Meroterpenes from endophytic fungus A1 of mangrove plant Scyphiphora hydrophyllacea.

Four new meroterpenes, guignardones F-I (1-4), together with two known compounds guignardones A (5) and B (6) were isolated from the endophytic fungus A1 of the mangrove plant Scyphiphora hydrophyllacea. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray crystallography. A possible biogenetic pathway of compounds 1-6 was also proposed. All compounds were evaluated for inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus.

Two new sesquiterpenes from endophytic fungus S49 of Cephalotaxus hainanensis.

Two new sesquiterpenes, 10,11,12-guaianetriol (1) and 1,10,11,12-guaianetetrol (2), were isolated from endophytic fungus S49 of Cephalotaxus hainanensis Li. Their structures were determined based on HR-ESI-MS and spectroscopic techniques (1D and 2D NMR).

A novel antioxidant 3,7-dihydroxy-isoflav-3-ene (DHIF) inhibits neointimal hyperplasia after vessel injury attenuating reactive oxygen species and nuclear factor-kappaB signaling.

Reactive oxygen species (ROS) contribute to neointimal smooth muscle proliferation by yet to be defined mechanisms. We examined the effects of a novel isoflavone 3,7-dihydroxy-isoflav-3-ene (DHIF) on development of neointimal lesions in relation to ROS elevations and cell signaling in injured arteries. Carotid arteries of rabbits treated with vehicle or DHIF were injured with a balloon catheter and effects on proliferation, apoptosis, vessel structure, ROS, NF-kappaB activation, cyclooxygenase and gene expression examined. Seven days after injury proliferating neointimal cells were reduced by 35% (P<0.05) whilst medial cell proliferation was attenuated by 16% (P<0.05). ROS levels were elevated fourfold in injured arteries of vehicle-treated rabbits. Treatment with DHIF prevented this elevation (P<0.05). Also, NF-kappaB was activated in neointimal cells from vehicle-treated rabbits, demonstrated by nuclear accumulation of NF-kappaB-p65. DHIF not only attenuated its nuclear accumulation but also suppressed NF-kappaB-p65 expression in neointimal cells. This was accompanied by a doubling of apoptotic cell numbers (P<0.05). Expression of cyclooxygenases Cox-1 and Cox-2 were also attenuated, by 74% and 50%, respectively (P<0.05), as was MCP-1. The antiproliferative effects of DHIF persisted at 14 days, and 28 days after injury neointima growth was attenuated by 50% (P<0.05). Thus, ROS stimulates neointima growth via mechanisms involving NF-kappaB activation, cyclooxygenases and MCP-1. DHIF's ability to attenuate NF-kappaB activation suggests that it may not only be useful in preventing restenosis but also in attenuating atherosclerosis.

Phase Ib single- and multiple-dose pharmacokinetic study of oral NV-52 in healthy volunteers.

BACKGROUND AND OBJECTIVE: NV-52 is a novel synthetic flavonoid thromboxane synthase (TXS) inhibitor that may be useful for the maintenance of remission in inflammatory bowel disease (IBD). This study was conducted to determine the single- and multiple-dose pharmacokinetics of NV-52 in nine healthy volunteers (five men, four women; mean [+/- SD] age 23 +/- 2 years). METHODS: NV-52 400 mg was administered once daily for 10 days (excluding day 2) in an open-label study. Plasma was sampled and urine was collected for 48 hours after the first and last doses. Plasma and urine unconjugated and total (unconjugated plus glucuronide and sulphate conjugated) NV-52 concentrations were measured using liquid chromatography-mass spectrometry. RESULTS: No adverse events were observed. Unconjugated and total NV-52 appeared and rose rapidly in plasma following the first dose. Time to maximum concentration values were 1.92 +/- 1.17 and 2.72 +/- 1.52 hours for unconjugated and total NV-52, respectively. Unconjugated and total NV-52 were eliminated with plasma half-lives of 13.12 +/- 17.31 and 18.03 +/- 19.06 hours, respectively, following the first dose. Pre-dose levels following multiple-dose administration were 135.17 +/- 120.03 and 751.9 +/- 679.74 ng/mL for unconjugated and total NV-52, respectively. Multiple-dose administration did not significantly alter the pharmacokinetics of NV-52. Renal elimination accounted for about 20-35% of the total (largely conjugated) drug but only 1% of unconjugated NV-52. CONCLUSIONS: Plasma concentrations of unconjugated NV-52 following single- and multiple-dose administration were well above the range found to be associated with suppression of colitis in a murine model of IBD.