INT-777, a bile acid receptor agonist, extenuates pancreatic acinar cells necrosis in a mouse model of acute pancreatitis

Li, Baiqiang; Yang, Na; Li, Chuling; Li, Chuwei; Gao, Kun; Xie, Xing; Dong, Xiaowu; Yang, Jing; Yang, Qi; Tong, Zhihui; Lu, Guotao; Li, Weiqin

doi:10.1016/j.bbrc.2018.05.120

Cited by 25 publications

(14 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, Wang et al [40] showed that TGR5 activated by INT-777 decreases oxidative stress and increases fatty acid β -oxidation in human podocytes treated with HG. Additionally, INT-777 extenuates pancreatic acinar cell necrosis by inhibiting ROS production and the NLRP3 inflammasome pathway [41]. Moreover, lithocholic acid (a natural agonist of TGR5) does not affect HG-induced elevation of ROS production in H9c2 cells [42].…”

Section: Discussionmentioning

confidence: 99%

Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress

Deng

Chen

Zhong

et al. 2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

High glucose- (HG-) induced cardiomyocyte injury is the leading cause of diabetic cardiomyopathy, which is associated with the induction of inflammatory responses and oxidative stress. TGR5 plays an important role in the regulation of glucose metabolism. However, whether TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury is unknown. Neonatal mouse cardiomyocytes were isolated and incubated in a HG medium. Protein and mRNA expression was detected by western blotting and RT-PCR, respectively. Cell apoptosis was determined by Hoechst 33342 staining and flow cytometry. After treatment of cells with HG, TGR5-selective agonist INT-777 reduced the increase in expression of proinflammatory cytokines and NF-κB, whereas pretreatment of cells with TGR5 shRNA significantly reduced the inhibitory effects of INT-777. We also found that INT-777 increased the protein expression of Nrf2 and HO-1. In the presence of TGR5 shRNA, the expression of Nrf2 and HO-1 was reduced, indicating that TGR5 may exert an antioxidant effect partially through the Nrf2/HO-1 pathway. Furthermore, INT-777 treatment inhibited HG-induced ROS production and apoptosis that were attenuated in the presence of TGR5 shRNA or ZnPP (HO-1 inhibitor). Activation of TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury and could be a pharmacological target for the treatment of diabetic cardiomyopathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress

Deng

Chen

Zhong

et al. 2019

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Moreover, in the pancreas, local accumulation of BAs molecules could inhibit autophagy of pancreatic acinar cells through FXR, leading to the increasing of apoptosis and necrotic apoptosis [42]. Our team previously found that the administration of INT-777 could protect AP in mice and improve pancreatic acinar cell necrosis [43]. Based on the above studies, we hypothesize that the imbalance of BAs, which may lead to the disorder in BAs metabolism and inflammatory response, thus affecting the organ function.…”

Section: Discussionmentioning

confidence: 91%

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Xie

Dong

et al. 2020

BMC Gastroenterol

Self Cite

View full text Add to dashboard Cite

Background: Recent studies have shown that bile acids (BAs) are closely related to metabolic and inflammatory diseases. Our study aimed to investigate whether circulating total bile acid (TBA) levels were associated with the severity of acute pancreatitis (AP). Methods: We retrospectively collected data on patients diagnosed with AP in a tertiary center from 01 January 2014 to 31 December 2016. The highest TBA value during the first 1,2,3,5,7 days after admission was determined as D1, D2, D3, D5, D7 TBA max. Patients were divided into the high TBA (HTBA) group and the normal TBA (NTBA) group according to whether the TBA max was ≥10 μmol/L. The prognosis and complications, including death, organ failure (OF) and pancreatic necrosis, were compared between the two groups. Logistic regression analysis and receiving operating characteristic (ROC) curve were used to evaluate the relationship between circulating TBA and organ failure in AP patients. Results: Through stratified analysis of each time period, we found that the incidence of OF in the HTBA group was significantly higher than that in the NTBA group, and the AP severity classification in the HTBA group was more serious than that in the NTBA group. In addition, according to the D7 TBA max values, the pancreatic necrosis rate, percutaneous catheter drainage (PCD) rate and mortality in the HTBA group were higher than those in the NTBA group. Multivariate regression analysis showed that HTBA (odds ratio (OR), 4.894; P = 0.002) was an independent risk factor for AP complicated with OF, which was verified in the grouping based on D7 TBA max. ROC analysis revealed that a circulating D7 TBA max cutoff point of 6.450 umol/L had optimal predictive value for the development of OF in AP patients with an area under the curve of the ROC curve (AUCROC) of 0.777. Conclusions: The increase of circulating TBA in early stage of AP is independently related to organ failure, which indicates the adverse prognosis of AP patients.

show abstract

“…Moreover, in the pancreas, local accumulation of BAs molecules could inhibit autophagy of pancreatic acinar cells through FXR, leading to the increasing of apoptosis and necrotic apoptosis [42]. Our team previously found that the administration of INT-777 could protect AP in mice and improve pancreatic acinar cell necrosis [43]. Based on the above studies, we hypothesize that the imbalance of BAs, may cause organ failure in AP patients with increased circulating TBA levels, which may lead to the disorder in BAs metabolism and inflammatory response, thus affecting the organ function.…”

Section: Discussionmentioning

confidence: 99%

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Xie

Dong

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Recent studies have shown that bile acids (BAs) are closely related to metabolic and inflammatory diseases. Our study aimed to investigate whether circulating total bile acid (TBA) levels were associated with the severity of acute pancreatitis (AP).Methods: We retrospectively collected data on patients diagnosed with AP in a tertiary center from 01 January 2014 to 31 December 2016. Patients were divided into the high TBA (HTBA) group and the normal TBA (NTBA) group according to whether the highest TBA value (TBAmax) within 7 days after admission was ≥10μmol/L. The prognosis and complications, including death, organ failure (OF) and pancreatic necrosis, were compared between the two groups. Univariate and multivariate logistic regression analysis were used to evaluate the relationship between circulating TBA and organ failure in AP patients.Results: 293 patients were included in this study, of whom 18.43% (54/293) were in the HTBA group. The incidence of OF in the HTBA group was significantly higher than that in the NTBA group (59.3% vs 17.2%; P < 0.001), and the AP severity classification in the HTBA group was more serious than that in the NTBA group. The pancreatic necrosis rate, percutaneous catheter drainage (PCD) rate, open surgery rate and mortality rate in the HTBA group were higher than those in the NTBA group. Multivariate regression analysis showed that HTBA (odds ratio (OR), 4.894; P = 0.002) was an independent risk factor for AP complicated with OF. Conclusions: The increase of circulating TBA in early stage of AP is independently related to organ failure, which indicates the adverse prognosis of AP patients.

show abstract

INT-777, a bile acid receptor agonist, extenuates pancreatic acinar cells necrosis in a mouse model of acute pancreatitis

Cited by 25 publications

References 35 publications

Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress

Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis

Contact Info

Product

Resources

About