay (ELISA), respectively. The level of creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), myoglobin (Mb) is examined by ELISA. The expression of Caspase-3, cleaved-Caspase-3, Bax, Bcl-2, phosphatase and tensin homolog deleted on chromosome ten (PTEN), and protein kinase B (AKT) was analyzed by western blot. Results: Data showed the expression of miR-194-5p was decreased in H/R-induced H9c2 cells and I/ R-induced mouse. Conversely, overexpression of miR-194-5p could improve cardiomyocyte damage in ischemic models in vivo and in vitro. Furthermore, mitogen-activated protein kinase 1 (MAPK1) was found as a direct target of miR-194-5p, which negatively regulated the expression of MAPK1. The up-regulation of MAPK1 inhibited the myocardial protection previously observed by miR-194-5p.Conclusions: Our study shows overexpression of miR-194-5p protects against H/R injury in vitro and cardiac I/R injury in vivo, which involves the inhibition of cardiac apoptosis and oxidative stress by targeting MAPK1 expression via PTEN/AKT pathway. These findings supply novel insights into potential therapeutic targets for cardiovascular diseases.

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“…Active caspase-1, an effector enzyme of the NLRP3 in ammasome, not only cleaves the cytokines pro-IL-1β and pro-IL-18 into their mature active forms (IL-1β and IL-18) but also cleaves GSDMD, which creates pores in the plasma membrane, thereby causing release of IL-1β and IL-18 from the cells [9]. Previous studies have found that global I/R injury can induce overactivation of the NLRP3 in ammasome, GSDMD and proin ammatory cytokines in the heart [8] and brain [28,29]. In this study, we established a systemic I/R model and assessed the NLRP3 in ammasome, GSDMD and downstream in ammatory factors in the heart and brain.…”

Section: Discussionmentioning

confidence: 99%

“…Pyroptosis is promoted by NLR family pyrin domaincontaining 3 (NLRP3) in ammasome activation and crosstalks with apoptosis [5], necrosis [6], and autophagy [7]. A large amount of evidence has demonstrated that activation of pyroptosis is essential for cardiac [8] and neurological [9] deterioration postresuscitation. Our previous in vivo [10] and in vitro [11] research found that I/R injury exacerbated neuronal damage by activating NLRP3-mediated neuroin ammation, which indicated that the inhibition of pyroptosis might be a potential therapeutic strategy for the improvement of cardiac and neurological function postresuscitation.…”

Section: Introductionmentioning

confidence: 99%

Alda-1, an Activator of ALDH2, Protects Cardiac and Neurological Function Postresuscitation by Inhibiting Pyroptosis in Swine

Diao¹,

Xu²,

Wang³

et al. 2021

Preprint

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PurposeThe enzyme aldehyde dehydrogenase 2 (ALDH2) has been shown to protect the heart and brain from oxidative stress injury, and this effect is related to the inhibition of pyroptosis. In the present study, we hypothesised that the ALDH2 activator N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would mitigate cardiac and neurological injury postresuscitation in a preclinical swine model of CA.MethodsFollowing 8 minutes of untreated ventricular fibrillation, and another 8 minutes of cardiopulmonary resuscitation (CPR), the swine randomly received either Alda-1 (0.88 mg/kg, n = 6) or saline (n=5) after restoration of spontaneous circulation (ROSC). Hemodynamic parameters and cardiac function were monitored, and serial blood samples were collected postresuscitation to detect biomarkers of cardiac and neurological injury. At 24 hours postresuscitation, first, neurological scores were evaluated, and then, the swine were sacrificed and pyroptosis-related proteins, proinflammatory cytokines, and oxidative stress were assessed in heart and brain samples.ResultsCardiac and neurological injury were significantly improved in the Alda-1 group compared with the CPR group postresuscitation. In addition, after treatment with Alda-1, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, Gasdermin D (GSDMD), and proinflammatory cytokine levels were markedly suppressed. Moreover, 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA), indicators of oxidative stress, were also significantly inhibited after Alda-1 administration, which was accompanied by increased ALDH2 activity and protein expression.ConclusionAlda-1 improves cardiac and neurological dysfunction postresuscitation in a swine model of CA, at least partly by inhibiting oxidative stress-mediated NLRP3 inflammasome activation and pyroptosis.

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N-acetylcysteine alleviates post-resuscitation myocardial dysfunction and improves survival outcomes via partly inhibiting NLRP3 inflammasome induced-pyroptosis

Cited by 22 publications

References 48 publications

Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway

Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway

miR-194-5p protects against myocardial ischemia/reperfusion injury via MAPK1/PTEN/AKT pathway

Alda-1, an Activator of ALDH2, Protects Cardiac and Neurological Function Postresuscitation by Inhibiting Pyroptosis in Swine

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