Melatonin mediated inhibition of EZH2-NOS2 crosstalk attenuates inflammatory bowel disease in preclinical in vitro and in vivo models

• Published in: Life sciences (1973) 2022-08, Vol.302, p.120655, Article 120655
• Main Authors: Sardoiwala, Mohammed Nadim, Mohanbhai, Soni Jignesh, Kushwaha, Avinash Chandra, Dev, Atul, Biswal, Liku, Sharma, Shyam Sunder, Choudhury, Subhasree Roy, Karmakar, Surajit
• Format: Article
• Language: English
• Subjects: Body weight loss; Colitis; Complications; Crosstalk; Dextran; Dextran sodium sulphate; Dextrans; Diarrhea; Epigenetic; Epigenetics; EZH2; Immunofluorescence; In vivo methods and tests; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory response; Intestine; Lipopolysaccharides; Macrophages; Melatonin; Molecular modelling; Pain; Signs and symptoms; Sodium sulfate; Sulfates; Therapeutic targets; Ulcerative colitis; Weight loss; Western blotting
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.120655

Inflammatory Bowel Disease is characterised by abdominal pain, diarrhoea, rectal bleeding and weight loss. Sometimes it may leads to severe health complications resulting in death of an individual. Current research efforts to highlight the role of melatonin in regulating EZH2, a master epigenetic regulator and its beneficiary effect in case of IBD management. Murine macrophages (RAW 264.7) were treated with lipopolysaccharides (LPS) to activate them for generating inflammatory response to investigate efficacy of melatonin in-vitro models. Similarly, for developing in vivo models, Dextran sodium sulphate (36–50 kDa) was used. Evaluations of anti-inflammatory activities were carried out by nitrite assay, western blotting, q-PCR, immunofluorescence, and histological studies. Reduction of epigenetic target, EZH2 by melatonin significantly improves the clinical symptoms of dextran sodium sulphate induced colitis and may be implicated as a potential therapeutic target in IBD management. The present study evaluates the efficacy of melatonin by epigenetic regulation in IBD models. Down regulation of EZH2 by melatonin reduced the chemical induced inflammatory insults in in vitro and in vivo models. Exploration of molecular pathways has revealed interlink of EZH2 and NOS2, a hallmark of inflammation. Molecular mechanistic action of melatonin is attributed to inhibition of the expression and physical interaction of EZH2 and NOS2. Our study highlights melatonin therapeutic effect via attenuating interaction between EZH2 and NOS2 which is beneficial in managing IBD treatment. [Display omitted]