Overexpression of Nrf2 Protects Against Lipopolysaccharide and Cerulein-Induced Pancreatitis In Vitro and In Vivo

Fu, Xu; Li, Peiwu; Yin, Wen; Ma, Li; Zhang, Bei; Zhen, Lingling; Meng, Yanfei; Han, Li; Wang, Yingzhen

doi:10.1097/mpa.0000000000001501

Cited by 10 publications

(5 citation statements)

References 21 publications

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“…Cerulein + lipopolysaccharide (LPS) are often used to induced acute pancreatitis in rodents and in cultured pancreatic acinar cells (Fu et al, 2020;Xiao et al, 2020). Our previous study found that treatment of AR42J cells with cerulein + LPS induced an obvious stress response in the ER (Ren et al, 2019a).…”

Section: Mfg-e8 Alleviates Er Stress In Pancreatic Exocrine Acinar Cellsmentioning

confidence: 99%

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Ren

Liu

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Excessive endoplasmic reticulum (ER) stress contributes significantly to the pathogenesis of exocrine acinar damage in acute pancreatitis. Our previous study found that milk fat globule EGF factor 8 (MFG-E8), a lipophilic glycoprotein, alleviates acinar cell damage during AP via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining cellular homeostasis. However, MFG-E8’s role in ER stress in pancreatic exocrine acinar cells has not been evaluated. To study this, thapsigargin, brefeldin A, tunicamycin and cerulein + LPS were used to induce ER stress in rat pancreatic acinar cells in vitro. L-arginine- and cerulein + LPS-induced acute pancreatitis in mice were used to study ER stress in vivo. The results showed that MFG-E8 dose-dependently inhibited ER stress under both in vitro and in vivo conditions. MFG-E8 knockout mice suffered more severe ER stress and greater inflammatory response after L-arginine administration. Mechanistically, MFG-E8 increased phosphorylation of FAK and STAT3 in cerulein + LPS-treated pancreatic acinar cells. The presence of specific inhibitors of αvβ3/5 integrin, FAK or STAT3 abolished MFG-E8’s effect on cerulein + LPS-induced ER stress in pancreatic acinar cells. In conclusion, MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells.

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Section: Mfg-e8 Alleviates Er Stress In Pancreatic Exocrine Acinar Cellsmentioning

confidence: 99%

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Ren

Liu

Zhang

et al. 2022

Front. Cell Dev. Biol.

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“…AP being an oxidative stress condition, the Nrf2/Keap1 signaling pathway is activated in the pancreas, but this not sufficient to prevent the disease [ 12 ]. Several studies have shown that the hyper-stimulation of Nrf2 via plant-derived natural compounds such as visnagin or hydroxytyrosol could be a promising strategy against the excessive oxidative stress that characterizes AP [ 41 , 84 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

“…[ 10 ]. Recent findings indicate that the nuclear factor E2-related factor 2 (Nrf2) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain-containing 3 (NLRP3) inflammasome pathways are strongly activated during the development of AP [ 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Cashew (Anacardium occidentale L.) Nuts Modulate the Nrf2 and NLRP3 Pathways in Pancreas and Lung after Induction of Acute Pancreatitis by Cerulein

et al. 2020

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Background: One of the most common co-morbidities, that often leads to death, associated with acute pancreatitis (AP) is represented by acute lung injury (ALI). While many aspects of AP-induced lung inflammation have been investigated, the involvement of specific pathways, such as those centered on nuclear factor E2-related factor 2 (Nrf2) and nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3), has not been fully elucidated. Methods: To investigate the effect of cashew (Anacardium occidentale L.) nuts on pancreatic and lung injury induced by cerulein injection, cerulein (50 μg/kg) was administered to CD1 mice for 10 h. Oral treatment with cashew nuts at a dose of 100 mg/kg was given 30 min and 2 h after the first cerulein injection. One hour after the final cerulein injection, mice were euthanized and blood, lung and pancreatic tissue samples were collected. Results: Cashew nuts were able to (1) reduce histological damage; (2) mitigate the induction of mast cell degranulation as well as the activity of myeloperoxidase and malondialdehyde; (3) decrease the activity levels of amylase and lipase as well as the levels of pro-inflammatory cytokines; and (4) enhance the activation of the Nrf2 pathway and suppress the activation of the NLRP3 pathway in response to cerulein in both pancreas and lung. Conclusions: Cashew nuts could have a beneficial effect not only on pancreatitis but also on lung injury induced by cerulein.

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“…In this work, AP cell models were successfully established by the treatment of LPS and CRE, and we observed that LPS and CRE reduced cell viability and facilitate inflammation and pyroptosis in acinar cells. Preceding studies have confirmed the effectiveness of the combination of LPS and CRE in AP models to induce oxidative stress, inflammation, and pyroptosis (5,41,42), further supporting the increase in pyroptosis in AP cell models.…”

Section: Discussionmentioning

confidence: 81%

Usp25 Upregulation Boosts GSDMD-Mediated Pyroptosis of Acinar Cells in Acute Pancreatitis

Liu

Zhang

2022

Shock

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Acute pancreatitis (AP) is an inflammation-associated disorder in the digestive system. Ubiquitin-specific peptidase 25 (USP25) can modulate inflammation in diseases. This study expounded on the role of USP25 in pyroptosis of acinar cells in AP. Acinar cells were treated with lipopolysaccharide (LPS) and caerulein (CRE) to induce AP. Afterward, the expression patterns of USP25, microRNA (miR)-10a-5p, and Krüppel-like factor 4 (KLF4) in acinar cells were examined. Then, acinar cell viability and levels of NLR family pyrin-domain containing 3 (NLRP3), cleaved caspase-1, cleaved N-terminal gasdermin D (GSDMD-N), interleukin (IL)-1β, and IL-18 were determined. We observed that USP25 was highly expressed in AP models, and silencing USP25 increased cell viability and inhibited pyroptosis of AP acinar cells. The bindings of USP25 to KLF4 and miR-10a-5p to KLF4 and the GSDMD 3′UTR sequence were validated. We found that USP25 binding to KLF4 inhibited ubiquitination degradation of KLF4, KLF4 transcriptionally decreased miR-10a-5p expression, and miR-10a-5p targeted GSDMD expression. Finally, rescue experiments proved that KLF4 overexpression or miR-10a-5p suppression enhanced pyroptosis of AP acinar cells. Overall, USP25 stabilized KLF4 expression through deubiquitination, limited miR-10a-5p expression, and increased GSDMD expression, finally promoting pyroptosis of acinar cells in AP.

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Overexpression of Nrf2 Protects Against Lipopolysaccharide and Cerulein-Induced Pancreatitis In Vitro and In Vivo

Cited by 10 publications

References 21 publications

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Cashew (Anacardium occidentale L.) Nuts Modulate the Nrf2 and NLRP3 Pathways in Pancreas and Lung after Induction of Acute Pancreatitis by Cerulein

Usp25 Upregulation Boosts GSDMD-Mediated Pyroptosis of Acinar Cells in Acute Pancreatitis

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