Current Chemical Biology - Volume 3, Issue 3, 2009

Hypoxia is a decrease in tissue oxygen concentration, normally caused by a reduction in the partial pressure of atmospheric oxygen. Due to the exposition to hypoxia, reactive oxygen species (ROS) are continuously generated and, therefore, increased risks of oxidative lesions have been reported. ROS may severely damage lipids, proteins and DNA. The most important source of ROS during hypoxia is the mitochondria, which release cytochrome c following oxidative damage. Once released, cytochrome c may activate the caspase cascade, switching on the apoptotic pathway. ROS generation is typically associated with brain injury. The brain contains low activity of antioxidants enzymes, it is rich in lipids and it has high metabolic activity. The combination of these factors makes the brain particularly vulnerable to oxidative stress. Also, it has recently been demonstrated that ROS acts as a physiological signal in many cells, including neurons. A protective role of ROS in neuronal plasticity has been suggested. Erythropoietin (EPO), one of the best-known mediators of the physiological response to hypoxia, has been recently reported in the central nervous system. Over the last few years, EPO has been shown to exert neuroprotection, and its role as an antioxidant agent is currently under discussion. In agreement with recent works, we will present the generation of ROS during exposure to hypoxia, and we will define what degree of oxidative stress is necessary to induce physiological adaptations. Moreover, the effects of EPO will be discussed according to its newly described role as an inhibitor of the oxidative stress.

This review will describe the recent advances in the field of oligosaccharides containing at least one unit of a polyhydroxylated piperidine or pyrrolidine. The review will cover both chemical and biological aspects concerning their preparation and/or occurrence in Nature as well as their biological properties which include glycosylase, and glycosyl transferase inhibition, among others. These enzymatic inhibitory properties are the basis for the potential use of the title compounds in viral infections, cancer and genetic disorders.

Copper has potent biocidal properties. Copper ions, either alone or in copper complexes, have been used for centuries to disinfect liquids, solids and human tissue. This manuscript reviews the biocidal mechanisms of copper and the current usages of copper and copper compounds as antibacterial, antifungal and antiviral agents, with emphasis on novel health related applications. These applications include the reduction of transmission of health-associated (nosocomial) pathogens, foodborne diseases, and dust mites loads and treatment of fungal foot infections and wounds. Possible future applications include filtration devices capable of deactivating viruses in solutions, such as contaminated blood products and breastmilk.

Enzymes are catalysts adapted to function in biological systems. This review shows how chemical processes contribute to the adaptations. The catalyst is exemplified by the 2-oxoglutarate dehydrogenase complex irreversibly degrading a branch point metabolite 2-oxoglutarate at the crossroad of carbon and nitrogen metabolism. According to the key metabolic position and multienzyme structure, the complex exhibits rich regulation, demonstrating main principles governing the catalysis within metabolic network. First, the catalyst structure influencing its kinetics is changed through the enzyme-ligand interactions. The ligands may either participate in catalysis as coenzymes, substrates and products, or be allosteric effectors binding to regulatory sites. Allostery enables enzymatic responses to general cellular signals, transmitted by second messengers (Ca2+), adenine nucleotide phosphorylation status or redox potential. Secondly, different regulators may interact through the protein structure effecting synergistic or antagonistic relationships through combined conformational stabilization or competitive binding. The latter is supported by common structural elements, e.g. adenine moiety, present in a number of biologically essential molecules. Thirdly, cellular systems may control the enzymatic catalysis by posttranslational modifications which may either effect or disable catalysis. The inactivation may be used for protection of catalyst itself and/or surrounding medium under conditions of metabolic impairment.

Protein digestion is a key procedure prior to mass spectrometry identification in proteome research. During the past decade, a variety of microfluidic enzymatic bioreactors have been developed for highly efficient proteolysis. This review focuses on the recent advances and the key strategies of microfluidic bioreactors for digesting and identifying proteins. The subjects covered include the fabrication of microfluidic systems, protease immobilization in microchannels, typical applications of microfluidic bioreactors in highly efficient proteolysis, and future prospects. It is expected that microfluidic bioreactors will become powerful tools in proteome research and will find wide applications in high throughput protein digestion and identification.

Background: The most potent angiogenic factor is the vascular endothelial growth factor (VEGF), and CD34 is an endothelial antigen that has been used to highlight the microvasculature vessel density (MVD) as a direct marker of the degree of neoangiogenesis. In the present study we report that VEGF expression and its relationship with MVD, in poorly and well differentiated colon adenocarcinoma, in order to consider the possibility of using the correlation between both antibodies as a prognostic factor. Materials and Methods: Tumor sections were stained by immunohistochemistry for CD34 and VEGF. Results: The mean of VEGF and CD34 did not show any significant differences between both types of tumors. Conclusion: The conventional factors taken into consideration were not significantly related to the angiogenic factors examined, so we could affirm that the correlation of both markers could be useful as prognostic factor.

Experiments with a cell culture of ascitic hepatoma A/He showed that dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in a complex with apolipoprotein A-I (apoA-I) stimulate synthesis of DNA and protein, whereas the hormones themselves do not have such an effect. The initiation mechanism of these processes was studied with synthetic oligonucleotides of (GCC)n type. A search over the international database (Gene Bank) revealed the presence of repetitions of this type in various mammalian genes, in particular, in the structure of promoter regions. IR spectroscopy was used to study the interaction mechanism of DHEA and DHEAS as well as their apoA-I complexes with the duplex CC(GCC)5 . GG(CGG)5. It was found that DHEA and DHEAS increase the orderliness of CC(GCC)5 . GGG(CGG)5 duplex according to the order - order structural transition, whereas their complexes DHEAS - apoA-I and DHEA - apoA-I incubated with the duplex, on the contrary, initiate disordering of the duplex secondary structure (the order - disorder transition), thus leading to its melting. Interaction of the duplex with these hormones results in the formation of hydrogen bonds involving SO3H, CO-groups and CH-bonds of DHEAS, and OH-group of the A-ring, CO and CH-bonds of DHEA. Active site of the duplex comprises CO, NH-bonds of nitrous bases, PO2 - and O4-C4-C5-O5- bonds of the sugar-phosphate chain. The role of duplex melting under the action of DHEA - apoA-I and DHEAS - apoAI complexes in the initiation mechanism of gene expression as well as the enhancement of DNA and protein synthesis are discussed.

Tobacco smoking is a highly addictive social behavior and a major cause of morbidity and mortality. It causes or exacerbates a multitude of pathological conditions and in both the adult and the fetus may have various detrimental effects. Tobacco smoke contains more than 4000 chemicals including a huge repertoire of addictive and/or toxic components including nicotine, benzene, cadmium, vinyl chloride, chromium and 2-naphthylamine, all of which are recognized carcinogens (WHO). All of these agents have been implicated in a myriad of pathological conditions. Nevertheless the mechanisms by which tobacco smoke induces these pathological changes is not clear. Several areas of particular relevance relate to smoke-induced connective tissue alterations and of course genetic changes. In the case of the former, smokeinduced skin and oral cavity related alterations in connective tissue have received some attention. In both cases matrix metalloproteinases (MMPs) are implicated in tissue degradation and reduced collagen synthesis. While such changes may not be life threatening, other smoke induced changes in organs such as the lungs or heart carry with them potential for significant increases in mortality or morbidity. The direct exposure endured by the lungs to inhaled smoke, whether as primary smoke from the cigarette or as secondary from the environment, now generally termed passive smoking, may be associated with altered MMP gene expression in lung airway epithelium and be related to development of chronic obstructive pulmonary disease or asthma. The present review will provide background on structure and function of the MMPs and examine the evidence that tobacco smoke alters MMP gene expression and MMP activity and the role these changes may play in connective tissue changes in tissues and cells. We will also discuss ongoing work in our laboratory which is directed to determining smoke-induced alterations in MMP release particularly in lung cells.

Galanthus nivalis agglutinin (GNA)-related lectin family, a superfamily of strictly mannose-binding specific lectins widespread among monotyledonous plants, is well-known to possess a broad range of biological functions such as anti-tumor, anti-fungal and anti-viral activities. Growing insights into the investigations of them provide us a principal force to start this review with a variety of evidences to landmark their biological activities, molecular mechanisms and potential therapeutic applications. Herein, we mainly focused on a comprehensive study on a great number of reported GNA-related lectins with the anti-tumor activity. On the trail of such clues, we studied some GNA-related lectins with anti-tumor effects and explored the apoptosis- and autophagy-induced activities and related molecular mechanisms. These inspiring results further provide us more convincing evidence to understand the anti-cancer molecular mechanisms implicated in apoptosis and autophagy. In addition, GNA-related lectins also possess marked anti-HIV activities and the specific molecular mechanisms are also explored herein. To sum up, GNA-related lectin family would play a key role as a potential drug in future therapeutics.

Members of the viral family Flaviviridae are a major cause of infectious diseases, such as hepatitis C, Dengue fever, Japanese encephalitis, Yellow fever or West Nile fever. Major efforts are therefore being made to identify medicines that can fight these infections. The genome of the Flaviviridae contains a single ORF that is translated into a precursor polyprotein which is processed in the host into several proteins. Amongst these, the nonstructural protein 3 (NS3) is formed from two domains that show distinct catalytic activities: a serine protease and a helicase activity. Since both activities are required for viral replication, there is a lot of interest in investigating NS3 as a potential drug target. On the basis of the structural information available, we shall assess here the druggability of the helicase domain of NS3.

Due to an oversight, there has been a misprinting of the symbol β at 4 instances on page 184, appearing as mere boxes instead of the symbol, in the article entitled “The Role of Fatty Acids in the Activity of the Uncoupling Proteins” by Maria del Mar Gonzalez-Barroso and Eduardo Rial, Current Chemical Biology, May 2009, Vol. 3(2), pp. 180-188.