Touny Aya A, Venkataraman Balaji, Almarzooqi Saeeda, Patil Rajesh B, Bhongade Bhoomendra A, Harjaček Miroslav, Rizvi Tahir A, Ojha Shreesh, Harihar Gowdru Shamanth Neralagundi, Subramanya Sandeep B
Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE.
Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Ahram Canadian University, 6th of October, Giza, Egypt.
Pharmacol Res Perspect. 2025 Aug;13(4):e70132. doi: 10.1002/prp2.70132.
Peroxisome proliferator-activated receptors (PPARs), functioning as nuclear receptors, regulate the expression of genes associated with inflammation, lipid metabolism, and glucose metabolism. The primary isotypes of PPARs are PPARα, PPARβ, and PPARγ. PPARγ is mostly expressed in adipose tissue and the colon. The activation of PPARγ modulates signaling pathways associated with metabolism and inflammation. Inflammatory bowel diseases (IBDs) include Crohn's disease and ulcerative colitis (UC). Ulcerative colitis is predominantly localized to the colon. Considering PPARγ's expression profile and its role in alleviating inflammation, there exists an opportunity to explore pharmaceutical targeting in the colon to diminish inflammation. We conducted molecular docking and dynamics investigations utilizing Morin hydrate (MH), a flavonoid derived from the Moraceae family, with the cocrystal structure of PPARγ and Nrf2. They demonstrated a consistent interaction. Consequently, we conducted comprehensive preclinical studies of these interactions utilizing both in vivo and in vitro models of colon inflammation. Our findings showed that MH reduced the disease activity index, colon length shortening, and myeloperoxidase enzyme activity in mice treated with dextran sodium sulfate (DSS). MH also safeguarded colon histology by reducing proinflammatory cytokines. MH induced Nrf2 nuclear translocation, enhanced antioxidant response, and elevated Nrf2 promoter activity. MH selectively enhanced PPARγ protein expression while leaving other PPAR isotypes unaffected. HT-29 cells, treated with tumor necrosis factor-alpha (TNFα) as an in vitro model of colon inflammation, exhibited a reduction in proinflammatory chemokines with exposure to MH. MH also enhanced PPARγ promoter activity. These findings demonstrate that MH is a potent agonist of Nrf2 and PPARγ, resulting in reduced colon inflammation.
过氧化物酶体增殖物激活受体（PPARs）作为核受体，调节与炎症、脂质代谢和葡萄糖代谢相关的基因表达。PPARs的主要亚型是PPARα、PPARβ和PPARγ。PPARγ主要在脂肪组织和结肠中表达。PPARγ的激活调节与代谢和炎症相关的信号通路。炎症性肠病（IBDs）包括克罗恩病和溃疡性结肠炎（UC）。溃疡性结肠炎主要局限于结肠。考虑到PPARγ的表达谱及其在减轻炎症中的作用，存在探索结肠药物靶向治疗以减轻炎症的机会。我们利用桑色素水合物（MH）（一种来自桑科的黄酮类化合物）与PPARγ和Nrf2的共晶体结构进行了分子对接和动力学研究。它们表现出一致相互作用。因此，我们利用结肠炎症的体内和体外模型对这些相互作用进行了全面的临床前研究.我们的研究结果表明，MH降低了用葡聚糖硫酸钠（DSS）处理小鼠的疾病活动指数、结肠长度缩短和髓过氧化物酶活性.MH还通过减少促炎细胞因子保护结肠组织学.MH诱导Nrf2核转位，增强抗氧化反应，并提高Nrf2启动子活性.MH选择性增强PPARγ蛋白表达，而不影响其他PPAR亚型。用肿瘤坏死因子-α（TNFα）作为结肠炎症体外模型处理的HT-29细胞，在暴露于MH时促炎趋化因子减少.MH还增强了PPARγ启动子活性。这些发现表明，MH是Nrf2和PPARγ的有效激动剂，可减轻结肠炎症。
