Diphenyl ditelluride targets brain selenoproteins in vivo: inhibition of cerebral thioredoxin reductase and glutathione peroxidase in mice after acute exposure

In this study, we investigated the effect of diphenyl ditelluride (PhTe)₂ administration (10 and 50?μmol/kg) on adult mouse behavioral performance as well as several parameters of oxidative stress in the brain and liver. Adult mice were injected with (PhTe)₂ or canola oil subcutaneously (s.c.) daily for 7?days. Results demonstrated that (PhTe)₂ induced prominent signs of toxicity (body weight loss), behavioral alterations and increased in lipid peroxidation in brain. 50?μmol/kg (PhTe)₂ inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), a redox sensitive enzyme. (PhTe)₂ caused an increase in cerebral non-protein thiol (NPSH) and protein thiol (PSH) groups. In the liver, 50?μmol/kg (PhTe)₂ decreased NPSH, but did not alter the content of protein thiol groups. (PhTe)₂ decreased cerebral antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and thioredoxin reductase (TrxR). In liver, (PhTe)₂ increase SOD and GR and decreased GPx activity. Results obtained herein suggest that the brain was more susceptible to oxidative stress induced by (PhTe)₂ than the liver. Furthermore, we have demonstrated for the first time that TrxR is an in vivo target for (PhTe)_2. Combined, these results highlight a novel molecular mechanism involved in the toxicity of (PhTe)₂. In particular the inhibition of important selenoenzymes (TrxR and GPx) seems to be involved in the neurotoxicity associated with (PhTe)₂ exposure in adult mice.     

Cellular transport and homeostasis of essential and nonessential metals

Metals can have a number of detrimental or beneficial effects in the cell, but first they must get in. Organisms have evolved transport mechanisms to get metals that are required, or essential into the cell. Nonessential metals often enter the cell through use of the machinery provided for essential metals. Much work has been done to advance our understanding of how these metals are transported across plasma and organelle membranes. This review provides an overview of essential and nonessential metal transport and homeostatic processes.     

Thyroid Hormones and Methylmercury Toxicity

Thyroid hormones are essential for cellular metabolism, growth, and development. In particular, an adequate supply of thyroid hormones is critical for fetal neurodevelopment. Thyroid hormone tissue activation and inactivation in brain, liver, and other tissues is controlled by the deiodinases through the removal of iodine atoms. Selenium, an essential element critical for deiodinase activity, is sensitive to mercury and, therefore, when its availability is reduced, brain development might be altered. This review addresses the possibility that high exposures to the organometal, methylmercury (MeHg), may perturb neurodevelopmental processes by selectively affecting thyroid hormone homeostasis and function.     

Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are the two ligands of the Tie-2 receptor, a receptor tyrosine kinase that is expressed on the endothelium. A balanced angiopoietin/Tie-2 system is critical for the maintenance of vascular integrity. We investigated the potential role of a disrupted angiopoietin/Tie-2 system on hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Using streptozotocin (STZ) mice subjected to myocardial ischemia, we examined the effects of shifting the Ang-2-to-Ang-1 ratio on myocardial infarction size, apoptosis, bone marrow (BM) cell-endothelial progenitor cell (EPC) differentiation, and angiogenesis. In control mice, myocardial ischemia increased expression of both Ang-2 and Tie-2. In STZ mice, Ang-2 expression was elevated, whereas Tie-2 expression was reduced, and neither was significantly altered by ischemia. Myocardial infarct size and apoptosis were increased in STZ compared with control mice. Using in vivo administration of an adenovirus containing Ang-1 or Ang-2, we found that shifting the Ang-2-to-Ang-1 ratio to favor Ang-1 reduced myocardial apoptosis and infarct size in STZ mice, while shifting the Ang-2-to-Ang-1 ratio to favor Ang-2 resulted in a significant increase in myocardial infarct size and apoptosis in control mice. Myocardial ischemia-stimulated BM cell-EPC differentiation was inhibited and myocardial angiogenesis was reduced in STZ mice. Systemic administration of Ad-Ang-1 restored BM cell-EPC differentiation and increased myocardial VEGF expression and angiogenesis in STZ mice. Our data demonstrate that disturbed angiopoietin/Tie-2 signaling contributes to the hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Restoration of the Ang-2-to-Ang-1 ratio may be a novel therapeutic strategy for the treatment of diabetic myocardial ischemic diseases.     

Bradykinin- and thrombin-induced increases in endothelial permeability occur independently of phospholipase C but require protein kinase C activation

We determined whether activation of phosphatidylinositol-specific phospholipase C (PI-PLC) and a subsequent increase in cytosolic calcium concentration ([Ca²⁺]_i) was an obligatory signaling event mediating the increase in transendothelial permeability induced by bradykinin (BK) and α-thrombin (α-T). Both BK and α-T (each at a concentration range of 0.01–1 μM) caused dose-dependent increases in transendothelial ¹²⁵I-albumin permeability in cultured bovine pulmonary artery endothelial cell monolayers. Both agonists also produced a rise in inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] by 10 sec that was followed by a prolonged increase in [Ca²⁺]_i. Pretreatment of endothelial cells with the PLC inhibitor, 1-(6-((17β-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dion [(U73122) at 10 μM for 15 min], prevented the increases in Ins(1,4,5)P₃ and [Ca²⁺]_i induced by both BK and α-T. However, inhibition of PLC with U73122 or another PLC inhibitor, neomycin, did not prevent the increase in endothelial permeability induced by either agonist. In contrast, depletion of cellular protein kinase C (PKC) with phorbol-12-myristate 13-acetate (0.01 μM for 20 hr) increased both BK- and α-T-induced phosphoinositide turnover but inhibited the agonist-induced increase in permeability. A PKC inhibitor, staurosporine (5 μM) likewise inhibited the BK-induced increase in endothelial cell permeability to albumin. We conclude that increases in endothelial permeability induced by the inflammatory mediators, BK and thrombin, can occur independently of PLC activation and increased [Ca²⁺]_i but that a PKC-dependent pathway is required for the permeability response. J. Cell. Physiol. 173:387–396, 1997. © 1997 Wiley-Liss, Inc.     

Manganese exposure among smelting workers: blood manganese–iron ratio as a novel tool for manganese exposure assessment

Unexposed control subjects (n = 106), power distributing and office workers (n = 122), and manganese (Mn)-exposed ferroalloy smelter workers (n = 95) were recruited to the control, low and high groups, respectively. Mn concentrations in saliva, plasma, erythrocytes, urine and hair were significantly higher in both exposure groups than in the controls. The Fe concentration in plasma and erythrocytes, however, was significantly lower in Mn-exposed workers than in controls. The airborne Mn levels were significantly associated with Mn/Fe ratio (MIR) of erythrocytes (eMIR) (r = 0.77, p < 0.01) and plasma (pMIR) (r = 0.70, p < 0.01). The results suggest that the MIR may serve as a useful biomarker to distinguish Mn-exposed workers from the unexposed, control population.