背景:管腔抗原的侵入和由物理上皮屏障破坏引起的异常免疫应答是溃疡性结肠炎(UC)的关键特征。受损的上皮功能的恢复对于维持粘膜稳态和疾病静止至关重要。目前UC的治疗主要集中在抑制炎症。然而,随着时间的推移,大多数患者对治疗没有反应或出现继发性耐药性,强调需要开发新的UC治疗靶点。我们的研究旨在从真武汤中确定一种新的改良草药配方的潜在目标,即CDD-2103,它在治疗慢性结肠炎中显示出有希望的疗效。
方法:使用组织损伤的体外和离体模型检查了CDD-2103对上皮屏障功能的影响,以及慢性结肠炎C57BL/6小鼠模型。在用CDD-2103处理后,采用转录组分析来描述结肠组织中的基因表达变化。
结果:我们的体内实验表明,CDD-2103剂量依赖性地降低了慢性结肠炎小鼠的疾病严重程度。CDD-2103的功效由杯状细胞损失的减少和紧密连接蛋白完整性的增强介导。机械上,CDD-2103通过激活可溶性鸟苷环化酶(sGC)介导的环磷酸鸟苷(cGMP)/PKG信号级联,抑制上皮细胞凋亡和紧密连接蛋白分解。分子对接分析显示CDD-2103衍生分子对sGC配体的强烈识别,保证进一步调查。
结论:我们的研究揭示了一种新型制剂CDD-2103,通过激活sGC调节的cGMP/PKG信号来恢复肠屏障功能。此外,我们的研究结果表明,靶向sGC可以成为UC治疗中促进黏膜愈合的有效方法.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.