A pilot study of alterations in oxidized angiotensinogen and antioxidants in pre-eclamptic pregnancy.

The oxidation status of angiotensinogen (AGT) may have a critical role in pre-eclampsia. We used a validated, quantitative, mass spectrometry-based method to measure the oxidized and total AGT levels in plasma of pre-eclamptic women (n = 17), normotensive-matched controls (n = 17), and healthy non-pregnant women (n = 10). Measurements of plasma glutathione peroxidase (GPx) activity and serum selenium concentrations were performed as markers of circulating antioxidant capacity. Higher proportions of oxidized AGT in plasma from pre-eclamptic women compared to matched normotensive pregnant controls (P = 0.006), whilst maintaining a similar total plasma AGT concentration were found. In the pre-eclamptic group, blood pressure were correlated with the proportion of oxidized AGT; no such correlation was seen in the normotensive pregnant women. Plasma GPx was inversely correlated with oxidized AGT, and there was an inverse association between serum selenium concentration and the proportion of oxidized AGT. This is the first time that oxidized AGT in human plasma has been linked directly to antioxidant status, providing a mechanism for the enhanced oxidative stress in pre-eclampsia. We now provide pathophysiological evidence that the conversion of the reduced form of AGT to its more active oxidized form is associated with inadequate antioxidant status and could indeed contribute to the hypertension of pre-eclampsia.

Combining ligand-based pharmacophore modeling, quantitative structure-activity relationship analysis and in silico screening for the discovery of new potent hormone sensitive lipase inhibitors.

Hormone sensitive lipase (HSL) has been recently implicated in diabetes and obesity, prompting attempts to discover new HSL inhibitors. Toward this end, we explored the pharmacophoric space of HSL inhibitors using four diverse sets of compounds. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of yielding a self-consistent and predictive quantitative structure-activity relationship (QSAR) (r = 0.822, n = 99, F = 11.1, r LOO (2) = 0.521, r PRESS (2) against 23 external test inhibitors = 0.522). Interestingly, two pharmacophoric models emerged in the QSAR equation suggesting at least two binding modes. These pharmacophores were employed to screen the National Cancer Institute (NCI) list of compounds and our in-house built database of established drugs and agrochemicals. Active hits included the safe herbicidal agent bifenox (IC 50 = 0.43 microM) and the nonsteroidal anti-inflammatory naproxen (IC 50 = 1.20 microM). Our active hits undermined the traditional believe that HSL inhibitors should possess covalent bond-forming groups.