Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis

Fan, Rong; Sui, Jidong; Dong, Xuepeng; Jing, Biao; Gao, Zhenming

doi:10.1016/j.freeradbiomed.2021.07.009

Cited by 77 publications

(48 citation statements)

References 45 publications

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“…Several forms of acinar cell death occur during SAP, namely, apoptosis, necrosis, pyroptosis, and ferroptosis ( Kang et al, 2014 ; Fan et al, 2021 ). Apoptosis is mainly responsible for cell death in mild acute pancreatitis while necrosis accounts for most of the cell death in SAP ( Bhatia, 2004a ).…”

Section: Discussionmentioning

confidence: 99%

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis

Sun

Zhang

et al. 2022

Front. Cell Dev. Biol.

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Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored.Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 μg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein–induced inflammation and necroptotic cell death.Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein–treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist.Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.

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Section: Discussionmentioning

confidence: 99%

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis

Sun

Zhang

et al. 2022

Front. Cell Dev. Biol.

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“…Previous studies reported that GSDMD is increased in AP, resulting in the release of proinflammatory cytokines (IL-1β) and then amplifies the local or systemic inflammatory effects [3,4]. Blocking the cascaded amplification of the inflammation improves the outcomes of AP [3,4].…”

Section: Discussionmentioning

confidence: 99%

“…The necrosis of acinar cells, the functional unit of the exocrine pancreas, is an important event in AP [1]. Although both ERS and GSDMD up-regulate the release of inflammatory cytokines from acinar cells in AP mice [3][4][5], their effects on the pathogenesis of AP remain unclear. Firstly, this study performed immunofluorescence staining on GSDMD and ER marker protein CALNEXIN [30] to explore the relationship between GSDMD and ER.…”

Section: Gsdmd In Endoplasmic Reticulum Of Acinar Cells Is Up-regulat...mentioning

confidence: 99%

“…Currently, there are no specific treatments for AP. Cleaved Gasdermin D (GSDMD) punches holes in mice acinar cell membrane, resulting in cell death and inflammatory factor release in AP [3,4]. Endoplasmic reticulum stress (ERS) is a key initiating factor in the development of AP [5], which also causes the release of cell contents and inflammatory cascade.…”

Section: Introductionmentioning

confidence: 99%

“…Acute lung injury is a common serious complication of AP, which leads to hypoxemia in experimental AP [4,15]. Hypoxia-inducible factor-1α (HIF-1α) ) is a transcription factor that is over-expressed in the presence of hypoxia [15].…”

Section: Introductionmentioning

confidence: 99%

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Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

et al. 2022

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Acute pancreatitis (AP) is one of the most common causes of hospitalization for gastrointestinal diseases, with high morbidity and mortality. Endoplasmic reticulum stress (ERS) and Gasdermin D (GSDMD) mediate AP, but little is known about their mutual influence on AP. Diosgenin has excellent anti-inflammatory and antioxidant effects. This study investigated whether Diosgenin derivative D (Drug D) inhibits L-arginine-induced acute pancreatitis through meditating GSDMD in the endoplasmic reticulum (ER). Our studies were conducted in a mouse model of L-arginine-induced AP as well as in an in vitro model on mouse pancreatic acinar cells. The GSDMD accumulation in ER was found in this study, which caused ERS of acinar cells. GSDMD inhibitor Disulfiram (DSF) notably decreased the expression of GSDMD in ER and TXNIP/HIF-1α signaling. The molecular docking study indicated that there was a potential interaction between Drug D and GSDMD. Our results showed that Drug D significantly inhibited necrosis of acinar cells dose-dependently, and we also found that Drug D alleviated pancreatic necrosis and systemic inflammation by inhibiting the GSDMD accumulation in the ER of acinar cells via the TXNIP/HIF-1α pathway. Furthermore, the level of p-IRE1α (a marker of ERS) was also down-regulated by Drug D in a dose-dependent manner in AP. We also found that Drug D alleviated TXNIP up-regulation and oxidative stress in AP. Moreover, our results revealed that GSDMD-/- mitigated AP by inhibiting TXNIP/HIF-1α. Therefore, Drug D, which is extracted from Dioscorea zingiberensis, may inhibit L-arginine-induced AP by meditating GSDMD in the ER by the TXNIP /HIF-1α pathway.

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Function and regulation of GPX4 in the development and progression of fibrotic disease

Zhao-bing

Zhu

Liu

et al. 2022

Journal Cellular Physiology

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Fibrosis is a common feature of fibrotic diseases that poses a serious threat to global health due to high morbidity and mortality in developing countries. There exist some chemical compounds and biomolecules associated with the development of fibrosis, including cytokines, hormones, and enzymes. Among them, glutathione peroxidase 4 (GPX4), as a selenoprotein antioxidant enzyme, is widely found in the embryo, testis, brain, liver, heart, and photoreceptor cells. Moreover, it is shown that GPX4 elicits diverse biological functions by suppressing phospholipid hydroperoxide at the expense of decreased glutathione (GSH), including loss of neurons, autophagy, cell repair, inflammation, ferroptosis, apoptosis, and oxidative stress. Interestingly, these processes are intimately related to the occurrence of fibrotic disease. Recently, GPX4 has been reported to exhibit a decline in fibrotic disease and inhibit fibrosis, suggesting that alterations of GPX4 can change the course or dictate the outcome of fibrotic disease. In this review, we summarize the role and underlying mechanisms of GPX4 in fibrosis diseases such as lung fibrosis, liver fibrosis, kidney fibrosis, cardiac fibrosis, and myelofibrosis.

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Wedelolactone alleviates acute pancreatitis and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis

Cited by 77 publications

References 45 publications

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis

Drug D, a Diosgenin Derive, Inhibits L-Arginine-Induced Acute Pancreatitis through Meditating GSDMD in the Endoplasmic Reticulum via the TXNIP/HIF-1α Pathway

Function and regulation of GPX4 in the development and progression of fibrotic disease

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