Oxidative Stress-Related Mechanisms in SARS-CoV-2 Infections.

The COVID-19 pandemic caused relatively high mortality in patients, especially in those with concomitant diseases (i.e., diabetes, hypertension, and chronic obstructive pulmonary disease (COPD)). In most of aforementioned comorbidities, the oxidative stress appears to be an important player in their pathogenesis. The direct cause of death in critically ill patients with COVID-19 is still far from being elucidated. Although some preliminary data suggests that the lung vasculature injury and the loss of the functioning part of pulmonary alveolar population are crucial, the precise mechanism is still unclear. On the other hand, at least two classes of medications used with some clinical benefits in COVID-19 treatment seem to have a major influence on ROS (reactive oxygen species) and RNS (reactive nitrogen species) production. However, oxidative stress is one of the important mechanisms in the antiviral immune response and innate immunity. Therefore, it would be of interest to summarize the data regarding the oxidative stress in severe COVID-19. In this review, we discuss the role of oxidative and antioxidant mechanisms in severe COVID-19 based on available studies. We also present the role of ROS and RNS in other viral infections in humans and in animal models. Although reactive oxygen and nitrogen species play an important role in the innate antiviral immune response, in some situations, they might have a deleterious effect, e.g., in some coronaviral infections. The understanding of the redox mechanisms in severe COVID-19 disease may have an impact on its treatment.

Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis.

The coronavirus-disease 2019 (COVID-19) was announced as a global pandemic by the World Health Organization. Challenges arise concerning how to optimally support the immune system in the general population, especially under self-confinement. An optimal immune response depends on an adequate diet and nutrition in order to keep infection at bay. For example, sufficient protein intake is crucial for optimal antibody production. Low micronutrient status, such as of vitamin A or zinc, has been associated with increased infection risk. Frequently, poor nutrient status is associated with inflammation and oxidative stress, which in turn can impact the immune system. Dietary constituents with especially high anti-inflammatory and antioxidant capacity include vitamin C, vitamin E, and phytochemicals such as carotenoids and polyphenols. Several of these can interact with transcription factors such as NF-kB and Nrf-2, related to anti-inflammatory and antioxidant effects, respectively. Vitamin D in particular may perturb viral cellular infection via interacting with cell entry receptors (angiotensin converting enzyme 2), ACE2. Dietary fiber, fermented by the gut microbiota into short-chain fatty acids, has also been shown to produce anti-inflammatory effects. In this review, we highlight the importance of an optimal status of relevant nutrients to effectively reduce inflammation and oxidative stress, thereby strengthening the immune system during the COVID-19 crisis.

Airway Exposure to Polyethyleneimine Nanoparticles Induces Type 2 Immunity by a Mechanism Involving Oxidative Stress and ATP Release.

Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 µM), the VDAC-1 inhibitor, DIDS (100 µM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 µM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity.

BACKGROUND: SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. AIM: To evaluate the role of oxidative stress-related molecules in COVID-19. METHOD: An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. RESULTS: We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. CONCLUSION: SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.

Recent Progress in Applicability of Exercise Immunology and Inflammation Research to Sports Nutrition.

This article focuses on how nutrition may help prevent and/or assist with recovery from the harmful effects of strenuous acute exercise and physical training (decreased immunity, organ injury, inflammation, oxidative stress, and fatigue), with a focus on nutritional supplements. First, the effects of ketogenic diets on metabolism and inflammation are considered. Second, the effects of various supplements on immune function are discussed, including antioxidant defense modulators (vitamin C, sulforaphane, taheebo), and inflammation reducers (colostrum and hyperimmunized milk). Third, how 3-hydroxy-3-methyl butyrate monohydrate (HMB) may offset muscle damage is reviewed. Fourth and finally, the relationship between exercise, nutrition and COVID-19 infection is briefly mentioned. While additional verification of the safety and efficacy of these supplements is still necessary, current evidence suggests that these supplements have potential applications for health promotion and disease prevention among athletes and more diverse populations.

Mathematical Modeling of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Network with Cytokine Storm, Oxidative Stress, Thrombosis, Insulin Resistance, and Nitric Oxide Pathways.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a systemic disease affecting not only the lungs but also multiple organ systems. Clinical studies implicate that SARS-CoV-2 infection causes imbalance of cellular homeostasis and immune response that trigger cytokine storm, oxidative stress, thrombosis, and insulin resistance. Mathematical modeling can offer in-depth understanding of the SARS-CoV-2 infection and illuminate how subcellular mechanisms and feedback loops underpin disease progression and multiorgan failure. We report here a mathematical model of SARS-CoV-2 infection pathway network with cytokine storm, oxidative stress, thrombosis, insulin resistance, and nitric oxide (NO) pathways. The biochemical systems theory model shows autocrine loops with positive feedback enabling excessive immune response, cytokines, transcription factors, and interferons, which can imbalance homeostasis of the system. The simulations suggest that changes in immune response led to uncontrolled release of cytokines and chemokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor α (TNFα), and affect insulin, coagulation, and NO signaling pathways. Increased production of NETs (neutrophil extracellular traps), thrombin, PAI-1 (plasminogen activator inhibitor-1), and other procoagulant factors led to thrombosis. By analyzing complex biochemical reactions, this model forecasts the key intermediates, potential biomarkers, and risk factors at different stages of COVID-19. These insights can be useful for drug discovery and development, as well as precision treatment of multiorgan implications of COVID-19 as seen in systems medicine.

GDF15: an emerging modulator of immunity and a strategy in COVID-19 in association with iron metabolism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-ß (TGF-ß) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.

Dynamic changes in macrophage metabolism modulate induction and suppression of Type I inflammatory responses.

During microbial infection, macrophages link recognition of microbial stimuli to the induction of Type I inflammatory responses. Such inflammatory responses coordinate host defense and pathogen elimination but induce significant tissue damage if sustained, so macrophages are initially activated to induce inflammatory responses but then shift to a tolerant state to suppress inflammatory responses. Macrophage tolerance is regulated by induction of negative regulators of TLR signaling, but its metabolic basis was not known. Here, we review recent studies that indicate that macrophage metabolism changes dynamically over the course of microbial exposure to influence a shift in the inflammatory response. In particular, an initial increase in oxidative metabolism boosts the induction of inflammatory responses, but is followed by a shutdown of oxidative metabolism that contributes to suppression of inflammatory responses. We propose a unifying model for how dynamic changes to oxidative metabolism influences regulation of macrophage inflammatory responses during microbial exposure.

Effect of Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors on the Course of COVID-19 in Kidney Transplant Recipients.

Coronavirus disease 19 (COVID-19) has been an ongoing pandemic since December 2019. Unfortunately, kidney transplant recipients are a high-risk group during the disease course, and scientific data are still limited in this patient group. Beyond the dosage of immunosuppressive drugs, pharmacological immunosuppression may also alter the infection response in the COVID-19 course. The effects of immunosuppressive agents on the development and process of infection should not be decided only by determining how potent they are and how much they suppress the immune system; it is also thought that the direct effect of the virus, increased oxidative stress, and cytokine storm play a role in the pathogenesis of COVID-19 disease. There are data about immunosuppressive drugs like calcineurin inhibitors (CNI) or mammalian target of rapamycin inhibitors (mTORi) therapy related to their beneficial effects during any infection course. Limited data suggest that the use of CNI or mTORi may have beneficial effects on the process. In this hypothetical review, the probable impacts of CNI and mTORi on the pathogenesis of the COVID-19 were investigated.

Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs).

Uncontrolled immune system activation amplifies end-organ injury in hypertension. Nonetheless, the exact mechanisms initiating this exacerbated inflammatory response, thereby contributing to further increases in blood pressure (BP), are still being revealed. While participation of lymphoid-derived immune cells has been well described in the hypertension literature, the mechanisms by which myeloid-derived innate immune cells contribute to T cell activation, and subsequent BP elevation, remains an active area of investigation. In this article, we critically analyze the literature to understand how monocytes, macrophages, dendritic cells, and polymorphonuclear leukocytes, including mast cells, eosinophils, basophils, and neutrophils, contribute to hypertension and hypertension-associated end-organ injury. The most abundant leukocytes, neutrophils, are indisputably increased in hypertension. However, it is unknown how (and why) they switch from critical first responders of the innate immune system, and homeostatic regulators of BP, to tissue-damaging, pro-hypertensive mediators. We propose that myeloperoxidase-derived pro-oxidants, neutrophil elastase, neutrophil extracellular traps (NETs), and interactions with other innate and adaptive immune cells are novel mechanisms that could contribute to the inflammatory cascade in hypertension. We further posit that the gut microbiota serves as a set point for neutropoiesis and their function. Finally, given that hypertension appears to be a key risk factor for morbidity and mortality in COVID-19 patients, we put forth evidence that neutrophils and NETs cause cardiovascular injury post-coronavirus infection, and thus may be proposed as an intriguing therapeutic target for high-risk individuals. © 2021 American Physiological Society. Compr Physiol 11:1575-1589, 2021.

Potential Interplay between Nrf2, TRPA1, and TRPV1 in Nutrients for the Control of COVID-19.

In this article, we propose that differences in COVID-19 morbidity may be associated with transient receptor potential ankyrin 1 (TRPA1) and/or transient receptor potential vanilloid 1 (TRPV1) activation as well as desensitization. TRPA1 and TRPV1 induce inflammation and play a key role in the physiology of almost all organs. They may augment sensory or vagal nerve discharges to evoke pain and several symptoms of COVID-19, including cough, nasal obstruction, vomiting, diarrhea, and, at least partly, sudden and severe loss of smell and taste. TRPA1 can be activated by reactive oxygen species and may therefore be up-regulated in COVID-19. TRPA1 and TRPV1 channels can be activated by pungent compounds including many nuclear factor (erythroid-derived 2) (Nrf2)-interacting foods leading to channel desensitization. Interactions between Nrf2-associated nutrients and TRPA1/TRPV1 may be partly responsible for the severity of some of the COVID-19 symptoms. The regulation by Nrf2 of TRPA1/TRPV1 is still unclear, but suggested from very limited clinical evidence. In COVID-19, it is proposed that rapid desensitization of TRAP1/TRPV1 by some ingredients in foods could reduce symptom severity and provide new therapeutic strategies.

Zinc against COVID-19? Symptom surveillance and deficiency risk groups.

A wide variety of symptoms is associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, and these symptoms can overlap with other conditions and diseases. Knowing the distribution of symptoms across diseases and individuals can support clinical actions on timelines shorter than those for drug and vaccine development. Here, we focus on zinc deficiency symptoms, symptom overlap with other conditions, as well as zinc effects on immune health and mechanistic zinc deficiency risk groups. There are well-studied beneficial effects of zinc on the immune system including a decreased susceptibility to and improved clinical outcomes for infectious pathogens including multiple viruses. Zinc is also an anti-inflammatory and anti-oxidative stress agent, relevant to some severe Coronavirus Disease 2019 (COVID-19) symptoms. Unfortunately, zinc deficiency is common worldwide and not exclusive to the developing world. Lifestyle choices and preexisting conditions alone can result in zinc deficiency, and we compile zinc risk groups based on a review of the literature. It is also important to distinguish chronic zinc deficiency from deficiency acquired upon viral infection and immune response and their different supplementation strategies. Zinc is being considered as prophylactic or adjunct therapy for COVID-19, with 12 clinical trials underway, highlighting the relevance of this trace element for global pandemics. Using the example of zinc, we show that there is a critical need for a deeper understanding of essential trace elements in human health, and the resulting deficiency symptoms and their overlap with other conditions. This knowledge will directly support human immune health for decreasing susceptibility, shortening illness duration, and preventing progression to severe cases in the current and future pandemics.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology.

NETosis is a program for formation of neutrophil extracellular traps (NETs), which consist of modified chromatin decorated with bactericidal proteins from granules and cytoplasm. Various pathogens, antibodies and immune complexes, cytokines, microcrystals, and other physiological stimuli can cause NETosis. Induction of NETosis depends on reactive oxygen species (ROS), the main source of which is NADPH oxidase. Activation of NADPH oxidase depends on increase in the concentration of Ca2+ in the cytoplasm and in some cases on the generation of ROS in mitochondria. NETosis includes release of the granule components into the cytosol, modification of histones leading to chromatin decondensation, destruction of the nuclear envelope, as well as formation of pores in the plasma membrane. In this review, basic mechanisms of NETosis, as well as its role in the pathogenesis of some diseases including COVID-19 are discussed.

The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System.

Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases.

Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19.

Coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a newly discovered highly pathogenic virus that was declared pandemic in March 2020 by the World Health Organization. The virus affects the respiratory system, produces an inflammatory storm that causes lung damage and respiratory dysfunction. It infects humans of all ages. The Covid-19 takes a more severe course in individuals with chronic metabolic diseases such as obesity, diabetes mellitus, and hypertension. This category of persons exhibits weak immune activity and decreased levels of endogenous antioxidants. Melatonin is a multifunctional signaling hormone synthesized and secreted primarily by the pineal gland. It is a potent antioxidant with immunomodulatory action and has remarkable anti-inflammatory effects under a variety of circumstances. Regarding Covid-19 and metabolic syndrome, adequate information about the relationship between these two comorbidities is required for better management of these patients. Since Covid-19 infection and complications involve severe inflammation and oxidative stress in people with obesity and diabetes, we anticipated the inclusion of melatonin, as powerful antioxidant, within proposed treatment protocols. In this context, melatonin is a potential and promising agent to help overcome Covid-19 infection and boost the immune system in healthy persons and obese and diabetic patients. This review summarizes some evidence from recently published reports on the utility of melatonin as a potential adjuvant in Covid-19-infected individuals with diabetes and obesity.

Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients.

Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.