Short-Chain Naphthoquinone Protects Against Both Acute and Spontaneous Chronic Murine Colitis by Alleviating Inflammatory Responses

Sonia Shastri; Tanvi Shinde; Krystel L Woolley; Jason A Smith; Nuri Gueven; Rajaraman Eri

doi:10.3389/fphar.2021.709973

Short-Chain Naphthoquinone Protects Against Both Acute and Spontaneous Chronic Murine Colitis by Alleviating Inflammatory Responses

Front Pharmacol. 2021 Aug 23:12:709973. doi: 10.3389/fphar.2021.709973. eCollection 2021.

Authors

Sonia Shastri¹, Tanvi Shinde^{1

2}, Krystel L Woolley³, Jason A Smith³, Nuri Gueven⁴, Rajaraman Eri¹

Affiliations

¹ Gut Health Laboratory, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, TAS, Australia.
² Centre for Food Innovation, Tasmanian Institute of Agriculture, University of Tasmania, Launceston, TAS, Australia.
³ School of Natural Sciences-Chemistry, College of Science and Engineering, University of Tasmania, Hobart, TAS, Australia.
⁴ School of Pharmacy and Pharmacology, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia.

Abstract

Ulcerative colitis (UC) is characterised by chronic, relapsing, idiopathic, and multifactorial colon inflammation. Recent evidence suggests that mitochondrial dysfunction plays a critical role in the onset and recurrence of this disease. Previous reports highlighted the potential of short-chain quinones (SCQs) for the treatment of mitochondrial dysfunction due to their reversible redox characteristics. We hypothesised that a recently described potent mitoprotective SCQ (UTA77) could ameliorate UC symptoms and pathology. In a dextran sodium sulphate- (DSS-) induced acute colitis model in C57BL/6J mice, UTA77 substantially improved DSS-induced body weight loss, disease activity index (DAI), colon length, and histopathology. UTA77 administration also significantly increased the expression of tight junction (TJ) proteins occludin and zona-occludin 1 (ZO-1), which preserved intestinal barrier integrity. Similar responses were observed in the spontaneous Winnie model of chronic colitis, where UTA77 significantly improved DAI, colon length, and histopathology. Furthermore, UTA77 potently suppressed elevated levels of proinflammatory cytokines and chemokines in colonic explants of both DSS-treated and Winnie mice. These results strongly suggest that UTA77 or its derivatives could be a promising novel therapeutic approach for the treatment of human UC.

Keywords: cytokines; endoplasmic reticulum stress; inflammatory bowel disease; naphthoquinones; tight junction proteins.