Structural insights of JAK2 inhibitors: pharmacophore modeling and ligand-based 3D-QSAR studies of pyrido-indole derivatives.

In this study we have performed pharmacophore modeling and built a 3D QSAR model for pyrido-indole derivatives as Janus Kinase 2 inhibitors. An efficient pharmacophore has been identified from a data set of 51 molecules and the identified pharmacophore hypothesis consisted of one hydrogen bond acceptor, two hydrogen bond donors and three aromatic rings, i.e. ADDRRR. A powerful 3D-QSAR model has also been constructed by employing Partial Least Square regression analysis with a regression coefficient of 0.97 (R(2)) and Q(2) of 0.95, and Pearson-R of 0.98.

Tramadol safety--cholinergic system of rat brain without nociception.

In the present investigation, changes in the levels of acetylcholinesterase (AChE) activity, acetylcholine (ACh) content, and the activity levels of plasma (PChE) and erythrocyte (EChE) cholinesterases as representatives of pseudocholinesterases were examined in different areas of the rat brain during the administration of the synthetic opioid analgesic drug tramadol (Ultram) without induction of pain. Male adult Wistar rats weighing 150 +/- 20 g were used. Tramadol was injected subcutaneously (s.c.) into the rats at 0, 24 and 48 h, and the changes in the above cholinergic parameters were recorded after the completion of 3, 6, 12, 24, 48 and 72 h. Following administration of single dose (for rats sacrificed at 24 h) and multiple doses (for rats sacrificed at 48 and 72 h) of tramadol, the ACh content showed an increase in all brain areas. Concurrently, the AChE activity was found to decrease in all the areas. PChE and EChE showed higher activity levels, with EChE showing a higher level of activity than PChE. The levels of all the parameters examined returned towards the control levels by about 24 h after the administration of single dose of tramadol. However, the ACh levels showed an elevation at 48 and 72 h (following double and triple doses, respectively). The AChE activity levels also showed a simultaneous increase at 48 and 72 h, presumably to balance the increase in ACh levels on longer treatment with tramadol. The observed changes in the cholinergic segment presumably do not cause any physiological lesion since they reverted to control levels after the time limit of change under tramadol influence. This observation indicates that tramadol can be administered safely both under nociceptive and non-nociceptive conditions.

Alterations in antioxidant enzyme activities and oxidative damage in alcoholic rat tissues: protective role of Thespesia populnea.

Recent advances in our understanding of the pathogenesis of alcohol-induced hepato-renal injury and the development of new approaches to its treatment have been reported in various works. This study involves alcohol-induced oxidative stress linked to the metabolism of ethanol involving both mitochondrial and peroxisomal fractions of liver and kidney. Alcohol treatment resulted in the depletion of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), Glutathione-S-Transferase (GST) activities, and reduced glutathione (GSH) content, higher level of malondialdehyde (MDA) and lower levels of protein carbonyls (PC) causing malfunction of hepatic and renal tissues, when compared to control rats. Thespesia populnea (TP) leaf extracts, administered to chronic alcohol ingested rats, were envisaged to possess significant antioxidant defence properties and help in the recovery of tissues from alcohol-induced oxidative damage. The results showed that degenerative changes in hepatic and renal cells of alcoholic groups were minimized by the administration of TP leaf extracts as also revealed by histopathological examination. The current findings indicate that treatment with TP extracts reduces alcohol-induced oxidative stress, thereby protecting the hepatic and renal tissue from alcohol-induced damage.