Design and synthesis of luotonin A-derived topoisomerase targeting scaffold with potent antitumor effect and low genotoxicity.

Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.

EZH2 as an Epigenetic Regulator of Cardiovascular Development and Diseases.

ABSTRACT: Enhancer of zeste homolog 2(EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2) and is responsible for catalyzing mono-, di-, and trimethylation of histone H3 at lysine-27(H3K27me1/2/3). Many noncoding RNAs or signaling pathways are involved in EZH2 functional alterations. This new epigenetic regulation of target genes is able to silence downstream gene expression and modify physiological and pathological processes in heart development, cardiomyocyte regeneration, and cardiovascular diseases, such as hypertrophy, ischemic heart diseases, atherosclerosis, and cardiac fibrosis. Targeting the function of EZH2 could be a potential therapeutic approach for cardiovascular diseases.

Efficacy of catheter ablation and surgical CryoMaze procedure in patients with long-lasting persistent atrial fibrillation and rheumatic heart disease: a randomized trial.

AIMS: Catheter ablation and surgical Maze procedure are effective in treating atrial fibrillation (AF) patients. However, there is no study that compares the effect of circumferential pulmonary vein isolation (CPVI) combined with substrate ablation after valvular surgery and the concomitant Maze procedure for the treatment of AF in patients with rheumatic heart disease (RHD). The aim of this study was to compare the effectiveness of CPVI combined with substrate modification and surgical Maze procedure using Saline-Irrigated Cooled-tip Radiofrequency Ablation (SICTRA) system for the treatment of long-lasting persistent AF in patients with RHD. METHODS AND RESULTS: Between January 2006 and June 2008, 99 patients with long-lasting persistent AF and RHD were randomly assigned to undergo valvular operation and CPVI combined with substrate modification 6 months after the surgery (Group A, 49 patients) or valvualr operation and concomitant Maze procedure (Group B, 50 patients). The mean follow-up periods were 15 ± 5 and 20 ± 8 months in Groups A and B, respectively. After one procedure, Group B had a significantly higher freedom from artial arrhythmias compared with Group A (82% in Group B vs. 55.2% in Group A, P < 0.001). Fifteen patients in Group A underwent a redo procedure. Six patients in Group B underwent catheter ablation and four were treated successfully. The cumulative rates of sinus rhythm were 71% in Group A and 88% in Group B (P < 0.001). CONCLUSION: The concomitant Cox Maze procedure using SICTRA is more effective than subsequent CPVI combined with substrate modification in treating patients with long-lasting persistent AF and RHD.