Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System.

BACKGROUND AND AIM: Here, we assess the effect of adjuvant antioxidant therapies in septic shock patients with organ dysfunction and their effect on the enzymatic and non-enzymatic antioxidant systems. METHODS: Randomized clinical trial run between 2018 and 2022. One hundred and thirty-one patients with septic shock were included in five groups with 25, 27, 24, 26 and 29 patients each. Group 1 received vitamin C (Vit C), Group 2 vitamin E (Vit E), Group 3 n-acetylcysteine (NAC), Group 4 melatonin (MT) and group 5 no treatment. All antioxidants were administered orally or through a nasogastric tube for 5 days as an adjuvant to standard therapy. RESULTS: All patients had multiple organ failure (MOF) and low Vit C levels. Vit C therapy decreased CRP, PCT and NO3-/NO2- but increased Vit C levels. The SOFA score decreased with MT in 75%, Vit C 63% and NAC 50% vs. controls 33% (p = 0.0001, p = 0.03 and p = 0.001 respectively). MT diminished lipid peroxidation (LPO) (p = 0.01) and improved total antioxidant capacity (TAC) (p = 0.04). Vit E increased thiol levels (p = 0.02) and tended to decrease LPO (p = 0.06). Selenium levels were decreased in the control group (p = 0.04). CONCLUSIONS: Antioxidants used as an adjuvant therapy in the standard treatment of septic shock decrease MOF and oxidative stress markers. They increase the TAC and thiols, and maintain selenium levels.

N-Acetyl Cysteine Restores the Diminished Activity of the Antioxidant Enzymatic System Caused by SARS-CoV-2 Infection: Preliminary Findings.

SARS-CoV-2 infects type II pneumocytes and disrupts redox homeostasis by overproducing reactive oxygen species (ROS). N-acetyl cysteine (NAC) is a precursor of the synthesis of glutathione (GSH) and it restores the loss of redox homeostasis associated to viral infections. The aim of the study is to evaluate the effect of the treatment with NAC on the enzymatic antioxidant system in serum from patients infected by SARS-CoV-2. We evaluated the enzymatic activities of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), -S-transferase (GST), and reductase (GR) by spectrophotometry and the concentrations of the glutathione (GSH), total antioxidant capacity (TAC), thiols, nitrites (NO2-), and lipid peroxidation (LPO) in serum. The activity of the extracellular super oxide dismutase (ecSOD) was determined by native polyacrylamide gels, and 3-nitrotyrosine (3-NT) was measured by ELISA. A decrease in the activities of the ecSOD, TrxR, GPx, GST GR, (p = 0 ≤ 0.1), and the GSH, TAC, thiols, and NO2- (p ≤ 0.001) concentrations and an increase in LPO and 3-NT (p = 0.001) concentrations were found in COVID-19 patients vs. healthy subjects. The treatment with NAC as an adjuvant therapy may contribute to a reduction in the OS associated to the infection by SARS-CoV-2 through the generation of GSH. GSH promotes the metabolic pathways that depend on it, thus contributing to an increase in TAC and to restore redox homeostasis.

Impact on the Clinical Evolution of Patients with COVID-19 Pneumonia and the Participation of the NFE2L2/KEAP1 Polymorphisms in Regulating SARS-CoV-2 Infection.

In patients with severe pneumonia due to COVID-19, the deregulation of oxidative stress is present. Nuclear erythroid factor 2 (NRF2) is regulated by KEAP1, and NRF2 regulates the expression of genes such as NFE2L2-KEAP1, which are involved in cellular defense against oxidative stress. In this study, we analyzed the participation of the polymorphisms of NFE2L2 and KEAP1 genes in the mechanisms of damage in lung disease patients with SARS-CoV-2 infection. Patients with COVID-19 and a control group were included. Organ dysfunction was evaluated using SOFA. SARS-CoV-2 infection was confirmed and classified as moderate or severe by ventilatory status and by the Berlin criteria for acute respiratory distress syndrome. SNPs in the gene locus for NFE2L2, rs2364723C>G, and KEAP1, rs9676881A>G, and rs34197572C>T were determined by qPCR. We analyzed 110 individuals with SARS-CoV-2 infection: 51 with severe evolution and 59 with moderate evolution. We also analyzed 111 controls. Significant differences were found for rs2364723 allele G in severe cases vs. controls (p = 0.02); for the rs9676881 allele G in moderate cases vs. controls (p = 0.04); for the rs34197572 allele T in severe cases vs. controls (p = 0.001); and in severe vs. moderate cases (p = 0.004). Our results showed that NFE2L2 rs2364723C>G allele G had a protective effect against severe COVID-19, while KEAP1 rs9676881A>G allele G and rs34197572C>T minor allele T were associated with more aggressive stages of COVID-19.

Tomography and Prognostic Indices in the State of the Art of Evaluation in Hospitalized Patients with COVID-19 Pneumonia.

Evaluation in medical emergencies of COVID-19 patients represents a challenge to regulate preventive and timely management. There are key imaging and laboratory tools to classify the severity. The aim of the study was to evaluate the chest CT score performance and prognostic indices in COVID-19 patients to predict the progression to critical illness. This was a retrospective study between run between April and December 2020, in which 109 patients were included. Patients of any age and gender and who required hospitalization due to a confirmed COVID-19 diagnosis by RT-PCR and chest CT and laboratory were analyzed. In 75% of them, there was at least one comorbidity, and 30% developed critical illness, and the average mortality was 10%. In 49.5%, there was a CORADS-5 on admission, and in 50%, there was a peripheral distribution of the interstitial infiltrate in the left lower lobe. The risk factors were FiO2, CT score > 18, and the NRL index. The combination of the high-risk Quick COVID-19 Severity Index (qCSI) plus CT score > 18 indices was the best prediction index for the development of a critical condition. The combined use of indices in infected COVID-19 patients showed diagnostic accuracy and predicted severity. Imaging and the laboratory tests are key tools independent of the wave of recurrence.

The Possible Role of Glucose-6-Phosphate Dehydrogenase in the SARS-CoV-2 Infection.

Glucose-6-phosphate dehydrogenase (G6PD) is the second rate-limiting enzyme of the pentose phosphate pathway. This enzyme is present in the cytoplasm of all mammalian cells, and its activity is essential for an adequate functioning of the antioxidant system and for the response of innate immunity. It is responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH), the first redox equivalent, in the pentose phosphate pathway. Viral infections such as SARS-CoV-2 may induce the Warburg effect with an increase in anaerobic glycolysis and production of lactate. This condition ensures the success of viral replication and production of the virion. Therefore, the activity of G6PD may be increased in COVID-19 patients raising the level of the NADPH, which is needed for the enzymatic and non-enzymatic antioxidant systems that counteract the oxidative stress caused by the cytokine storm. G6PD deficiency affects approximately 350-400 million people worldwide; therefore, it is one of the most prevalent diseases related to enzymatic deficiency worldwide. In G6PD-deficient patients exposed to SARS-CoV-2, the amount of NADPH is reduced, increasing the susceptibility for viral infection. There is loss of the redox homeostasis in them, resulting in severe pneumonia and fatal outcomes.

The Possible Role of Glucose-6-Phosphate Dehydrogenase in the SARS-CoV-2 Infection

Glucose-6-phosphate dehydrogenase (G6PD) is the second rate-limiting enzyme of the pentose phosphate pathway. This enzyme is present in the cytoplasm of all mammalian cells, and its activity is essential for an adequate functioning of the antioxidant system and for the response of innate immunity. It is responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH), the first redox equivalent, in the pentose phosphate pathway. Viral infections such as SARS-CoV-2 may induce the Warburg effect with an increase in anaerobic glycolysis and production of lactate. This condition ensures the success of viral replication and production of the virion. Therefore, the activity of G6PD may be increased in COVID-19 patients raising the level of the NADPH, which is needed for the enzymatic and non-enzymatic antioxidant systems that counteract the oxidative stress caused by the cytokine storm. G6PD deficiency affects approximately 350–400 million people worldwide;therefore, it is one of the most prevalent diseases related to enzymatic deficiency worldwide. In G6PD-deficient patients exposed to SARS-CoV-2, the amount of NADPH is reduced, increasing the susceptibility for viral infection. There is loss of the redox homeostasis in them, resulting in severe pneumonia and fatal outcomes.

Hyperglycemia and Loss of Redox Homeostasis in COVID-19 Patients.

The infection with SARS-CoV-2 impairs the glucose-insulin axis and this contributes to oxidative (OS) and nitrosative (NSS) stress. Here, we evaluated changes in glucose metabolism that could promote the loss of redox homeostasis in COVID-19 patients. This was comparative cohort and analytical study that compared COVID-19 patients and healthy subjects. The study population consisted of 61 COVID-19 patients with and without comorbidities and 25 healthy subjects (HS). In all subjects the plasma glucose, insulin, 8-isoprostane, Vitamin D, H2S and 3-nitrotyrosine were determined by ELISA. The nitrites (NO2-), lipid-peroxidation (LPO), total-antioxidant-capacity (TAC), thiols, glutathione (GSH) and selenium (Se) were determined by spectrophotometry. The glucose, insulin and HOMA-IR (p < 0.001), 8-isoprostanes, 3-nitrotyrosine (p < 0.001) and LPO were increased (p = 0.02) while Vitamin D (p = 0.01), H2S, thiols, TAC, GSH and Se (p < 0.001) decreased in COVID-19 patients in comparison to HS. The SARS-CoV-2 infection resulted in alterations in the glucose-insulin axis that led to hyperglycemia, hyperinsulinemia and IR in patients with and without comorbidities. These alterations increase OS and NSS reflected in increases or decreases in some oxidative markers in plasma with major impact or fatal consequences in patients that course with metabolic syndrome. Moreover, subjects without comorbidities could have long-term alterations in the redox homeostasis after infection.

The kidnapping of mitochondrial function associated with the SARS-CoV-2 infection.

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) leads to multi-organ failure associated with a cytokine storm and septic shock. The virus evades the mitochondrial production of interferons through its N protein and, from that moment on, it hijacks the functions of these organelles. The aim of this study was to show how the virus kidnaps the mitochondrial machinery for its benefit and survival, leading to alterations of serum parameters and to nitrosative stress (NSS). In a prospective cohort of 15 postmortem patients who died from COVID-19, six markers of mitochondrial function (COX II, COX IV, MnSOD, nitrotyrosine, Bcl-2 and caspase-9) were analyzed by the immune colloidal gold technique in samples from the lung, heart, and liver. Biometric laboratory results from these patients showed alterations in hemoglobin, platelets, creatinine, urea nitrogen, glucose, C-reactive protein, albumin, D-dimer, ferritin, fibrinogen, Ca²âº, K⁺, lactate and troponin. These changes were associated with alterations in the mitochondrial structure and function. The multi-organ dysfunction present in COVID-19 patients may be caused, in part, by damage to the mitochondria that results in an inflammatory state that contributes to NSS, which activates the sepsis cascade and results in increased mortality in COVID-19 patients.

Alteration in the Lipid Profile and the Desaturases Activity in Patients With Severe Pneumonia by SARS-CoV-2.

The kidnapping of the lipid metabolism of the host's cells by severe acute respiratory syndrome (SARS-CoV-2) allows the virus to transform the cells into optimal machines for its assembly and replication. Here we evaluated changes in the fatty acid (FA) profile and the participation of the activity of the desaturases, in plasma of patients with severe pneumonia by SARS-CoV-2. We found that SARS-CoV-2 alters the FA metabolism in the cells of the host. Changes are characterized by variations in the desaturases that lead to a decrease in total fatty acid (TFA), phospholipids (PL) and non-esterified fatty acids (NEFAs). These alterations include a decrease in palmitic and stearic acids (p ≤ 0.009) which could be used for the formation of the viral membranes and for the reparation of the host's own membrane. There is also an increase in oleic acid (OA; p = 0.001) which could modulate the inflammatory process, the cytokine release, apoptosis, necrosis, oxidative stress (OS). An increase in linoleic acid (LA) in TFA (p = 0.03) and a decreased in PL (p = 0.001) was also present. They result from damage of the internal mitochondrial membrane. The arachidonic acid (AA) percentage was elevated (p = 0.02) in the TFA and this can be participated in the inflammatory process. EPA was decreased (p = 0.001) and this may decrease of pro-resolving mediators with increase in the inflammatory process. The total of NEFAs (p = 0.03), PL (p = 0.001), cholesterol, HDL and LDL were decreased, and triglycerides were increased in plasma of the COVID-19 patients. Therefore, SARS-CoV-2 alters the FA metabolism, the changes are characterized by alterations in the desaturases that lead to variations in the TFA, PL, and NEFAs profiles. These changes may favor the replication of the virus but, at the same time, they are part of the defense system provided by the host cell metabolism in its eagerness to repair damage caused by the virus to cell membranes.

Antioxidants and pentoxifylline as coadjuvant measures to standard therapy to improve prognosis of patients with pneumonia by COVID-19.

The type 2 coronavirus causes severe acute respiratory syndrome (SARS-CoV-2) and produces pneumonia with pulmonary alveolar collapse. In some cases it also causes sepsis and septic shock. There is no specific treatment for coronavirus disease 2019 (COVID-19). Vitamin C (Vit C), Vitamin E (Vit E), N-acetylcysteine (NAC) and Melatonin (MT) increase the intracellular content of GSH, kidnap free radicals and protect DNA, proteins in the cytosol and lipids in cell membranes. Pentoxifylline (Px) has anti-inflammatory activities. Here we evaluate the effect of Vit C, Vit E, NAC, and MT plus Px in COVID-19 patients with moderate and severe pneumonia. 110 patients of either sex were included. They were divided into five groups with 22 patients each. Group 1 received Vit C + Px, group 2 Vit E + Px, group 3 NAC + Px, group 4 MT + Px, and group 5 only Px. Oxidative stress (OS) markers such as lipid peroxidation (LPO) levels, total antioxidant capacity (TAC) and nitrites (NO2 -) were evaluated in plasma. The antioxidant therapy improved the survival scores including the Sequential Organ Failure Assessment (SOFA), the Acute Physiology and chronic Health Evaluation II (Apache II), the Simplified Acute Physiology Score II (SAPS II), the Critical Illness Risk Score, Launched during COVID-19 crisis (COVIDGRAM) and the Glasgow Coma Scale (GCS). We found that LPO (p≤0.04) and inflammation markers such as interleukin-6 (IL-6, p≤ 0.01), C reactive protein (CRP, p ≤ 0.01) and procalcitonin (PCT, p ≤ 0.05) were elevated. TAC (p ≤ 0.03) and NO2 - (p ≤ 0.04) found themselves diminished in diminished in COVID-19 patients upon admission to the hospital. The different antioxidants reversed this alteration at the end of the treatment. The treatment with antioxidant supplements such as Vit C, E, NAC, and MT plus Px could decelerate the aggressive and lethal development of COVID-19. Antioxidant therapy can be effective in this pandemia since it improves the survival scores including SOFA, Apache II, SAPS II, COVIDGRAM, GCS by lowering the LPO, IL-6, CRP, PCT and increasing systemic TAC and NO2 -.

Is Antioxidant Therapy a Useful Complementary Measure for Covid-19 Treatment? An Algorithm for Its Application.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes the corona virus disease-19 which is accompanied by severe pneumonia, pulmonary alveolar collapses and which stops oxygen exchange. Viral transmissibility and pathogenesis depend on recognition by a receptor in the host, protease cleavage of the host membrane and fusion. SARS-CoV-2 binds to the angiotensin converting enzyme 2 receptor. Here, we discuss the general characteristics of the virus, its mechanism of action and the way in which the mechanism correlates with the comorbidities that increase the death rate. We also discuss the currently proposed therapeutic measures and propose the use of antioxidant drugs to help patients infected with the SARS-CoV-2. Oxidizing agents come from phagocytic leukocytes such as neutrophils, monocytes, macrophages and eosinophils that invade tissue. Free radicals promote cytotoxicity thus injuring cells. They also trigger the mechanism of inflammation by mediating the activation of NFkB and inducing the transcription of cytokine production genes. Release of cytokines enhances the inflammatory response. Oxidative stress is elevated during critical illnesses and contributes to organ failure. In corona virus disease-19 there is an intense inflammatory response known as a cytokine storm that could be mediated by oxidative stress. Although antioxidant therapy has not been tested in corona virus disease-19, the consequences of antioxidant therapy in sepsis, acute respiratory distress syndrome and acute lung injury are known. It improves oxygenation rates, glutathione levels and strengthens the immune response. It reduces mechanical ventilation time, the length of stay in the intensive care unit, multiple organ dysfunctions and the length of stay in the hospital and mortality rates in acute lung injury/acute respiratory distress syndrome and could thus help patients with corona virus disease-19.