Reactive oxygen species in biological systems: Pathways, associated diseases, and potential inhibitors-A review.

Reactive oxygen species (ROS) are produced under normal physiological conditions and may have beneficial and harmful effects on biological systems. ROS are involved in many physiological processes such as differentiation, proliferation, necrosis, autophagy, and apoptosis by acting as signaling molecules or regulators of transcription factors. In this case, maintaining proper cellular ROS levels is known as redox homeostasis. Oxidative stress occurs because of the imbalance between the production of ROS and antioxidant defenses. Sources of ROS include the mitochondria, auto-oxidation of glucose, and enzymatic pathways such as nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. The possible ROS pathways are NF-κB, MAPKs, PI3K-Akt, and the Keap1-Nrf2-ARE signaling pathway. This review covers the literature pertaining to the possible ROS pathways and strategies to inhibit them. Additionally, this review summarizes the literature related to finding ROS inhibitors.

Quercetin Antagonizes the Sedative Effects of Linalool, Possibly through the GABAergic Interaction Pathway.

Sedatives promote calmness or sleepiness during surgery or severely stressful events. In addition, depression is a mental health issue that negatively affects emotional well-being. A group of drugs called anti-depressants is used to treat major depressive illnesses. The aim of the present work was to evaluate the effects of quercetin (QUR) and linalool (LIN) on thiopental sodium (TS)-induced sleeping mice and to investigate the combined effects of these compounds using a conventional co-treatment strategy and in silico studies. For this, the TS-induced sleeping mice were monitored to compare the occurrence, latency, and duration of the sleep-in response to QUR (10, 25, 50 mg/kg), LIN (10, 25, 50 mg/kg), and diazepam (DZP, 3 mg/kg, i.p.). Moreover, an in silico investigation was undertaken to assess this study's putative modulatory sedation mechanism. For this, we observed the ability of test and standard medications to interact with various gamma-aminobutyric acid A receptor (GABAA) subunits. Results revealed that QUR and LIN cause dose-dependent antidepressant-like and sedative-like effects in animals, respectively. In addition, QUR-50 mg/kg and LIN-50 mg/kg and/or DZP-3 mg/kg combined were associated with an increased latency period and reduced sleeping times in animals. Results of the in silico studies demonstrated that QUR has better binding interaction with GABAA α3, ß1, and γ2 subunits when compared with DZP, whereas LIN showed moderate affinity with the GABAA receptor. Taken together, the sleep duration of LIN and DZP is opposed by QUR in TS-induced sleeping mice, suggesting that QUR may be responsible for providing sedation-antagonizing effects through the GABAergic interaction pathway.

Food Polyphenols and Type II Diabetes Mellitus: Pharmacology and Mechanisms.

Type II diabetes mellitus and its related complications are growing public health problems. Many natural products present in our diet, including polyphenols, can be used in treating and managing type II diabetes mellitus and different diseases, owing to their numerous biological properties. Anthocyanins, flavonols, stilbenes, curcuminoids, hesperidin, hesperetin, naringenin, and phenolic acids are common polyphenols found in blueberries, chokeberries, sea-buckthorn, mulberries, turmeric, citrus fruits, and cereals. These compounds exhibit antidiabetic effects through different pathways. Accordingly, this review presents an overview of the most recent developments in using food polyphenols for managing and treating type II diabetes mellitus, along with various mechanisms. In addition, the present work summarizes the literature about the anti-diabetic effect of food polyphenols and evaluates their potential as complementary or alternative medicines to treat type II diabetes mellitus. Results obtained from this survey show that anthocyanins, flavonols, stilbenes, curcuminoids, and phenolic acids can manage diabetes mellitus by protecting pancreatic ß-cells against glucose toxicity, promoting ß-cell proliferation, reducing ß-cell apoptosis, and inhibiting α-glucosidases or α-amylase. In addition, these phenolic compounds exhibit antioxidant anti-inflammatory activities, modulate carbohydrate and lipid metabolism, optimize oxidative stress, reduce insulin resistance, and stimulate the pancreas to secrete insulin. They also activate insulin signaling and inhibit digestive enzymes, regulate intestinal microbiota, improve adipose tissue metabolism, inhibit glucose absorption, and inhibit the formation of advanced glycation end products. However, insufficient data are available on the effective mechanisms necessary to manage diabetes.

Haptoglobin polymorphism modulates cardiometabolic impacts of four consecutive weeks, dawn to sunset Ramadan intermittent fasting among subjects with overweight/obesity.

AIMS: Haptoglobin (Hp) is a multifaceted marker of inflammation, and mediates the interplay between obesity, inflammation, and cardiometabolic dysfunction. However, the role of the Hp phenotype in modulating intermittent fasting (IF)-induced cardiometabolic changes remains to be elucidated. METHODS: Hp phenotype was determined for the study subjects. Cardiometabolic markers were assessed before and at the end of four consecutive weeks, dawn to sunset IF. RESULTS: A total of 114 subjects (75 males and 39 females, 38.7 ± 11.7 years, body mass index (BMI) of 30.41 ± 5.09 kg/m2) were recruited. Hp2-2 (n = 55, 48.2 %) and Hp2-1 (n = 53, 46.5 %) were the predominant phenotypes. Significant reductions were observed in serum Hp, IL-6, TNF-α, triglycerides (TG), total cholesterol (TC), LDL, BMI, and fat mass (FM), while a significant elevation was observed in serum CD163, HDL, and IL-10 at the end of the IF month for the whole population. Based on the Hp polymorphism, significant decreases in Hp, BMI, FM, TG, LDL, and TNF-α, with significant increases in HDL and CD163 levels were observed among subjects with Hp2-2 and Hp2-1 phenotypes. A more pronounced reduction in FM was reported in subjects with Hp2-2 in comparison with Hp2-1. CONCLUSION: Hp gene polymorphism modulates IF-induced changes in cardiometabolic markers. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN18205186; https://trialsearch.who.int/?TrialID=ISRCTN18205186.

Ramadan Intermittent Fasting Is Associated with Changes in Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Metabolically Healthy Obese Subjects.

Background and Objectives: Dietary modification is the principal approach to the management of hyperlipidemia in adults. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of plasma cholesterol and a target for novel lipid-lowering pharmacotherapies. This study aimed to explore how circulating levels of PCSK9 changed during Ramadan intermittent fasting in metabolically healthy obese subjects. Materials and Methods: This cross-sectional study used convenience sampling to recruit 55 overweight and obese participants (22 females and 33 males) who observed Ramadan fasting. Body weight and composition, glucoregulatory factors, serum PCSK9 concentration, dietary intake, and physical activity were assessed 1 week before and at the end of Ramadan fasting. Results: The median (interquartile range) age was 35 (22) years, and body mass index was 30.2 (5.4). We found significant (p < 0.05) increases in serum levels of PCSK9, serum insulin, insulin resistance, and leptin at the end of Ramadan compared with pre-fasting levels. Significant (p < 0.05) reductions in body weight, waist circumference, systolic and diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and adiponectin were also observed at the end of Ramadan. Conclusions: Observing Ramadan fasting was associated with increased PCSK9 levels in metabolically healthy obese subjects. The complex relationships between PCSK9 and insulin resistance and dysregulation of adipokine secretion in relation to dietary and lifestyle modifications during Ramadan warrant further research.

Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells.

PURPOSE: Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. METHODS: MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. RESULTS: MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. CONCLUSIONS: These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.

Vitamin A levels are decreased but not influenced by glucose- or lipid-lowering medications in subjects with type 2 diabetes.

BACKGROUND AND AIM: Type 2 diabetes (T2D) is a complex polygenic disease with unclear mechanisms. Clinical studies on the association of vitamin A with T2D in humans are still controversial. Herein, we aimed to investigate the plasma levels of vitamin A, predictor factors, and its correlations with clinical phenotypes in Emirati population. The effect of glucose-and lipid-lowering medications on vitamin A levels was also studied. METHODS: A cross-sectional cohort comprised 158 T2D-subjects and 90 healthy controls were recruited from the United Arab Emirates National Diabetes Study (UAEDIAB). All anthropometric, clinical, and biomedical measurements were collected. Plasma levels of vitamin A were determined using ELISA assay. RESULTS: Levels of vitamin A were significantly lower in T2D-subjects compared to healthy control (p < 0.01). Vitamin A levels were unaffected by gender base and inversely correlated with age, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), waist circumference, triglycerides, and body mass index (BMI). Regression analysis revealed that HbA1c and age are predictors for vitamin A. Intake of glucose- or lipid-lowering medications showed no effect on vitamin A levels. CONCLUSION: HbA1c and age are predictors for low levels of vitamin A among Emirati-T2D subjects. No influence of glucose and lipid-lowering medications on the plasma levels of vitamin A.

Combined intake of glucose-and lipid-lowering medications further elevates plasma levels of PCSK9 in type 2 diabetes patients.

BACKGROUND AND AIM: This study examined the status of plasma levels of protein convertase subtilisin/kexin 9 (PCSK9) in association with glucose-and lipid-lowering medications in subjects with type 2 diabetes (T2D). METHODS: This study comprised 177 diabetics and 115 non-diabetic subjects recruited from the United Arab Emirates National Diabetes Study (UAEDIAB). Clinical and biomedical data were collected by standard techniques. Plasma levels of PCSK9 were determined using ELISA. RESULTS: PCSK9 levels were higher in diabetics than non-diabetics (P < 0.001). Diabetics with disease duration >5 years, HbA1c > 7.0%, or male subjects, had significantly higher levels of PCSK9 than their counterparts (P < 0.05). Regression analysis revealed that HbA1c and age are predictors for PCSK9 in T2D subjects. Diabetic subjects with abnormal lipids profile on lipid-lowering medications had a higher level of PCSK9 compared to those with normal lipids profile (85.6 ± 40.5 vs. 63.7 ± 39.5 ng/ml, respectively; P < 0.01). Diabetics on combined intake of insulin and oral glucose-lowering drugs had higher levels of PCSK9 than those not taking any (86.1 ± 41.6 vs 69.7 ± 36.1 ng/ml, respectively; P < 0.05). The highest levels of PCSK9 however, were in diabetics on combined lipid- and glucose-lowering therapy when compared to those, not on any (96.2 ± 34.0 vs 66.0 ± 35.1 ng/ml, respectively; P < 0.01). CONCLUSIONS: Age and HbA1c are the most predictors for the elevated levels of PCSK9 in Emirati T2D subjects. Combined therapy of glucose-and lipid-lowering medications further elevates plasma levels of PCSK9 in diabetic subjects.

Waist circumference is a major determinant of oxidative stress in subjects with and without metabolic syndrome.

AIM: Oxidative stress (OS) plays a major role in pathogenic mechanisms associated with metabolic syndrome (Mets) yet the main component of Mets contributing most to OS is not well elucidated. Hence, the aim of this study was to investigate the oxidative-antioxidative status in Mets subjects and to determine the main predicting component of OS. METHODS: Anthropometric measures, fasting blood glucose, lipid profile, antioxidant enzymes [catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx)], reduced glutathione (GSH), malondialdehyde (MDA) and protein carbonyl were assessed in 172 adult UAE residents. International Diabetes Federation criteria were used for Mets diagnosis. Mets Scores (0-5) were calculated and assigned per subject based on number of components. RESULTS: Of all participants, 22.1% had Mets and 49.4% had large waist circumference (WC). Significant lower levels of catalase, SOD, GPx and GSH, and higher levels of MDA and protein carbonyl were observed in subjects with Mets. In addition, catalase, SOD, GPx, and GSH correlated negatively, while MDA and protein carbonyl correlated positively with almost all Mets components. Similar trend of correlations was noticed with Mets Scores. When adjusted for age and gender, linear regression analysis revealed that subjects with large WC demonstrated significantly lower levels of antioxidative enzymes and GSH, and higher levels of MDA and protein carbonyl. Consequently, WC emerged as the best predictor of OS. CONCLUSIONS: The degree of OS is dependent on the Mets Scores, and WC contributes independently to increased OS among adults in UAE.

Ramadan diurnal intermittent fasting modulates SOD2, TFAM, Nrf2, and sirtuins (SIRT1, SIRT3) gene expressions in subjects with overweight and obesity.

AIM: A growing body of evidence supports the impact of intermittent fasting on normalizing body metabolism and lowering oxidative stress and inflammation. Mounting evidence confirms that oxidative stress and chronic inflammation trigger the way for the development of metabolic diseases, such as diabetes. This research was conducted to evaluate the impact of Ramadan intermittent fasting (RIF) on the expression of cellular metabolism (SIRT1 and SIRT3) and antioxidant genes (TFAM, SOD2, and Nrf2). METHODS: Fifty-six (34 males and 22 females) overweight and obese subjects and six healthy body weight controls were recruited and monitored before and after Ramadan. RESULTS: Results showed that the relative gene expressions in obese subjects in comparison to counterpart expressions of controls for the antioxidant genes (TFAM, SOD2, and Nrf2) were significantly increased at the end of Ramadan, with percent increments of 90.5%, 54.1% and 411.5% for the three genes, respectively. However, the metabolism-controlling gene (SIRT3) showed a highly significant (P < 0.001) downregulation accompanied with a trend for reduction in SIRT1 gene at the end of Ramadan month, with percent decrements of 61.8% and 10.4%, respectively. Binary regression analysis revealed significant positive correlation (P < 0.05) between high energy intake (>2000 Kcal/day vs. <2000 Kcal/day) and expressions of SOD2 and TFAM (r = 0.84 and r = 0.9, respectively). CONCLUSION: Results suggest that RIF ameliorates the genetic expression of antioxidant and anti-inflammatory, and metabolic regulatory genes. Thus, RIF presumably may entail a protective impact against oxidative stress and its adverse metabolic-related derangements in non-diabetic obese patients.

Relationship of salivary adipocytokines, diet quality, physical activity, and nutrition status in adult Emirati females in United Arab Emirates.

AIMS: The United Arab Emirates (UAE) ranks as the fifth most obese country with increasing cardio-metabolic risks. In this paper, relationships of salivary adipocytokines (markers of cardio-metabolic syndrome), diet quality and physical activity in 90 normal-weight, overweight and obese (30 subjects in each group) Emirati adult females were investigated. METHODS: A cross-sectional research design was adopted. Anthropometric measurements, diet quality and physical activity questionnaires were administered. Overnight fasting saliva was collected to determine levels of adiponectin, interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-α). RESULTS: Salivary adiponectin was significantly lower, while TNF-α was higher in obese than normal-weight subjects. IL-10 displayed a lower trend in obese subjects. Though diet quality and physical activity did not exhibit significant differences among the three groups, better diet quality and higher physical activity level were reported among normal-weight subjects. Salivary TNF-α correlated positively with body mass index (BMI) (r = 0.37; p < 0.001) and waist circumference (r = 0.31; p < 0.001), while adiponectin correlated negatively with BMI (r = -0.28; p < 0.05). IL-10 showed negative trend in correlation with obesity measures. Correlations were not observed between diet quality and physical activity with salivary adipocytokines. Interestingly, a significant negative correlation emerged between diet quality and neck circumference (r = -0.24; p < 0.05). CONCLUSION: Our findings demonstrate that salivary adipocytokines correlate with obesity measures and can serve as convenient adjunct method in predicting cardio-metabolic risks in the population.

Elevated Levels of Estrogen Suppress Hepcidin Synthesis and Enhance Serum Iron Availability in Premenopausal Women.

Clinical and experimental observations have long suggested that elevated levels of estrogen associate with increased serum iron availability. Additionally, recent work has shown that estrogen can downregulate hepcidin synthesis in vitro. This study aims at assessing whether the ability of estrogen to downregulate hepcidin synthesis translates into changes in serum iron status. Hepcidin synthesis was evaluated in MCF-7, Hep-G2 and SKOV-3 cells treated with increasing concentrations of estrogen and cultured for up to 24 h post treatment. The correlation between levels of serum estrogen, hepcidin and iron was assessed using serum samples collected from 153 premenopausal women at random and samples collected from 6 women at days 1, 5, 10, 16, 21 and 28 of the monthly cycle. Estrogen-treated MCF-7 cells showed a significant reduction in hepcidin synthesis, especially at 20 nM/24 h E2 treatment. Hepcidin synthesis was also significantly reduced in Hep-G2 and SKOV-3 cells at 20 nM/24 h E2 treatment. In serum samples collected at random, estrogen (P=0.022; R=-0.213) and iron (P=0.028; R=-0.316) correlated negatively with hepcidin and positively with each other (P=0.033; R=0.319). An overall similar pattern was also observed in monthly cycle-timed samples. These findings suggest that elevated levels of estrogen reduce hepcidin synthesis as means of enhancing serum iron content in menstruating women.

Plasma levels of Apolipoprotein A1 and Lecithin:Cholesterol Acyltransferase in type 2 diabetes mellitus: Correlations with haptoglobin phenotypes.

BACKGROUND: Previous studies have demonstrated that hemoglobin-haptoglobin (Hb-Hp) complex plays a role in developing vascular complications in type 2 diabetes mellitus (T2DM). The complexes bind with Apolipoprotein A1 (ApoA1) of high-density lipoprotein (HDL), affecting the function of Lecithin:Cholesterol Acyltransferase (LCAT), and impairing the reverse cholesterol transport mechanism (RCT). This study investigated the influence of Hp phenotypes on serum levels of ApoA1 and LCAT in patients with T2DM. METHODS: The study comprised 131 T2DM patients and 111 matching healthy controls. Fasting blood glucose, HbA1C, and lipid profile were determined by chemistry autoanalyzer, LCAT and ApoA1 by ELISA, and Hp phenotypes by gel electrophoresis. RESULTS: Irrespective of Hp phenotypes, fasting blood glucose, HbA1C, and lipid profile were significantly higher in patients than in controls, while HDL-cholesterol, ApoA1, and LCAT were lower. ApoA1 correlated positively with LCAT (r=0.223, p=0.024) and HDL-cholesterol (r=0.255, 0.003) in patients only. When Hp polymorphism was taken into account, the levels of LCAT and ApoA1 were significantly lower in patients with Hp2-2 than that in patients of Hp1-1 and/or Hp2-1. Correlations between ApoA1 and each of HDL-cholesterol and LCAT (r=0.239, p=0.046, and r=0.252, p=0.040, respectively) were also observed, but only in patients with Hp2-2 phenotype. CONCLUSIONS: The reduced levels of LCAT and ApoA1 observed in this study support the suggestion that T2DM patients with Hp2-2 phenotype could have altered RCT mechanism and increased risk of developing cardiovascular disease.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome components among young adult females.

AIMS: Occurrence of metabolic syndrome (MetS) in the United Arab Emirates (UAE) is rising steadily, with subsequent increase in the prevalence of type 2 diabetes and cardiovascular disease (CVD). Recent studies have shown that PCSK9 plays a substantial role in atherogenic dyslipidemia. Hence, the aim of this study was to assess level of PCSK9 and its relationship with MetS components among young adult females. METHODS: This study was carried out on 137 adult females over 18 years of age residing in the UAE. Subjects were categorized into two groups according to waist circumferences (WC): normal (<80cm; n=41) and large (≥80cm; n=96). Anthropometric and biochemical parameters in the fasting state (glucose, insulin, lipid profile, and PCSK9) were determined using conventional techniques. Homeostasis model assessment of insulin resistance (HOMA-IR) and MetS scores were calculated as appropriate. RESULTS: PCSK9 was lower in subjects with large WC compared to normal WC (p=0.016). PCSK9 correlated negatively with measures of obesity (p<0.05), and positively with IR (r=0.425, p<0.001). Multiple linear regression analysis revealed that the strongest predictor of PCSK9 was IR (B=6.213; p<0.001), followed by WC (B=-2.488; p<0.001) and triglycerides (B=0.897; p=0.013). CONCLUSION: Results from this study demonstrate that PCSK9 correlates with some components of metabolic syndrome and central obesity in young females. Such findings support the suggestion of using PCSK9 inhibitors in the management of MetS to modify risk for development of CVD.

Prevalence and epidemiological characteristics of vaginal candidiasis in the UAE.

Vaginal candidiasis (VC) continues to be a health problem to women worldwide. Although the majority of VC cases are caused by Candida albicans (C. albicans), non-albicans Candida spp. like C. glabrata and C. tropicalis are emerging as important and potentially resistant opportunistic agents of VC. The objective of this study was to evaluate the prevalence and epidemiology of VC in the UAE through retrospective analysis of pertinent data compiled by the microbiology and infection control unit at Latifa Hospital, Dubai between 2005 and 2011. The incidence of VC significantly increased from 10.76% in 2005 to 17.61% in 2011; average prevalence was 13.88%. C. albicans occurred at a frequency of 83.02%, C. glabrata at 16.5% and C. tropicalis at 1.2%. A single C. dubliniensis isolate was identified in the sample population. The percentage of C. albicans significantly decreased from 83.02% in the sample population as a whole to 60.8% in subjects over 45 years of age (P < 0.01) and that of C. glabrata, C. tropicalis and C. krusei significantly increased from 13.88%, 0.9% and 0.03% to 29.7%, 6.7% and 1.4% (P < 0.05) respectively. The incidence of VC in the UAE is on the rise and the frequency of non-albicans Candida spp. is noticeably increasing especially in postmenopausal women.

Estrogen-dependent changes in serum iron levels as a translator of the adverse effects of estrogen during infection: a conceptual framework.

Elevated levels of estrogen often associate with increased susceptibility to infection. This has been attributed to the ability of estrogen to concomitantly enhance the growth and virulence of pathogens and suppress host immunity. But the exact mechanism of how estrogen mediates such effects, especially in cases where the pathogen and/or the immune components in question do not express estrogen receptors, has yet to be elucidated. Here we propose that translating the adverse effects of estrogen during infection is dependent to a significant degree upon its ability to manipulate iron homeostasis. For elevated levels of estrogen alter the synthesis and/or activity of several factors involved in iron metabolism including hypoxia inducible factor 1α (HIF-1α) and hepcidin among others. This leads to the inhibition of hepcidin synthesis in hepatocytes and the maintenance of ferroportin (FPN) integrity on the surface of iron-releasing duodenal enterocytes, hepatocytes, and macrophages. Intact FPN permits the continuous efflux of dietary and stored iron into the circulation, which further enhances pathogen growth and virulence on the one hand and suppresses host immunity on the other. This new conceptual framework may help explain a multitude of disparate clinical and experimental observations pertinent to the relationship between estrogen and infection.

Total antioxidant capacity and ischemia modified albumin in beta thalassemia.

BACKGROUND: Total antioxidant capacity (TAC) and ischemia modified albumin (IMA) are common parameters used to assess the status of oxidative stress under different conditions. This study reports on TAC and levels of IMA in patients with beta-thalassemia major. METHODS: Blood specimens were collected from 98 subjects (55 beta-thalassemia major patients and 43 healthy controls). Serum levels of IMA and TAC were determined using conventional biochemical methods. Serum levels of ferritin, iron, TIBC, ALT, bilirubin, total protein, and albumin were measured using automated chemistry analyzers. RESULTS: Levels of TIBC were significantly lower, and those of ferritin, iron, percentage of transferrin saturation, ALT, total and direct bilirubin were significantly higher in patients than in controls. No significant differences were observed between patients and controls with respect to total protein and albumin. TAC levels, expressed as mM Trolox equivalents, were significantly lower in patients than in controls (0.197 +/- 0.106 vs. 0.274 +/- 0.122, p < 0.01). Serum levels of IMA (ABSU) were significantly higher in patients than in controls (0.543 +/- 0.124 vs. 0.452 +/- 0.085, p < 0.01). Spearman univariate analysis demonstrated significant inverse correlations of TAC with both IMA and ferritin (r = -0.307, p < 0.05 and r = -0.395, p < 0.01, respectively) and significant direct correlation of IMA with ferritin (r = 0.519, p < 0.01). CONCLUSIONS: This study demonstrates the presence of a significant inverse correlation between total antioxidant capacity and IMA; this further argues for the inclusion of IMA as one of the oxidative stress markers in thalassemic patients.

Protein antioxidants in thalassemia.

It is common knowledge that thalassemic patients are under significant oxidative stress. Chronic hemolysis, frequent blood transfusion, and increased intestinal absorption of iron are the main factors that result in iron overload with its subsequent pathophysiologic complications. Iron overload frequently associates with the generation of redox-reactive labile iron, which in turn promotes the production of other reactive oxygen species (ROS). If not neutralized, uncontrolled production of ROS often leads to damage of various intra- and extracellular components such as DNA, proteins, lipids, and small antioxidant molecules among others. A number of endogenous and exogenous defense mechanisms can neutralize and counteract the damaging effects of labile iron and the reactive substances associated with it. Endogenous antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and ferroxidase, may directly or sequentially terminate the activities of ROS. Nonenzymatic endogenous defense mechanisms include metal binding proteins (ceruloplasmin, haptoglobin, albumin, and others) and endogenously produced free radical scavengers (glutathione (GSH), ubiquinols, and uric acid). Exogenous agents that are known to function as antioxidants (vitamins C and E, selenium, and zinc) are mostly diet-derived. In this review, we explore recent findings related to various antioxidative mechanisms operative in thalassemic patients with special emphasis on protein antioxidants.

Haptoglobin polymorphism in relation to antioxidative enzymes activity in type 2 diabetes mellitus.

BACKGROUND: Increased oxidative stress and impaired antioxidative capacity are common findings in diabetics. This study reports on the status of antioxidative enzymes in relation to haptoglobin (Hp) polymorphism in type 2 diabetes. METHODS: The study comprised 165 type 2 diabetic patients and 94 controls. Erythrocytic superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT), and plasmatic ceruloplasmin ferroxidase (Cp) were measured by spectrophotometry and Hp phenotypes were determined by gel electrophoresis. RESULTS: Irrespective of Hp phenotype, while the activities of Cp ferroxidase and GPx were significantly higher in patients than in controls, those of SOD were significantly lower. No significant differences observed for CAT. However, significant Hp-phenotype dependent differences were observed between patients and controls regarding the activity of these enzymes. While ferroxidase activity in Hp2-2 patients was significantly higher than that in Hp1-1 or Hp2-1 patients, that of SOD and GPx were significantly lower. When patients were analyzed as a single group, Spearman's univariate analysis has demonstrated that HbA1c positively correlates with ferroxidase activity and negatively correlates with levels of GPx and SOD. However, when patients were treated as separate Hp-dependent groups, similar but stronger correlations between these variable were noted only in the case of Hp2-2 patients. CONCLUSIONS: These findings suggest that Hp polymorphism has some bearing on the activity of antioxidative enzymes in type 2 diabetes and that Hp2-2 diabetics are under increased oxidative stress as compared with those expressing Hp1-1 or Hp2-1.

Ischemia modified albumin: an oxidative stress marker in ß-thalassemia major.

BACKGROUND: Ischemia modified albumin (IMA) is an altered type of serum albumin that forms under conditions of oxidative stress. This study reports on the levels and clinical significance of IMA in patients with ß-thalassemia major. METHODS: Blood specimens were collected from 166 subjects (101 ß-thalassemia major patients and 65 healthy controls). Serum levels of IMA, ferritin, malondialdehyde (MDA), ferroxidase, transaminases, total protein, and albumin were determined using conventional methods. RESULTS: Serum levels of IMA (ABSU) were significantly higher in patients than in controls (0.725±0.155 vs 0.554±0.154, p=0.000). Similarly, higher levels were also observed for ferritin, MDA, ferroxidase, and transaminases. No significant differences were observed between patients and controls with respect to total protein and albumin. Spearman univariate analysis demonstrated significant correlation between IMA and ferritin, MDA, ferroxidase, and transaminases. Multiple linear regression analysis revealed significant association of IMA with ferritin and ferroxidase after adjusting for the other variables (r=0.343, p=0.002; r=0.228, p=0.029 respectively). MDA however, correlated significantly with ferritin only (r=0.654, p=0.000). CONCLUSION: Our findings suggest that increased levels of IMA in thalassemic patients are likely to be a result of iron-induced oxidative stress and hence its potential significance as a new marker of oxidative stress in such patients.