Elsevier

International Immunopharmacology

Volume 31, February 2016, Pages 223-232
International Immunopharmacology

Isoliquiritigenin ameliorates dextran sulfate sodium-induced colitis through the inhibition of MAPK pathway

https://doi.org/10.1016/j.intimp.2015.12.024Get rights and content

Highlights

  • Isoliquiritigenin attenuated the dextran sulfate sodium (DSS)-induced colitis.

  • Isoliquiritigenin suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-κB.

  • Isoliquiritigenin ameliorated the DSS-induced colitis through the inhibition of MAPK pathway.

Abstract

Isoliquiritigenin (isoLQ), a chalcone found in licorice, has shown a variety of biological activity including anti-inflammatory and antioxidative effects, and the distribution of isoLQ in gastrointestinal tract was higher than any other tissues. Thus, we evaluated whether or not isoLQ attenuated the dextran sulfate sodium (DSS)-induced colitis by observing the physiological changes (body weight loss, diarrhea, bleeding stool, overall disease activity index (DAI) scores, colon length), histopathological analysis and myeloperoxidase (MPO) activities of esophagus and colon. Also, the MAPK pathways including phosphorylation of ERK1/2, p38, and AKT, and the activation of NK-κB were evaluated in colon tissue. Interestingly, the reduction of body weight and colon length, increase of diarrhea, bloody stool, DAI scores and MPO activity, and histologic disturbances in DSS-induced colitis were recovered by isoLQ treatment. Also, isoLQ treatment suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-κB compared to those in DSS-induced colitis mice. In addition, the distributions of isoLQ in colon were relatively higher in DSS-induced colitis models. All of these results suggested that isoLQ has potential activity to ameliorate the DSS-induced colitis through the inhibition of MAPK pathway.

Introduction

Inflammatory bowel diseases (IBD), represented mainly by ulcerative colitis (UC) and Crohn's disease (CD), are relapsing gastrointestinal diseases characterized by intestinal inflammation [1]. Both of UC and CD are associated with intestinal and extra-intestinal symptoms including body weight reduction, diarrhea with bloody stool, fever, gastric dysmotility and shortening of the colon [2], [3]. Although the etiology of this disease is not known, it is widely believed that IBD results from tissue damages such as abnormal mucosal immune reactions followed by an inflammatory cascade [4], [5]. One of recent approaches to target molecular pathways that mediate IBD, such as mitogen-activated protein kinases (MAPKs) and/or NK-κB, is emerging [6]. It has been documented that MAPKs have been implicated in the pathogenesis of IBD and the elevated activation of MAPKs has been observed in IBD patients [7], [8], [9]. Also, the involvement of NF-κB in IBD, a pivotal inflammatory regulator, is well known [10], [11]. Although glucocorticosteroids and 5-aminosalicylic acid (5-ASA) are available as therapeutic agents for IBD, also known to regulate MAPK signaling [12], [13], [14], the adverse effects of these drugs limited their wide use for IBD treatment [15], [16], [17].

Thus, in order to discover potential therapeutic agents for IBD treatment, isoliquiritigenin found in licorice (Fig. 1) was selected for evaluation in the acute dextran sodium sulfate (DSS)-induced colitis mice model, based on the literatures regarding its preferential tissue distribution to gastrointestinal tract [4], [18] and its activities relevant to IBD treatment [19], [20], [21], [22]. Therefore, the efficacy of isoLQ in DSS-induced colitis model was determined in the present study. In addition, the expression of NF-κB and the activation of MAPKs in the colon tissue were measured along with the colon tissue distribution of isoLQ.

Section snippets

Chemicals

IsoLQ (Fig. 1) was synthesized and purified in College of Pharmacy, Dongguk University (Goyang, South Korea) according to the previously reported method [23]. Purity was determined to be > 98.0% based on analyses using HPLC with UV absorbance detection and ultroperformance liquid chromatographic tandem mass spectrometry (UPLC-MS/MS). Especially, the purity of isoLQ, especially to prove the non-contamination of synthetic isoLQ with liquiritigenin (LQ), an isoform of isoLQ, was determined by NMR

Effects of isoLQ on DAI scores including body weight loss and diarrhea, bleeding in stool

A combinatorial DAI, which incorporated body weight loss, diarrhea and bleeding in stool, was used to assess the therapeutic effects of isoLQ in DSS-induced colitis model (Fig. 3). DSS administration was associated with significant clinical changes such as weight loss and the appearance of pasty to liquid bloody stool, which is reflected by a gradual increase in the DAI scores that reached a maximum of 5.14 ± 1.21 at day 10. The difference in body weight loss and the scores of diarrhea and

Discussion

In the present study, DSS-induced colitis models (DSS group) displayed abnormally physiological conditions like body weight loss, diarrhea, bloody stools, and shortened colon. To investigate the underlying pathway of isoLQ to ameliorate DSS-induced colitis in mice, 30 mg/kg of isoLQ is chosen based on our preliminary study (Fig. 2). In DSSA and DSSI groups, these physiological conditions of DSS group were well improved (Fig. 3, Fig. 4). Furthermore, this improvement was also supported by the

Conflict of interest

No conflict of interest.

Acknowledgments

This work was supported by the GRRC program of Gyeonggi province (GRRC-DONGGUK2015-B01), the Agricultural Biotechnology Development Program (No. 114071-3), Ministry of Agriculture, Food and Rural Affairs, and a grant from the Korean Health Technology R&D Project through the Korean Health Industry Development Institute (KHIDI) (grant number: HI14C0556), funded by the Ministry of Health & Welfare, Republic of Korea.

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