Baicalein

Atherosclerosis (AS) progression is driven by multiple interconnected pathological mechanisms. Among them, vascular senescence is both a key accelerator and consequence, interacting with other processes to promote AS development. Traditional monotherapies were limited to achieve synergistic therapeutic effects due to low oral bioavailability and insufficient multi-target efficacy. To overcome these limitations, we developed a baicalein-copper network (Cu-MON) for oral delivery of atorvastatin (ATV), forming a synergistic therapeutic system (CMA). Cu-MON significantly prolonged the gastrointestinal residence and increased the oral bioavailability of ATV without requiring additional excipients. Crucially, Cu-MON regulated senescence-associated genes, enhanced DNA repair pathways, and mitigated DNA damage, effectively counteracting vascular aging. The integrated CMA system combined enzymatic and non-enzymatic dual antioxidant systems to scavenge multiple ROS species. Furthermore, CMA reprogrammed macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, modulated the PPAR-γ/LXR-α/ABCA-1 pathway to enhance cholesterol efflux, inhibited foam cell formation, and regulated hepatic and systemic cholesterol homeostasis. In ApoE^-/- mice, CMA markedly reduced aortic plaque burden and fibrosis, while Cu-MON attenuated key features of AS, including decreased ROS, inflammation, DNA damage, and cellular senescence. The CMA demonstrates high synergistic efficacy and biosafety, offering a novel multi-target oral drug strategy for AS treatment.

Hypertension and dyslipidemia are prevalent comorbidities that synergistically increase cardiovascular risk. This study aims to systematically investigate the multi-component therapeutic mechanisms of safflower (Carthamus tinctorius L.) against this comorbidity.

Disease-related targets for hypertension and dyslipidemia were retrieved from GeneCards, OMIM, and TTD databases. Active components of safflower were screened from TCMSP based on oral bioavailability (OB ≥ 30 %) and drug-likeness (DL ≥ 0.18). Intersection targets were analyzed via functional enrichment and protein-protein interaction (PPI) network. Molecular docking simulations validated binding affinities between key components and core targets using AutoDock Vina.

Fifty-nine shared therapeutic targets were identified. Enrichment analysis highlighted critical pathways including the AGE-RAGE signaling pathway in diabetic complications, lipid and atherosclerosis, and TNF signaling pathway. PPI network analysis identified eight hub targets (ICAM1, ESR1, VCAM1, EGFR, TNF, IL2, PPARG, MMP9). Molecular docking predicted strong binding energies (< -7 kcal/mol) between 11 active components (e.g., baicalein, baicalin, kaempferol) and six core targets, suggesting synergistic therapeutic effects through multi-target modulation.

This integrative study is the first to systematically reveal safflower's multi-component, multi-target, multi-pathway" mechanism against hypertension-dyslipidemia comorbidity, providing a theoretical basis for its clinical application. However, these computational findings are predictive and require further experimental validation.