Selenoprotein P, rather than glutathione peroxidase, as a potential marker of septic shock and related syndromes.

BACKGROUND/AIMS: Oxidative stress is involved in sepsis-related endothelium dysfunction. Selenoprotein-P (Sel-P), the main plasma selenoprotein, may have high antioxidant potential, and binds to endothelium. We hypothesize that, in septic shock, and similar syndromes such as systemic inflammatory response syndrome (SIRS), Sel-P binds massively to endothelium, causing a drop in Sel-P plasma concentration. METHODS: Plasma Se, Sel-P and albumin concentrations, and glutathione peroxidase (GPx) activity were measured in patients with septic shock and SIRS with organ failure (S group, n = 7 and n = 3, respectively) admitted to the intensive care unit (ICU) and compared to non-SIRS patients (NS group, n = 11) and healthy volunteers (HV group, n = 7). RESULTS: On ICU admission, plasma Sel-P concentrations were 70% lower in the S group than in the other groups [15 (10-26) vs. 44 (29-71) and 50 (45-53) nmol/l] and were lower in nonsurviving septic-shock patients. GPx activity did not differ between groups. Sel-P was significantly lower before ICU death in the 3 deceased patients of the S group (septic shock) than in the 3 patients of the non-SIRS group. CONCLUSIONS: Early decrease in Sel-P plasma concentrations was specifically observed in septic shock and was similar in SIRS patients whereas GPx activity remained unchanged. Further studies are needed to determine whether Sel-P can be an early marker of septic shock linked to microvascular injury.

Arsenic trioxide and acute promyelocytic leukemia: clinical and biological.

Arsenic has recently been identified as an effective drug in the treatment of newly diagnosed and relapsed acute promyelocytic leukemia. Indeed, arsenic trioxide combined with all-trans retinoic acid shows a synergistic effect. Mechanistically, arsenic targets the key leukemogenic protein PML-RARalpha, setting up a new example of molecular target-based cancer therapy.

Are copper, zinc and selenium in erythrocytes valuable biological indexes of nutrition and pathology?

The real significance of the level of trace elements copper, zinc and selenium in erythrocytes is still a matter of debate. This review is an evaluation of the potential value of copper, zinc and selenium in red blood cells in physiology, nutrition and pathology, taking into account the other commonly used indices and the analytical difficulty encountered for erythrocyte determinations. The main analytical methods and reference values in erythrocytes are also presented. The literature of the last 3 decades was analyzed. On the basis of these papers, the role of erythrocyte copper in various pathologies should be re-investigated, especially when they include inflammatory processes or hormonal changes. The main interest of zinc determination in red blood cells concerns thyroid pathology. In general, the value of selenium in erythrocytes agrees with selenium in serum and its determination is often unnecessary.

The effect of hemoglobin A and S on the volume- and pH-dependence of K-Cl cotransport in human erythrocyte ghosts.

K-Cl cotransport is abnormally active in erythrocytes containing positively charged hemoglobins such as Hb S (SS: beta6 Glu --> Val) or Hb C (CC: beta6 Glu --> Lys). The relatively younger age of erythrocytes in these diseases cannot completely account for the increased K-Cl cotransport activity. It has been suggested that these positively charged Hb may interact with the K-Cl cotransport system or one of its regulators and induce changes in its functional activity. We report here data on the volume- and pH-dependence of K-Cl cotransport in ghosts obtained from normal and sickle erythrocytes, and on the effect of addition of either Hb A or Hb S before resealing. In erythrocyte ghosts prepared with the gel column method to contain minimal amounts of Hb, (white ghosts, WG), K-Cl cotransport has similar magnitude in normal and sickle erythrocytes, is not inhibited by alkaline pH and it is volume-independent. Addition of low concentrations of Hb A to WG from normal erythrocytes decreases the magnitude of K-Cl cotransport and restores its volume dependency, but not its pH sensitivity. Addition of Hb S to WG from either normal or sickle erythrocytes restores the volume-dependent component of K-Cl cotransport and increases the magnitude of flux mediated by this transporter. Thus, Hb A and Hb S seem to affect in different manners the functional properties of K-Cl cotransport.

Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients.

OBJECTIVES: To confirm early, marked decrease in plasma selenium concentrations in patients admitted to a surgical and medical intensive care unit (ICU), and to study this decrease according to the presence or absence of systemic inflammatory response syndrome (SIRS), sepsis, or direct ischemia-reperfusion. DESIGN: Prospective, observational study. SETTINGS: Collaboration between the adult ICU of a 1,100-bed general hospital and a biochemical research laboratory of a university medical center. PATIENTS: One hundred thirty-four consecutive surgical and medical ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In the first 31 patients, plasma and urine selenium concentrations were measured by electrothermal atomic absorption spectrometry on admission and once weekly during their ICU stay. These values were compared first with severity scores, criteria for SIRS, sepsis, and organ system failure taken on admission, and then with nosocomial infection, organ system failure during ICU stay, and hospital mortality. An early, low mean plasma selenium concentration was observed in these patients compared with selenium laboratory reference values. Plasma selenium, measured on ICU admission, inversely correlated with Acute Physiology and Chronic Health Evaluation II or Simplified Acute Physiology II scores. Patients with SIRS had lower selenium concentrations than those without SIRS. Mean urine selenium losses were normal in the first 31 patients. Plasma selenium concentration was low in all patients with severe sepsis and septic shock (range 0.20 to 0.72 micromol/L) and in those patients with ischemia-reperfusion from aortic cross-clamping (range 0.34 to 0.68 micromol/L). Despite recommended specific selenium supplementation, plasma selenium concentrations remained low for >2 wks in patients with SIRS. However, there was a slight increase in plasma selenium concentrations in surviving SIRS patients, whereas plasma selenium concentrations decreased in nonsurviving patients. The frequency of ventilator-associated pneumonia, organ system failure, and mortality was three times higher in patients with low plasma selenium concentration at the time of admission (selenium < or =0.70 micromol/L) than for the other patients. CONCLUSIONS: In severely ill ICU patients with SIRS, we observed an early 40% decrease in plasma selenium concentrations, reaching values observed in deleterious nutritional selenium deficiency. This prolonged decrease in selenium concentrations could explain the three-fold increase in morbidity and mortality rates in these patients compared with other ICU patients. The efficacy of selenium treatment in SIRS patients with a high gravity index score or hypoperfusion needs further investigation.

[Glutathione peroxidases: value of their determination in clinical biology]. / Les glutathion peroxydases: intérêt de leur dosage en biologie clinique.

The role of glutathione peroxidase in the oxidative metabolism and recent advances in the demonstration of the consequences of the desequilibrium in the proxidant/antioxidant balance on biological molecules oxidation, intracellular signals transduction, apoptosis and necrosis, have led to new approach in the knowledge of many pathological processes. Methods for determining antioxidant capacity have been developed. The measurement of glutathione peroxidase activity is a key step in the study of oxidative stress. Its determination in clinical biology needs optimal conditions for standardised assays which will be used for epidemiological studies aimed to evaluate the role of nutritional factors involved in the pathogeny of diseases caused or accompanied by oxidative stress.

[Selenium, glutathione peroxidase, peroxides and platelet functions]. / Sélénium, glutathion peroxydase, peroxydes et fonctions plaquettaires.

In the last five years, there has been a renewal of interest in the protective role of selenium in vascular disorders, inspired by experimental evidence that this trace element could modulate leukotriene and prostaglandin synthesis in both endothelial cells and platelets. In people living in low-selenium areas, a relationship has been established between a decrease in plasma selenium and an increase in the risk of coronary disease, atherosclerosis, platelet hyperaggregability and synthesis of proaggregant and proinflammatory compounds like thromboxane A2 and leukotrienes. Selenium, as an essential part of glutathione peroxidase, takes part in the reduction of hydrogen peroxides and lipid peroxides. The concentration of these peroxides, in turn, regulates the activities of cyclooxygenase and lipooxygenase pathways, ultimately influencing the production of eicosanoids and modulating the balance between a proaggregatory and antiaggregatory state. Recent evidence shows that selenium, via its action on glutathione peroxidase activity, may be primarily responsible for the regulation of the endogenous hydroperoxide level. In human platelets, the activity of glutathione peroxidase is particularly high and is very sensitive to the requirement of selenium. This sensitivity could explain why platelets of selenium-deficient subjects show increased aggregation, thromboxane B2 production and synthesis of the lipoxygenase-derived compounds. In these deficient subjects, selenium administration increases platelet glutathione peroxidase activity and inhibits platelet hyperaggregation and leukotriene synthesis. These results support the hypothesis that selenium supplementation has a positive effect on platelet aggregation in selenium-deficient subjects. In France, more than 10% of the population is selenium-deficient and long-term supplementation with low doses of selenium could have a beneficial effect on the prevention of both thrombosis and coronary heart disease in these subjects.

Hemoglobin variants and activity of the (K+Cl-) cotransport system in human erythrocytes.

To determine if the activation of the (K+Cl-) cotransport system observed in hemoglobin (Hb) S- or C-containing erythrocytes is related either to a global change of isoelectric point of the Hb molecule or to the specific location of these mutations on the position 6 of the beta chain of Hb, we studied the (K+Cl-) cotransport system in erythrocytes containing beta chain variants exhibiting either the Glu----Lys substitution observed in position beta 6 in Hb C (Hb E: beta 26 Glu----Lys; Hb O-Arab: beta 121 Glu----Lys; Hb Siriraj:beta 7 Glu----Lys) or the Glu----neutral residue substitution observed in position beta 6 in Hb S (Hb G-San Jose: beta 7 Glu----Gly; Hb D Punjab or D-Los Angeles: beta 121 Glu----Gln). The K transport mediated by the (K+Cl-) cotransport was increased in AC, AS and A-Siriraj and A-San Jose red blood cells and was similar to AA control in the other variants. These results indicate that an enhanced (K+Cl-) cotransport is not a property of all positively charged Hb variants, but it is mainly associated with mutations occurring at the beta 6 or beta 7 residues. An interaction of Hb with the cell membrane mediated by the disappearance of one of the negative charged residues (Glu) at this site of the A helix of the beta chain is the most likely candidate for the persistent activation of the (K+Cl-) cotransport system in these Hb variants.

K+ efflux in deoxygenated sickle cells in the presence or absence of DIOA, a specific inhibitor of the [K+, Cl-] cotransport system.

The ouabain bumetanide resistant (OBR) K+ efflux was investigated in deoxygenated sickle cells in comparison to oxygenated ones, by using a specific inhibitor of the [K+, Cl-] co-transport system, [(DihydroIndenyl)Oxy] Alkanoic acid (DIOA). A DIOA sensitive and a DIOA resistant K+ efflux were measured in deoxygenated sickle cells. The DIOA sensitive K+ efflux shared the properties of the [K+, Cl-] co-transport system, being stimulated by decreased pH and hypoosmolarity. This DIOA sensitive K+ efflux represented 70% of the total K+ efflux at pH 7.0 and at low pO2 (10-15 mmHg). Thus, a small reduction in Ph effectively stimulated the [K+, Cl-] co-transport system in deoxygenated condition, and this may contribute significantly to the sickle cell dehydration. We conclude that at pH lower than 7.4, the [K+, Cl-] co-transport system is permanently activated in sickle cells and leads to sickle cell dehydration in both oxygenated and deoxygenated conditions.

Inhibition of K+ efflux and dehydration of sickle cells by [(dihydroindenyl)oxy]alkanoic acid: an inhibitor of the K+ Cl- cotransport system.

[(Dihydroindenyl)oxy]alkanoic acid (DIOA) was recently introduced as a potent inhibitor of the K+Cl- cotransport system without side effects on other cation transport systems [Garay, R. P., Nazaret, C., Hannaert, P.A. & Cragoe, E. J., Jr. (1988) Mol. Pharmacol. 33, 696-701]. In sickle cells, an abnormal activation of this K+Cl- cotransport system was proposed to be involved in cell K+ loss and dehydration. We found that DIOA inhibited the abnormal sickle cell K+ loss and specifically reduced sickle cell density upon stimulation of the net outward K+Cl- cotransport--i.e., low pH, hypoosmolarity, and activation by N-ethylmaleimide. DIOA opens another therapeutic approach to sickle cell disease by inhibiting cell dehydration, which favors HbS polymerization and reduces erythrocyte deformability.