Cardioprotective and chemosensitizing effects of novel Danshensu derivatives

OBJECTIVE To investigate the cardioprotective effect of novel danshensu derivatives against doxorubicin(Dox)cardiotoxicity and their synergistic anti-tumor effect with Dox on breast cancer cells.METHODS Two new Danshensu derivatives were synthesized by conjugation with tetramethylpyrizine and/or4-(3-thioxo-3 H-1,2-dithiol-4-yl)-benzoic acid and tested for protective effects against Dox induced cardiotoxicity in cell and zebrafish.H9c2 cardiomyoblasts were co-treated with Dox and Danshensu derivatives for 24 h and then were measured for cell viability and cytotoxicity by MTT and LDH assays.The expression levels of mitochondrial biogenesis related proteins PGC-1α,NRF-1and Nrf2 were detected by Western blotting and qPCR.Moreover,in a Dox-induced cardiotoxicity model of zebrafish,zebrafish embryos were treated with Dox for 36 h,followed by measurement of numerous ventricular function parameters including heart rate,stroke volume,cardiac output and fractional shortening.In addition,the synergistic anti-tumor effects of the Danshensu derivatives and Dox had been studied in MCF-7 breast cancer cells.The effects of the Danshensu derivatives on the cell death and metabolism of MCF-7 cells were measured using apoptosis assay and Seahorse Metabolic Analyzers respectively.RESULTS Our results showed that the Danshensu derivatives were more potent than the parental compounds in ameliorating Dox-induced cytotoxicity in H9c2 cells and significantly preserving stroke volume of heart function in Dox-treated zebrafish.Further mechanistic studies identified that the danshensu derivatives increased mitochondrial copy numbers and protein expressions of PGC-1α,NRF-1 and Nrf2 in H9c2 cells.In addition,the Danshensu derivatives enhanced Dox-induced apoptosis,and decreased glycolysis and mitochondrial function in MCF-7 tumor cells.CONCLUSION Our results revealed that two new Danshensu derivatives displayed promising cardioprotective effects against Dox induced cardiotoxicity both in vivo and in vitro,at least partially through activating mitochondrial biogenesis.Also,the new Danshensu derivatives potentiated the anticancer effects of Dox in breast tumor cells involving induction of glycolytic inhibition and mitochondrial dysfunction.

Effects of transgenic Cry1A＋CpTI cotton and Cry1Ac toxin on the parasitoid, Campoketis chlorideae （Hymenoptera：Ichneumonidae）

The effect of transgenic double genes, Cry1A + CpTI cotton and Cry1Ac toxinon the parasitoid, Campoketis chlorideae Uchida of cotton bollworm, Helicoverpa armigera (Huebner),was investigated in the laboratory. Helicoverpa armigera larvae when in the first, second and thirdinstar could not survive if fed on transgenic cotton leaves. Consequently, C. chlorideae larvaecould not complete their development if parasitizing on such hosts. After H. armigera larvae werereared on transgenic or traditional cotton leaves for 12-48 hours, they were parasitized by C.chlorideae females. Parasitized larvae continued to feed on transgenic or traditional cotton for12-48 h. The present results showed that the body weight of larvae of the parasitoids weresignificantly reduced when parasitized hosts fed on transgenic cotton leaves compared to those fedon traditional cotton. Duration of egg and larvae stage were significantly prolonged, pupal andadult weight of C. chloridae was decreased when the host larvae fed on transgenic cotton leaveslonger than 48 h. The development duration of C. chlorideae pupae on the hosts fed on transgeniccotton leaves in each treatment was not significantly different from those of controls. Thelongevity of parasitoid females and males fed with a solution containing Cry1Ac toxin was notsignificantly different with that of the control.