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ABSTRACT: The objective of the study was to evaluate the effect of ethyl pyruvate (EP) in ameliorating liver injury in rats with severe acute pancreatitis (SAP) and its possible mechanism.
Rats were randomly divided into control group, SAP group, and EP-treated group. Then, the tissue specimens were harvested for morphological studies, immunohistochemistry examination, reverse transcriptase-polymerase chain reaction, and Western blot analysis. The DNA-binding activity of nuclear factor κB was measured by electrophoretic mobility shift assay. The concentrations of serum amylase, alanine aminotransferase, and pancreatic tissue malondialdehyde and the activity of myeloperoxidase in the liver were determined.
Treatment with EP after SAP was associated with a reduction in the severity of SAP and liver injury. Treatment with EP significantly decreased the hepatic mRNA expression of tumor necrosis factor α and interleukin 1β and ameliorated the activity of myeloperoxidase in the liver in SAP rats. Compared with the SAP group, treatment with EP significantly decreased the infiltration of inflammatory cells and markedly inhibited hepatic nuclear factor κB DNA binding; EP therapy dramatically inhibited high-mobility group box 1 expression from inflamed hepatic tissue.
Our results demonstrate that EP might play a therapeutic role in liver inflammation in this SAP model, and these beneficial effects of EP are because of the modulation of high-mobility group box 1 and other inflammatory cytokine responses.
Pancreas 07/2012; 41(5):729-37. · 2.39 Impact Factor
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ABSTRACT: BACKGROUND: Systemic inflammatory mediators have an important role in the development of acute pancreatitis. In this study, we investigated the effect of ethyl pyruvate (EP) on pancreas injury in rats with severe acute pancreatitis (SAP) and its possible mechanism. METHODS: We randomly allocated rats into the following three experimental groups: control and SAP- and EP-treated. Then, we recorded the mortality rate. We harvested tissue specimens for morphological studies, streptavidin-peroxidase immunohistochemistry examination, and Western blot analysis. We tested the levels of pancreatic tissue malondialdehyde and the activity of serum amylase, myeloperoxidase in the pancreas. In addition, we studied nuclear factor-κB (NF-κB) activation, tumor necrosis factor-α levels, and high mobility group box 1 protein expression levels in the pancreas. RESULTS: Treatment with EP after SAP was associated with a reduction in the severity of SAP and pancreas injury. Treatment with EP significantly decreased the expression of tumor necrosis factor-α and high mobility group box 1, and ameliorated malondialdehyde concentration and myeloperoxidase activity in the pancreas in SAP rats. Compared with the SAP group, treatment with EP significantly decreased the number of inflammatory cell infiltration, markedly inhibited pancreatic NF-κB DNA binding, and increased the survival rates. CONCLUSIONS: This study demonstrates that preventing the activation of NF-κB by EP ameliorates tissue injury associated with experimental murine acute pancreatitis. This result provides an important insight into the molecular biology of acute pancreatitis.
Journal of Surgical Research 06/2012; · 2.25 Impact Factor
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ABSTRACT: High mobility group box chromosomal protein 1 (HMGB1) is a lately discovered candidate molecule identified as an important extracellular mediator in systemic inflammation. Systemic inflammation results in endothelial cell activation and microvascular injury. In the present study, we investigated the effects of HMGB1 on the activation of human umbilical vein endothelial cells (HUVECs) and defined pathways activated by HMGB1.
HUVECs obtained by collagenase treatment of umbilical cord veins were stimulated in vitro with HMGB1. The activation of HUVECs was studied regarding (i) the kinetics of tumor necrosis factor-α (TNF-α) production in HUVECs, (ii) HMGB1-induced up-regulation of receptor for advanced glycation end products (RAGE), (iii) HMGB1-induced nuclear translocation of nuclear factor kappa B (NF-κB) in HUVECs, (iv) the activation of signalling transduction pathways.
HUVECs activation was stimulated by HMGB1 partially in a RAGE-dependent manner. Additionally, the HMGB1-induced activation of HUVECs was significantly inhibited by anti-RAGE monoclonal antibody and Ethyl pyruvate (EP) that had been shown to be an effective anti-inflammatory agent. Short-term prestimulation of HUVECs with HMGB1 caused a time-dependent increase in the secretion of TNF-α and expression of RAGE. Furthermore, HMGB1 stimulation resulted in nuclear translocation of transcription factor NF-κB. Most importantly, pretreatment with anti-RAGE monoclonal antibody significantly decreased the amounts of TNF-α and inhibited the nuclear translocation of NF-κB. Additionally in HUVECs cultures, EP specifically inhibited activation of NF-κB signaling pathway that are critical for TNF-α release.
In conclusion, Our data present a link between HMGB1and RAGE function of endothelial cells and demonstrate the pathway activated by HMGB1. These findings may provide a novel therapeutic strategy to improve the endothelial cells function.
Immunobiology 02/2010; 215(12):956-62. · 3.20 Impact Factor
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ABSTRACT: To investigate the role of high-mobility group box 1 (HMGB1) in the development of intestinal barrier injury of severe acute pancreatitis (SAP) and to examine the effect of ethyl pyruvate (EP) on intestinal inflammation in rats with SAP.
Rats were randomly divided into the following experimental groups: control, SAP, and EP treated. Then, the distal ileum was harvested for morphological studies, streptavidin-peroxidase immunohistochemistry examination, and Western blot analysis. The concentrations of plasma amylase, endotoxin, and diamine oxidase (DAO) and the activity of myeloperoxidase (MPO) in the intestine were determined.
We found that the expression of HMGB1 was up-regulated in the ileal mucosa within 6 hours and then remained elevated for more than 48 hours after SAP. Meanwhile, the levels of plasma amylase, endotoxin, and DAO and the activity of MPO in the intestinal mucosa were rapidly increased after SAP. Whereas treatment with EP significantly decreased the expression of intestinal HMGB1, the levels of plasma amylase, endotoxin, and DAO ameliorated the activity of MPO in the intestine in SAP rats.
Our results demonstrate that HMGB1 participates in intestinal barrier injury in SAP and EP might play a therapeutic role in intestinal inflammation in this SAP model.
Pancreas 09/2009; 39(2):216-23. · 2.39 Impact Factor
