Monocarbonyl curcumin analog A2 potently inhibits angiogenesis by inducing ROS-dependent endothelial cell death.

Excessive and abnormal vessel growth plays a critical role in the pathogenesis of many diseases, such as cancer. Angiogenesis is one of the hallmarks of cancer growth, invasion, and metastasis. Discovery of novel antiangiogenic agents would provide new insights into the mechanisms of angiogenesis, as well as potential drugs for cancer treatment. In the present study, we investigated the antiangiogenic activity of a series of monocarbonyl analogs of curcumin synthesized previously in our lab. We found that curcumin analog A2 displayed the full potential to be developed as a novel antiangiogenic agent. Curcumin analog A2 at and above 20 µM dramatically inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro, new microvessels sprouting from the rat aortic rings ex vivo and newly formed microvessels in chicken chorioallantoic membranes (CAMs) and Matrigel plus in vivo. We further demonstrated that curcumin analog A2 exerted its antiangiogenic activity mainly through inducing endothelial cell death via elevating NADH/NADPH oxidase-derived ROS. Curcumin analog A2 at the antiangiogenic concentrations also triggered autophagy in HUVECs, but this process is neither a pre-requisite for toxicity, leading to the cell death nor a protective response against the toxicity of curcumin analog A2. In conclusion, we demonstrate for the first time the potent antiangiogenic activity of the monocarbonyl curcumin analog A2, which could serve as a promising potential therapeutic agent for the prevention and treatment angiogenesis-related diseases, such as cancer.

Oxymatrine induces A549 human non­small lung cancer cell apoptosis via extrinsic and intrinsic pathways.

Oxymatrine is one of the primary natural compounds extracted from the Sophora flavescens, and has been reported to exhibit numerous pharmacological properties including cancer­preventive and anti­cancer effects, however the mechanisms as to how oxymatrine exhibits anti­proliferative activity in non­small cell lung carcinoma cells remains uncertain. The present study aimed to explore the mechanism of its anti­cancer effect, and whether it is due to apoptosis induction and anti­migration in the A549 lung cancer cell line. Detection of morphological alterations, MTT analysis, Hoechst/propidium iodide dual staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assays verified that oxymatrine induced A549 cell apoptosis. The caspase pan­inhibitor z­VAD­FMK resulted in disappearance of oxymatrine­elicited nuclei fragmentation via Hoechst 33342 staining. JC­1 staining demonstrated a decrease in mitochondrial membrane potential which further verified the induction of apoptosis by oxymatrine. The caspase­3, 8 and 9 activities of oxymatrine­treated cells were activated, which suggested that extrinsic and intrinsic apoptotic pathways were involved in the anti­proliferative effects of oxymatrine in A549 cells. Furthermore, the wound healing assay verified the anti­migratory effects of oxymatrine in A549 cells.

[Effect of adiponectin postconditioning against myocardial ischemia/reperfusion injury in rats and role of ADP/PI3K/Akt pathway in adiponectin postconditioning].

OBJECTIVE: To investigate the effects of adiponectin(ADP) postconditioning against myocardial ischemia/reperfusion injury(MIRI) in rats and role of ADP/PI3K/Akt pathway in ADP postconditioning. METHODS: SD rat was connected to ventilator by tracheal intubation under anesthesia, then left anterior descending coronary artery (LAD) was threaded between left auricle and pulmonary artery cone after exposing heart by surgery. MIRI model was induced by ligation of LAD for 30 min and the following reperfusion for 120 min. Rats were divided randomly into 5 groups (n=12):① Sham group:LAD was threaded without ligation; ② MIRI group; ③ADP group (ADP postconditioning) were subjected to intravenous injection of ADP when LAD ligation for 10 min and the ligation held for 20 min after that, then reperfusion for 120 min; ④ ADP+LY294002 group were subjected to injection of ADP and LY294002 when LAD ligation for 10 min, the other steps were the same as ADP group; ⑤ LY294002 group were subjected to injection of LY294002 when LAD ligation for 10 min, the other steps were the same as ADP group. Titers of lactate dehydrogenase(LDH) and cardiac troponin I(cTnI) in plasma were observed, expressions of PI3K, Akt, phosphorylated-Akt(p-Akt), ADP mRNA, ADPR1 mRNA and PI3k mRNA in myocardial tissue were measured. RESULTS: Compared with sham group, the levels of LDH and cTnI in MIRI group were increased (P<0.05); Compared with MIRI group, the levels of LDH and cTnI in ADP group were decreased (P<0.05); Compared with ADP group, the levels of LDH and cTnI were increased in LY294002 applying groups(P<0.05). Compared with MIRI group, the expressions of PI3K, p-Akt, ADP mRNA, ADPR1 mRNA and PI3K mRNA were increased in ADP group (P<0.05), the above mentioned 5 parameters in LY294002 applying groups were decreased(P<0.05). CONCLUSIONS: ADP postconditioning could reduce MIRI in rats, the protective effect might have relation to ADP/PI3k/Akt pathway.