Effects of diesel exhaust, heavy metals and pesticides on various organ systems: possible mechanisms and strategies for prevention and treatment

Environmental pollutants have a significant impact on the ecosystem and disrupt balance between environment, human and non-human components that result in deleterious effects to all forms of life. Identifying environmental factors for potential imbalance are extremely crucial for devising strategies for combating such toxic dysregulation. Automobile exhaust (in air), heavy metals (in food and water) and pesticides (in air, food, soil and water) are the most common environmental pollutants and their short and long-term exposures can cause hazardous effects in humans leading to systemic disorders involving lungs, kidney and immune systems. Mechanisms involved in genesis of such toxic effects have revealed complex, interactive pathways. Strategies for the protection of homeostasis and health, viz., general preventive measures, nutritional supplements and herbal agents have been described, to counter these pollutants induced damaging effects on various body systems.     

The divergent TGF-beta ligand Dawdle utilizes an activin pathway to influence axon guidance in Drosophila

Axon guidance is regulated by intrinsic factors and extrinsic cues provided by other neurons, glia and target muscles. Dawdle (Daw), a divergent TGF-beta superfamily ligand expressed in glia and mesoderm, is required for embryonic motoneuron pathfinding in Drosophila. In daw mutants, ISNb and SNa axons fail to extend completely and are unable to innervate their targets. We find that Daw initiates an activin signaling pathway via the receptors Punt and Baboon (Babo) and the signal-transducer Smad2. Furthermore, mutations in these signaling components display similar axon guidance defects. Cell-autonomous disruption of receptor signaling suggests that Babo is required in motoneurons rather than in muscles or glia. Ectopic ligand expression can rescue the daw phenotype, but has no deleterious effects. Our results indicate that Daw functions in a permissive manner to modulate or enable the growth cone response to other restricted guidance cues, and support a novel role for activin signaling in axon guidance.     

The monomer/dimer transition of enzyme I of the Escherichia coli phosphotransferase system

Enzyme I (EI) is the first protein in the phosphotransfer sequence of the bacterial phosphoenolpyruvate:glycose phosphotransferase system. This system catalyzes sugar phosphorylation/transport and is stringently regulated. Since EI homodimer accepts the phosphoryl group from phosphoenolpyruvate (PEP), whereas the monomer does not, EI may be a major factor in controlling sugar uptake. Previous work from this and other laboratories (e.g. Dimitrova, M. N., Szczepanowski, R. H., Ruvinov, S. B., Peterkofsky, A., and Ginsburg A. (2002) Biochem. 41, 906-913), indicate that K(a) is sensitive to several parameters. We report here a systematic study of K(a) determined by sedimentation equilibrium, which showed that it varied by 1000-fold, responding to virtually every parameter tested, including temperature, phosphorylation, pH (6.5 versus 7.5), ionic strength, and especially the ligands Mg(2+) and PEP. This variability may be required for a regulatory protein. Further insight was gained by analyzing EI by sedimentation velocity, by near UV CD spectroscopy, and with a nonphosphorylatable active site mutant, EI-H189Q, which behaved virtually identically to EI. The singular properties of EI are explained by a model consistent with the results reported here and in the accompanying paper (Patel, H. V., Vyas, K. A., Mattoo, R. L., Southworth, M., Perler, F. B., Comb, D., and Roseman, S. (2006) J. Biol. Chem. 281, 17579-17587). We suggest that EI and EI-H189Q each comprise a multiplicity of conformers and progressively fewer conformers as they dimerize and bind Mg(2+) and finally PEP. Mg(2+) alone induces small or no detectable changes in structure, but large conformational changes ensue with Mg(2+)/PEP. This effect is explained by a "swiveling mechanism" (similar to that suggested for pyruvate phosphate dikinase (Herzberg, O., Chen, C. C., Kapadia, G., McGuire, M., Carroll, L. J., Noh, S. J., and Dunaway-Mariano, D. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2652-2657)), which brings the C-terminal domain with the two bound ligands close to the active site His(189).     

Fish oil and vascular endothelial protection: bench to bedside

Fish oil is recommended for the management of hypertriglyceridemia and to prevent secondary cardiovascular disorders. Fish oil is a major source of ω-3-polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Clinical studies suggest that fish oil not only prevents the incidence of detrimental cardiovascular events, but also lowers the cardiovascular mortality rate. In addition to a classic lipid-lowering action, ω-3-PUFAs in fish oil could regulate blood pressure and enhance vascular integrity and compliance. Additionally, ω-3-PUFAs have the ability to protect vascular endothelial cells by decreasing oxidative stress, halting atherosclerotic events, and preventing vascular inflammatory and adhesion cascades. Intriguingly, recent studies have demonstrated that ω-3-PUFAs improve the function of vascular endothelium by enhancing the generation and bioavailability of endothelium-derived relaxing factor (nitric oxide) through upregulation and activation of endothelial nitric oxide synthase (eNOS). This certainly opens up a new area of research identifying potential mechanisms influencing fish oil-mediated functional regulatory action on vascular endothelium. We address in this review the potential of fish oil to prevent vascular endothelial dysfunction and associated cardiovascular disorders. Moreover, the mechanisms pertaining to fish oil-mediated eNOS activation and nitric oxide generation in improving endothelial function are delineated. We finally suggest the importance of further studies to determine the dose adjustment of fish oil with an optimal ratio of EPA and DHA for achieving consistent cardiovascular protection.     

Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome

A protective association between bilirubin and atherosclerosis/ischemic heart disease clearly exists in vivo. However, the relationship between bilirubin and in vivo oxidative stress parameters in a clinical population remains poorly described. The aim of this study was to assess whether persons expressing Gilbert syndrome (GS; i.e., unconjugated hyperbilirubinemia) are protected from thiol oxidation and to determine if this, in addition to their improved lipoprotein profile, could explain reduced oxidized low-density lipoprotein (oxLDL) status in them. Forty-four matched GS and control subjects were recruited and blood was prepared for the analysis of lipid profile and multiple plasma antioxidants and measures of oxidative stress. GS subjects possessed elevated plasma reduced thiol (8.03±1.09 versus 6.75±1.39 nmol/mg protein; P<0.01) and glutathione concentrations (12.7±2.39 versus 9.44±2.45 μM; P<0.001). Oxidative stress status (reduced:oxidized glutathione; GSH:GSSG) was significantly improved in GS (0.49±0.16 versus 0.32±0.12; P<0.001). Protein carbonyl concentrations were negatively associated with bilirubin concentrations and were significantly lower in persons with >40 μM bilirubin versus controls (<17.1 μmol/L; P<0.05). Furthermore, absolute oxLDL concentrations were significantly lower in GS subjects (P<0.05). Forward stepwise regression analysis revealed that bilirubin was associated with increased GSH:GSSG ratio and reduced thiol concentrations, which, in addition to reduced circulating LDL, probably decreased oxLDL concentrations within the cohort. In addition, a marked reduction in total cholesterol concentrations in hyperbilirubinemic Gunn rats is presented (Gunn 0.57±0.09 versus control 1.69±0.40 mmol/L; P<0.001), arguing for a novel role for bilirubin in modulating lipid status in vivo. These findings implicate the physiological importance of bilirubin in protecting from atherosclerosis by reducing thiol and subsequent lipoprotein oxidation, in addition to reducing circulating LDL concentrations.     

In silico study of interaction between rice proteins enhanced disease susceptibility 1 and phytoalexin deficient 4, the regulators of salicylic acid signalling pathway

Enhanced disease susceptibility 1 (EDS1), a plant-specific protein has homology with the eukaryotic lipase in their N-terminal halves and a unique domain at its C-termini. EDS1 is known to be an important regulator of biotic stress and an essential component of basal immunity. EDS1 interacts with its positive co-regulator phytoalexin deficient 4 (PAD4), resulting in mobilization of the salicylic acid defence pathway. Limited information regarding this interaction in rice is available. To study this interaction, a model of EDS1 and PAD4 proteins from rice was generated and validated with Accelrys DS software version 3.1 using bioinformatics interface. The in silico docking between the two proteins showed a significant protein-protein interaction between rice EDS1 and PAD4, suggesting that they form a dimeric protein complex, which, similar to that in Arabidopsis, is perhaps also important for triggering the salicylic acid signalling pathway in plants.