Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity.

AIMS: Aldosterone plays a crucial role in cardiovascular disease. 'Systemic' inhibition of its mineralocorticoid receptor (MR) decreases atherosclerosis by reducing inflammation and oxidative stress. Obesity, an important cardiovascular risk factor, is an inflammatory disease associated with increased plasma aldosterone levels. We have investigated the role of the 'endothelial' MR in obesity-induced endothelial dysfunction, the earliest stage in atherogenesis. METHODS AND RESULTS: C57BL/6 mice were exposed to a normal chow diet (ND) or a high-fat diet (HFD) alone or in combination with the MR antagonist eplerenone (200 mg/kg/day) for 14 weeks. Diet-induced obesity impaired endothelium-dependent relaxation in response to acetylcholine, whereas eplerenone treatment of obese mice prevented this. Expression analyses in aortic endothelial cells isolated from these mice revealed that eplerenone attenuated expression of pro-oxidative NADPH oxidase (subunits p22phox, p40phox) and increased expression of antioxidative genes (glutathione peroxidase-1, superoxide dismutase-1 and -3) in obesity. Eplerenone did not affect obesity-induced upregulation of cyclooxygenase (COX)-1 or prostacyclin synthase. Endothelial-specific MR deletion prevented endothelial dysfunction in obese (exhibiting high 'endogenous' aldosterone) and in 'exogenous' aldosterone-infused lean mice. Pre-incubation of aortic rings from aldosterone-treated animals with the COX-inhibitor indomethacin restored endothelial function. Exogenous aldosterone administration induced endothelial expression of p22phox in the presence, but not in the absence of the endothelial MR. CONCLUSION: Obesity-induced endothelial dysfunction depends on the 'endothelial' MR and is mediated by an imbalance of oxidative stress-modulating mechanisms. Therefore, MR antagonists may represent an attractive therapeutic strategy in the increasing population of obese patients to decrease vascular dysfunction and subsequent atherosclerotic complications.

The role of a transcrustal shear zone in orogenic gold mineralization at the Aijanahalli Mine, Dharwar Craton, South India

The Ajjanahalli gold mine is spatially associated with a Late Archean craton-scale shear zone in the eastern Chitradurga greenstone belt of the Dharwar craton, India. Gold mineralization is hosted by an similar to100-m-wide antiform in a banded iron formation. Original magnetite and siderite are replaced by a peak metamorphic alteration assemblage of chlorite, stilpnomelane, minnesotaite, sericite, ankerite, arsenopyrite, pyrite, pyrrhotite, and gold at ca. 300degrees to 350degreesC. Elements enriched in the banded iron formation include Ca, Mg, C, S, An, As, Bi. Cu, Sb, Zn, Pb, Se, Ag, and Te, whereas in the wall rocks As, Cu, Zn, Bi, Ag, and An are only slightly enriched. Strontium correlates with CaO, MgO, CO2, and As, which indicates cogenetic formation of arsenopyrite and Mg-Ca carbonates. The greater extent of alteration in the Fe-rich banded iron formation layers than in the wall rock reflects the greater reactivity of the banded iron formation layers. The ore fluids, as interpreted from their isotopic composition (delta(18)O = 6.5-8.5parts per thousand; initial Sr-87/Sr-86 = 0.7068-0.7078), formed by metamorphic devolatilization of deeper levels of the Chitradurga greenstone belt. Arsenopyrite, chalcopyrite, and pyrrhotite have delta(34)S values within a narrow range between 2.1 and 2.7 per mil, consistent with a sulfur source in Chitradurga greenstone belt lithologies. Based on spatial and temporal relationships between mineralization, local structure development, and sinistral strike-slip deformation in the shear zone at the eastern contact of the Chitradurga greenstone belt, we suggest that the Ajjanahalli gold mineralization formed by fluid infiltration into a low strain area within the first-order structure. The ore fluids were transported along this shear zone into relatively shallow crustal levels during lateral terrane accretion and a change from thrust to transcurrent tectonics. Based on this model of fluid flow, exploration should focus on similar low strain areas or potentially connected higher order splays of the first-order shear zone.

Immuno-reactive proteins from Mycobacterium immunogenum useful for serodiagnosis of metalworking fluid hypersensitivity pneumonitis.

Metalworking fluid-associated hypersensitivity pneumonitis (MWF-HP) is a pulmonary disease caused by inhaling microorganisms present in the metalworking fluids used in the industrial sector. Mycobacterium immunogenum is the main etiological agent. Among the clinical, radiological and biological tools used for diagnosis, serological tests are important. The aim of this study was to identify immunogenic proteins in M. immunogenum and to use recombinant antigens for serological diagnosis of MWF-HP. Immunogenic proteins were detected by two-dimensional Western blot and candidate proteins were identified by mass spectrometry. Recombinant antigens were expressed in Escherichia coli and tested by enzyme-linked immunosorbent assay (ELISA) with the sera of 14 subjects with MWF-HP and 12 asymptomatic controls exposed to M. immunogenum. From the 350 spots visualized by two-dimensional gel electrophoresis with M. immunogenum extract, 6 immunogenic proteins were selected to be expressed as recombinant antigens. Acyl-CoA dehydrogenase antigen allowed for the best discrimination of MWF-HP cases against controls with an area under the receiver operating characteristics (ROC) curve of 0.930 (95% CI=0.820-1), a sensitivity of 100% and a specificity of 83% for the optimum threshold. Other recombinant antigens correspond to acyl-CoA dehydrogenase FadE, cytosol aminopeptidase, dihydrolipoyl dehydrogenase, serine hydroxymethyltransferase and superoxide dismutase. This is the first time that recombinant antigens have been used for the serodiagnosis of hypersensitivity pneumonitis. The availability of recombinant antigens makes it possible to develop standardized serological tests which in turn could simplify diagnosis, thus making it less invasive.

Oligodendroglia metabolically support axons and contribute to neurodegeneration.

Oligodendroglia support axon survival and function through mechanisms independent of myelination, and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been proposed. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and use. Here we show that the most abundant lactate transporter in the central nervous system, monocarboxylate transporter 1 (MCT1, also known as SLC16A1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and in mouse models of, amyotrophic lateral sclerosis, suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons.