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Traditional Chinese medicine uses a systemic treatment approach,targeting multiple etiological factors simultaneously.Danhong injection (DHI),a very popular Chinese medicine injection composed of water-soluble extracts of Radix Salvia miltiorrhiza (Danshen) and Flos Carthamus tinctorius L.(Honghua),is reported to be effective for many cardiovascular conditions.The primary active ingredients of DHI,and their systemic and interrelated mechanism have not been evaluated in an established myocardial ischemia/reperfusion (MI/R) injury model.We identified the main active constituents in DHI,including hydroxysafflor yellow A (A),salvianolic acid B (B),and Danshensu (C),by HPLC fingerprint analysis and assessed their effect on I/R injury rats and cardiomyocytes.These 3 compounds and DHI all decreased the levels of IL-1,TNF-α,and MDA,and increased those of IL-10 and SOD activity in vivo and in vitro,and had anti-apoptotic effects,as shown by flow cytometric analysis and TUNEL assay.Moreover,these compounds increased phosphorylation of Akt and ERK1/2 in cardiomyocytes.Interestingly,we found A,B,and C,exerted prominent effect compared with two other ingredients on inhibiting inflammation,reducing oxidative stress,alleviating apoptosis through decreasing NF-κB level and increasing Nrf2 expression and lower caspase-3 activity,respectively.Compounds A,B,and C are the main active ingredients of DHI.Compound A exerted a more prominent anti-inflammatory effect than B and C,by decreasing NF-κB levels; compound B had more powerful anti-oxidative capacity than A and C,by increasing Nrf2 expression; and compound C had stronger anti-apoptotic ability than A and B,by lowering caspase-3 activity.Our results elucidate the mechanisms by which DHI protects against MI/R induced injury.