Modular-Based Synergetic Mechanisms of Jasminoidin and Ursodeoxycholic Acid in Cerebral Ischemia Therapy.

Objectives

Jasminoidin (JA) and ursodeoxycholic acid (UA) have been shown to exert synergistic effects on cerebral ischemia (CI) therapy, but the underlying mechanisms remain to be elucidated.

Objective

To elucidate the synergistic mechanisms involved in the combined use of JA and UA (JU) for CI therapy using a driver-induced modular screening (DiMS) strategy.

Methods

Network proximity and topology-based approaches were used to identify synergistic modules and driver genes from an anti-ischemic microarray dataset (ArrayExpress, E-TABM-662). A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in 30 Sprague Dawley rats, divided into sham, vehicle, JA (25 mg/mL), UA (7 mg/mL), and JU (JA:UA = 1:1) groups. After 90 minutes of ischemia, infarct volume and neurological deficit scores were evaluated. Western blotting was performed 24 h after administration to validate key protein changes.

Results

Six, eleven, and four drug-responsive On_modules were identified for JA, UA, and JU, respectively. Three synergistic modules (Sy-modules, JU-Mod-7, 8, and 10) and 12 driver genes (e.g., NRF1, FN1, CUL3) were identified, mainly involving the PI3K-Akt and MAPK pathways and regulation of the actin cytoskeleton. JA and UA synergistically reduced infarct volume and neurological deficit score (2.5, p < 0.05) in MCAO/R rats. In vivo studies demonstrated that JU suppressed the expression of CUL3, FN1, and ITGA4, while it increased that of NRF1.

Conclusions

JU acts synergistically on CI-reperfusion injury by regulating FN1, CUL3, ITGA4, and NRF1 and inducing the PI3K-Akt, MAPK, and actin cytoskeleton pathways. DiMS provides a new approach to uncover mechanisms of combination therapies.