Endogenous non-enzymatic antioxidants in the human body

In the current issue of Circulation , Anker and colleagues1 report that elevated levels of uric acid (UA) predict mortality and the need for heart transplantation in patients with congestive heart failure (HF). Serum concentrations of UA added important prognostic information alone and when combined with measures of cardiac function (ejection fraction) and patient functional status (maximal oxygen consumption with exercise) and were independent of renal function, serum sodium, serum urea, diuretic usage, and patient age. Receiver operating curve analysis identified a cutoff of 585 μmol/L (9.8 mg/dL) as the best mortality predictor. This finding is not only potentially of value in patient management but also raises extremely interesting questions regarding the pathophysiological underpinnings of this finding. See p 1991 A consideration of the mechanism of UA production and metabolism offers insight into the relationship between UA levels and HF outcomes. Indeed, accumulating data support the idea that UA, in addition to being a potentially valuable prognostic marker, possesses specific toxic or other properties that could contribute to HF pathophysiology. Moreover, UA levels may reflect xanthine oxidase (XO) pathway activity, which has the potential to contribute to the progression of left ventricular dysfunction by interfering with myocardial energetics2 and myofilament calcium sensitivity.3 UA is a metabolic byproduct of purine metabolism (Figure). Serum UA may increase in the failing circulation because of increased generation, decreased excretion, or a combination of the 2 factors. There are several possible contributors to increased UA production in HF, including increased abundance and activity of XO,4 increased conversion of …

Introduction: Oxidative stress and lipid peroxidation are pointed as possible factors in the development of colorectal cancer (CRC). The aim of this study was to assess the serum malondialdehyde (MDA) and non-enzymatic antioxidants concentration (albumin, bilirubin, uric acid, and ferritin) and their relation with the stage and histopathologic size (pT) of CRC. Methods: One hundred and twenty patients with clinically and histopathologically confirmed CRC and the need for surgical treatment were included in a cross-sectional study. All patients were divided into groups according to the disease stage and depth of tumor invasion. The control group included 30 subjects with no signs of malignant and inflammatory bowel disease. The patients and controls did not receive vitamin supplementation. Peripheral venous blood was sampled before the surgical treatment of CRC patients and on the day of the examination of control subjects for determination of serum MDA and the concentration of the non-enzymatic antioxidants. Results: The serum levels of MDA were progressively increased in CRC patients with the highest level in the fourth stage of disease and pT4 group. Ferritin levels increased significantly with the CRC stage and decreased with the depth of bowel wall invasion. Serum albumin concentration significantly decreased with increasing stage and increasing depth of tumor invasion of the intestinal wall, while serum bilirubin level showed no change compared to the control group. Serum uric acid concentration was significantly higher in CRC patients, but no difference was observed with CRC progression. It was confirmed that serum albumin significantly negatively correlated with the CRC stage (rho = −0.649, p < 0.001), while serum MDA significantly positively correlated with the CRC stage (rho = 0.750, p < 0.001). Conclusion: These results indicate that serum MDA concentrations are related to the progression of CRC, to which the imbalance in non-enzymatic antioxidants also contributes.

Oxidative stress is related to the pathogenesis of mood disorders, and the level of oxidative stress may differ between bipolar disorder (BD) and major depressive disorder (MDD). This study aimed to detect the differences in non-enzymatic antioxidant levels between BD and MDD and assess the predictive values of non-enzymatic antioxidants in mood disorders by applying a machine learning model. Peripheral uric acid (UA), albumin (ALB), and total bilirubin (TBIL) were measured in 1,188 participants (discover cohort: 157 with BD and 544 with MDD; validation cohort: 119 with BD and 95 with MDD; 273 healthy controls). An extreme gradient boosting (XGBoost) model and a logistic regression model were used to assess the predictive effect. All three indices differed between patients with mood disorders and healthy controls; in addition, the levels of UA in patients with BD were higher than those of patients with MDD. After treatment, UA levels increased in the MDD group, while they decreased in the BD group. Finally, we entered age, sex, UA, ALB, and TBIL into the XGBoost model. The area under the curve (AUC) of the XGBoost model for distinguishing between BD and MDD reached 0.849 (accuracy = 0.808, 95% CI = 0.719-0.878) and for distinguishing between BD with depression episode (BD-D) and MDD was 0.899 (accuracy = 0.891, 95% CI = 0.856-0.919). The models were validated in the validation cohort. The most important feature distinguishing between BD and MDD was UA. Peripheral non-enzymatic antioxidants, especially the UA, might be a potential biomarker capable of distinguishing between BD and MDD.

Objective: Oxidative stress and antioxidant deficiency play key roles in the pathogenesis of gastrointestinal damage associated with Crohn's disease (CD). Serum bilirubin, uric acid (UA) and albumin are non-enzymatic antioxidants that play a role in oxidative stress control. In this study, it was aimed to evaluate the change in serum bilirubin, UA and albumin levels due to disease activity. Material and Method: This study was designed as a single-center, cross-sectional and retrospective. The clinical and demographic data of the patients, disease activity, as well as serum albumin, UA, and bilirubin values were recorded from the hospital database. Study variables were statistically analyzed between patient and control groups based on disease activity. Results: A total of 234 people, 114 with CD and 120 with controls, were included in the study. Total bilirubin, direct bilirubin and albumin levels were found to be significantly lower in the CD than in the health control (p=0.045, p

ObjectiveThis study aimed to investigate the associations between serum nonenzymatic antioxidants and major depressive disorder or bipolar disorder in adolescents.MethodsCross-sectional (410 adolescents: 178 patients with major depressive disorder, 54 patients with bipolar disorder, and 178 healthy controls) and longitudinal (72 adolescents: 55 patients with major depressive disorder and 17 patients with bipolar disorder) analyses were conducted. Antioxidant levels were measured and correlated with diagnosis and Hamilton Depression Rating Scale scores. Treatment-related changes in uric acid, albumin, and total bilirubin were assessed in the longitudinal cohort.ResultsPatients with major depressive disorder and bipolar disorder showed higher uric acid (p = 0.019) and lower albumin and total bilirubin (p < 0.001) than in controls. Multivariate regression analysis identified uric acid as a risk factor for major depressive disorder (odds ratio = 2.52, p = 0.003) and bipolar disorder (odds ratio = 4.66, p = 0.001), whereas albumin and total bilirubin were protective factors (p < 0.001). Post-treatment, uric acid decreased in patients with major depressive disorder (336.7 ± 82.5 to 314.1 ± 76.5 µmol/L, p = 0.017) and bipolar disorder (341.9 ± 106.8 to 314.5 ± 102.4 µmol/L, p = 0.013), whereas total bilirubin increased in patients with major depressive disorder (8.8 ± 3.4 to 11.0 ± 4.6 µmol/L, p = 0.001). Uric acid was correlated positively with Hamilton Depression Rating Scale scores in patients with major depressive disorder (r = 0.32, p < 0.001) and showed a trend in patients with bipolar disorder (r = 0.33, p = 0.06). Total bilirubin showed an inverse correlation with Hamilton Depression Rating Scale scores in patients with major depressive disorder (r = -0.30, p = 0.002).ConclusionAdolescent patients with major depressive disorder and bipolar disorder exhibit antioxidant imbalances. Elevated uric acid may act as a risk factor, whereas reduced albumin and total bilirubin appear protective, suggesting their role as biomarkers for disease status and treatment response.

Serum and whole blood Zn, Cu and Mn profiles and their relation to redox status in lung cancer patients

ObjectiveTo investigate changes in peripheral blood non-enzymatic antioxidant levels in patients with major depressive disorder (MDD) and bipolar disorder (BD) across different disease stages from a laboratory perspective, and to explore their potential clinical applications.MethodsThis single-center retrospective case-control study was conducted at Hunan Provincial Brain Hospital between January and December 2023. A total of 290 participants aged ≥ 16 years were enrolled, including 140 BD patients, 72 MDD patients, and 78 healthy controls (HC). Between-group comparisons for two groups were performed using independent samples t-tests, and one-way analysis of variance (ANOVA) was employed for multi-group comparisons of continuous variables. Analysis of covariance (ANCOVA) was further used to compare serum levels of uric acid (UA), albumin (Alb), and total bilirubin (TBIL) among the MDD, BD, and HC groups, with age and sex as covariates. Multivariable logistic regression analyses were conducted to identify independent predictors of MDD and BD. Receiver operating characteristic (ROC) curves were generated based on predicted probabilities from the regression models. Statistical significance was set at a two-tailed P < 0.05.ResultsCompared with HC, MDD patients exhibited significantly lower serum UA levels (P = 0.022), whereas BD patients demonstrated significantly higher UA levels (P = 0.006); both patient groups showed markedly reduced TBIL and Alb levels (all P < 0.0001). BD patients presented elevated UA, Alb, and TBIL levels during manic episodes and decreased levels during depressive episodes. The combined detection of these indices yielded an area under the curve (AUC) of 0.919 for MDD (sensitivity: 75.6%; specificity: 90.0%) and 0.842 for BD (sensitivity: 67.9%; specificity: 89.7%). MDD patients with hospitalization duration ≤ 15 days had higher serum UA levels, which were negatively correlated with hospitalization duration (r = −0.28). In contrast, BD patients with hospitalization duration ≤ 15 days exhibited lower UA, Alb, and TBIL levels, with UA positively correlated with hospitalization duration (r = 0.19). BD patients in depressive episodes who received antidepressants had significantly prolonged hospitalization (P < 0.0001).ConclusionSerum UA level could serve as a potential biomarker for distinguishing MDD from BD, with lower UA levels observed in MDD patients and relatively higher levels in BD patients. The combined detection of UA, Alb, and TBIL demonstrated favorable diagnostic performance for both disorders, and was associated with the length of hospital stay. Furthermore, antidepressant use during the depressive episode of BD may be associated with prolonged hospital stay. These findings may help improve the early differential diagnosis and clinical management of MDD and BD, and provide a reference for individualized treatment and hospitalization strategies in clinical practice.

Biomarkers of Oxidative Stress and Antioxidant Defense

Male infertility is conditioned in up to 25% genetically, but environmental factors are equally important. Dependencies analyzed here in this area have not been studied using such an approach so far. Therefore, they are innovative and constitute an important aspect of multi-range interdependencies. That is why we analyzed factors shaping male reproductive condition: glutathione, bilirubin, uric acid, chemical elements (Ca, Na, Mn, Fe, Mo, Li, V, Co, Ag, Ba, Tl, Al, Ni, Sn, B, Pb, Be), and genetic polymorphism (genotypes CC and TT of IL-4v.C589T(rs2243250). We studied infertile men from polluted Poland region with semen perturbations and healthy with normozoospermia. We described semen abnormalities according to standard criteria. The population of patients with infertility consisted of 76 men with different fertility disorders. The control group consisted of 87 men with normozoospermia. The majority of infertile men came from Central Poland. The collection of biological samples and seminological tests were conducted by qualified medicians from the andrology clinic and by the authors of this paper (semen morphological parameters). Seminological analyses were based on macro- and microscopic analysis of ejaculate to verify semen volume, time of liquefaction, sperm density, motility, presence of agglutination, presence of leukocytes, and percentage of pathological forms. Concentrations of chemical elements in the blood were analyzed (ICP-MS). In serum, non-enzymatic antioxidants (glutathione GSH, bilirubin, uric acid) and lipid peroxidation intensity were qualified (Cayman Chemicals Co.). In researching gene polymorphisms connected with male infertility, molecular analysis was conducted (PCR-RFLP) and applied to chromosome 5: gene IL-4v.C589T. We found poorer antioxidative defense in infertile men, whilst the higher levels of uric acid, compared to healthy, may act as a deteriorating factor. High correlations between glutathione and uric acid in the infertile and healthy implicated that non-enzymatic antioxidants undergo mutual regulation. It also applies to patients with IL-4v.C589T polymorphism. Interactions between non-enzymatic antioxidants and chemical elements were particularly noticeable in men with CC genotype. The most important modulator appeared to be sodium, while boron was the most meaningful in the interactions. Higher concentration of bilirubin, uric acid, and GSH in men with TT (0.687 mg·dL-1, 6.097 mg·dL-1, 6.345 µM), compared to CC genotype (0.652 mg·dL-1, 4.980 mg·dL-1, 4.630 µM) suggest a better functionality of antioxidative barrier. Estimating the importance of unfavorable changes arising from oxidative stress about the functionality of non-enzymatic antioxidants and correlations with MDA in men's serum allows a complete look at the determinants of male infertility. Among genetic polymorphisms, genotypes TT and CC of IL-4v.C589T gene show their influence on generating fertility perturbations. They had an indirect but differentiated effect on antioxidant mechanisms involving bilirubin, uric acid, and glutathione. Therefore, we conclude that IL-4v.C589T polymorphism differentiated the body's response to environmental stressors. The results presented in our paper on IL-4v.C589T polymorphism and conclusions formulated on their basis are consistent with literature data, indicating the lack of a direct relationship between polymorphism studied and male infertility. However, the primary intention of this paper was, to a lesser extent, to exclude or confirm a direct relationship between studied polymorphism and male infertility. We wanted a broader approach to the subject and to establish relationships between genetic aspects and antioxidant parameters of defense mechanisms. Therefore, we were more interested in the status of antioxidant defense and its relationships to the genetic factor in groups of people with a fixed genotype. We obtained a more detailed picture of the sum of genetic aspects and parameters related to antioxidant defense. Non-enzymatic defense, chemical elements, and genetic polymorphisms are related to and shape male reproductive potential. Our results may be helpful in the diagnosis of male infertility; they will enable the reduction of idiopathic cases and the implementation of targeted and more effective treatment. Identification of environmental stressors and their correlations with fertility disorders can help eliminate or reduce the impact of factors unfavorable to fertility. This shows the new importance of environmental and immunogenetic factors, oxidative stress, and genetic polymorphisms in male fertility.

Objective To investigate the clinical value of serum bilirubin, malondialdehyde and uric acid in the diagnosis of coronary heart disease. Methods From February 2014 to March 2016, 116 patients with coronary heart disease were selected as the observation group, in the same period, 100 healthy persons were selected as control group, the serum uric acid, malondialdehyde and bilirubin levels of two groups were compared and analyzed, and the clinical effects of the combined detection of the above three indexes in the patients with different classification of coronary heart disease were analyzed. Results The serum bilirubin level in the observation group was significantly lower than that in the control group, the levels of malondialdehyde and uric acid were significantly higher than those in the control group, the difference was significant (P<0.05). With the severity of coronary artery stenosis, the serum bilirubin level decreased gradually, the MDA and uric acid increased gradually, and the differences were significant (P<0.05). Conclusions Coronary heart disease patients has low serum bilirubin, high uric acid and high performance of malondialdehyde, it can provide reliable basis for the diagnosis and condition monitoring of coronary heart disease with the results of biochemical indicators. Key words: Coronary heart disease; Uric acid; Malondialdehyde; Serum bilirubin; Joint diagnosis

Uric Acid: A Clearer Focus

Objective To investigate the plasma non-enzyme antioxidants levels in chronic schizophrenic patients with tardive dyskinesia (TD). Methods The plasma levels of albumin (Alb), bilirubin (Bil) and uric acid (UA) in schizophrenic patients with TD (TD group，n=60) and without TD (non-TD group，n=60) and healthy volunteers (control group，n=45) were assayed by using full automatic biochemical analysor. The plasma antioxidants levels were compared among three groups by one-way ANOVA. Psychopathological symptoms and severities of TD were assessed by using the Positive and Negative Symptom Scale（PANSS）and Abnormal Involuntary Movement Scale (AIMS) respectively，the relationships of the plasma antioxidants levels and the clinical traits of TD were analyzed. Results Plasma Alb and Bil in control group ［(46.8±3.4) g/L，(12.7±3.3) μmol/L］ were significantly higher than those in TD ［(40.2±2.5) g/L，(9.2±2.1) μmol/L］ and non-TD ［(41.2±2.3) g/L，(10.2±3.1) μmol/L］ groups (all P<0.001)，but there were no significant differences on plasma UA concentrations among the three groups (F=1.42，P=0.234). There was significant difference on the Alb concentrations between the TD and non-TD group (P=0.033)，and trend significant difference on Bil levels (P=0.052). In TD group，the total score of AIMS were negatively related with Bil concentrations (r=-0.373，P=0.008) and negative sub-score of PANSS (r=-0.262，P=0.044). Conclusions The non-enzyme antioxidants might be involved in the pathophysiology of TD. Key words: Antipsychotic agents; Dyskinesia，drug-induced; Plasma; Antioxidant; Albumins; Bilirubin; Uric acid

This study aimed at evaluating the serum redox status in type 2 diabetes mellitus (T2DM) accompanied with an imbalance in iron concentrations. Diabetic patients were grouped according to serum iron levels [normal (DNFe), low (DLFe), and high (DHFe)], and their clinical and redox parameters [total sulfhydryl groups (tSH), uric acid (UA), and total bilirubin (tBILI) as non-enzymatic antioxidants, and malondialdehyde (MDA) and advanced oxidation products of proteins (AOPP) as markers of oxidative stress] were determined. Glucose and HbA1c levels in the T2DM patients did not differ in function of serum iron. T2DM was associated with reduced tSH levels. In the diabetic patients, tSH, UA, and tBILI negatively correlated with MDA, as well as HbA1c with UA. Accordingly, AOPP and MDA were higher in the diabetic groups compared to the controls. The reduced antioxidant capacity was particularly pronounced in the DLFe group, which was further characterized by lower levels of UA and tBILI compared to the other groups. Subsequently, the level of MDA in the DLFe group was higher compared to the DNFe and DHFe groups. The positive correlation between serum iron levels and the antioxidants UA and tBILI, in conjunction with the negative correlation between serum iron levels and the markers of oxidative stress in the diabetic patients, corroborated the indication that comparatively higher level of oxidative stress is present when T2DM coexists with decreased iron levels. T2DM-associated redox imbalance is characterized by a decrease in serum total sulfhydryl groups and low serum iron-associated reduction in uric acid and total bilirubin levels, accompanied by increased oxidative stress markers. The relatively noninvasive and simple determination of these parameters may be of considerable interest in monitoring the pathophysiological processes in T2DM patients, and may provide useful insights into the effects of potential therapeutic or nutritional interventions.

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. The oxidative stress in diabetes was greatly increased due to prolonged exposure to hyperglycemia and impairment of oxidant/antioxidant equilibrium. Proteins and lipids are among the prime targets for oxidative stress. In the present study, the oxidative stress was evaluated in 55 diabetic patients and 40 healthy subjects by measuring the levels of protein oxidation, lipid peroxidation and some enzymatic and nonenzymatic antioxidants. The oxidative products of protein (PCG) and lipid peroxidation (MDA) and nitric oxide levels in plasma of NIDDM patients were significantly increased. However, the levels of enzymatic (GPx, SOD, catalase in RBC) and nonenzymatic (beta-carotene, retinol, vitamin C & E and uric acid) antioxidants of RBC showed a significant decrease in NIDDM patients compared to normal subjects. Serum protein analysis by polyacrylamide gel electrophoresis (PAGE) showed the significant difference in the ceruloplasmin, transferrin, albumin, retinal binding protein, etc. in diabetic patients compared to healthy controls. In conclusion, the results suggest that increased protein oxidation, lipid peroxidation and NO levels, decreases the levels of enzymatic and nonenzymatic antioxidants and playing a major role in diabetic complications.

Introduction: Glaucoma is a neurodegenerative eye condition and is characterized by raised intraocular pressure. When left untreated, patients may gradually experience visual field loss, and even lose their sight completely. Aim: This study aimed to evaluate plasma enzymatic and nonenzymatic antioxidants levels and haematological parameters in glaucoma patients in Bayelsa State, Nigeria. Methods: A cross-sectional study design was used in this investigation to examine the relationship between variables, and a total of 80 subjects comprising; 50 glaucoma patients and 30 apparently healthy control subjects selected for the study. Following standard operating protocols, five milliliters of venous blood were aseptically drawn from each patient via the cubital fossa region and dispensed in ethylene diamine tetra-acetic acid and plain sample containers. The blood sample was used for determination of antioxidants: uric acid, albumin, bilirubin, Superoxide dismutase, catalase, and malondialdehyde using spectrophotometric techniques, and haematological parameters: packed cell volume, haemoglobin, total white blood cell count, neutrophil, lymphocytes, eosinophils, basophils, monocytes, and platelet count were measured using the Sysmex automated haematological analyzer. Statistical analysis was done using Special Package for Social Sciences (SPSS) version 23.0 and p&lt;0.05 was considered statistically significant. Results: The serum concentration of non-enzymatic antioxidants (uric acid, albumin, total bilirubin and conjugated bilirubin) levels in the glaucoma patients were significantly (p&lt;0.05) lower than the non-glaucomatous subjects. Serum superoxide dismutase, catalase and malondialdehyde levels showed no significant difference when compared with the control subjects. Packed cell volume, haemoglobin, total white blood cell count, and platelets showed no significant (p&gt;0.05) difference in the glaucoma patients compared to the control subjects. However, a statistically significant decrease in eosinophil count (p&lt;0.05) was observed in glaucoma patients compared to control subjects which indicated a significant association between glaucoma and eosinopenia. Conclusion: This finding suggests that the reduced uric acid, albumin, total bilirubin, conjugated bilirubin and eosinophil levels may be a potential risk for glaucoma.