Role of p-MKK7 in myricetin-induced protection against intestinal ischemia/reperfusion injury.

Abstract

Intestinal ischemia reperfusion (I/R) may cause inflammation-, oxidative stress-, and apoptosis-related tissue injuries and facilitate bacterial infection, leading to multiple organ failure. Myricetin, a flavonoid, is found to have diverse biological effects including anti-inflammatory, anti-oxidative, and anti-bacterial effects. Based on our pre-experiment, we proposed that myricetin pretreatment (25, 50mg/kg) could ameliorate intestinal I/R injury and myricetin-induced modulation on MKK7/JNK signal pathway might play a key role in the amelioration. The present study was designed to verify the proposal by using both rat intestinal I/R model in vivo and hypoxia/reoxygenation (H/R)-injured intestinal epithelial cell line (IEC-6 cells) model in vitro. The results confirmed our proposal. Myricetin selectively ameliorated I/R- and H/R-induced injuries in vivo and in vitro respectively without significantly affecting the corresponding normal controls. Myricetin significantly alleviated I/R-induced rat intestinal injury by reducing the generation of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 and by reducing MPO activity. Myricetin significantly reduced oxidative stress through decreasing MDA level and increasing the levels of SOD and GSH in the intestinal tissues compared with I/R control rats. Myricetin significantly decreased apoptosis by selectively down-regulating the expression of p-MKK7 and p-JNK without affecting MKK7 and JNK, inhibiting Bax, caspase-3 protein expression, and up-regulating Bcl-2 protein expression in I/R-injured jejunum of rats. In vitro study indicated that MKK7 siRNA transfection significantly decreased both MKK7 and p-MKK7 and other apoptosis-related proteins, partially simulating myricetin-induced anti-apoptotic effects. MKK7 siRNA transfection+myricetin could not further decrease MKK7, p-MKK7, and other apoptosis-related proteins, suggesting that inhibition of MKK7/JNK pathway plays a key role in myricetin-induced protection against intestinal I/R. MKK7 overexpression by cDNA transfection abrogated myricetin-reduced apoptosis-related protein expression, confirming that the MKK7/JNK signal pathway is the key target for myricetin-induced amelioration. The present study indicated that pretreatment of myricetin induced selective protection against intestinal I/R injury without significantly affecting corresponding normal controls and p-MKK7 was the key target, suggesting that myricetin is worth further translational studies.

• Authors: Yuchao Sun, Mengqiao Lian, Yuan Lin, Bin Xu, Yanli Li, Jin Wen, Dapeng Chen, Ming Xu, Marwan Almoiliqy, Li Wang
• Journal: Pharmacological research (Pharmacol Res) Vol. 129 Pg. 432-442 (03 2018) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 29154988 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017. Published by Elsevier Ltd.

Chemical References

• Flavonoids
• Protective Agents
• RNA, Small Interfering
• myricetin
• MAP Kinase Kinase 7

Topics

• Animals
• Cell Line
• Flavonoids (pharmacology, therapeutic use)
• Intestine, Small (pathology)
• MAP Kinase Kinase 7 (genetics, metabolism)
• Male
• Protective Agents (pharmacology, therapeutic use)
• RNA, Small Interfering (genetics)
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, metabolism)