Indomethacin induces free radical-mediated changes in renal brush border membranes

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in clinical medicine. One disadvantage of their use, however, is the occurrence of adverse effects in the kidneys. The side effects produced in this organ have been classically attributed to the inhibitory effect of these drugs on the activity of cyclooxygenase, a key enzyme in prostaglandin synthesis. Our earlier work with indomethacin, a commonly used NSAID, has shown that oxidative stress and mitochondrial dysfunction occur in the kidney in response to the drug. In view of this, this study looked into the effect of indomethacin on brush border membranes (BBM) from the kidney, as these biomembranes are prime targets of oxygen free radicals. Rats, fasted overnight, were dosed with indomethacin (20 mg/kg) by gavage and sacrificed 24 h later. BBM were isolated from the kidneys by polyethylene glycol precipitation. It was found that there was an increase in levels of products of peroxidation and a fall in the level of alpha-tocopherol in the BBM from indomethacin-dosed rats. These BBM also exhibited impaired glucose transport. The lipid composition of the membranes was also found to be altered. Alterations in lipids were associated with up-regulation of phospholipase A<SUB>2</SUB>. Pretreatment with L-arginine, a nitric oxide donor, protected against these effects of indomethacin. Thus, this study suggests that indomethacin induces impairment in structure and function of BBM in the kidney, with these effects possibly mediated by free radicals and activation of phospholipases. We postulate that such alterations may be important in the pathogenesis of NSAID-induced nephropathy

Integrative analysis of Multiple Sclerosis using a systems biology approach

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory-demyelinating events in the central nervous system. Despite more than 40 years of MS research its aetiology remains unknown. This study aims to identify the most frequently reported and consistently regulated molecules in MS in order to generate molecular interaction networks and thereby leading to the identification of deregulated processes and pathways which could give an insight of the underlying molecular mechanisms of MS. Driven by an integrative systems biology approach, gene-expression profiling datasets were combined and stratified into "Non-treated" and "Treated" groups and additionally compared to other disease patterns. Molecular identifiers from dataset comparisons were matched to our Multiple Sclerosis database (MuScle; www.padb.org/muscle ). From 5079 statistically significant molecules, correlation analysis within groups identified a panel of 16 high-confidence genes unique to the naïve MS phenotype, whereas the "Treated" group reflected a common pattern associated with autoimmune disease. Pathway and gene-ontology clustering identified the Interferon gamma signalling pathway as the most relevant amongst all significant molecules, and viral infections as the most likely cause of all down-stream events observed. This hypothesis-free approach revealed the most significant molecular events amongst different MS phenotypes which can be used for further detailed studies