Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

Qiu, Yu-bao; Wan, Bin-bin; Liu, Gang; Wu, Yaxian; Chen, Dan; Lu, Mengji; Chen, Junliang; Rong, Yu; Chen, Daozhen; Pang, Qingfeng

doi:10.21203/rs.3.rs-34579/v2

Cited by 9 publications

(13 citation statements)

References 39 publications

(56 reference statements)

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“…It is reported that ML385 could directly bind to the NEH1 region of Nrf2 and consequently prevent the binding of Nrf2 and ARE sequence, thus inhibiting the activation of Nrf2/ARE pathway 52 . ML385 has been widely used in former studies to investigate the protective effects of Nrf2/ARE pathway 53,54 . In our study, we found that ML385 significantly inhibited the sustain of TJs and the decreased expression of MMPs.…”

Section: Discussionsupporting

confidence: 52%

GYY4137 protected the integrity of the blood‐brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis

Cui

Chen

et al. 2021

The FASEB Journal

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Injury to the blood‐brain barrier (BBB) plays a vital role in sepsis‐associated encephalopathy (SAE), which is one of the most common complications of sepsis. GYY4137, a new synthetic compound of hydrogen sulfide (H2S), has extensive biological benefits. In this study, we focused on the protective effects of GYY4137 on the BBB in septic mice and the underlying mechanisms. The results suggested that whether administrated at the same time or 3 hours after LPS injection, GYY4137 both significantly alleviated the clinical symptoms and the long‐term prognosis. Besides, GYY4137 improved the pathological abnormalities of septic mice. Moreover, the degradation of tight junctions in the BBB was considerably inhibited by GYY4137. In addition, GYY4137 significantly attenuated inflammation and apoptosis in the brain. Furthermore, GYY4137 activated the Nrf2/ARE pathway through the sulfhydrylation of Keap1 and inhibited oxidative stress. ML385, the specific inhibitor of Nrf2, significantly reversed the protective effects of GYY4137 in sepsis mice. In conclusion, this study indicated that through the sulfhydrylation of Keap1, GYY4137 activated the Nrf2/ARE pathway and exerted anti‐inflammatory, anti‐apoptotic and antioxidant effects in septic mice that consequently protected the integrity of the BBB and improved the clinical outcome of sepsis. Our findings suggest that GYY4137 might be a promising agent for the treatment of SAE.

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Section: Discussionsupporting

confidence: 52%

GYY4137 protected the integrity of the blood‐brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis

Cui

Chen

et al. 2021

The FASEB Journal

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“…Genetic or pharmacological suppression of Nrf2 expression could increase sorafenib’s anticancer activity in both vitro and tumor xenograft models [ 7 ]. While in other stress-induced diseases, ferroptosis inhibition resulting from Nrf2 activation helps protect against oxidative stress and maintain tissue homeostasis [ 27 , 30 , 31 ]. Consequently, targeting Nrf2-regulated ferroptosis as a therapeutic strategy should take specific pathological contexts into account.…”

Section: Several Canonical Ferroptosis Modulatorsmentioning

confidence: 99%

Ferroptosis in liver disease: new insights into disease mechanisms

et al. 2021

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Characterized by excessive iron accumulation and lipid peroxidation, ferroptosis is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other well-known cell death. In recent years, ferroptosis has been quickly gaining attention in the field of liver diseases, as the liver is predisposed to oxidative injury and generally, excessive iron accumulation is a primary characteristic of most major liver diseases. In the current review, we first delineate three cellular defense mechanisms against ferroptosis (GPx4 in the mitochondria and cytosol, FSP1 on plasma membrane, and DHODH in mitochondria), along with four canonical modulators of ferroptosis (system Xc−, nuclear factor erythroid 2-related factor 2, p53, and GTP cyclohydrolase-1). Next, we review recent progress of ferroptosis studies delineating molecular mechanisms underlying the pathophysiology of several common liver diseases including ischemia/reperfusion-related injury (IRI), nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), hemochromatosis (HH), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). Furthermore, we also highlight both challenges and promises that emerged from recent studies that should be addressed and pursued in future investigations before ferroptosis regulation could be adopted as an effective therapeutic target in clinical practice.

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“…Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) is a vital regulator in intracellular oxidation homeostasis as well as lipid peroxidation. Activation of Nrf2 inhibits ferroptosis against ALI, such as intestinal ischemia/reperfusion‐induced ALI, seawater drowning‐induced ALI, and LPS‐induced ALI 43–45 . ATF3 represses Nrf2‐mediated signaling by directly binding to Nrf2 protein, and meanwhile, ATF3 promoter contains the consensus antioxidant response element (ARE), the binding site for Nrf2 46,47 .…”

Section: Discussionmentioning

confidence: 99%

“…Activation of Nrf2 inhibits ferroptosis against ALI, such as intestinal ischemia/reperfusion-induced ALI, seawater drowninginduced ALI, and LPS-induced ALI. [43][44][45] ATF3 represses Nrf2-mediated signaling by directly binding to Nrf2 protein, and meanwhile, ATF3 promoter contains the consensus antioxidant response element (ARE), the binding site for Nrf2. 46,47 Further study may focus on the crosstalk between ATF3 and Nrf2 to explore a new mechanism for the pro-ferroptotic effect of ATF3.…”

Section: Discussionmentioning

confidence: 99%

Nickel oxide nanoparticles induce apoptosis and ferroptosis in airway epithelial cells via ATF3

Liu

Cheng

et al. 2022

Environmental Toxicology

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Exposure to nickel oxide nanoparticles (NiONPs), which have been widely produced and applied in industry, leads to adverse pulmonary and systemic effects. The aim of this study is to investigate the involvement of apoptosis and ferroptosis in NiONPsinduced acute lung injury (ALI). Intratracheal instillation of NiONPs into mice elevated the levels of pro-inflammatory cytokines, neutrophils, and proteins in the bronchoalveolar lavage fluid, and triggered apoptosis and ferroptosis in the lung tissues. Consistently, NiONPs-induced apoptosis and ferroptosis were observed in in vitro experiments using human lung epithelial cells. Activating transcription factor 3 (ATF3), a stress-inducible transcription factor, was upregulated by NiONPs exposure in both murine lung tissues and human lung epithelial cells. Moreover, human lung epithelial cells with ATF3 deficiency exhibited a lower level of apoptosis and ferroptosis when exposed to NiONPs. Collectively, our findings demonstrated that ATF3 was responsive to NiONPs exposure, and promoted NiONPs-induced apoptosis and ferroptosis in lung epithelial cells, indicating that ATF3 is a potential biomarker and therapeutic target for NiONPs-associated ALI.

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Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

Cited by 9 publications

References 39 publications

GYY4137 protected the integrity of the blood‐brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis

GYY4137 protected the integrity of the blood‐brain barrier via activation of the Nrf2/ARE pathway in mice with sepsis

Ferroptosis in liver disease: new insights into disease mechanisms

Nickel oxide nanoparticles induce apoptosis and ferroptosis in airway epithelial cells via ATF3

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