Design, synthesis, biological evaluation and molecular docking of alkoxyaurones as potent pancreatic lipase inhibitors.

Aurones are a minor subgroup of flavonoids. Unlike other subgroups such as chalcones, flavones, and isoflavones, aurones have not been extensively explored as pancreatic lipase inhibitors. In this work, we studied the pancreatic lipase inhibitory potency of synthetic aurone derivatives. Thirty-six compounds belonging to four series (4,6-dihydroxyaurone, 6-hydroxyaurone, 4,6-dialkoxyaurone, and 6-alkoxyaurone) were designed and synthesized. Their in vitro inhibitory activities were determined by spectrophotometric assay in comparison with quercetin and orlistat. Alkoxyaurone derivatives with long-chain (6-10 carbons) alkoxy substituents showed greater potency. Of them, 4,6-dialkoxyaurone 8 displayed the highest activity against pancreatic lipase (IC50 of 1.945 ± 0.520 µM) relative to quercetin (IC50 of 86.98 ± 3.859 µM) and orlistat (IC50 of 0.0334 ± 0.0015 µM). Fluorescence quenching measurement confirmed the affinity of alkoxyaurone derivatives to pancreatic lipase. Kinetic study showed that 8 inhibited lipase through a competitive mechanism (Ki of 1.288 ± 0.282 µM). Molecular docking results clarified the role of long-chain substituents on ring A in interacting with the hydrophobic pockets and pushing the inhibitor molecule closer to the catalytic triad. The findings in this study may contribute to the development of better pancreatic lipase inhibitors with aurone structure.

Left ventricular dysfunction causing ischemia in patients with patent coronary arteries.

BACKGROUND: New onset of heart failure (HF) is an indication for the assessment of coronary artery disease. The aim of this study was to clarify the mechanistic causes of new onset HF associated with ischemic electrocardiograph (EKG) changes and chest pain in patients with patent or minimally diseased coronary arteries. METHODS: Twenty consecutive patients (Group A) were retrospectively reviewed if they had an history of new onset of HF, chest pain, electrocardiographic changes indicating ischemia (ST depression or T wave inversion in at least two consecutive leads and a negative coronary angiogram [CA]) and did not require percutaneous coronary intervention or coronary artery bypass grafting. A 1:1 matched cohort (Group B) was adopted to validate the results. RESULTS: All patients had a negative CA. The majority of subjects in Group A had a higher left ventricular end diastolic pressure (LVEDP) when compared to the control group (p<0.05). Similarly, the aortic diastolic (AOD) pressure was lower in Group A than in Group B (p<0.05). In patients with elevated LVEDP and low AOD, with a coronary perfusion pressure (CPP) <20 mmHg, deep T wave inversion in two consecutive leads were more frequently observed. When the CPP was between 20-30 mmHg, a mild ST depression were more frequently recorded (p<0.05). Conversely, when the CPP was >30 mmHg, only mild non-specific ST-T changes or normal EKG were observed. CONCLUSIONS: In patients with HF and EKG changes suggestive of ischemia in at least two consecutive leads, a lower AOD could aggravate ischemia in patients with elevated left ventricular end diastolic pressure.

GermSAGE: a comprehensive SAGE database for transcript discovery on male germ cell development.

GermSAGE is a comprehensive web-based database generated by Serial Analysis of Gene Expression (SAGE) representing major stages in mouse male germ cell development, with 150,000 sequence tags in each SAGE library. A total of 452,095 tags derived from type A spermatogonia (Spga), pachytene spermatocytes (Spcy) and round spermatids (Sptd) were included. GermSAGE provides web-based tools for browsing, comparing and searching male germ cell transcriptome data at different stages with customizable searching parameters. The data can be visualized in a tabulated format or further analyzed by aligning with various annotations available in the UCSC genome browser. This flexible platform will be useful for gaining better understanding of the genetic networks that regulate spermatogonial cell renewal and differentiation, and will allow novel gene discovery. GermSAGE is freely available at http://germsage.nichd.nih.gov/