Sofalcone is a synthetic chalcone being used as a gastric mucosa protective agent in Japan. Sofalcone contains a 1,3-diaryl-2-propen-1-one moiety, which is a common chemical scaffold in naturally occurring chalcones. The α,β-unsaturated carbonyl group (Michael reaction acceptor) has electrophilic properties. We investigated the biochemical mechanisms by which sofalcone activated the cytoprotective and anti-inflammatory nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2)-heme oxygenase (HO)-1 pathway. Furthermore, we investigated whether the activation of this pathway was involved in sofalcone -mediated protective effects in an experimental colitis model. Sofalcone induced HO-1 protein expression, which was dependent on increased nuclear accumulation of Nrf2 in human colon carcinoma cells. In addition, Sofalcone reacted with nucleophilic thiol compounds to form Michael adducts. A reduced form of sofalcone (SFCR) in which the Michael reaction acceptor was deactivated, did not exert biological or chemical activity. Biotin-tagged sofalcone bound to Kelch-like ECH-associated protein 1 (KEAP1), a cytosolic repressor of Nrf2. This binding was prevented by pretreatment with sofalcone and a thiol compound but not with SFCR. Furthermore, sofalcone treatment induced dissociation of the Nrf2-KEAP1 complex. Rectal administration of sofalcone alleviated colon damage and inflammation and increased colon nuclear accumulation of Nrf2 and HO-1 levels in a dinitrobenzene sulfonic acid-induced rat colitis model. The protective effects of sofalcone against colon damage and inflammation were significantly inhibited by co-administration of an HO-1 inhibitor. In conclusion, sofalcone activated the Nrf2-HO-1 pathway by covalently binding to KEAP1 via Michael addition, and may confer anti-colitic effects by inducing Nrf2 activation.

中文翻译：

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Sofalcone是一种胃保护药物，与KEAP1共价结合以激活Nrf2，从而产生抗结肠炎活性。

Sofalcone是在日本用作胃黏膜保护剂的合成查尔酮。Sofalcone包含1,3-二芳基-2-丙-1-酮部分，这是天然存在的查耳酮中常见的化学支架。α，β-不饱和羰基（迈克尔反应受体）具有亲电特性。我们调查了生化机制，通过其soflclcone激活细胞保护性和抗炎性核因子-类红细胞2（NF-E2）p45相关因子2（Nrf2）-血红素加氧酶（HO）-1途径。此外，我们调查了这种途径的激活是否参与了实验性结肠炎模型中的沙发螺介素介导的保护作用。Sofalcone诱导HO-1蛋白表达，其依赖于人类结肠癌细胞中Nrf2的核积累增加。此外，Sofalcone与亲核硫醇化合物反应形成迈克尔加合物。迈克尔逊反应受体失活的还原形式的沙发草酮（SFCR）没有发挥生物或化学活性。带有生物素标签的沙发螺酮与Kelch样ECH相关蛋白1（KEAP1）结合，后者是Nrf2的胞质阻遏物。通过用索非尔酮和硫醇化合物预处理而不是SFCR可以防止这种结合。此外，沙发酮处理诱导Nrf2-KEAP1复合体的解离。在二硝基苯磺酸诱导的大鼠结肠炎模型中，直肠施用沙发碱可减轻结肠损伤和炎症，并增加Nrf2和HO-1水平的结肠核积累。并用HO-1抑制剂可显着抑制沙发螺酮对结肠损伤和炎症的保护作用。