Qu Lejing, Jiao Meizhi, Zhang Zilong, Ou Yuanyuan, Zhao Xue, Zhang Yajun, Zhao Xinfeng
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, 710069, China.
The Second Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, China.
Chin Med. 2025 Jan 27;20(1):15. doi: 10.1186/s13020-025-01065-6.
Cutaneous hypertrophic scar is a fibro-proliferative hard-curing disease. Recent studies have proved that antagonists of angiotensin II type 1 receptor (ATR) and agonists of type 2 receptor (ATR) were able to relieve hypertrophic scar. Therefore, establishing new methods to pursue dual-target lead compounds from Chinese herbs is in much demand for treating scar.
To this end, we immobilized ATR or ATR onto the surface of silica gel from cell lysates through a specific covalent bond by bioorthogonal chemistry. The columns containing immobilized ATR or ATR were jointly utilized to pursue potential bioactive compounds simultaneously binding to ATR and ATR from the extract of Rhei Radix et Rhizoma. Their functions on ATR and ATR expressions were investigated by in vitro and in vivo experiments.
Aloe-emodin and emodin were identified as the potential bioactive compounds binding to both of the two receptors, thereby improving the appearance and pathomorphology of hypertrophic scar. They blocked the ATR pathway to down-regulate the expression of transforming growth factor-β1 (TGF-β1) and stimulate matrix metalloproteinase-1 (MMP-1) expression. As such, the expression of collagen I/III reduced. Conversely, the bindings of the two compounds to ATR reduced the production of nuclear factor-кB1 (NF-кB1), whereby the generation of interleukin-6 (IL-6) was blocked.
We reasoned that aloe-emodin and emodin had the potential to become dual-target candidates against hypertrophic scar through the regulation of ATR and ATR signaling pathways. It showed considerable potential to become a universal strategy for pursuing multi-target bioactive compounds from Chinese herbs by the utilization of diverse immobilized receptors in a desired order.
皮肤肥厚性瘢痕是一种纤维增殖性硬皮病。最近的研究证明，血管紧张素II 1型受体（ATR）拮抗剂和2型受体（ATR）激动剂能够缓解肥厚性瘢痕。因此，建立从中药中寻找双靶点先导化合物的新方法对于治疗瘢痕非常必要。
为此，我们通过生物正交化学将ATR或ATR通过特定共价键固定在硅胶表面，从细胞裂解物中制备而成。含有固定化ATR或ATR的柱子被联合用于从大黄提取物中寻找同时结合ATR和ATR的潜在生物活性化合物。通过体外和体内实验研究它们对ATR和ATR表达的作用。
芦荟大黄素和大黄素被鉴定为与两种受体都结合的潜在生物活性化合物，从而改善了肥厚性瘢痕的外观和病理形态。它们阻断ATR途径以下调转化生长因子-β1（TGF-β1）的表达并刺激基质金属蛋白酶-1（MMP-1）的表达。因此，I/III型胶原蛋白的表达降低。相反，这两种化合物与ATR的结合减少了核因子-кB1（NF-кB1）的产生，从而阻断了白细胞介素-6（IL-6）的产生。
我们推断芦荟大黄素和大黄素有可能通过调节ATR和ATR信号通路成为抗肥厚性瘢痕的双靶点候选药物。通过按所需顺序利用多种固定化受体从中药中寻找多靶点生物活性化合物，这显示出成为一种通用策略的巨大潜力。
