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1.
Cells ; 11(6)2022 03 09.
Article in English | MEDLINE | ID: covidwho-1731953

ABSTRACT

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.


Subject(s)
COVID-19 , Hyperglycemia , Insulin Resistance , Selenium , Antioxidants/metabolism , Glucose , Glutathione/metabolism , Homeostasis , Humans , Hyperglycemia/complications , Insulin/metabolism , Oxidation-Reduction , Oxidative Stress , SARS-CoV-2 , Sulfhydryl Compounds , Vitamin D , Vitamins
2.
Eur Rev Med Pharmacol Sci ; 26(2): 715-721, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1675570

ABSTRACT

OBJECTIVE: As N-acetylcysteine (NAC) is promising as a re-purposed drug for the adjunctive or supportive treatment of serious COVID-19, this article aimed to describe current evidence. MATERIALS AND METHODS: A search was performed in PubMed/Medline for "NAC", "viral Infection", COVID-19", oxidative stress", "inflammation", retrieving preclinical and clinical studies. RESULTS: NAC is a pleiotropic molecule with a dual antioxidant mechanism; it may neutralize free radicals and acts as a donor of cysteine, restoring the physiological pool of GSH. Serious COVID-19 patients have increased levels of reactive oxygen species (ROS) and free radicals and often present with glutathione depletion, which prompts a cytokine storm. NAC, which acts as a precursor of GSH inside cells, has been currently used in many conditions to restore or protect against GSH depletion and has a wide safety margin. In addition, NAC has anti-inflammatory activity independently of its antioxidant activity. CONCLUSIONS: Clinical and experimental data suggest that NAC may act on the mechanisms leading to the prothrombotic state observed in severe COVID-19.


Subject(s)
Acetylcysteine/therapeutic use , COVID-19/drug therapy , Acetylcysteine/chemistry , Antioxidants/chemistry , COVID-19/metabolism , COVID-19/virology , Glutathione/chemistry , Glutathione/metabolism , Humans , Oxidative Stress , Randomized Controlled Trials as Topic , Reactive Oxygen Species/metabolism , SARS-CoV-2/isolation & purification , Virus Diseases/drug therapy , Virus Diseases/metabolism
3.
Sci Adv ; 8(5): eabl8920, 2022 02 04.
Article in English | MEDLINE | ID: covidwho-1673337

ABSTRACT

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.


Subject(s)
Dexamethasone/pharmacology , Dipeptidases/genetics , Ferroptosis/drug effects , Ferroptosis/genetics , Gene Expression Regulation/drug effects , Glutathione/metabolism , Receptors, Glucocorticoid/metabolism , Carbolines/adverse effects , Carbolines/pharmacology , Cell Line , Dipeptidases/metabolism , Fluorescent Antibody Technique , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Gene Knockdown Techniques , Humans , Immunophenotyping , Oxidation-Reduction/drug effects , Piperazines/adverse effects , Piperazines/pharmacology
4.
Oxid Med Cell Longev ; 2021: 9221693, 2021.
Article in English | MEDLINE | ID: covidwho-1438138

ABSTRACT

OBJECTIVE: Aminothiols (glutathione (GSH), cysteinylglycine (CG)) may play an important role in the pathogenesis of coronavirus disease 2019 (COVID-19), but the possible association of these indicators with the severity of COVID-19 has not yet been investigated. METHODS: The total content (t) and reduced forms (r) of aminothiols were determined in patients with COVID-19 (n = 59) on admission. Lung injury was characterized by computed tomography (CT) findings in accordance with the CT0-4 classification. RESULTS: Low tGSH level was associated with the risk of severe COVID-19 (tGSH ≤ 1.5 µM, mild vs. moderate/severe: risk ratio (RR) = 3.09, p = 0.007) and degree of lung damage (tGSH ≤ 1.8 µM, CT < 2 vs. CT ≥ 2: RR = 2.14, p = 0.0094). The rGSH level showed a negative association with D-dimer levels (ρ = -0.599, p = 0.014). Low rCG level was also associated with the risk of lung damage (rCG ≤ 1.3 µM, CT < 2 vs. CT ≥ 2: RR = 2.28, p = 0.001). Levels of rCG (ρ = -0.339, p = 0.012) and especially tCG (ρ = -0.551, p = 0.004) were negatively associated with platelet count. In addition, a significant relationship was found between the advanced oxidation protein product level and tGSH in patients with moderate or severe but not in patients with mild COVID-19. CONCLUSION: Thus, tGSH and rCG can be seen as potential markers for the risk of severe COVID-19. GSH appears to be an important factor to oxidative damage prevention as infection progresses. This suggests the potential clinical efficacy of correcting glutathione metabolism as an adjunct therapy for COVID-19.


Subject(s)
COVID-19/diagnosis , Dipeptides/blood , Glutathione/blood , Advanced Oxidation Protein Products/blood , Aged , Amino Acids, Sulfur/blood , Biomarkers/blood , COVID-19/blood , COVID-19/pathology , Dipeptides/metabolism , Female , Glutathione/metabolism , Humans , Lung/diagnostic imaging , Lung/pathology , Male , Middle Aged , Oxidation-Reduction , SARS-CoV-2/isolation & purification , Severity of Illness Index
5.
J Med Virol ; 93(9): 5446-5451, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363689

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become a global health issue and develops into a broad range of illnesses from asymptomatic to fatal respiratory diseases. SARS-CoV-2 infection is associated with oxidative stress that triggers cytokine production, inflammation, and other pathophysiological processes. Glutathione-S-transferase (GST) is an important enzyme that catalyzes the conjugation of glutathione (GSH) with electrophiles to protect the cell from oxidative damage and participates in the antioxidant defense mechanism in the lungs. Thus, in this study, we investigated the role of GSTM1 and GSTT1 gene polymorphism with COVID-19 susceptibility, as well as its outcome. The study included 269 RT-PCR confirmed COVID-19 patients with mild (n = 149) and severe (n = 120) conditions. All subjects were genotyped for GSTM1 and GSTT1 by multiplex polymerase chain reaction (mPCR) followed by statistical analysis. The frequency of GSTM1-/- , GSTT1-/- and GSTM1-/- /GSTT1-/- was higher in severe COVID-19 patients as compared to mild patients but we did not observe a significant association. In the Cox hazard model, death was significantly 2.28-fold higher in patients with the GSTT1-/- genotype (p = 0.047). In combination, patients having GSTM1+/+ and GSTT1-/- genotypes showed a poor survival rate (p = 0.02). Our results suggested that COVID-19 patients with the GSTT1-/- genotype showed higher mortality.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , Glutathione Transferase/genetics , Polymorphism, Genetic , SARS-CoV-2/pathogenicity , Adult , Aged , Alleles , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , COVID-19 Nucleic Acid Testing , Female , Follow-Up Studies , Gene Expression , Gene Frequency , Glutathione/metabolism , Humans , Male , Middle Aged , Oxidative Stress , Proportional Hazards Models , Severity of Illness Index
6.
Int J Mol Sci ; 22(15)2021 Jul 21.
Article in English | MEDLINE | ID: covidwho-1325680

ABSTRACT

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.


Subject(s)
COVID-19/complications , COVID-19/immunology , Diabetic Nephropathies/complications , Diabetic Nephropathies/immunology , Angiotensin-Converting Enzyme 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Glutathione/metabolism , Humans , Neuropilin-1/metabolism , SARS Virus/immunology , Vitamin D/metabolism
7.
BMC Complement Med Ther ; 21(1): 192, 2021 Jul 05.
Article in English | MEDLINE | ID: covidwho-1317123

ABSTRACT

BACKGROUND: Lippia javanica (lemon bush) is commonly used in the treatment of respiratory ailments, including asthma in southern African countries but there is no scientific evidence to support this claim. This study investigated the anti-inflammatory, antioxidant and anti-asthmatic effects of L. javanica using a rat model of asthma. METHODS: A 5% w/v L. javanica tea infusion was prepared and characterised by liquid chromatography-mass spectrometer (LC-MS). Animals were intraperitoneally sensitized with ovalbumin (OVA) and subsequently challenged intranasal with OVA on day 15 except the control group. Animals were grouped (n = 5/group) for treatment: unsensitised control, sensitised control, sensitised + prednisolone and sensitised + L. javanica at 50 mg/kg/day and 100 mg/kg/day - equivalent to 1 and 2 cups of tea per day, respectively. After 2 weeks of treatment, bronchoalveolar lavage fluid (BALF) was collected for total and differential white blood cell (WBC) count. Nitric oxide (NO), lipid peroxidation and antioxidants were also assessed in BALF. Ovalbumin specific IgE antibody and inflammatory cytokines: IL-4, IL-5, IL-13 and TNF-alpha were measured in serum. Lung and muscle tissues were histological examined. RESULTS: L. javanica was rich in phenolic compounds. OVA sensitisation resulted in development of allergic asthma in rats. L. javanica treatment resulted in a reduction in total WBC count as well as eosinophils, lymphocytes and neutrophils in BALF. L. javanica inhibited Th2-mediated immune response, which was evident by a decrease in serum IgE and inflammatory cytokines: IL-4, IL-5, IL-13 and TNF-α. L. javanica treatment also reduced malondialdehyde (MDA) and NO, and increased superoxide dismutase, glutathione and total antioxidant capacity. Histology showed significant attenuation of lung infiltration of inflammatory cells, alveolar thickening, and bronchiole smooth muscle thickening. CONCLUSION: L. javanica suppressed allergic airway inflammation by reducing Th2-mediated immune response and oxidative stress in OVA-sensitized rats which may be attributed to the presence of phenolic compound in the plant. This finding validates the traditional use of L. javanica in the treatment of respiratory disorders.


Subject(s)
Asthma/drug therapy , Lippia , Teas, Herbal , Animals , Antioxidants/metabolism , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Cytokines/blood , Disease Models, Animal , Eosinophils/metabolism , Glutathione/metabolism , Immunoglobulin E/blood , Leukocyte Count , Lung/pathology , Lymphocytes/metabolism , Malondialdehyde/metabolism , Neutrophils/metabolism , Nitric Oxide/metabolism , Oxidative Stress/drug effects , Rats, Wistar , Superoxide Dismutase/metabolism , Th2 Cells/drug effects
8.
Int J Mol Sci ; 22(7)2021 Mar 30.
Article in English | MEDLINE | ID: covidwho-1299437

ABSTRACT

Host-directed therapy using drugs that target cellular pathways required for virus lifecycle or its clearance might represent an effective approach for treating infectious diseases. Changes in redox homeostasis, including intracellular glutathione (GSH) depletion, are one of the key events that favor virus replication and contribute to the pathogenesis of virus-induced disease. Redox homeostasis has an important role in maintaining an appropriate Th1/Th2 balance, which is necessary to mount an effective immune response against viral infection and to avoid excessive inflammatory responses. It is known that excessive production of reactive oxygen species (ROS) induced by viral infection activates nuclear factor (NF)-kB, which orchestrates the expression of viral and host genes involved in the viral replication and inflammatory response. Moreover, redox-regulated protein disulfide isomerase (PDI) chaperones have an essential role in catalyzing formation of disulfide bonds in viral proteins. This review aims at describing the role of GSH in modulating redox sensitive pathways, in particular that mediated by NF-kB, and PDI activity. The second part of the review discusses the effectiveness of GSH-boosting molecules as broad-spectrum antivirals acting in a multifaceted way that includes the modulation of immune and inflammatory responses.


Subject(s)
Glutathione/metabolism , Virus Diseases/drug therapy , Virus Replication/drug effects , Animals , Antiviral Agents/pharmacology , Humans , NF-kappa B/metabolism , Oxidation-Reduction/drug effects , Protein Disulfide-Isomerases/metabolism , Reactive Oxygen Species/metabolism , Virus Diseases/metabolism
9.
BMC Complement Med Ther ; 21(1): 192, 2021 Jul 05.
Article in English | MEDLINE | ID: covidwho-1296592

ABSTRACT

BACKGROUND: Lippia javanica (lemon bush) is commonly used in the treatment of respiratory ailments, including asthma in southern African countries but there is no scientific evidence to support this claim. This study investigated the anti-inflammatory, antioxidant and anti-asthmatic effects of L. javanica using a rat model of asthma. METHODS: A 5% w/v L. javanica tea infusion was prepared and characterised by liquid chromatography-mass spectrometer (LC-MS). Animals were intraperitoneally sensitized with ovalbumin (OVA) and subsequently challenged intranasal with OVA on day 15 except the control group. Animals were grouped (n = 5/group) for treatment: unsensitised control, sensitised control, sensitised + prednisolone and sensitised + L. javanica at 50 mg/kg/day and 100 mg/kg/day - equivalent to 1 and 2 cups of tea per day, respectively. After 2 weeks of treatment, bronchoalveolar lavage fluid (BALF) was collected for total and differential white blood cell (WBC) count. Nitric oxide (NO), lipid peroxidation and antioxidants were also assessed in BALF. Ovalbumin specific IgE antibody and inflammatory cytokines: IL-4, IL-5, IL-13 and TNF-alpha were measured in serum. Lung and muscle tissues were histological examined. RESULTS: L. javanica was rich in phenolic compounds. OVA sensitisation resulted in development of allergic asthma in rats. L. javanica treatment resulted in a reduction in total WBC count as well as eosinophils, lymphocytes and neutrophils in BALF. L. javanica inhibited Th2-mediated immune response, which was evident by a decrease in serum IgE and inflammatory cytokines: IL-4, IL-5, IL-13 and TNF-α. L. javanica treatment also reduced malondialdehyde (MDA) and NO, and increased superoxide dismutase, glutathione and total antioxidant capacity. Histology showed significant attenuation of lung infiltration of inflammatory cells, alveolar thickening, and bronchiole smooth muscle thickening. CONCLUSION: L. javanica suppressed allergic airway inflammation by reducing Th2-mediated immune response and oxidative stress in OVA-sensitized rats which may be attributed to the presence of phenolic compound in the plant. This finding validates the traditional use of L. javanica in the treatment of respiratory disorders.


Subject(s)
Asthma/drug therapy , Lippia , Teas, Herbal , Animals , Antioxidants/metabolism , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Cytokines/blood , Disease Models, Animal , Eosinophils/metabolism , Glutathione/metabolism , Immunoglobulin E/blood , Leukocyte Count , Lung/pathology , Lymphocytes/metabolism , Malondialdehyde/metabolism , Neutrophils/metabolism , Nitric Oxide/metabolism , Oxidative Stress/drug effects , Rats, Wistar , Superoxide Dismutase/metabolism , Th2 Cells/drug effects
11.
Redox Biol ; 45: 102041, 2021 09.
Article in English | MEDLINE | ID: covidwho-1263367

ABSTRACT

Viral infections sustain their replication cycle promoting a pro-oxidant environment in the host cell. In this context, specific alterations of the levels and homeostatic function of the tripeptide glutathione have been reported to play a causal role in the pro-oxidant and cytopathic effects (CPE) of the virus. In this study, these aspects were investigated for the first time in SARS-CoV2-infected Vero E6 cells, a reliable and well-characterized in vitro model of this infection. SARS-CoV2 markedly decreased the levels of cellular thiols, essentially lowering the reduced form of glutathione (GSH). Such an important defect occurred early in the CPE process (in the first 24 hpi). Thiol analysis in N-acetyl-Cys (NAC)-treated cells and membrane transporter expression data demonstrated that both a lowered uptake of the GSH biosynthesis precursor Cys and an increased efflux of cellular thiols, could play a role in this context. Increased levels of oxidized glutathione (GSSG) and protein glutathionylation were also observed along with upregulation of the ER stress marker PERK. The antiviral drugs Remdesivir (Rem) and Nelfinavir (Nel) influenced these changes at different levels, essentially confirming the importance or blocking viral replication to prevent GSH depletion in the host cell. Accordingly, Nel, the most potent antiviral in our in vitro study, produced a timely activation of Nrf2 transcription factor and a GSH enhancing response that synergized with NAC to restore GSH levels in the infected cells. Despite poor in vitro antiviral potency and GSH enhancing function, Rem treatment was found to prevent the SARS-CoV2-induced glutathionylation of cellular proteins. In conclusion, SARS-CoV2 infection impairs the metabolism of cellular glutathione. NAC and the antiviral Nel can prevent such defect in vitro.


Subject(s)
COVID-19 , Glutathione , Glutathione/metabolism , Glutathione Disulfide/metabolism , Humans , Oxidation-Reduction , RNA, Viral , SARS-CoV-2
12.
Front Immunol ; 12: 598601, 2021.
Article in English | MEDLINE | ID: covidwho-1170084

ABSTRACT

Cryptococcal meningitis (CM) is the leading cause of mortality among patients infected with human immunodeficiency virus (HIV). Although treatment strategies for CM are continually being developed, the mortality rate is still high. Therefore, we need to explore more therapeutic strategies that are aimed at hindering its pathogenic mechanism. In the field of CM, several studies have observed rapid iron accumulation and lipid peroxidation within the brain, all of which are hallmarks of ferroptosis, which is a type of programmed cell death that is characterized by iron dependence and lipid peroxidation. In recent years, many studies have confirmed the involvement of ferroptosis in many diseases, including infectious diseases such as Mycobacterium tuberculosis infection and coronavirus disease-2019 (COVID-19). Furthermore, ferroptosis is considered as immunogenic and pro-inflammatory as the ferroptotic cells release damage-associated molecular pattern molecules (DAMPs) and alarmin, both of which regulate immunity and pro-inflammatory activity. Hence, we hypothesize that there might be a relationship between this unique cell death modality and CM. Herein, we review the evidence of ferroptosis in CM and consider the hypothesis that ferroptotic cell death may be involved in the cell death of CM.


Subject(s)
COVID-19/metabolism , Ferroptosis , Iron/metabolism , Lipid Peroxidation , Meningitis, Cryptococcal/metabolism , Tuberculosis/metabolism , COVID-19/immunology , COVID-19/pathology , Ferroptosis/immunology , Glutathione/metabolism , Humans , Inflammation/immunology , Lipid Metabolism , Meningitis, Cryptococcal/immunology , Meningitis, Cryptococcal/pathology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Tuberculosis/immunology , Tuberculosis/pathology
13.
Hum Exp Toxicol ; 40(2): 325-341, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1067095

ABSTRACT

To assess the chondroprotective effect and influence of N,N'-bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3-oxopyrazol-4-yl) sebacamide (dpdo) that was synthesized through the reaction of phenazone with sebacoyl chloride and screened for its biological activity especially as anti-arthritic and anti-inflammatory agent in a monoiodoacetate (MA)-induced experimental osteoarthritis (OA) model. Thirty male albino rats weighing "190-200 g" were divided randomly into three groups (10 each): control, MA-induced OA, and MA-induced OA + dpdo. In MA-induced OA rat, the tumor necrosis factor alpha, interleukin 6, C-reactive protein, rheumatoid factors, reactive oxygen species, as well as all the mitochondrial markers such as mitochondria membrane potential, swelling mitochondria, cytochrome c oxidase (complex IV), and serum oxidative/antioxidant status (malondialdehyde level and activities of myeloperoxidase and xanthine oxidase) are elevated. Also, the activity of succinate dehydrogenase (complex II), levels of ATP, the level of glutathione (GSH), and thiol were markedly diminished in the MA-induced OA group compared to the normal control rats. These findings showed that mitochondrial function is associated with OA pathophysiological alterations and high gene expressions of (IL-6, TNF-a, and IL-1b) and suggests a promising use of dpdo as potential ameliorative agents in the animal model of OA and could act as anti-inflammatory agent in case of severe infection with COVID-19. It is clearly appeared in improving the bone cortex and bone marrow in the treated group with the novel compound in histological and transmission electron microscopic sections which is a very important issue today in fighting severe infections that have significant effects on the blood indices and declining of blood corpuscles like COVID-19, in addition to declining the genotoxicity and inflammation induced by MA in male rats. The novel synthesized compound was highly effective in improving all the above mentioned parameters.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Osteoarthritis/drug therapy , SARS-CoV-2 , Adenosine Triphosphate/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Bone and Bones/drug effects , Bone and Bones/pathology , Bone and Bones/ultrastructure , C-Reactive Protein/analysis , Cytochromes c/metabolism , Cytokines/metabolism , Disease Models, Animal , Glutathione/metabolism , Iodoacetic Acid , Lipid Peroxidation/drug effects , Male , Matrix Metalloproteinases/metabolism , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/physiology , Osteoarthritis/chemically induced , Osteoarthritis/metabolism , Osteoarthritis/pathology , Rats , Reactive Oxygen Species/metabolism , Succinate Dehydrogenase/metabolism
14.
Free Radic Biol Med ; 165: 184-190, 2021 03.
Article in English | MEDLINE | ID: covidwho-1056615

ABSTRACT

Several recent reviews have suggested a role of oxidative stress in the pathophysiology of COVID-19, but its interplay with disease severity has not been revealed yet. In the present study, we aimed to investigate the association between the severity of COVID-19 and oxidative stress parameters. Clinical data of 77 patients with COVID-19 admitted to the hospital were analyzed and divided into moderate (n = 44) and severe (n = 33) groups based on their clinical condition. Production of oxidant (hydrogen peroxide) and defense antioxidants (total antioxidant capacity, reduced and oxidized glutathione, glutathione s-transferase), and oxidative damage (malondialdehyde, carbonyl, and sulfhydryl) were assessed using the serum samples. The results revealed that severe patients who presented high serum leukocyte count and CRP level stayed for a longer period in the hospital. However, there was no correlation observed between the oxidative stress parameters and degree of COVID-19 severity in the present study. In conclusion, these results indicate that the disease severity may not be a detrimental factor contributing to the changes in the redox profile of hospitalized patients with COVID-19.


Subject(s)
COVID-19/metabolism , Oxidative Stress/physiology , SARS-CoV-2/physiology , Adult , Aged , Brazil/epidemiology , COVID-19/epidemiology , Cohort Studies , Disease Progression , Disease Susceptibility , Female , Glutathione/metabolism , Glutathione Transferase/metabolism , Humans , Hydrogen Peroxide/metabolism , Male , Middle Aged , Prospective Studies
15.
Life Sci ; 269: 119099, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1036398

ABSTRACT

AIMS: Azithromycin is widely used broad spectrum antibiotic recently used in treatment protocol of COVID-19 for its antiviral and immunomodulatory effects combined with Hydroxychloroquine or alone. Rat models showed that Azithromycin produces oxidative stress, inflammation, and apoptosis of myocardial tissue. Rosuvastatin, a synthetic statin, can attenuate myocardial ischemia with antioxidant and antiapoptotic effects. This study aims to evaluate the probable protective effect of Rosuvastatin against Azithromycin induced cardiotoxicity. MAIN METHOD: Twenty adult male albino rats were divided randomly into four groups, five rats each control, Azithromycin, Rosuvastatin, and Azithromycin +Rosuvastatin groups. Azithromycin 30 mg/kg/day and Rosuvastatin 2 mg/kg/day were administrated for two weeks by an intragastric tube. Twenty-four hours after the last dose, rats were anesthetized and the following measures were carried out; Electrocardiogram, Blood samples for Biochemical analysis of lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). The animals sacrificed, hearts excised, apical part processed for H&E, immunohistochemical staining, and examined by light microscope. The remaining parts of the heart were collected for assessment of Malondialdehyde (MDA) and Reduced Glutathione (GSH). KEY FINDINGS: The results revealed that Rosuvastatin significantly ameliorates ECG changes, biochemical, and Oxidative stress markers alterations of Azithromycin. Histological evaluation from Azithromycin group showed marked areas of degeneration, myofibers disorganization, inflammatory infiltrate, and hemorrhage. Immunohistochemical evaluation showed significant increase in both Caspase 3 and Tumor necrosis factor (TNF) immune stain. Rosuvastatin treated group showed restoration of the cardiac muscle fibers in H&E and Immunohistochemical results. SIGNIFICANCE: We concluded that Rosuvastatin significantly ameliorates the toxic changes of Azithromycin on the heart.


Subject(s)
Anti-Bacterial Agents/adverse effects , Azithromycin/adverse effects , Cardiotoxicity/prevention & control , Rosuvastatin Calcium/pharmacology , Animals , Anti-Bacterial Agents/administration & dosage , Antioxidants/administration & dosage , Antioxidants/pharmacology , Apoptosis/drug effects , Azithromycin/administration & dosage , COVID-19/drug therapy , Cardiotoxicity/etiology , Disease Models, Animal , Glutathione/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/chemically induced , Inflammation/prevention & control , Male , Malondialdehyde/metabolism , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Rosuvastatin Calcium/administration & dosage
16.
J Biol Chem ; 295(39): 13458-13473, 2020 09 25.
Article in English | MEDLINE | ID: covidwho-1023994

ABSTRACT

My interest in biological chemistry proceeded from enzymology in vitro to the study of physiological chemistry in vivo Investigating biological redox reactions, I identified hydrogen peroxide (H2O2) as a normal constituent of aerobic life in eukaryotic cells. This finding led to developments that recognized the essential role of H2O2 in metabolic redox control. Further research included studies on GSH, toxicological aspects (the concept of "redox cycling"), biochemical pharmacology (ebselen), nutritional biochemistry and micronutrients (selenium, carotenoids, flavonoids), and the concept of "oxidative stress." Today, we recognize that oxidative stress is two-sided. It has its positive side in physiology and health in redox signaling, "oxidative eustress," whereas at higher intensity, there is damage to biomolecules with potentially deleterious outcome in pathophysiology and disease, "oxidative distress." Reflecting on these developments, it is gratifying to witness the enormous progress in redox biology brought about by the science community in recent years.


Subject(s)
Hydrogen Peroxide/metabolism , Glutathione/metabolism , Humans , Oxidation-Reduction , Oxidative Stress
17.
Free Radic Biol Med ; 161: 84-91, 2020 12.
Article in English | MEDLINE | ID: covidwho-1023568

ABSTRACT

There is a marked variation in mortality risk associated with COVID-19 infection in the general population. Low socioeconomic status and other social determinants have been discussed as possible causes for the higher burden in African American communities compared with white communities. Beyond the social determinants, the biochemical mechanism that predisposes individual subjects or communities to the development of excess and serious complications associated with COVID-19 infection is not clear. Virus infection triggers massive ROS production and oxidative damage. Glutathione (GSH) is essential and protects the body from the harmful effects of oxidative damage from excess reactive oxygen radicals. GSH is also required to maintain the VD-metabolism genes and circulating levels of 25-hydroxyvitamin D (25(OH)VD). Glucose-6-phosphate dehydrogenase (G6PD) is necessary to prevent the exhaustion and depletion of cellular GSH. X-linked genetic G6PD deficiency is common in the AA population and predominantly in males. Acquired deficiency of G6PD has been widely reported in subjects with conditions of obesity and diabetes. This suggests that individuals with G6PD deficiency are vulnerable to excess oxidative stress and at a higher risk for inadequacy or deficiency of 25(OH)VD, leaving the body unable to protect its 'oxidative immune-metabolic' physiological functions from the insults of COVID-19. An association between subclinical interstitial lung disease with 25(OH)VD deficiencies and GSH deficiencies has been previously reported. We hypothesize that the overproduction of ROS and excess oxidative damage is responsible for the impaired immunity, secretion of the cytokine storm, and onset of pulmonary dysfunction in response to the COVID-19 infection. The co-optimization of impaired glutathione redox status and excess 25(OH)VD deficiencies has the potential to reduce oxidative stress, boost immunity, and reduce the adverse clinical effects of COVID-19 infection in the AA population.


Subject(s)
COVID-19/pathology , Glucosephosphate Dehydrogenase Deficiency/genetics , Oxidative Stress/physiology , Reactive Oxygen Species/metabolism , Vitamin D Deficiency/genetics , African Americans/statistics & numerical data , COVID-19/mortality , Cytokine Release Syndrome/pathology , Glucosephosphate Dehydrogenase/genetics , Glucosephosphate Dehydrogenase Deficiency/metabolism , Glutathione/metabolism , Humans , SARS-CoV-2 , Vitamin D/analogs & derivatives , Vitamin D/metabolism
18.
Front Cell Infect Microbiol ; 10: 569709, 2020.
Article in English | MEDLINE | ID: covidwho-1004672

ABSTRACT

Accumulating evidence suggests that there are important contributions to coronavirus disease (COVID-19) from redox imbalance and improperly coordinated iron, which cause cellular oxidative damage and stress. Cells have developed elaborate redox-dependent processes to handle and store iron, and their disfunction leads to several serious diseases. Cellular reductants are important as reactive oxygen species (ROS) scavengers and to power enzymatic repair mechanisms, but they also may help generate toxic ROS. These complicated interrelationships are presented in terms of a cellular redox/iron/ROS triad, including ROS generation both at improperly coordinated iron and enzymatically, ROS interconvertibility, cellular signaling and damage, and reductant and iron chelator concentration-dependent effects. This perspective provides the rational necessary to strongly suggest that COVID-19 disrupts this interdependent triad, producing a substantial contribution to the ROS load, which causes direct ROS-induced protein and phospholipid damage, taxes cellular resources and repair mechanisms, and alters cellular signaling, especially in the more critical acute respiratory distress syndrome (ARDS) phase of the infection. Specific suggestions for therapeutic interventions using reductants and chelators that may help treat COVID-19 are discussed.


Subject(s)
COVID-19/metabolism , Iron/metabolism , Oxidative Stress , Reactive Oxygen Species/metabolism , SARS-CoV-2/metabolism , Antioxidants/metabolism , Antioxidants/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Glutathione/metabolism , Hemoglobins/metabolism , Humans , Hydroxyl Radical/metabolism , Inflammation , Iron Chelating Agents/pharmacology , Iron Chelating Agents/therapeutic use , Models, Biological , Oxidation-Reduction , Reducing Agents/pharmacology , Reducing Agents/therapeutic use , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/metabolism
19.
Eur Rev Med Pharmacol Sci ; 24(23): 12500-12509, 2020 12.
Article in English | MEDLINE | ID: covidwho-995007

ABSTRACT

OBJECTIVE: Since the emergence of coronavirus disease (COVID-19), the death toll has been increasing daily. Many risk factors are associated with a high mortality rate in COVID-19. Establishment of a common pathway among these risk factors could improve our understanding of COVID-19 severity and mortality. This review aims at establishing this common pathway and its possible effect on COVID-19 mortality. MATERIALS AND METHODS: The current review was executed in five consecutive stages starting from determining the risk factors of COVID-19 mortality and trying to find a common pathway among them depending on the available literature. This was followed by proposing a mechanism explaining how this common pathway could increase the mortality. Finally, its potential role in managing COVID-19 was proposed. RESULTS: This review identified this common pathway to be a low baseline of reduced glutathione (i.e., GSH) level. In particular, this review provided an in-depth discussion regarding the pathophysiology by which COVID-19 leads to GSH depletion, tissue damage, and acute respiratory distress syndrome. In addition, the current review demonstrated how GSH depletion could result in failure of the immune system and rendering the end organs vulnerable to damage from the oxidative stress. CONCLUSIONS: This preclinical study shows that GSH depletion may have a central role in COVID-19 mortality and pathophysiology. Therefore, elevating the GSH level in tissues may decrease the severity and mortality rates of COVID-19.


Subject(s)
COVID-19/mortality , Cytokine Release Syndrome/immunology , Glutathione/metabolism , Acute Lung Injury/metabolism , Age Factors , Antioxidants/metabolism , Apoptosis , COVID-19/immunology , COVID-19/metabolism , Cytokine Release Syndrome/metabolism , Diabetes Mellitus/epidemiology , Diabetes Mellitus/metabolism , Glutathione/immunology , Humans , Hypertension/epidemiology , Hypertension/metabolism , Macrophages/immunology , Myocardial Ischemia/epidemiology , Myocardial Ischemia/metabolism , Obesity/epidemiology , Obesity/metabolism , Reactive Oxygen Species/metabolism , Respiratory Distress Syndrome/metabolism , Risk Factors , SARS-CoV-2 , Smoking/epidemiology , Smoking/metabolism
20.
J Pineal Res ; 69(3): e12676, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-620325

ABSTRACT

Melatonin is a chronobiotic hormone, which can regulate human diseases like cancer, atherosclerosis, respiratory disorders, and microbial infections by regulating redox system. Melatonin exhibits innate immunomodulation by communicating with immune system and influencing neutrophils to fight infections and inflammation. However, sustaining redox homeostasis and reactive oxygen species (ROS) generation in neutrophils are critical during chemotaxis, oxidative burst, phagocytosis, and neutrophil extracellular trap (NET) formation. Therefore, endogenous antioxidant glutathione (GSH) redox cycle is highly vital in regulating neutrophil functions. Reduced intracellular GSH levels and glutathione reductase (GR) activity in the neutrophils during clinical conditions like autoimmune disorders, neurological disorders, diabetes, and microbial infections lead to dysfunctional neutrophils. Therefore, we hypothesized that redox modulators like melatonin can protect neutrophil health and functions under GSH and GR activity-deficient conditions. We demonstrate the dual role of melatonin, wherein it protects neutrophils from oxidative stress-induced apoptosis by reducing ROS generation; in contrast, it restores neutrophil functions like phagocytosis, degranulation, and NETosis in GSH and GR activity-deficient neutrophils by regulating ROS levels both in vitro and in vivo. Melatonin mitigates LPS-induced neutrophil dysfunctions by rejuvenating GSH redox system, specifically GR activity by acting as a parallel redox system. Our results indicate that melatonin could be a potential auxiliary therapy to treat immune dysfunction and microbial infections, including virus, under chronic disease conditions by restoring neutrophil functions. Further, melatonin could be a promising immune system booster to fight unprecedented pandemics like the current COVID-19. However, further studies are indispensable to address the clinical usage of melatonin.


Subject(s)
Antioxidants/therapeutic use , Glutathione/metabolism , Melatonin/therapeutic use , Neutrophils/drug effects , Animals , Antioxidants/pharmacology , Apoptosis/drug effects , COVID-19/drug therapy , Coronavirus Infections/drug therapy , Drug Evaluation, Preclinical , Female , Glutathione Reductase/metabolism , Humans , Male , Melatonin/pharmacology , Mice , Mitochondria/metabolism , NADPH Oxidases/metabolism , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism
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