Computer search for molecular mechanisms of ulcerogenic action of non-steroidal anti-inflammatory drugs

Peptic ulcers are the most frequent side effect of therapy with non-steroidal anti-inflammatory drugs (NSAIDs). Good experimental evidence exists that pathogenesis of peptic ulcers cannot be attributed only to inhibition of cyclooxygenases. The knowledge about other molecular mechanisms of drug action associated with development of peptic ulcers could be useful for design of new safer NSAIDs. However, considerable time and material resources are needed for corresponding experimental studies. For simplification of the experimental search, we have developed an approach for in silico identification of putative molecular mechanisms of drug actions associated with their side effects. We have generated a data set of 85 NSAIDs, which includes information about their structures and side effects. Unknown molecular mechanisms of action of these NSAIDs were evaluated by the computer program PASS (Prediction of Activity Spectra for Substances) predicting more than 3000 molecular mechanisms of action based on structural formula of sub-stances. Statistically significant associations have been found between predicted molecular mechanisms of action and development of peptic ulcers. Twenty six molecular mechanisms of action probably associated with development of peptic ulcers have been found: two of them were known previously and 24 were quite new. Analyzing Gene Ontology data, data on signal and metabolic pathways, and available MEDLINE publication data, we proposed hypotheses on the role of 10 molecular mechanisms of action in the pathogenesis of peptic ulcer.     

FTIR microspectroscopic analysis of the effects of certain drugs on oxidative stress and brain protein structure

This study reports the changes in lipids and proteins of different brain areas of nicotine, D+-amphetamine, and nicotine and D+-amphetamine treated rats by monitoring lipid peroxidation and protein beta-sheet formation using infrared microspectroscopy. Compared with the untreated brain samples, the peroxide level is relatively higher in the amphetamine-treated brain sections, both in the cortex and hippocampus area. However, this peroxide increase is attenuated when administering amphetamine plus nicotine. Analogous drug-dependent trends for protein beta-sheet content are observed, which suggests a connection between lipid oxidation involved in oxidative stress and beta-sheet protein structure generally present in neurodegenerative diseases. The above property of nicotine is of interest, in the sense that it might reduce the production of beta-amyloid proteins in Alzheimer's disease.     

Transformation of physiological gastroprotective effects of glucocorticoids into pathological ulcerogenic consequences

The study was designed to investigate how physiological gastroprotective action of glucocorticoids could be transformed to pathological proulcerogenic effect. Time-dependent effects of single injection of dexamethasone on stress-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in fasted rats. Dexamethasone injected at the same dose attenuated or aggravated the stress-induced gastric erosions depending on the time of the injection. In case of dexamethasone injection 1-12 hrs before stress, we observed its gastroprotective action. Further increase in the time interval caused transformation of the gastroprotective action of dexamethasone to proulcerogenic effect. Accordingly to the results obtained, dexamethasone-induced long-lasting maintenance of blood glucose levels accompanied with signs of catabolic effect as well as dexamethasone-induced corticosterone deficiency may be responsible, at least partly, for the transformation of gastroprotective effect of dexamethasone to the proulcerogenic one.     

The effects of ultraviolet light and certain drugs on Ia-bearing Langerhans cells in murine epidermis

Langerhans cells and indeterminate cells are immune macrophages of the epidermis and have Ia markers on their surface. Because of their position in the epidermis, they are subject to many environmental toxins like ultraviolet light. Also medications like cortisone applied topically to the skin could have important effects on these cells. We have used an anti-Ia serum and an indirect immunofluorescent technique to study Langerhans cells in epidermal sheets. We found that shortwave ultraviolet light (250–320 nm) and ultraviolet B (280–320nm) increased the density of Ia-bearing cells (Langerhans cells) in the skin. Psoralens and ultraviolet A (PUVA) (320–400 nm) depleted the skin of Ia-bearing cells, an effect which takes 2 weeks to produce but which persists for several weeks after stopping treatment. Triamcinolone acetonide administered topically or intraperitoneally also depletes the skin of Ia-bearing cells. These agents, light and steroids, either destroy the Ia-bearing cells or remove the Ia markers from the cellular surface.