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.     

Alcoholism and heredity: biological basis of the predisposition to alcoholism

Authors critically review current data about biochemical-physiological factors mediating genetic predisposition to alcoholism. Results of genetic investigation of the ethanol and acetaldehyde metabolism and the facts about enzyme polymorphism of systems of the ethanol biotransformation and genetic polymorphism of particular enzymes are summarized. Data about possible determinants of nervous system sensitivity to ethanol action are considered. The investigation of genetic basis of phenomena imminent to alcoholism by use of laboratory animals is discussed.     

Antimicrobial peptides and their use in medicine

The review presents the current classification of antimicrobial peptides (AMP), which are the main component of innate immunity. The mechanism of their action and the molecular basis of the formation of resistance towards these peptides are described. Data on the use of AMP for the treatment of various infectious diseases, as well as the state of the art in genetic therapy using AMP, are given.     

Bacillus cereus enterotoxins

Data about Bacillus cereus different enterotoxins including hemolysin (HBL), nonhemolytic enterotoxin (NHE), enterotoxin (T), and emesis-inducing thermostable enterotoxin (ETE) are summarized in the article. Information about synthesis of different diarrhea-inducing and emesis-inducing enterotoxins, methods of their purification, structure, functions, and mechanisms of action are presented. Commercial kits for identification of B. cereus enterotoxins causing food-associated diarrhea are listed.     

Plant mutants with altered responses to cytokinins

Compared with other phytohormones, relatively little is known about the biosynthesis and the molecular action of cytokinins. A number of plant mutants with changed response to, or requirement for cytokinins are now available. It is likely that the biochemical and molecular genetic analysis of these mutants will contribute considerably to our understanding of the nature of cytokinin action.     

Critical factors in assessing risk from exposure to nasal carcinogens

Anatomical, physiological, biochemical and molecular factors that contribute to chemical-induced nasal carcinogenesis are either largely divergent between test species and humans, or we know very little of them. These factors, let alone the uncertainty associated with our knowledge gap, present a risk assessor with the formidable task of making judgments about risks to human health from exposure to chemicals that have been identified in rodent studies to be nasal carcinogens. This paper summarizes some of the critical attributes of the hazard identification and dose–response aspects of risk assessments for nasal carcinogens that must be accounted for by risk assessors in order to make informed decisions. Data on two example compounds, dimethyl sulfate and hexamethylphosphoramide, are discussed to illustrate the diversity of information that can be used to develop informed hypotheses about mode of action and decisions on appropriate dosimeters for interspecies extrapolation. Default approaches to interspecies dosimetry extrapolation are described briefly and are followed by a discussion of a generalized physiologically based pharmacokinetic model that, unlike default approaches, is flexible and capable of incorporating many of the critical species-specific factors. Recent advancements in interspecies nasal dosimetry modeling are remarkable. However, it is concluded that without the development of research programs aimed at understanding carcinogenic susceptibility factors in human and rodent nasal tissues, development of plausible modes of action will lag behind the advancements made in dosimetry modeling.     

Molecular correlates of the murine Xce locus

The murine Xce locus, first identified by Bruce Cattanach, influences the primary choice of the X chromosome to be inactivated. Methylation of a GC-rich region (DXPas34) that includes multiple 34 bp repeats and lies some 15 kb 3' to Xist has been shown to vary with Xce haplotype. The degree of methylation on the active X chromosome at this locus represents one of the few molecular correlates of Xce action currently available. Data relating to the specificity and other characteristics of this association are presented.     

Comparative analysis of sensitivity of cholinesterases of different origin to reversible bis-onium inhibitors

Analytical review of literature data has been carried out about kinetic parameters of cholinesterases (ChE) of various animals (vertebrates and squids) with 45 reversible bis-onium inhibitors forming homologous series with regularly changing structure. Values of competitive, non-competitive, and generalized inhibitory constants are compared. Interspecies and intraspecies differences are revealed in sensitivity of ChE to bis-onium inhibitors. Results of conformational analysis of molecules of the studied ligands are presented. Data on population of individual conformations are compared with values of anticholinesterase efficiency. Conclusions are made about mechanisms of action of the studied compounds and the predominant site of their sorption. The presented data are discussed from the point of view of comparative enzymology and in the light of the current information about structure of active center of cholinesterases.     

Exploring the molecular mechanism of karrikins and strigolactones

Karrikins and strigolactones are novel plant growth regulators that contain similar molecular features, but very little is known about how they elicit responses in plants. A tentative molecular mechanism has previously been proposed involving a Michael-type addition for both compounds. Through structure-activity studies with karrikins, we now propose an alternative mechanism for karrikin and strigolactone mode of action that involves hydrolysis of the butenolide ring.     

The role of the electromechanical and reaction-diffusion system of intraneuronal information processing in brain function

The experimental data of previous papers are considered as a basis for the hypothesis about intraneuronal system controlled by cyclic nucleotides and changing the membrane permeability upon creating the generatory potential. This system is suggested to be an extremal molecular regulator in which the price of action per single operation approximates the physical limit. The electro-mechanical intraneuronal system is capable of solving multidimensional physical problems by means of molecular "digital" hypersound holo-gram coded by DNA molecular text which is an image of functions of target search.     

Pathogenicity factors of opportunistic enterobacteria and its role in development of diarrhea

The data of pathogenicity factors of opportunistic enterobacteria, including Klebsiella, Enterobacter, Citrobacter, Proteus, Providencia and Hafnia species are submitted. The genetic control and a role of pathogenicity factors of opportunistic enterobacteria in development of diarrhea syndrome are presented. Data about adhesins, hemolysins, cytotoxic necrotizing factors and bacterial modulins are described. The characteristic of cytotonic and cytotoxic enterotoxins, including LT, ST, Shiga-like and cytolethal toxins, and mechanisms of diarrheagenic action are analysed. The role of bacterial lipopolysaccharide (endotoxin) and induction of locally synthesized proinflammatory cytokins in pathogenisis of diarrhea are discussed.     

The microbial oxidation of methanol: The prosthetic group of the alcohol dehydrogenase of Pseudomonas sp. M27: a new oxidoreductase prosthetic group

1. The purified alcohol dehydrogenase of Pseudomonas sp. M27, whose action is independent of nicotinamide nucleotides, has absorption peaks at 280mmu and at 350mmu with little or no absorption at or above 450mmu. 2. It does not fluoresce, but green-fluorescent material, diffusible on dialysis, is produced when the enzyme is treated with acid or alkali or when it is boiled. 3. Evidence is presented that the enzyme is not a flavoprotein. 4. Kinetic studies show a correlation between enzyme inactivation by acid, alkali or heat and liberation of the fluorescent material. 5. Some purification of the fluorescent material was achieved, but definite identification was not possible; the major component has a fluorescence maximum at about 460mmu with excitation maxima at about 260mmu and 365mmu. 6. Data are given (including absorption and fluorescence spectra) that support the suggestion that the prosthetic group of the enzyme is a pteridine derivative. 7. Possible mechanisms of action of the enzyme are discussed.     

A window on disease pathogenesis and potential therapeutic strategies: molecular imaging for arthritis

Novel molecular imaging techniques are at the forefront of both preclinical and clinical imaging strategies. They have significant potential to offer visualisation and quantification of molecular and cellular changes in health and disease. This will help to shed light on pathobiology and underlying disease processes and provide further information about the mechanisms of action of novel therapeutic strategies. This review explores currently available molecular imaging techniques that are available for preclinical studies with a focus on optical imaging techniques and discusses how current and future advances will enable translation into the clinic for patients with arthritis.     

Linking tumor cell cytotoxicity to mechanism of drug action: an integrated analysis of gene expression, small-molecule screening and structural databases

An integrated, bioinformatic analysis of three databases comprising tumor-cell-based small molecule screening data, gene expression measurements, and PDB (Protein Data Bank) ligand-target structures has been developed for probing mechanism of drug action (MOA). Clustering analysis of GI50 profiles for the NCI's database of compounds screened across a panel of tumor cells (NCI60) was used to select a subset of unique cytotoxic responses for about 4000 small molecules. Drug-gene-PDB relationships for this test set were examined by correlative analysis of cytotoxic response and differential gene expression profiles within the NCI60 and structural comparisons with known ligand-target crystallographic complexes. A survey of molecular features within these compounds finds thirteen conserved Compound Classes, each class exhibiting chemical features important for interactions with a variety of biological targets. Protein targets for an additional twelve Compound Classes could be directly assigned using drug-protein interactions observed in the crystallographic database. Results from the analysis of constitutive gene expressions established a clear connection between chemo-resistance and overexpression of gene families associated with the extracellular matrix, cytoskeletal organization, and xenobiotic metabolism. Conversely, chemo-sensitivity implicated overexpression of gene families involved in homeostatic functions of nucleic acid repair, aryl hydrocarbon metabolism, heat shock response, proteasome degradation and apoptosis. Correlations between chemo-responsiveness and differential gene expressions identified chemotypes with nonselective (i.e., many) molecular targets from those likely to have selective (i.e., few) molecular targets. Applications of data mining strategies that jointly utilize tumor cell screening, genomic, and structural data are presented for hypotheses generation and identifying novel anticancer candidates.     

Kinesin backsteps

Kinesin-1 is a walking machine that takes ~8?nm steps along microtubules. Some aspects of the molecular mechanism of walking are now clear, but many are not. In the present paper, we discuss currently controversial points, focusing on the pathways by which kinesin takes occasional backsteps. Backsteps represent failures of the forwards-biasing mechanism. By studying the mechanochemistry of backstepping, one can learn much about the underlying molecular mechanisms responsible for forwards directional bias in the walking action.     

Properties and characterization of low molecular weight inhibitor of calmodulin-dependent cAMP phosphodiesterase from rat liver

We have identified two different species of inhibitors of calmodulin-dependent cAMP phosphodiesterase: 1) a low molecular weight (LMW) and 2) a high molecular weight (HMW) form. These inhibitors are extracted from rat liver. Both LMW and HMW inhibitors are heat-stable, acidic in nature and lose activity with prolonged storage and/or repeated freezing and thawing. The low molecular weight inhibitor has been purified to about 7,000-fold with 300% recovery. LMW inhibits calmodulin-dependent cAMP phosphodiesterase regardless of the source of calmodulin (e.g. fat, brain, heart, erythrocytes). LMW appears to be lipid in nature with a molecular weight of 1,500-5,000. The role of these inhibitors in diabetes and mechanism of action of insulin is presented.     

Plant hormone mutants

Many of the basic facts about plant hormones are still obscure, including biosynthetic pathways and their regulation. Furthermore, our knowledge of the molecular steps between hormones and their action is extremely limited. The increasing collection of isogenic genotypes differing in hormone synthesis or responses offers great promise for future research.     

Purification and some properties of alkaline pullulanase from a strain of bacillus no. 202-1, an alkalophilic microorganism.

Pullulanase (pullulan 6-glucanohydrolase EC 3.2.1.41) was purified about 290-fold from the culture fluid of Bacillus No. 202-1 by DEAE-cellulose adsorption, acetone fractionation, (NH4) 2SO4 precipitation and DEAE--cellulose column chromatography followed by Sephadex G-200 molecular sieve chromatography. The enzyme gave a single band of protein by disc polyacrylamide gel electrophoresis. The molecular weight was estimated as 92 000 by sodium dodecyl sulfate gel electrophoresis. The isolectric point was lower than pH 2.5. The optimum pH for enzyme action was about 8.5-9.0. The action of the enzyme on amylopectin and glycogen resulted in increase in the iodine coloration of 85% and 70%, respectively. The enzyme completely hydrolyzed 1,6-alpha-glucosidic linkages in amylopectin, glycogen and pullulan.     

Polygalacturonic acid/endo-polygalacturonase system: a kinetic study in batch reactors

The enzymatic depolymerization of the pectic substance polygalacturonic acid (PGA) is studied in batch reactor. The number-average molecular weight of native substrate is estimated, using a simple and quick technique, to be approximately 11.1 kDa, the polymeric chains consisting on average of 63 galacturonic acid units. The effect of enzyme concentration was studied varying biocatalyst loading from 6 to 242 mg/L. The experiments were repeated at substrate concentrations ranging from 0.5 to 5 g/L. Data obtained at both short reaction time (20 min) and prolonged enzyme action (up to 350 min) are correlated using different kinetic equations, and the parameter values are discussed.     

Pharmacological characterisation of spider antimicrobial peptides

Most spider antimicrobial peptides share a common mechanism of membrane permeabilisation and the innate immune systems of the pathogen. In this review, we present recent accounts of the application at the preclinical level that should be tried and the range of bioactivities and their particular structure can be harnessed for molecular engineering applications and in drug design. Structural analyses such as amino acid sequence and circular dichroism are described. Conductance measurements and pharmacological studies of the action on the inner or outer membranes of anti-microbe will reveal more about the mode of action of the antimicrobial peptides of spider.