Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China.
Centre for Chinese Herbal Medicine Drug Development, Hong Kong Baptist University, Hong Kong SAR, China; School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.
J Ethnopharmacol. 2024 Nov 15;334:118570. doi: 10.1016/j.jep.2024.118570. Epub 2024 Jul 11.
The invasion of luminal antigens and an aberrant immune response resulting from a disrupted physical epithelial barrier are the key characteristics of ulcerative colitis (UC). The restoration of damaged epithelial function is crucial for maintaining mucosal homeostasis and disease quiescence. Current therapies for UC primarily focus on suppressing inflammation. However, most patients fail to respond to therapy or develop secondary resistance over time, emphasizing the need to develop novel therapeutic targets for UC. Our study aimed to identify the potential targets of a novel modified herbal formula from the Zhen Wu Decoction, namely CDD-2103, which has demonstrated promising efficacy in treating chronic colitis.
The effect of CDD-2103 on epithelial barrier function was examined using in vitro and ex vivo models of tissue injury, as well as a chronic colitis C57BL/6 mouse model. Transcriptomic analysis was employed to profile gene expression changes in colonic tissues following treatment with CDD-2103.
Our in vivo experiments demonstrated that CDD-2103 dose-dependently reduced disease severity in mice with chronic colitis. The efficacy of CDD-2103 was mediated by a reduction in goblet cell loss and the enhancement of tight junction protein integrity. Mechanistically, CDD-2103 suppressed epithelial cell apoptosis and tight junction protein breakdown by activating the soluble guanynyl cyclase (sGC)-mediated cyclic guanosine monophosphate (cGMP)/PKG signaling cascade. Molecular docking analysis revealed strong sGC ligand recognition by the CDD-2103-derived molecules, warranting further investigation.
Our study revealed a novel formulation CDD-2103 that restores intestinal barrier function through the activation of sGC-regulated cGMP/PKG signaling. Furthermore, our findings suggest that targeting sGC can be an effective approach for promoting mucosal healing in the management of UC.
溃疡性结肠炎（UC）的关键特征是腔抗原的侵袭和异常免疫反应，以及物理上皮屏障的破坏。恢复受损的上皮功能对于维持黏膜内稳态和疾病缓解至关重要。目前 UC 的治疗主要集中在抑制炎症上。然而，大多数患者在治疗过程中无法产生反应，或者随着时间的推移会产生继发性耐药，这强调了需要为 UC 开发新的治疗靶点。我们的研究旨在确定一种来自真武汤的新型改良草药配方（即 CDD-2103）的潜在靶点，该配方在治疗慢性结肠炎方面显示出了良好的疗效。
使用组织损伤的体外和离体模型以及慢性结肠炎 C57BL/6 小鼠模型，研究 CDD-2103 对上皮屏障功能的影响。采用转录组分析方法对 CDD-2103 治疗后的结肠组织基因表达变化进行分析。
我们的体内实验表明，CDD-2103 可剂量依赖性地降低慢性结肠炎小鼠的疾病严重程度。CDD-2103 的疗效是通过减少杯状细胞丢失和增强紧密连接蛋白完整性来介导的。机制上，CDD-2103 通过激活可溶性鸟苷酸环化酶（sGC）介导的环鸟苷酸（cGMP）/蛋白激酶 G（PKG）信号级联来抑制上皮细胞凋亡和紧密连接蛋白降解。分子对接分析显示 CDD-2103 衍生分子与 sGC 具有很强的配体识别能力，值得进一步研究。
本研究揭示了一种新型配方 CDD-2103，它通过激活 sGC 调节的 cGMP/PKG 信号来恢复肠道屏障功能。此外，我们的研究结果表明，靶向 sGC 可能是促进 UC 黏膜愈合的一种有效方法。
