A strategy for selective screening of dual-target bioactive compounds against hypertrophic scar through inhibiting angiotensin II type 1 receptor while stimulating type 2 receptor from Chinese herbs.

Background: Cutaneous hypertrophic scar is a fibro-proliferative hard-curing disease. Recent studies have proved that antagonists of angiotensin II type 1 receptor (AT₁R) and agonists of type 2 receptor (AT₂R) 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.

Methods: To this end, we immobilized AT₁R or AT₂R onto the surface of silica gel from cell lysates through a specific covalent bond by bioorthogonal chemistry. The columns containing immobilized AT₁R or AT₂R were jointly utilized to pursue potential bioactive compounds simultaneously binding to AT₁R and AT₂R from the extract of Rhei Radix et Rhizoma. Their functions on AT₁R and AT₂R expressions were investigated by in vitro and in vivo experiments.

Results: 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 AT₁R 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 AT₂R reduced the production of nuclear factor-кB1 (NF-кB1), whereby the generation of interleukin-6 (IL-6) was blocked.

Conclusion: We reasoned that aloe-emodin and emodin had the potential to become dual-target candidates against hypertrophic scar through the regulation of AT₁R and AT₂R 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.