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Abstract

Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity—91.20%, specificity—92.00%; NFK: sensitivity—92.37%, specificity—92.00%; AGEs: sensitivity—99,02%, specificity—100%) and convalescents (KN: sensitivity—82.22%, specificity—84.00%; NFK: sensitivity—82,86%, specificity—86,00%; DT: sensitivity—100%, specificity—100%; AGE: sensitivity—100%, specificity—100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents.

A comparison of the levels protein glycoxidation products in patients infected with the SAR-CoV-2 virus, convalescents, and healthy controls, including in reference to the severity of COVID-19

Tryptophan concentration was significantly lower in COVID-19 patients than in the control group (p < 0.0001) and convalescents (p = 0.0498), and significantly lower in convalescents than in the control group (p < 0.0001). In turn, KN, NFK, DT, and AGE levels were significantly higher in COVID-19 patients than in healthy controls (p < 0.0001), and significantly higher in convalescents than in the control group (p < 0.0001). In addition, KN and NFK levels were higher in patients infected with the SARS-CoV-2 virus than in the control group (p = 0.0009, p = 0.0394) (Fig. A–E). An analysis of protein glycoxidation products revealed no significant differences in COVID-19 patients with different severity of symptoms evaluated based on the MEWS (Table ). However, tryptophan concentration decreased, whereas KN, NFK, and DT concentrations increased with the aggravation of disease symptoms (Table ). In turn, a comparison of patients with mild/moderate symptoms and moderately severe/severe symptoms revealed that the concentrations of all protein glycoxidation products were higher in MEWS 3 + 4 subgroups than in MEWS 1 + 2 subgroups (tryptophan p = 0.0021, KN p = 0.0051, NFK = 0.0187, dityrosine p = 0.0213, AGEs p = 0.0065) (Fig. E,G–J).Figure 2Comparison of the levels protein glycoxidation products: in COVID-19 patients, convalescents, and the control group (A, B, C, D, E); in COVID-19 patients with mild/moderate (1 + 2) and moderately severe/severe (3 + 4) symptoms (F, G, H, I, J). Key: AGEs advanced glycation end products.

Discussion

According to the literature, oxidative and nitrosative stress influences the pathogenesis and severity of infections with the SARS-CoV-2 virus,,, and the present study was undertaken to evaluate nitrosative stress parameters (NO, S-nitrosothiols, and NT) and protein glycoxidation products (tryptophan, KN, NFK, DT, and AGEs) in COVID-19 patients and convalescents, and to examine the above parameters in COVID-19 patients with different severity of disease symptoms evaluated based on the MEWS. The concentrations of NO, NT, S-nitrosothiols, KN, NFK, DT, and AGEs were higher, whereas tryptophan concentration was lower in COVID-19 patients than in the control group and convalescents. The study demonstrated that in patients with a history of COVID-19, the levels of KN, NFK, DT, and AGEs were significantly higher, whereas tryptophan concentration was significantly lower than in persons who had never been infected with the SARS-CoV-2 virus. Significant differences in nitrosative stress parameters and protein glycoxidation products were observed among COVID-19 patients with different disease severity. In addition, protein glycoxidation products were useful diagnostic biomarkers for differentiating COVID-19 patients and convalescents from healthy subjects. This is the first study to analyze changes in the levels of nitrosative stress and protein glycoxidation products in convalescents, and it provides valuable information for predicting long-term consequences of COVID-19.