Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

Liu, Zhengru; Qi, Mingming; Tian, Shan; Yang, Qian; Liu, Jian; Wang, Siwei; Ji, Mengyao; Yu, Rong; Zeng, Suqi; Li, Jinting; Ye, Wei; Dong, Weiguo

doi:10.3389/fcell.2021.806850

Cited by 5 publications

(8 citation statements)

References 33 publications

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“…1D). Another study has shown that USP25 is prominently expressed in AP (15), but the underlying role of USP25 in pyroptosis of acinar cells in AP remains unclear. The expression levels of USP25 in AP cell models were examined, and it was found that the treatment of LPS and CRE notably upregulated USP25 expression levels ( P < 0.01, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, USP25 knockdown blocks the activation of NF-κB and the production of proinflammatory cytokines in cells infected with RNA virus (45), and the activation of NF-κB is known to maintain inflammation and acinar injury in AP (46). USP25 propels the progression of AP in CRE-treated mice via activating the STAT3 pathway, and Stat3 binding to the NLRP3 promoter exacerbates NLRP3/ caspase-1-mediated pyroptosis of neurons in mice with epilepsy (15,47). Altogether, the above evidence indicated the alleviative role of silencing USP25 in pyroptosis of acinar cells treated with LPS and CRE.…”

Section: Discussionmentioning

confidence: 99%

“…Ubiquitin-specific peptidase 25 ( USP25 ), belonging to the USP subgroup of the DUBs family, is reported to be associated with the transcription of inflammatory genes (14). Besides, a recent study has shown that USP25 exacerbates AP and AP-related organ injury by promoting the release of proinflammatory factors (15). At present, limited effort has been made to reveal the functions of USP25 on pyroptosis of acinar cells in AP.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Liu

Zhang

2022

Shock

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“…STAT pathway up-regulation inflammation (32,33) resulting in persistent and intensified inflammation (26). TLR9 is expressed in resident immune cells of the pancreas, which are predominantly represented by macrophages, and it is an important DAMP receptors upstream of inflammasome activation, and caspase-1, and NLRP3 inflammasome are required for the development of inflammation in AP (20,27).…”

Section: The Mechanism Of Acute Pancreatitismentioning

confidence: 99%

The Mechanism of Lung and Intestinal Injury in Acute Pancreatitis: A Review

Liu¹,

Wen²,

Wang³

et al. 2022

Front. Med.

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Acute pancreatitis (AP), as a common cause of clinical acute abdomen, often leads to multi-organ damage. In the process of severe AP, the lungs and intestines are the most easily affected organs aside the pancreas. These organ damages occur in succession. Notably, lung and intestinal injuries are closely linked. Damage to ML, which transports immune cells, intestinal fluid, chyle, and toxic components (including toxins, trypsin, and activated cytokines to the systemic circulation in AP) may be connected to AP. This process can lead to the pathological changes of hyperosmotic edema of the lung, an increase in alveolar fluid level, destruction of the intestinal mucosal structure, and impairment of intestinal mucosal permeability. The underlying mechanisms of the correlation between lung and intestinal injuries are inflammatory response, oxidative stress, and endocrine hormone secretion disorders. The main signaling pathways of lung and intestinal injuries are TNF-α, HMGB1-mediated inflammation amplification effect of NF-κB signal pathway, Nrf2/ARE oxidative stress response signaling pathway, and IL-6-mediated JAK2/STAT3 signaling pathway. These pathways exert anti-inflammatory response and anti-oxidative stress, inhibit cell proliferation, and promote apoptosis. The interaction is consistent with the traditional Chinese medicine theory of the lung being connected with the large intestine (fei yu da chang xiang biao li in Chinese). This review sought to explore intersecting mechanisms of lung and intestinal injuries in AP to develop new treatment strategies.

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“…4 The death of intestinal epithelial cells (IECs) and the disruption of TJs are important causes of intestinal barrier dysfunction. 5 TJs are complex, highly dynamic structures composed of a variety of transmembrane proteins, often located between two adjacent cells at the apical tip of the epithelium, thus sealing the intercellular space, limiting the penetration of toxic molecules within the cavity while allowing the absorption of nutrients and moisture. 6 Once the TJ is damaged, this protective mechanism is disrupted, allowing toxins and bacteria from the gut to transfer to the abdominal cavity or other body organs, resulting in a series of symptoms such as bloody diarrhea, bacterial migration, and even sepsis, which can have serious consequences.…”

mentioning

confidence: 99%

Inhibition of angiotensin II type 1 receptor reduces oxidative stress damage to the intestinal barrier in severe acute pancreatitis

Gao

Jiang

Wang

et al. 2023

The Kaohsiung J of Med Scie

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Intestinal barrier injury is a common complication of severe acute pancreatitis (SAP), which is often accompanied by intestinal mucosal barrier injury and results in serious consequences. However, the exact mechanism remains unclear. We aimed to investigate whether angiotensin II type 1 receptor (AT1)‐mediated oxidative stress is involved in SAP intestinal barrier injury and assessed the effects of inhibiting this pathway. The SAP model was established by retrograde bile duct injection of sodium taurocholate (5%). The rats were divided into three groups: the control group (SO), the SAP group (SAP), and the azilsartan intervention group (SAP + AZL). Serum amylase, lipase, and other indexes were measured to evaluate SAP severity in each group. Histopathological changes in the pancreas and intestine were evaluated by HE staining. The oxidative stress of intestinal epithelial cells was detected by superoxide dismutase and glutathione. We also detected the expression and distribution of intestinal barrier‐related proteins. The results showed that the serum indexes, the severity of tissue damage, and the level of oxidative stress in the SAP + AZL group were significantly lower than in the SAP group. Our study provided hitherto undocumented evidence of AT1 expression in the intestinal mucosa, confirming that AT1‐mediated oxidative stress is involved in SAP intestinal mucosal injury, and inhibiting this pathway could effectively reduce intestinal mucosal oxidative stress injury, providing a new and effective target for the treatment of SAP intestinal barrier injury.

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Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

Cited by 5 publications

References 33 publications

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

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

The Mechanism of Lung and Intestinal Injury in Acute Pancreatitis: A Review

Inhibition of angiotensin II type 1 receptor reduces oxidative stress damage to the intestinal barrier in severe acute pancreatitis

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