Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2017; 23(25): 4508-4516
Published online Jul 7, 2017. doi: 10.3748/wjg.v23.i25.4508
Treatment with dimethyl fumarate ameliorates liver ischemia/reperfusion injury
Chie Takasu, Nosratola D Vaziri, Shiri Li, Lourdes Robles, Kelly Vo, Mizuki Takasu, Christine Pham, Seyed H Farzaneh, Mitsuo Shimada, Michael J Stamos, Hirohito Ichii
Chie Takasu, Nosratola D Vaziri, Shiri Li, Lourdes Robles, Kelly Vo, Mizuki Takasu, Christine Pham, Seyed H Farzaneh, Michael J Stamos, Hirohito Ichii, Department of Surgery, Medicine, University of California, Irvine, CA 92868, United States
Chie Takasu, Mitsuo Shimada, Departments of Surgery, Institute of Health Biosciences, the University of Tokushima, Tokushima, Tokushima 770-8503, Japan
Author contributions: Takasu C, Li S, Robles L and Ichii H designed the research; Takasu C, Li S, Robles L, Vo K, Takasu M and Pham C performed the research; Li S, Takasu C and Farzaneh SH analyzed the data; Vaziri ND, Takasu C, Shimada M, Stamos MJ and Ichii H wrote the paper.
Institutional review board statement: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the University of California, Irvine, within which the work was undertaken and that it conforms to the provisions of the Declaration of Helsinki.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of University of California, Irvine.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at hichii@uci.edu.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Hirohito Ichii, MD, PhD, Department of Surgery, Medicine, University of California, Irvine, 333 City Boulevard West Suite 1205, Orange, CA 92868, United States. hichii@uci.edu
Telephone: +1-714-4568698 Fax: +1-714-4568796
Received: January 24, 2017
Peer-review started: February 1, 2017
First decision: March 3, 2017
Revised: May 18, 2017
Accepted: June 12, 2017
Article in press: June 12, 2017
Published online: July 7, 2017
Processing time: 164 Days and 2.5 Hours
Abstract
AIM

To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI).

METHODS

Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined.

RESULTS

Histological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group.

CONCLUSION

DMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.

Keywords: Inflammation; Reactive oxidative stress; Nrf2; Ischemia; Dimethyl fumarate; Liver

Core tip: In this study, we reveal that (1) administration of dimethyl fumarate (DMF) significantly reduced tissue damage, improved liver function; and (2) DMF attenuated oxidative stress and inflammation, and raised anti-oxidant status in rats with hepatic ischemia/reperfusion injury (I/RI). These findings suggest that DMF treatment could be a promising strategy to improve clinical outcome in patients with liver I/RI.