Thiol level and total oxidant/antioxidant status in patients with COVID-19 infection.

BACKGROUND: Accumulating evidence suggests that oxidative stress is closely related to the pathogenesis and severity of COVID-19 infection. Here, we attempted to compare thiol, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) levels between COVID-19 patients who need and do not need intensive care unit (ICU) support, and determine whether these markers could be used as predictors of ICU admission. METHODS: We recruited 86 patients with COVID-19 infection and classified them into two groups according to the level of care: ICU group (n = 40) and non-ICU group (n = 46). Thiol, TAS, TOS, and OSI levels were determined and compared between the two groups. RESULTS: The levels of thiol and TAS in serum were markedly lower in ICU patients than in the non-ICU patients. On the contrary, TOS and OSI levels were markedly higher. Inflammatory markers, including white blood cell, neutrophil, C-reactive protein, procalcitonin, and ferritin, were negatively correlated with the thiol and TAS, and positively correlated with the TOS and OSI. We determined that areas under the ROC curve for thiol, TAS, TOS, and OSI were 0.799, 0.778, 0.713, and 0.780, respectively. CONCLUSIONS: Our results revealed that the increase in oxidative stress and decrease in antioxidant levels in COVID-19-infected patients were associated with worsening of disease. Thiol, TAS, TOS, and OSI parameters can be used to distinguish between ICU patients and those who do not, among which thiol was the best predictor of ICU requirement.

Total Antioxidant Capacity and Total Oxidant Status and Disease Severity in a Cohort Study of COVID-19 Patients.

BACKGROUND: Previous reports have suggested the role of oxidative stress in progression of COVID-19 infection, but there is limited information regarding the effect of antioxidant capacity and total oxidant status of patients with COVID-19 on disease severity. In the present study, we aimed to investigate the relationship between total antioxidant capacity (TAC), total oxidant status (TOS), TAC/TOS levels, and disease severity in hospitalized patients with COVID-19. METHODS: This cohort study was carried out at Masih Daneshvari Hospital in Tehran, Iran, from September 2020 to October 2020. Clinical data of 331 patients with COVID-19 admitted to the hospital were analyzed and divided into mild, moderate, and severe groups (needed oxygen, intubation, and mechanical ventilation). The patients' TAC, TOS, and TAC/TOS levels were assessed using the serum samples by colorimetric assay kit. RESULTS: We found no significant difference in serum levels of TAC, TOS, and TAC/TOS in terms of the disease severity. CONCLUSIONS: These results indicated that total antioxidant capacity and total oxidant status may not be the determining factor on the disease severity.

Environmentally persistent free radicals enhance SARS-CoV-2 replication in respiratory epithelium.

Epidemiological evidence links lower air quality with increased incidence and severity of COVID-19; however, mechanistic data have yet to be published. We hypothesized air pollution-induced oxidative stress in the nasal epithelium increased viral replication and inflammation. Nasal epithelial cells (NECs), collected from healthy adults, were grown into a fully differentiated epithelium. NECs were infected with the ancestral strain of SARS-CoV-2. An oxidant combustion by-product found in air pollution, the environmentally persistent free radical (EPFR) DCB230, was used to mimic pollution exposure four hours prior to infection. Some wells were pretreated with antioxidant, astaxanthin, for 24 hours prior to EPFR-DCB230 exposure and/or SARS-CoV-2 infection. Outcomes included viral replication, epithelial integrity, surface receptor expression (ACE2, TMPRSS2), cytokine mRNA expression (TNF-α, IFN-ß), intracellular signaling pathways, and oxidative defense enzymes. SARS-CoV-2 infection induced a mild phenotype in NECs, with some cell death, upregulation of the antiviral cytokine IFN-ß, but had little effect on intracellular pathways or oxidative defense enzymes. Prior exposure to EPFR-DCB230 increased SARS-CoV-2 replication, upregulated TMPRSS2 expression, increased secretion of the proinflammatory cytokine TNF-α, inhibited expression of the mucus producing MUC5AC gene, upregulated expression of p21 (apoptosis pathway), PINK1 (mitophagy pathway), and reduced levels of antioxidant enzymes. Pretreatment with astaxanthin reduced SARS-CoV-2 replication, downregulated ACE2 expression, and prevented most, but not all EPFR-DCB230 effects. Our data suggest that oxidant damage to the respiratory epithelium may underly the link between poor air quality and increased COVID-19. The apparent protection by antioxidants warrants further research.

Evaluation of the Relationship Between Aquaporin-1, Hepcidin, Zinc, Copper, and Iron Levels and Oxidative Stress in the Serum of Critically Ill Patients with COVID-19.

Our study aims to determine the relationship between hepcidin, aquaporin (AQP-1), copper (Cu), zinc (Zn), iron (Fe) levels, and oxidative stress in the sera of seriously ill COVID-19 patients with invasive mechanical ventilation. Ninety persons with and without COVID-19 were taken up and separated into two groups. The first group included seriously COVID-19 inpatients having endotracheal intubation in the intensive care unit (n = 45). The second group included individuals who had negative PCR tests and had no chronic disease (the healthy control group n = 45). AQP-1, hepcidin, Zn, Cu, Fe, total antioxidant status (TAS), and total oxidant status (TOS) were studied in the sera of both groups, and the relations of these levels with oxidative stress were determined. When the COVID-19 patient and the control groups were compared, all studied parameters were found to be statistically significant (p < 0.01). Total oxidant status (TOS), oxidative stress index (OSI), and AQP-1, hepcidin, and Cu levels were increased in patients with COVID-19 compared to healthy people. Serum TAC, Zn, and Fe levels were found to be lower in the patient group than in the control group. Significant correlations were detected between the studied parameters in COVID-19 patients. Results indicated that oxidative stress may play an important role in viral infection due to SARS-CoV-2. We think that oxidative stress parameters as well as some trace elements at the onset of COVID-19 disease will provide a better triage in terms of disease severity.

Redox imbalance in COVID-19 pathophysiology.

BACKGROUND: The pathophysiologic significance of redox imbalance is unquestionable as numerous reports and topic reviews indicate alterations in redox parameters during corona virus disease 2019 (COVID-19). However, a more comprehensive understanding of redox-related parameters in the context of COVID-19-mediated inflammation and pathophysiology is required. METHODS: COVID-19 subjects (n = 64) and control subjects (n = 19) were enrolled, and blood was drawn within 72 h of diagnosis. Serum multiplex assays and peripheral blood mRNA sequencing was performed. Oxidant/free radical (electron paramagnetic resonance (EPR) spectroscopy, nitrite-nitrate assay) and antioxidant (ferrous reducing ability of serum assay and high-performance liquid chromatography) were performed. Multivariate analyses were performed to evaluate potential of indicated parameters to predict clinical outcome. RESULTS: Significantly greater levels of multiple inflammatory and vascular markers were quantified in the subjects admitted to the ICU compared to non-ICU subjects. Gene set enrichment analyses indicated significant enhancement of oxidant related pathways and biochemical assays confirmed a significant increase in free radical production and uric acid reduction in COVID-19 subjects. Multivariate analyses confirmed a positive association between serum levels of VCAM-1, ICAM-1 and a negative association between the abundance of one electron oxidants (detected by ascorbate radical formation) and mortality in COVID subjects while IL-17c and TSLP levels predicted need for intensive care in COVID-19 subjects. CONCLUSION: Herein we demonstrate a significant redox imbalance during COVID-19 infection affirming the potential for manipulation of oxidative stress pathways as a new therapeutic strategy COVID-19. However, further work is requisite for detailed identification of oxidants (O2•-, H2O2 and/or circulating transition metals such as Fe or Cu) contributing to this imbalance to avoid the repetition of failures using non-specific antioxidant supplementation.

Oxidant- induced preconditioning: A pharmacologic approach for triggering renal 'self defense'.

Acute kidney injury (AKI) is a common event, occurring in ~5% and ~35% of hospitalized and ICU patients, respectively. The development of AKI portends an increased risk of morbidity, mortality, prolonged hospitalization, and subsequent development of chronic kidney disease (CKD). Given these facts, a multitude of experimental studies have addressed potential methods for inducing AKI prevention in high-risk patients. However, successful clinical translation of promising experimental data has remained elusive. Over the past decade, our laboratory has focused on developing a method for safely triggering AKI protection by inducing "kidney preconditioning" in mice by the intravenous administration of a combination of Fe sucrose (FeS) + tin protoporphyrin (SnPP). These agents induce mild, but short lived, 'oxidant stress' which synergistically activate a number of kidney 'self-defense' pathways (e.g., Nrf2, ferritin, IL-10). Within 18-24 h of Fe/SnPP administration, marked protection against diverse forms of experimental toxic and ischemic AKI results. FeS/SnPP-mediated reductions in kidney injury can also indirectly decrease injury in other organs by mitigating the so called "organ cross talk" phenomenon. Given these promising experimental data, three phase 1b clinical trials were undertaken in healthy subjects and patients with stage 3 or 4 CKD. These studies demonstrated that FeS/SnPP were well tolerated and that they up-regulated the cytoprotective Nrf2, ferritin, and IL-10 pathways. Two subsequent phase 2 trials, conducted in patients undergoing 'on-pump' cardiovascular surgery or in patients hospitalized with COVID 19, confirmed FeS/SnPP safety. Furthermore, interim data analyses revealed statistically significant improvements in several clinical parameters. The goals of this review are to: (i) briefly discuss the historical background of renal "preconditioning"; (ii) present the experimental data that support the concept of FeS/SnPP- induced organ protection; and (iii) discuss the initial results of clinical trials that suggest the potential clinical utility of an 'oxidant preconditioning' strategy.

Inhibition of the Cell Uptake of Delta and Omicron SARS-CoV-2 Pseudoviruses by N-Acetylcysteine Irrespective of the Oxidoreductive Environment.

The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.

The Predictive Value of Oxidative Stress Index in Patients with Confirmed SARS-COV-2 Infection.

Disbalance balance between oxidants and antioxidants is called oxidative stress and could be presented as oxidative stress index (OSI). OSI is determined by the reactive oxygen metabolites (d-ROM test) to assess oxidants and the plasma antioxidant capacity test (PAT test) to measure antioxidants. The aim of the study was to evaluate the predictive value of OSI in the disease COVID-19. d-ROMs results were the highest in the SARS-CoV-2 POSITIVE group (365+/-112), lower in the SARS-CoV-2 NEGATIVE group (314+/-72.4), and the lowest in an INTENSIVE CARE UNIT group (ICU) (277+/-142) U.Carr. PAT test values were the lowest in the SARS-CoV-2 POSITIVE group (2762+/-387), higher in the ICU group (2772 +/-786), and the highest in the SARS-CoV-2 NEGATIVE group (2808+/-470), and are not statistically significantly different (P>0.05), while OSI was: healthy with average value of 49 and the critical ill with average value of 109 (P = 0.016). Cut-offs for predicting ICUs admission was at OSI 62, with 80.0% sensitivity and 68.2% specificity.

Topological Relationships Cytoskeleton-Membrane Nanosurface-Morphology as a Basic Mechanism of Total Disorders of RBC Structures.

The state of red blood cells (RBCs) and their functional possibilities depend on the structural organization of the membranes. Cell morphology and membrane nanostructure are compositionally and functionally related to the cytoskeleton network. In this work, the influence of agents (hemin, endogenous oxidation during storage of packed RBCs, ultraviolet (UV) radiation, temperature, and potential of hydrogen (pH) changes) on the relationships between cytoskeleton destruction, membrane nanostructure, and RBC morphology was observed by atomic force microscope. It was shown that the influence of factors of a physical and biochemical nature causes structural rearrangements in RBCs at all levels of organization, forming a unified mechanism of disturbances in relationships "cytoskeleton-membrane nanosurface-cell morphology". Filament ruptures and, consequently, large cytoskeleton pores appeared. The pores caused membrane topological defects in the form of separate grain domains. Increasing loading doses led to an increase in the number of large cytoskeleton pores and defects and their fusion at the membrane nanosurfaces. This caused the changes in RBC morphology. Our results can be used in molecular cell biology, membrane biophysics, and in fundamental and practical medicine.

Oxidative stress and decreased Nrf2 level in pediatric patients with COVID-19.

The aim of this study was to investigate the change in nuclear factor erythroid 2-related factor (Nrf2), which plays a critical role in cytoprotection against oxidative stress, in pediatric patients with coronavirus disease 2019 (COVID-19) infection positivity, and to evaluate the relationship between Nrf2 and oxidative balance. The study included 40 children with confirmed COVID-19 infection and 35 healthy children. The groups were compared in respect of Nrf2, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), in addition to clinical findings of fever, cough, shortness of breath, contact history, and demographic data of age and gender. The mean Nrf2 values and TAS levels were determined to be statistically significantly low (p < 0.001) and the TOS level and OSI were statistically significantly high in the children with COVID-19 compared to the control group. A significant positive correlation was determined between Nrf2 and TAS (p < 0.01); as the Nrf2 value increased, so the TAS value increased. A significant negative correlation was determined between Nrf2 and TOS and OSI (p < 0.01); as the Nrf2 value increased, there was determined to be a significant decrease in the TOS and OSI values. COVID-19 infection in pediatric patients causes a decrease in the Nrf2 level. By causing a decrease in the TAS level and an increase in the TOS and OSI levels, the decrease in Nrf2 may explain the tissue damage which can be caused by COVID-19.

Forecasting of Oxidant/Antioxidant levels of COVID-19 patients by using Expert models with biomarkers used in the Diagnosis/Prognosis of COVID-19.

BACKGROUND: Early detection of oxidant-antioxidant levels and special care in severe patients are important in combating the COVID-19 epidemic. However, this process is costly and time consuming. Therefore, there is a need for faster, reliable and economical methods. METHODS: In this study, antioxidant/oxidant levels of patients were estimated by Expert-models using biomarkers, which are effective in the diagnosis/prognosis of COVID-19 disease. For this purpose, Expert-models were trained and created between the white-blood-cell-count (WBC), lymphocyte-count (LYM), C-reactive-protein (CRP), D-dimer, ferritin values of 35 patients with COVID-19 and antioxidant/oxidant parameter values of the same patients. Error criteria and R2 ratio were taken into account for the performance of the models. The validity of the all models was checked by the Box-Jenkis-method. RESULTS: Antioxidant/Oxidant levels were estimated with 95% confidence-coefficient using the values of WBC, LYM, CRP, D-dimer, ferritin of different 500 patients diagnosed with COVID-19 with the trained models. The error rate of all models was low and the coefficients of determination were sufficient. In the first data set, there was no significant difference between measured antioxidant/oxidant levels and predicted antioxidant/oxidant levels. This result showed that the models are accurate and reliable. In determining antioxidant/oxidant levels, LYM and ferritin biomarkers had the most effect on models, while WBC and CRP biomarkers had the least effect. The antioxidant/oxidant parameter estimated with the highest accuracy was Native-Thiol divided by Total-Thiol. CONCLUSIONS: The results showed that the antioxidant/oxidant levels of infected patients can be estimated accurately and reliably with LYM, ferritin, D-dimer, WBC, CRP biomarkers in the COVID-19 outbreak.

Oxidant and antioxidant balance in patients with COVID-19.

BACKGROUND: A crucial balance exists between oxidant and antioxidant mechanisms in the functional immune system. We aimed to evaluate the contributions of balance between these systems to coronavirus disease 2019 (COVID-19), a devastating pandemic caused by viral infection. METHOD: We analyzed serum oxidant and antioxidant stress parameters according to the clinical and demographic characteristics of children and adults with COVID-19 and compared them against the values of healthy controls. Serum native thiol (NT), total thiol (TT), disulfide, total antioxidant status, total oxidant status, and ischemia-modified albumin levels were evaluated and compared between groups. RESULTS: A total of 79 children and 74 adults were evaluated in the present study, including 46 children and 40 adults with COVID-19, 33 healthy children, and 34 healthy adults. TT, NT, and disulfide levels were significantly lower in the adult COVID-19 group than in all other groups (p = .001, p = .001, and p = .005, respectively). Additionally, TT and NT levels were significantly lower in both pediatric and adult COVID-19 cases with severe disease course than mild/moderate course. TT and NT levels were identified as predictors for the diagnosis of the adult COVID-19 cases and as independent predictors for disease severity in both children and adults with COVID-19. CONCLUSION: Parameters that reveal the oxidant and antioxidant capacity, including TT and NT, appear to be good candidates for the accurate prediction of the clinical course among patients with COVID-19.

Short-term inhibition of SARS-CoV-2 by hydrogen peroxide in persistent nasopharyngeal carriers.

Asymptomatic and convalescent coronavirus disease 2019 (COVID-19) subjects may carry severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for months in their upper respiratory ways. Desiring to permanently clean the mucosal surfaces, we investigated the chemical agents that fit to rapidly degrade the virus. Among these, hydrogen peroxide, initially tested by two of us for tolerability, showed both good performance and acceptable side effects (burning sensation for 15-20 s). We contacted circles of family physicians and the ATS Milano (Territorial Assistance and Prevention Service), and we tested this procedure on eight persistent carriers of SARS-CoV-2, performing swabs before the procedure and after it until the reappearance of the virus or until 14 days (the incubation period), keeping the surfaces clean with a hypertonic solution. Our patients had a median time from exposure or symptom onset of 111 days, and three had relapsed after being declared "cured" (two consecutive negative swabs after quarantine). One patient had a baseline negative swab and was excluded, and two successfully ended the 14 days' course, four suppressed viral elimination for 72 h, and one for 48 h, all rebounding to weak positive (cycle thresholds above 24). Although temporarily effective, such measures may have some place in the control of viral shedding to protect the most fragile subjects.

Predicting Severity and Intrahospital Mortality in COVID-19: The Place and Role of Oxidative Stress.

SARS-CoV-2 virus causes infection which led to a global pandemic in 2020 with the development of severe acute respiratory syndrome. Therefore, this study was aimed at examining its possible role in predicting severity and intrahospital mortality of COVID-19, alongside with other laboratory and biochemical procedures, clinical signs, symptoms, and comorbidity. This study, approved by the Ethical Committee of Clinical Center Kragujevac, was designed as an observational prospective cross-sectional clinical study which was conducted on 127 patients with diagnosed respiratory COVID-19 viral infection from April to August 2020. The primary goals were to determine the predictors of COVID-19 severity and to determine the predictors of the negative outcome of COVID-19 infection. All patients were divided into three categories: patients with a mild form, moderate form, and severe form of COVID-19 infection. All biochemical and laboratory procedures were done on the first day of the hospital admission. Respiratory (p < 0.001) and heart (p = 0.002) rates at admission were significantly higher in patients with a severe form of COVID-19. From all observed hematological and inflammatory markers, only white blood cell count (9.43 ± 4.62, p = 0.001) and LDH (643.13 ± 313.3, p = 0.002) were significantly higher in the severe COVID-19 group. We have observed that in the severe form of SARS-CoV-2, the levels of superoxide anion radicals were substantially higher than those in two other groups (11.3 ± 5.66, p < 0.001) and the nitric oxide level was significantly lower in patients with the severe disease (2.66 ± 0.45, p < 0.001). Using a linear regression model, TA, anosmia, ageusia, O2 -, and the duration at the ICU are estimated as predictors of severity of SARS-CoV-2 disease. The presence of dyspnea and a higher heart rate were confirmed as predictors of a negative, fatal outcome. Results from our study show that presence of hypertension, anosmia, and ageusia, as well as the duration of ICU stay, and serum levels of O2 - are predictors of COVID-19 severity, while the presence of dyspnea and an increased heart rate on admission were predictors of COVID-19 mortality.

Can charcoal improve outcomes in COVID-19 infections?

COVID-19 infection causes considerable morbidity and mortality, especially to those who are aged, have impaired renal function and are obese. We propose to examine the potential utility of oral activated charcoal with the hypothesis that such treatment would lower absorption of microbiome derived toxins and ameliorate systemic oxidant stress and inflammation.

Harnessing inflammation resolving-based therapeutic agents to treat pulmonary viral infections: What can the future offer to COVID-19?

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.