"Alphabet" Selenoproteins: Their Characteristics and Physiological Roles.

Selenium (Se) is a metalloid that is recognized as one of the vital trace elements in our body and plays multiple biological roles, largely mediated by proteins containing selenium-selenoproteins. Selenoproteins mainly have oxidoreductase functions but are also involved in many different molecular signaling pathways, physiological roles, and complex pathogenic processes (including, for example, teratogenesis, neurodegenerative, immuno-inflammatory, and obesity development). All of the selenoproteins contain one selenocysteine (Sec) residue, with only one notable exception, the selenoprotein P (SELENOP), which has 10 Sec residues. Although these mechanisms have been studied intensely and in detail, the characteristics and functions of many selenoproteins remain unknown. This review is dedicated to the recent data describing the identity and the functions of several selenoproteins that are less known than glutathione peroxidases (Gpxs), iodothyronine deiodinases (DIO), thioredoxin reductases (TRxRs), and methionine sulfoxide reductases (Msrs) and which are named after alphabetical letters (i.e., F, H, I, K, M, N, O, P, R, S, T, V, W). These "alphabet" selenoproteins are involved in a wide range of physiological and pathogenetic processes such as antioxidant defense, anti-inflammation, anti-apoptosis, regulation of immune response, regulation of oxidative stress, endoplasmic reticulum (ER) stress, immune and inflammatory response, and toxin antagonism. In selenium deficiency, the "alphabet" selenoproteins are affected hierarchically, both with respect to the particular selenoprotein and the tissue of expression, as the brain or endocrine glands are hardly affected by Se deficiency due to their equipment with LRP2 or LRP8.

"Alphabet" Selenoproteins: Implications in Pathology.

Selenoproteins are a group of proteins containing selenium in the form of selenocysteine (Sec, U) as the 21st amino acid coded in the genetic code. Their synthesis depends on dietary selenium uptake and a common set of cofactors. Selenoproteins accomplish diverse roles in the body and cell processes by acting, for example, as antioxidants, modulators of the immune function, and detoxification agents for heavy metals, other xenobiotics, and key compounds in thyroid hormone metabolism. Although the functions of all this protein family are still unknown, several disorders in their structure, activity, or expression have been described by researchers. They concluded that selenium or cofactors deficiency, on the one hand, or the polymorphism in selenoproteins genes and synthesis, on the other hand, are involved in a large variety of pathological conditions, including type 2 diabetes, cardiovascular, muscular, oncological, hepatic, endocrine, immuno-inflammatory, and neurodegenerative diseases. This review focuses on the specific roles of selenoproteins named after letters of the alphabet in medicine, which are less known than the rest, regarding their implications in the pathological processes of several prevalent diseases and disease prevention.

Systemic redox modifications in senile cataract.

UNLABELLED: Recent studies on cataract formation focus on a primary role of systemic oxidative stress, generated outside the lens. Plasma inflammatory markers are associated with senile cataract. OBJECTIVE: The aim of this study was to find correlations between blood oxidative stress markers and some inflammatory plasma markers in cataractous patients. DESIGN AND METHODS: The blood samples were collected from 38 patients (aged 50 to 80). Patients were subdivided according to two criteria. Considering age criteria, presenile and senile cataract groups were formed. According to the absence or presence of other ocular comorbidities (age-related macular degeneration, glaucoma), pure cataract and nonpure cataract groups were constituted. Fifteen age and sex matched healthy subjects were selected for the control group. RESULTS: In our study, for all groups of patients, the measured markers of oxidative stress were modified vs. control values. Plasma antioxidant capacity, plasma antioxidant "gap", cholesterol and albumin/globulin levels were significantly decreased while RBC SOD activity, RBC catalase activity and plasma ceruloplasmin were significantly increased. Inflammatory markers, ceruloplasmin and albumin/globulins were correlated with different parameters of oxidative stress. CONCLUSION: The blood redox values and the level of some inflammatory markers demonstrate that senile cataract is a systemic disease with an inflammatory component.

Diabetic foot patients with and without retinopathy and plasma oxidative stress.

OBJECTIVE: The first aim of this study was to evaluate some plasma oxidative stress markers in diabetic patients (type2 diabetes mellitus) with peripheral arteriopathy. Secondly, these patients were divided into two groups considering the presence or absence of retinopathy. The differences in the levels of the oxidative stress parameters could be important to select patients prone to develop multiple vascular complications, including retinopathy. PATIENTS AND METHODS: Forty hospitalized type II diabetic patients, aged between 40 and 70, with stage III or IV foot ulceration according to the Wagner classification, had an ophthalmologic evaluation for retinopathy. Among them, 23 were with retinopathy with different grades of severity and 17 were without retinopathy. Twenty healthy subjects served as a control group. Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total serum proteins, serum uric acid and plasma ceruloplasmin levels were determined and compared. RESULTS: Plasma levels for fasting glucose, glycosylated hemoglobin, ceruloplasmin and serum concentrations for fructosamine and uric acid were significantly increased in diabetic foot patients vs. control subjects. Comparing the two groups of patients, with and without retinopathy, the concentrations of ceruloplasmin and uric acid were significantly increased in diabetic patients with retinal disease. In diabetic patients with retinopathy, positive correlations were calculated between glycated hemoglobin and fructosamine concentrations and between glycated hemoglobin and ceruloplasmin. CONCLUSION: Diabetic foot patients with retinopathy have increased plasma levels of uric acid and ceruloplasmin. These plasma compounds could be important in the pathogenesis of retinal disease. Two aspects should be considered when these high values are analysed. First, these antioxidant compounds may become prooxidant in diabetic vascular environment. Secondly, it is not known whether these modified plasma oxidative stress parameters are cause or effect in diabetic complication development.

Plasma redox status and premature onset of senile cataract.

UNLABELLED: Dysfunction of the lens due to opacification is called cataract. Senile cataract is associated with old age. It is estimated that the need for cataract extractions would be diminished by half if onset of cataract would be delayed by only ten years. It thus appears crucial to have a better characterization of the etiology of cataract to detect modifiable factors. It seems that oxidative stress may play an important role in cataractogenesis. Also, it was demonstrated that some plasma constituents correlate with human cataract location. OBJECTIVE: We supposed that in senile cataract the oxidative insult may be systemic and not only at the lens level. The aim of our study was to evaluate the blood redox status in cataractous patients aged between 50-65. DESIGN AND METHODS: The blood samples were collected from 15 patients with pure nuclear cataract and/or posterior subcapsular cataract, without metabolic or somatic diseases and from 15 age and sex matched controls. Carbonyl content of plasma proteins was evaluated with 2,4-dinitro-phenyl-hydrazine method. The a-oxoaldehydes were measured in the presence of Girard T reactive. The lipid peroxides concentration was assessed measuring malondialdehyde concentration using thiobarbituric acid. For the other plasma parameters we used kits. RESULTS: The levels of plasma protein carbonyls and malondialdehyde were significantly increased in the cataract group. The plasma levels of: total proteins, globulins, total thiols, fasting glucose, triglycerides and alpha-oxoaldehydes were not modified comparing the groups. Plasma concentrations of albumin and cholesterol were significantly decreased. CONCLUSION: The study underlies the presence of an increased plasma oxidative stress in cataractous patients. The abnormal oxidative stress parameters are linked to the premature development of senile cataract. Preventive therapy in order to delay the onset of senile cataract requires more research work on plasma oxidative stress markers.

Oxidative stress parameters in hemodialysis patients with or without diabetes.

Oxidative stress (imbalance of antioxidant and prooxidants in favour of the later) is considered to be a feature of diabetes and chronic renal failure. Carbonyl stress defined as accumulation of reactive carbonyl compounds due to excess production or disturbed clearance from the body is thought to amplify oxidative stress in these conditions. The accumulation of carbonyl compounds can be also a consequence of oxidative stress. A vicious cycle can thus be formed. We have studied the association between carbonyl stress markers (dicarbonyl compounds, Amadori products) and oxidative stress markers (total plasmatic thiols and malondialdehyde level) in hemodialysed patients with or without diabetes taking into account the levels of possible excess substrates (glucose and triglycerides). We have concluded that hemodialysed diabetes patients are more susceptible to oxidative stress than hemodialysed patients without diabetes.

Free radical activity in obese patients with type 2 diabetes mellitus.

UNLABELLED: Oxidative stress plays critical roles in the pathogenesis of various diseases. The aim of the present study was to investigate the relationship between oxidative stress, measured by plasma dicarbonyls and plasma antioxidant defence, measured by reduced glutathione (G-SH) in the whole blood, protein thiols in the plasma and erythrocyte superoxide dismutase activity in obese and obese with type-2 diabetes mellitus subjects, clinically free of complications. Twenty obese patients with type-2 diabetes mellitus and twenty nondiabetic obese patients were examined and compared with twenty healthy controls (matched for age and sex against the obese patients with or without diabetes). RESULTS: Obese patients and obese diabetic patients had lower blood glutathione than control subjects (p<0.02 and respectively p<0.04) and higher plasma MDA, an end product of lipid peroxidation (p<0.004 and respectively p<0.01). There was a significant difference between plasma MDA from obese and obese diabetic subjects (p<0.05). Plasma thiols (expressed as micromol/mg protein) did not differ between the three groups. Plasma dicarbonyls concentrations were significantly increased in obese (p<0.043) and obese diabetic patients (p<0.047) and SOD activity (U/g Hb) was significantly decreased in obese (p<0.0 ) and obese diabetic patients (p<0.05) compared to controls. Analysing the results of our study, which show that most of the markers of oxidative stress are modified in the same way in obesity and obesity with diabetes mellitus type 2, we suppose that obesity leads to oxidative stress which can contribute to obesity-associated diseases such as diabetes mellitus.

Influence of epoietinum therapy on the oxidative stress in haemodialysis patients.

BACKGROUND: The causes of oxidative stress in haemodialysis (HD) patients are still controversial. Beside the uraemic state and dialysis-related factors, adjuvant drug therapies such as epoietinum (rHuEpo) and intravenous iron were involved. METHODS: Several parameters related to oxidative stress were assessed by spectrophotometry in stable HD patients, treated for at least 2 months with epoietinum (n = 14; mean dose = 97.7 +/- 19.1 U/kg/week) or not (n = 15), none of them on iron therapy, and in 13 controls. Plasma thiobarbituric acid-reactive substances (TBARS) were used as markers of reactive species generation. Erythrocyte and plasma antioxidant systems, reflected by non-protein erythrocyte thiols, and erythrocyte enzyme activities -- superoxide dismutase (SOD), glutathione peroxidase, catalase and plasma total thiols, respectively -- were also investigated. RESULTS: There were no differences between HD subgroups regarding haemoglobin levels. Plasma TBARS was increased in all HD patients as opposed to controls, irrespective of rHuEpo therapy. In addition, no change in antioxidant status parameters between rHuEpo-treated and -untreated patients was observed. Except for SOD, the other antioxidant indices were higher in all HD patients versus controls. CONCLUSIONS: These results suggest that (1) chronic HD patients appear to have simultaneously enhanced reactive species generation and antioxidative systems efficiency, and (2) epoietinum therapy did not change their oxidative status, at least in the absence of concomitant iron supplementation and at similar haemoglobin levels.

The effect of fasting on the parameters of the antioxidant defence system in the blood of vegetarian human subjects.

OBJECTIVES: Although the evidence is strong that fasting has anti-tumor, anti-inflammatory and anti-ageing actions, the mechanisms responsible for these phenomena are still unclear. An ameliorated antioxidative defence with fasting may be the cause of such effects. The objective of the present work was to determine the influence of fasting on antioxidant systems in healthy young vegetarian humans. DESIGN AND METHODS: We measured Trolox Equivalents Antioxidant Capacity (TEAC) of plasma, erythrocytes superoxide dismutase (SOD) activity, blood glutathione peroxidase (GPx) activity, level of total blood non-proteic thiols (TBNT), plasma ceruloplasmin activity, plasma level of NO metabolites (the sum of nitrites and nitrates, NOx), in 18 healthy young humans (age 20-27 years) after 12h (overnight fasting) and 80h of fasting. RESULTS: Trolox Equivalents Antioxidant Capacity of plasma, the level of total blood nonproteic thiols, plasma ceruloplasmin activity and plasma concentration of nitrites and nitrates were significantly increased after 80h of fasting. Superoxide dismutase activity and glutathione peroxidase activity were lower after 80h of fasting. CONCLUSIONS: Our results suggest that fasting induces the "reorganisation" of antioxidative defence lines: fasting increases especially plasma protective systems (total antioxidant capacity of plasma, plasma ceruloplasmin activity) and decreases an erythrocytes antioxidant enyzme (superoxide dismutase) and blood glutathione peroxidase.

Serum cholinesterase activity correlates with serum insulin, C-peptide and free fatty acids levels in patients with type 2 diabetes.

When compared with values recorded in 14 control subjects, the 15 overweight patients with type 2 diabetes displayed significantly increased activities of serum alanineaminotransferase (172% of mean values in controls), gamma-glutamyltransferase (253%) and cholinesterase (139%). A much wider dispersion of individual values for the two firstly mentioned enzymes was however noted so that their correlation with serum triglycerides levels were weaker (r = 0.373; p < 0.05 and r = 0.451; p < 0.05 respectively) than the same correlation obtained for serum cholinesterase (r = 0.760; p < 0.001). In two other studies including 28 controls and 30 diabetic patients serum cholinesterase was found to be significantly correlated with serum levels of insulin (r = 0.622; p < 0.001), C-peptide (r = 0.652; p < 0.001) and free fatty acid (r = 0.821; p < 0.001). Circumstantial evidence is provided that insulin resistance and an increased flux of free fatty acids from adipose tissue to the liver would stimulate the hepatic synthesis of serum cholinesterase.